UREMIC MEDIUM INCREASES CYTOKINE-INDUCED PAI-1 SECRETION BY CULTURED ENDOTHELIAL-CELLS

The overall fibrinolytic activity is depressed in patients with chroni c renal failure where a prothrombotic state is described, thereby enha ncing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasmin ogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics we re studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant co ncentration of t-PA and PAI-1 was found among the groups studied. Afte r stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)- alpha, the HUVEC supernatant levels of PAI-1 in the uremics were highe r than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, t hereby depressing the fibrinolytic system. This impaired endothelial f ibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia. (C) 1998 Elsevier, Paris.