Similarly, an enhanced cardiovascular risk has been reported in patients with CKD not on dialysis. Using endothelial cells in culture, our group has previously characterized the endothelial activation and damage occurring in association with CKD. When exposed to growth media containing sera from patients on hemodialysis, cells showed morphological alterations, increased proliferation, signs of inflammation with no evidence of apoptosis, and an increased thrombogenicity of the generated extracellular matrix. A more recent proteomic approach revealed that there are changes in the expression of some molecules related to inflammation, such as HMGB1 and aldose reductase, and to oxidative stress, such as superoxide dismutase and glutathione peroxidase. These changes were correlated with the activation of the transcription factor NFkB. Most of the studies on the endothelial damage in CKD patients have been conducted in patients undergoing hemodialysis treatment. In the present study, we have investigated the relative contribution of uremia and renal replacement therapies, hemodialysis and peritoneal dialysis, to the development of endothelial damage in patients with CKD. We applied two different approaches: ex vivo analysis of plasma markers of endothelial activation and damage, and in vitro evaluation of the signaling mechanisms involved. The present study was focused to discern the contribution of uremia and the RRT to the development of endothelial activation and damage. The ex vivo and in vitro approaches applied revealed that uremia per se causes a Everolimus proinflammatory state on the endothelium, as derived from results in pre-dialysis patients. The hemodialysis technique with the current advances did not exhibit a damaging effect on the endothelium additionally to that observed in patients with advanced CKD managed conservatively. Interestingly, peritoneal dialysis was the most proinflammatory condition, as demonstrated by a higher presence of soluble markers of endothelial activation and damage in plasma, and a more intense activation of both p38 MAPK and NFkB signaling pathways in cultured endothelial cells. These effects could be attributed, at least in part, to the glucose and its degradation products present in the PD dialysis fluids. Endothelial activation and damage could be the earliest indicator of subclinical cardiovascular disease. In the laboratory, measurement of plasma levels of different molecules and/or other elements, either discharged or up-regulated in an activated endothelium, could be useful to assess endothelial damage and activation. Considering that to date there is no universal marker of endothelial damage, we have evaluated different indicators. Soluble adhesion receptors were evaluated by a multiplex system and showed significant activation of the endothelium in all uremic patients, being more notable in the PreD and PD groups. In relation to VWF plasma levels, our present data is consistent with previous observations in hemodialyzed patients being significantly higher in all the uremic patients than in controls. However, the short range in which values are included might explain the lack of differences found between the studied groups. Levels of circulating endothelial cells have been described to correlate well with VWF plasma levels. There is previous evidence generated in HD patients of increased CEC and their association with future cardiovascular events. In our present study, blood CEC counts were higher in all the uremic patients when compared to the control group, especially in the group of peritoneal dialysis.