ACKD Mechanisms of Vascular Calcification in Kidney Disease Sinee Disthabanchong and Praopilad Srisuwarn The increase in prevalence and severity of vascular calcification in chronic kidney disease is a result of complex interactions be- tween changes in the vascular bed, mineral metabolites, and other uremic factors. Vascular calcification can occur in the intima and the media of arterial wall. Under permissive conditions, vascular smooth muscle cells (VSMCs) can transform to osteoblast- like phenotype. The membrane-bound vesicles released from transformed VSMCs and the apoptotic bodies derived from dying VSMCs serve as nucleating structures for calcium crystal formation. Alterations in the quality and the quantity of endogenous calcification inhibitors also give rise to an environment that potentiates calcification. Q 2019 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Endothelium, Calciprotein particles, Fetuin-A, Matrix-gla protein, Magnesium C ardiovascular disease is the leading cause of death among patients with kidney disease. In addition to diabetes, hypertension, dyslipidemia, and inflammation, the increase in prevalence and severity of vascular calcifica- tion (VC) as a result of complex interactions between changes in vascular bed and adaptive responses of bone and mineral factors has long been recognized as another important element implicating in the development of car- diovascular disease in patients with chronic kidney dis- ease (CKD). VC, once develops, is likely to progress resulting in worsening hypertension, congestive heart failure, cardiac hypertrophy, and myocardial infarction. The present review focuses on the mechanism of VC in kidney disease. TYPES OF VASCULAR CALCIFICATION Tunica intima is composed of a protective layer of endothe- lial cells supported by internal elastic lamina. The normal endothelium regulates vascular tone and exerts anticoagu- lant, antiplatelet, and fibrinolytic properties. Endothelial cells release nitric oxide (NO) and prostacyclin to reduce platelet aggregation, monocyte and leukocyte adhesion, and vascular smooth muscle cell (VSMC) proliferation. Damage to the endothelium is an inciting event in the development of atherosclerosis and intimal calcification. 1 Tunica media is composed of a layer of contractile VSMCs supported by external elastic lamina. Smooth muscle is essential in maintaining blood pressure through contrac- tion and relaxation. VSMCs normally have a low prolifer- ative rate, but under mineral stress, contractile VSMCs can undergo phenotypic change to an active synthetic phenotype with an increased proliferation rate and secre- tory ability. 2,3 This phenotypic change of VSMCs in combination with elastin break is the starting point of medial calcification. ATHEROSCLEROSIS AND INTIMAL CALCIFICATION Endothelial dysfunction occurs after a sustained exposure to risk factors including diabetes, hypertension, smoking, dyslipidemia, systemic inflammation, and renal dysfunc- tion. Detailed reviews on the mechanism of atherosclerosis can be found elsewhere. 2,4,5 In brief, a damage to endothelial cells increases endothelial permeability to low-density lipoprotein (LDL), resulting in a retention of cholesterol-rich particles in the subendothelium. This local inflammation recruits more inflammatory cells including monocytes and T-lymphocytes. Monocytes differentiate into macrophages, which phagocytize the LDL- cholesterol complex. Oxidized LDL is particularly toxic causing the death of lipid-laden macrophages which leads to the formation of foam cells (Fig 1). The accumulation of these dead macrophages forms necrotic core releasing toxic substances into the local environment. Contractile VSMCs from tunica media then adopt an active synthetic phenotype, proliferate, and migrate to the intima. These synthetic VSMCs produce collagen resulting in a forma- tion of fibrous cap. The intense inflammation stimulates angiogenesis producing fragile capillaries that are charac- teristic of unstable plaque. Further inflammation leads to plaque rupture. Microcalcification in the atherosclerotic plaque occurs after a release of apoptotic bodies (ABs) and necrotic debris from dead macrophages and VSMCs. These ABs and necrotic debris serve to nucleate calcium- phosphate apatite crystal at the site of injury. Circulating mineral complexes can also be released from matrix vesi- cles (MVs) derived from VSMCs and macrophages. AB and MV nucleation sites allow the deposition of basic calcium-phosphate crystals that gradually crystalize to form hydroxyapatite crystals. The presence of microcalci- fication nuclei induce further cycles of inflammation causing propagation of the damage and instability of the atherosclerotic plaque. 6 In the presence of proosteogenic condition such as increased serum calcium and phosphate, the migrated VSMCs can differentiate into chondrocytes and osteoblast-like cells, leading to a properly regulated mineralization process. Further calcification can some- times stabilize the plaque by acting as a barrier toward the spread of inflammation. From the Division of Nephrology, Department of Medicine, Faculty of Med- icine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Financial Disclosure: S.D. received travel grants and an honorarium from Amgen, Sanofi, and Kyowa Hakko Kirin. P.S. has no financial interests to declare. Address correspondence to Sinee Disthabanchong, MD, Division of Nephrology, Department of Medicine Ramathibodi Hospital, 270 Rama VI Road, 7th floor, Building 1, Phayathai Bangkok, 10400 Thailand. E-mails: sinee.dis@mahidol.ac.th; sineemd@hotmail.com Ó 2019 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2019.08.014 Adv Chronic Kidney Dis. 2019;26(6):417-426 417