Dyslipidemia in Patients with Chronic Kidney Disease: An Updated Overview

Abstract

Dyslipidemia is a potentially modifiable cardiovascular risk factor. Whereas the recommendations for the treatment target of dyslipidemia in the general population are being more and more rigorous, the 2013 Kidney Disease: Improving Global Outcomes clinical practice guideline for lipid management in chronic kidney disease (CKD) presented a relatively conservative approach with respect to the indication of lipid lowering therapy and therapeutic monitoring among the patients with CKD. This may be largely attributed to the lack of high-quality evidence derived from CKD population, among whom the overall feature of dyslipidemia is considerably distinctive to that of general population. In this review article, we cover the characteristic features of dyslipidemia and impact of dyslipidemia on cardiovascular outcomes in patients with CKD. We also review the current evidence on lipid lowering therapy to modify the risk of cardiovascular events in this population. We finally discuss the association between dyslipidemia and CKD progression and the potential strategy to delay the progression of CKD in relation to lipid lowering therapy.

Keywords: Dyslipidemias; Kidney diseases; Risk.

Fig. 1.

Metabolic pathway of exogenous and endogenous lipoproteins. The exogenous pathway involves trafficking of dietary lipids to peripheral organs, and ultimately to the liver. Long chain fatty acids derived from hydrolyzed dietary lipids are transformed to triglyceride (TG) in lymphatic endothelial cells, and are packaged with, apolipoprotein B-48 (ApoB-48) as well as apolipoprotein E (ApoE) and apolipoprotein C (ApoC) to form chylomicrons. Chylomicrons secreted into intestinal lymphatic circulation reach systemic circulation via thoracic duct. Chylomicrons are hydrolyzed by lipoprotein lipase (LPL) that is anchored on the surface of capillary endothelium in adipose tissue, and heart and skeletal muscles to release free fatty acids (FFAs), and shrink to chylomicron remnants. Chylomicron remnants bind to low-density lipoprotein receptor (LDLR) thorough ApoE-mediated mechanism, and are rapidly cleared from the circulation. The endogenous pathway delivers hepatically derived lipoproteins to the periphery, providing energy source during fasting. Hepatocytes esterify fatty acids to form TG, which are packaged into very low-density lipoprotein (VLDL) particles with apoB-100. Circulating VLDL particles are hydrolyzed by LPL to release FFAs, and are referred to as intermediate-density lipoprotein (IDL). About 50% of IDL particles are removed by hepatocytes via ApoE-mediated binding to LDLR. The remainder of IDL particles are further processed by hepatic lipase (HL) to form low-density lipoprotein (LDL) particles. LDL particles may be removed from the circulation by hepatocytes via apoB-100-mediated binding to LDLR, or may serve as a source of cholesterol deposit in the peripheral tissue, triggering a subsequent atherosclerotic process.

Fig. 2.

Schematic diagram for the function of lipoprotein lipase (LPL). LPL is anchored on the surface of capillary endothelial cells, and plays a key role in the hydrolysis of triglyceride (TG)-rich lipoproteins (i.e., chylomicron and very low-density lipoprotein [VLDL]). Apolipoprotein C-II (ApoC-II) on the surface of TG-rich lipoproteins is a co-factor required to activate LPL. LPL degrades TG to release two free fatty acids (FFAs) and one monoacylglycerol molecule, and transforms chylomicron and VLDL into chylomicron remnants and intermediate-density lipoprotein.

Fig. 3.

High-density lipoprotein (HDL) metabolism in reverse cholesterol transport. Apolipoprotein A-I (ApoA-I) is secreted by liver and intestine, as nascent HDL particles. Free cholesterol is acquired from macrophages and other peripheral cells, where ApoA-I promotes the efflux of free cholesterol from macrophages via ATP-binding cassette subfamily member 1 (ABCA1). The efflux of free cholesterol from macrophages is also mediated by ATP-binding cassette subfamily G member 1 (ABCG1). Lecithin-cholesterol acyltransferase (LCAT), a plasma enzyme associated with HDL, esterifies free cholesterol to cholesteryl ester (CE) inside HDL particle to form mature HDL particles. CE inside mature HDL particles can be untaken by hepatocytes via scavenger receptor class B type I (SR-BI), a receptor for HDL that mediates the selective transfer of CE to hepatocytes and recycling of the dissociated HDL particles. Alternatively, CE inside mature HDL can be transferred to apolipoprotein B-containing lipoproteins, such as very low-density lipoprotein (VLDL) and chylomicron that are rich with triglyceride (TG), in exchange of TG by cholesteryl ester transfer protein (CETP), and then cleared the circulation by low-density lipoprotein receptor (LDLR)-mediated endocytosis of hepatocytes. LDL, low-density lipoprotein; IDL, intermediate-density lipoprotein .

Fig. 4.

Defective metabolism of major lipoproteins in chronic kidney disease (CKD). Red and blue arrows indicate upregulation/increased activity and downregulation/decreased activity in CKD, respectively. LDLR, low-density lipoprotein receptor; LDL, low-density lipoprotein; SR-BI, scavenger receptor class B type I; LPL, lipoprotein lipase; FFA, free fatty acid; ApoE, apolipoprotein E; ApoC, apolipoprotein C; ApoB, apolipoprotein B; TG, triglyceride; CETP, cholesteryl ester transfer protein; CE, cholesteryl ester; HDL, high-density lipoprotein; HL, hepatic lipase; VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; ApoA-I, apolipoprotein A-I; ABCG1, ATP-binding cassette subfamily G member 1; ABCA1, ATP-binding cassette subfamily member 1.