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HDL metabolism and activity in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is associated with development of atherosclerosis and premature death from cardiovascular disease. The predisposition of patients with CKD to atherosclerosis is driven by inflammation, oxidative stress and dyslipidemia, all of which are common features of this condition. Markers of dyslipidemia in patients with advanced CKD are impaired clearance and heightened oxidation of apolipoprotein-B-containing lipoproteins and their atherogenic remnants, and a reduction of the plasma concentration, antioxidant, and anti-inflammatory properties of high-density lipoprotein (HDL). Studies in animal models of CKD indicate that the disease promotes lipid accumulation in the artery wall and kidney, leading to atherosclerosis, glomerulosclerosis and tubulointerstitial injury. These effects seem to be mediated by an increased cellular influx of lipids, elevated cellular production and reduced cellular catabolism of fatty acids, and impaired antioxidant, anti-inflammatory and reverse lipid transport properties of HDL. Available pharmacological therapies have been largely ineffective in ameliorating oxidative stress, inflammation, HDL deficiency and/or dysfunction, and the associated atherosclerosis and cardiovascular disease in patients with end-stage renal disease. This Review aims to provide an overview of the mechanisms and consequences of CKD-induced HDL deficiency and dysfunction.

Key Points

  • Chronic kidney disease (CKD) is associated with oxidative stress, inflammation and profound dysregulation of lipid metabolism

  • The combination of dyslipidemia, proteinuria, oxidative stress and inflammation in patients with CKD results in an accumulation of lipids in the artery wall and in the diseased kidney tissue

  • The harmful effect of increased lipid influx in the kidney and arterial tissues is compounded by impaired cellular lipid efflux caused by high-density lipoprotein (HDL) deficiency and dysfunction

  • The increase in tissue lipid burden associated with CKD leads to foam cell formation, cytotoxicity and progression of renal disease and atherosclerosis

  • Efficacy of therapeutic interventions to retard progression of renal disease and atherosclerosis in patients with CKD depends on the ability to attenuate oxidative stress and inflammation, reverse HDL deficiency and restore HDL antioxidant and anti-inflammatory properties

  • Currently available pharmacological options that target dyslipidemia are ineffective, unsafe and/or poorly tolerated by patients with end-stage renal disease

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Figure 1: VLDL metabolism.
Figure 2: Proposed mechanisms by which advanced CKD results in increased influx, impaired efflux and accumulation of lipids in the artery wall and renal tissue, events that accelerate atherosclerosis and progression of renal disease.

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Correspondence to Nosratola D. Vaziri.

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M. Navab and A. M. Fogelman declare an association with the following company: Bruin Pharmaceuticals. N. D. Vaziri declares no competing interests.

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Vaziri, N., Navab, M. & Fogelman, A. HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol 6, 287–296 (2010). https://doi.org/10.1038/nrneph.2010.36

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