Cholesterol Metabolism in CKD

Abstract

Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.

Keywords: Cholesterol transport; atherosclerosis; cardiovascular disease (CVD); chronic kidney disease (CKD); dyslipidemia; high-density lipoprotein (HDL); inflammation; lipid-lowering therapy; low-density lipoprotein (LDL); nontraditional risk factor; reactive oxygen species (ROS); statin therapy; uremic toxins.

Figure 1. CKD and CVD risk factors and their interplay

Traditional risk factors are found in both the CKD and non-CKD population. Nontraditional risk factors may result from or be worsened by CKD and negatively impact the cardiovascular system in the CKD population.

Figure 2. Reverse cholesterol transport in chronic kidney disease

CKD alters lipoprotein composition through multiple mechanisms, not all of which are understood. Loss of protein is thought to contribute, as is augmented production of ROS. Inflammation and ROS may lead to accumulation of modified LDL (mLDL), such as highly oxidized LDL (oxLDL) or carbamylated LDL (cLDL). Internalization of modified LDL in macrophages occurs via the major scavenger receptors (CD36, SRA-1, LOX1) and contributes to foam cell formation. The presence of mLDL enhances expression of the ABCG1 transporter. In CKD, an elevated level of ACAT-2 facilitates formation and domination of cholesterol esters. Removal of free cholesterol from macrophages proceeds via SR-B1, which contributes to HDL formation through both ABC transporters (ABC) A1 and ABCG1. Cholesterol and phospholipids are eliminated through formation of nascent HDL from circulating Apo-AI. ABCA1 and ABCG1 show additive activity in promoting macrophage reverse cholesterol transport. Nascent HDL is generated when Apo-AI interacts with ABCA1. Uptake of free cholesterol and its conversion to cholesterol ester is mediated by LCAT and results in transformation of HDL3 to HDL2. In kidney disease, conversion of HDL3 to HDL2 is impaired because of LCAT deficiency. CETP mediates transfer of cholesterol ester from HDL to triglyceride rich lipoproteins - VLDL. In CKD, increased activity of CETP is detected, which contributes to low plasma HDL. In uremic patients on maintenance hemodialysis, cholesterol efflux capacity of HDL is markedly reduced when compared to HDL from healthy subjects. Moreover, anti-oxidative and antiinflammatory functions of HDL are impaired due to reduced activity of PON1. HDL from CKD patients loses its vasoprotective properties, inhibiting NO production and increasing vascular cell adhesion Oxidative modifications of HDL limit the ability of HDL to bind to SR-B1 to unload esterified cholesterol to the liver. Abbreviations: ABCA1 and G1, ATP-binding cassette sub-family A1 and G1 members; ACAT, acyl coenzyme A:cholesterol acyltransferase; apoA-I; apolipoprotein A-I; CETP, cholesteryl ester transfer protein;; HDL, high density lipoprotein; LCAT, lecithin cholesterol acyltransferase; LOX1, lectin-like oxidized LDL receptor 1; NO, nitric oxide; PON1, serum paraoxonase/arylesterase 1; ROS, reactive oxygen species; SRA1/B1, scavenger receptor class A member 1/class B member 1; VLDL, very low density lipoprotein.

Figure 3. Changes in HDL functions mediated by CKD

Small dense HDL particles dominate in individuals with CKD. Chronic pro-inflammatory conditions activate macrophages, releasing myeloperoxidase (MPO). MPO-derived oxidants modify HDL, which impairs the functioning of HDL-associated enzymes, such as paraoxonase 1 (PON1), nitric oxide (NO) synthase and lecithin cholesterol acyltransferase (LCAT). These enzymes are essential for anti-oxidative, anti-inflammatory and vasoprotective properties of unmodified HDL.

Figure 4. CKD-mediated progression of atherosclerosis

Pro-inflammatory cytokines and uremic toxins are elevated in the serum of CKD patients. These substances directly modify LDL, and either directly or through modified LDL, activate inflammatory pathways. Enhanced uremic toxins and modified LDL – carbamylated or oxidized (cLDL or oxLDL), mediate the release of adhesion molecules and reactive oxygen species (ROS). Activation of pro-inflammatory signaling pathways leads to endothelial injury and dysfunction, vascular smooth muscle cell proliferation and CVD progression.