Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines

Background. Chronic renal failure (CRF) is associated with an increased ris k of ischaemic heart disease (IHD), but the mechanisms responsible are cont roversial. We investigated the relationship of two sets of candidate mechan isms-indices of LDL oxidation and markers of inflammatory activity-with vas cular endothelial dysfunction (VED). Methods. We carried out cross-sectional analysis of 23 dialysed and 16 non- dialysed CRF patients, 28 healthy controls, and 20 patients with stable ang ina and normal renal function. The following were determined: (i) LDL oxida tion by Cu2+ and ultraviolet light, serum autoantibodies to oxidized LDL (o xLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. Results. Endothelium-dependent vasodilatation (EDV) was lower in angina, pr e-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compa red with controls, vWf (P < 0.005) and adhesion molecules (VCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-I (P =0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL choles terol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxid ation was similar in all groups. Autoantibodies to oxLDL were raised in ang ina (P<0.005) and predialysis (P=0.006), but were absent in most dialysed p atients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevate d in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-a correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r = -0.43 to + 0.70. all P < 0.05). Conclusions. Endothelial dysfunction is unrelated to LDL oxidation, suggest ing that LDL oxidation might not be a major cause of VED in CRF. In contras t VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chron ic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.