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  • Review Article
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An update on the lipid nephrotoxicity hypothesis

Abstract

When the 'lipid nephrotoxicity hypothesis' was proposed in 1982, it brought together several disparate experimental findings in hyperlipidemia and renal disease to suggest that concomitant hyperlipidemia and proteinuria would cause self-perpetuating renal disease once the initial glomerular insult was no longer present. This process would be analogous to atherosclerosis. Since 1982, increasing evidence has supported the hypothesis that lipid abnormalities contribute to both atherosclerosis and glomerulosclerosis. In this Review, we discuss research developments that are relevant to the lipid nephrotoxicity hypothesis. We describe how inflammatory stress accompanying chronic kidney disease modifies lipid homeostasis by increasing cholesterol uptake mediated by lipoprotein receptors, inhibiting cholesterol efflux mediated by the ATP-binding cassette transporter 1 and impairing cholesterol synthesis in peripheral cells. As a result of these events, cholesterol relocates to and accumulates in renal, vascular, hepatic and possibly other tissues. The combination of increased cellular cholesterol influx and reduced efflux causes injury in some tissues and lowers the plasma cholesterol level. In addition, inflammatory stress causes a degree of statin resistance via unknown mechanisms. These phenomena alter traditional understanding of the pathogenesis of lipid-mediated renal and vascular injury and could influence the clinical evaluation of renal and cardiovascular risk and the role of lipid-lowering treatment in affected patients.

Key Points

  • Atherogenic dyslipidemia in association with proteinuria can occur early in primary kidney disease, when the measured glomerular filtration rate is within the healthy range

  • Many animal models and clinical studies suggest that dyslipidemia contributes to progressive renal disease, as was originally suggested by the 'lipid nephrotoxicity hypothesis'

  • Renal pathophysiological changes driven by atherogenic dyslipidemia include inflammatory stress, oxidative stress, endoplasmic reticulum stress, endothelial dysfunction and activation of the renin–angiotensin system

  • Inflammatory stress modifies lipid homeostasis through changes in lipoprotein composition and in cholesterol distribution among plasma, tissues and cellular organelles

  • Emerging evidence from clinical trials suggests that statins reduce proteinuria and possibly the rate of kidney function loss in patients with renal disease and dyslipidemia

  • Some experimental evidence suggests that inflammatory stress might cause 'statin resistance' and reduced the effectiveness of statin treatment

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Figure 1: Proposed mechanisms by which atherogenic dyslipidemia drives renal pathophysiological changes.

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Acknowledgements

Our group's research is supported by Kidney Research UK (RP37/2008), the Moorhead Trust, the Royal Free Hospital Special Trustees Grant-115 973 Program 2006CB503907, and the National Natural Science Foundation of China (30772295, 30871159 and Key Program, No. 30530360).

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Ruan, X., Varghese, Z. & Moorhead, J. An update on the lipid nephrotoxicity hypothesis. Nat Rev Nephrol 5, 713–721 (2009). https://doi.org/10.1038/nrneph.2009.184

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