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Conference of the NATO-Advanced-Study-Institute on Free Radicals, Nitric Oxide and Inflammation, Antalya, Turkey, 23 September - 04 October 2001, vol.344, pp.132-152, (Full Text)
Patients with end-stage renal disease (ESRD) have a reduced life expectancy due to an accelerated rate of cardiovascular disease (CVD). In patients with chronic renal failure, cardiovascular morbidity and mortality are higher than in non-uremic controls. The overall risk of cardiac death in the uremic population is increased by a factor of 5 to 20. Traditional risk factors, such as hypertension, dyslipidemia, smoking, advanced age, gender, high-fat diet, physical inactivity, left ventricular hypertrophy, an early CVD-related death in a close relative, hyperparathyroidism, hyperfibrinogenemia and diabetes mellitus may account for the increased cardiovascular mortality rate in these patients. Non-traditional risk factors might also contribute to the high cardiovascular mortality rate in dialysis patients. Prominent among these are oxidative and carbonyl stress, oxidized low density lipoprotein (ox-LDL), advanced glycation end-products (AGEs), accumulation of asymmetrical dimethyl arginine (ADMA) and hyperhomo-cysteinemia. Atherosclerosis is accepted as a common mechanism underlying all CVDs. It is a disease of large and medium sized arteries, which in its more advanced stages affects all three coats of the arterial wall. This artery wall disease is progressive and multifactorial. There is increasing evidence that atherosclerosis should be considered as an inflammatory disease. Chronic inflammation, as evidenced by increased levels of proinflammatory cytokines and C-reactive protein (CRP), is a common feature in dialysis patients. Endothelial cell activation which is induced by a number of mediators including, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), thrombin, and ox-LDL preludes migration of monocytes to the subendothelial space. The adhesion of leukocytes are mediated by adhesion molecules on the endothelial cell membrane that mainly belong to two protein families: the selectins and adhesion molecules of the immunoglobulin superfamily. Expression of adhesion molecules has been demonstrated in various cell types forming the atherosclerotic plaque. Increased ROS generation and decreased antioxidant defenses have been implicated in the pathogenesis of oxidative stress in uremia. Oxidized LDL (ox-LDL) is an important component of the atherogenic cascade. Oxidized LDLs activate endothelial cells to express surface adhesion molecules for circulating monocytes and lymphocytes, are chemotactic for the same cell types, and are more avidly taken up by macrophages in the subendothelial space to form foam cells. Advanced glycation renders tissues, cells and lipoproteins more susceptible to atherogenesis. AGEs generate reactive oxygen intermediates and can play a role in atherogenesis through oxidant stress. In chronic renal insufficiency NO production is reduced due to accumulation of ADMA, an endogenous competitive inhibitor of NO synthase and decreased L-arginine synthase activity. Accumulation of ADMA may be an important pathogenic factor for atherosclerosis in chronic renal failure and ADMA may be a new uremic toxin. Homocysteine accumulates in chronic renal patients due to both decreased clearance and impairment of renal metabolic function. The pathogenesis of homocysteine-induced vascular damage is not fully understood. The vascular changes in hyperhomocysteinemia are rather multifactorial.