End-stage renal disease (
ESRD) is associated with accelerated
atherosclerosis and premature death from
cardiovascular disease. These events are driven by oxidative stress
inflammation and
lipid disorders.
ESRD-induced
lipid abnormalities primarily stem from dysregulation of
high-density lipoprotein (
HDL), triglyceride-rich
lipoprotein metabolism, and oxidative modification of
lipoproteins. In this context, production and plasma concentration of Apo-I and Apo-II are reduced, HDL maturation is impaired, HDL composition is altered, HDL
antioxidant and anti-inflammatory functions are depressed, clearance of
triglyceride-rich
lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentration is elevated in
ESRD. The associated defect in HDL maturation is largely caused by acquired
lecithin-cholesterol acyltransferase deficiency while its
triglyceride enrichment is due to hepatic
lipase deficiency.
Hypertriglyceridemia, abnormal composition, and impaired clearance of
triglyceride-rich
lipoproteins and their remnants are mediated by down-regulation of
lipoprotein lipase, hepatic
lipase,
very low-density lipoprotein (
VLDL) receptor, and
LDL receptor-related protein, relative reduction in
ApoC-II/
ApoC-III ratio, up-regulation of
acyl-CoA cholesterol acyltransferase, and elevated plasma level of
cholesterol ester-poor
prebeta HDL. Impaired clearance and accumulation of oxidation-prone VLDL and
chylomicron remnants and abnormal
LDL composition in the face of oxidative stress and
inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of
lipids is compounded by impaired HDL-mediated reverse
cholesterol transport leading to foam cell formation which is the central event in
atherosclerosis plaque formation and subsequent plaque
rupture,
thrombosis, and tissue damage.