Uremic medium increases cytokine-induced PAI-1 secretion by cultured endothelial cells.

The overall fibrinolytic activity has been reported to be depressed in the plasma of patients with chronic renal failure in the face of hypercoagulation, thereby facilitating vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been delucidated. To evaluate the effect of the uremic enviroment on the fibrinolytic activity of endothelial cells, we studied human umbelical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, and measured t-PA and PAI-1 in the supernatant before and after cytokine stimulation. We studied 20 adult patients with severe or end-stage renal failure: 11 of them on conservative dietary treatment (CT) and 9 on maintenance hemodialysis (MHD); 8 healthy subjects served as controls. After stimulation with IL-1, IL-6 and TNF alfa, the HUVEC supernatant levels of PAI-1 in the CT patient group and MHD patient group were higher than in the control group, whereas the supernatant levels of t-PA did not differ in the three groups. These results provide evidence that uremic serum, under appropriate conditions, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. The impaired endothelial fibrinolytic response following hypercoagulation could favour vascular events, that at present are the major cause of morbility and mortality in patients with chronic uremia.