Chronic kidney disease (CKD) is highly prevalent and a multiplier of cardiovascular disease (CVD) and cannot be completely explained by traditional Framinghan risk factors. Consequently, greater emphasis has been placed in nontraditional risk factors, such as inflammation, endothelial dysfunction, sympathetic overactivation, protein-energy wasting oxidative stress, vascular calcification, and volume overload. The accumulation of uremic toxins (and the involvement of genetic factors) is responsible for many of the clinical consequences of a condition known as uremia. In this brief paper, we discuss mechanisms involved in the vascular damage of CKD patients, aiming to point out that important factors beyond hypertension are largely responsible for endothelial activation and increased CVD risk, with potential impact on risk stratification and development of novel therapeutic options. 1. Introduction Chronic kidney disease (CKD) is a disease in exponential growth, and, along with other chronic diseases, is responsible for 25 million deaths per year, mainly due to the multiplication of cardiovascular disease (CVD) [1]. Cardiovascular disease is independently associated with CKD, and this cardiovascular risk cannot be completely explained by traditional Framinghan risk factors (age, lifestyle, left ventricular hypertrophy, dyslipidemia, hypertension, and diabetes mellitus) [2]. Consequently, greater emphasis has been placed in nontraditional risk factors, such as inflammation, endothelial dysfunction, sympathetic overactivation, protein-energy wasting oxidative stress, vascular calcification, and volume overload [3, 4]. In patients with stage 5 CKD, CVD risk is five times greater than in the general population, even after stratification for age, sex, race, and diabetes [5]. Hypertension is very common in this population, and its prevalence increases with progression of the disease. Moreover, with retention of sodium, expansion of extracellular volume, and activation of renin angiotensin system, all highly prevalent in CKD, hypertension becomes refractory to treatment and an universal condition in advanced stages of CKD. However, hypertension alone, although important and highly prevalent, cannot by itself justify the enormous cardiovascular burden in CKD. In the progression of CKD, the kidneys lose their ability to effectively remove toxic compounds from the bloodstream for subsequent formation of urine, resulting in its accumulation in the body. The accumulation of these uremic toxins (and the involvement of genetic factors) is responsible for many of the
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