Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.
BACKGROUND
Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular 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 angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (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, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared 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-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha 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, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.
Bolton
C H
CH
University Division of Medicine, Medical School Unit, Southmead Hospital, Bristol, BS10 5NB, UK.
Downs
L G
LG
Victory
J G
JG
Dwight
J F
JF
Tomson
C R
CR
Mackness
M I
MI
Pinkney
J H
JH
D000328:Adult; D000787:Angina Pectoris / Q000097:blood / Q000503:physiopathology; D001323:Autoantibodies / Q000097:blood; D001794:Blood Pressure; D002097:C-Reactive Protein / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood*; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology*; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood / Q000503:physiopathology* / Q000628:therapy; D008077:Lipoproteins, LDL / Q000097:blood* / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory; D012016:Reference Values; D006435:Renal Dialysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014664:Vasodilation; D014841:von Willebrand Factor / Q000032:analysis
D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D008076:Cholesterol, HDL; D016207:Cytokines; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D014841:von Willebrand Factor; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D005340:Fibrinogen; D002097:C-Reactive Protein; D003404:Creatinine