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Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

Nature Reviews Nephrology volume 17, pages 528–542 (2021)Cite this article

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Abstract

Chronic kidney disease (CKD) induces modifications in lipid and lipoprotein metabolism and homeostasis. These modifications can promote, modulate and/or accelerate CKD and secondary cardiovascular disease (CVD). Lipid and lipoprotein abnormalities — involving triglyceride-rich lipoproteins, LDL and/or HDL — not only involve changes in concentration but also changes in molecular structure, including protein composition, incorporation of small molecules and post-translational modifications. These alterations modify the function of lipoproteins and can trigger pro-inflammatory and pro-atherogenic processes, as well as oxidative stress. Serum fatty acid levels are also often altered in patients with CKD and lead to changes in fatty acid metabolism — a key process in intracellular energy production — that induce mitochondrial dysfunction and cellular damage. These fatty acid changes might not only have a negative impact on the heart, but also contribute to the progression of kidney damage. The presence of these lipoprotein alterations within a biological environment characterized by increased inflammation and oxidative stress, as well as the competing risk of non-atherosclerotic cardiovascular death as kidney function declines, has important therapeutic implications. Additional research is needed to clarify the pathophysiological link between lipid and lipoprotein modifications, and kidney dysfunction, as well as the genesis and/or progression of CVD in patients with kidney disease.

Key points

  • HDL and LDL modifications in chronic kidney disease (CKD) increase cardiovascular risk; targeting these modifications might lead to the development of novel therapeutic strategies.

  • In CKD, alterations in proteome content, metabolic solute accumulation and post-translational modifications convert HDL from an anti-inflammatory to a pro-inflammatory molecule and enhance the pro-inflammatory character of LDL.

  • HDL modifications, and the altered correlation between HDL levels and cardiovascular risk in patients with CKD compared with the general population, support the concept that HDL function, rather than HDL cholesterol levels, influences cardiovascular risk.

  • The contribution of non-atherosclerotic cardiovascular disease to cardiovascular risk in patients with CKD increases with declining kidney function, which further contributes to an altered correlation between lipoprotein levels and overall cardiovascular risk in these patients.

  • Deregulated fatty acid metabolism and mitochondrial dysfunction not only negatively affect the heart but also contribute to kidney pathology by promoting inflammation and fibrosis; autophagy has protective effects.

  • Accumulation of saturated fatty acids triggers mitochondrial and cell damage in the kidney, whereas the polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid are renoprotective.

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Fig. 1: Lipoprotein structure, classification and metabolism.
Fig. 2: Dyslipidaemia in CKD.
Fig. 3: Effects of changes in HDL and LDL composition in CKD.
Fig. 4: Impaired fatty acid metabolism and mitochondrial overload contribute to inflammation, fibrosis and cellular damage in kidney.

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References

  1. Soppert, J., Lehrke, M., Marx, N., Jankowski, J. & Noels, H. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv. Drug Deliv. Rev. 159, 4–33 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Brewer, H. B. Jr., Remaley, A. T., Neufeld, E. B., Basso, F. & Joyce, C. Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 24, 1755–1760 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Weiner, D. E. & Sarnak, M. J. Managing dyslipidemia in chronic kidney disease. J. Gen. Intern. Med. 19, 1045–1052 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ferro, C. J. et al. Lipid management in patients with chronic kidney disease. Nat. Rev. Nephrol. 14, 727–749 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Lamprea-Montealegre, J. A. et al. Chronic kidney disease, lipids and apolipoproteins, and coronary heart disease: the ARIC study. Atherosclerosis 234, 42–46 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Lee, P. H. et al. Hypertriglyceridemia: an independent risk factor of chronic kidney disease in Taiwanese adults. Am. J. Med. Sci. 338, 185–189 (2009).

    Article  PubMed  Google Scholar 

  7. Chu, M., Wang, A. Y., Chan, I. H., Chui, S. H. & Lam, C. W. Serum small-dense LDL abnormalities in chronic renal disease patients. Br. J. Biomed. Sci. 69, 99–102 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Vickers, K. C. & Remaley, A. T. HDL and cholesterol: life after the divorce? J. Lipid Res. 55, 4–12 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258–1270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gajjala, P. R., Fliser, D., Speer, T., Jankowski, V. & Jankowski, J. Emerging role of post-translational modifications in chronic kidney disease and cardiovascular disease. Nephrol. Dial. Transplant. 30, 1814–1824 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Chen, H. et al. Combined clinical phenotype and lipidomic analysis reveals the impact of chronic kidney disease on lipid metabolism. J. Proteome Res. 16, 1566–1578 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Afshinnia, F. et al. Impaired beta-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD. J. Am. Soc. Nephrol. 29, 295–306 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Kruger, C. et al. Proximal tubular cell-specific ablation of carnitine acetyltransferase causes tubular disease and secondary glomerulosclerosis. Diabetes 68, 819–831 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nordestgaard, B. G. & Varbo, A. Triglycerides and cardiovascular disease. Lancet 384, 626–635 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber, T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977).

    Article  CAS  PubMed  Google Scholar 

  17. Rader, D. J. & Hovingh, G. K. HDL and cardiovascular disease. Lancet 384, 618–625 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Nguyen, T. D. & Schulze, P. C. Lipid in the midst of metabolic remodeling – therapeutic implications for the failing heart. Adv. Drug Deliv. Rev. 159, 120–132 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Thompson, S. et al. Cause of death in patients with reduced kidney function. J. Am. Soc. Nephrol. 26, 2504–2511 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Marx, N. et al. Mechanisms of cardiovascular complications in chronic kidney disease: research focus of the Transregional Research Consortium SFB TRR219 of the University Hospital Aachen (RWTH) and the Saarland University. Clin. Res. Cardiol. 107, 120–126 (2018).

    Article  PubMed  Google Scholar 

  21. Bajaj, A. et al. Lipids, apolipoproteins, and risk of atherosclerotic cardiovascular disease in persons with CKD. Am. J. Kidney Dis. 73, 827–836 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lamprea-Montealegre, J. A. et al. Apolipoprotein B, triglyceride-rich lipoproteins, and risk of cardiovascular events in persons with CKD. Clin. J. Am. Soc. Nephrol. 15, 47–60 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Chang, T. I. et al. Inverse association between serum non-high-density lipoprotein cholesterol levels and mortality in patients undergoing incident hemodialysis. J Am Heart Assoc. 7, e009096 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zewinger, S. et al. HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J. Am. Soc. Nephrol. 25, 1073–1082 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuma, A. et al. Impact of low-density lipoprotein cholesterol on decline in estimated glomerular filtration rate in apparently healthy young to middle-aged working men. Clin. Exp. Nephrol. 22, 15–27 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Muntner, P., Coresh, J., Smith, J. C., Eckfeldt, J. & Klag, M. J. Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int. 58, 293–301 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Schaeffner, E. S. et al. Cholesterol and the risk of renal dysfunction in apparently healthy men. J. Am. Soc. Nephrol. 14, 2084–2091 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Fox, C. S. et al. Predictors of new-onset kidney disease in a community-based population. JAMA 291, 844–850 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Rahman, M. et al. Relation of serum lipids and lipoproteins with progression of CKD: The CRIC study. Clin. J. Am. Soc. Nephrol. 9, 1190–1198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Haynes, R. et al. Effects of lowering LDL cholesterol on progression of kidney disease. J. Am. Soc. Nephrol. 25, 1825–1833 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Charytan, D. M. et al. Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial. J. Am. Coll. Cardiol. 73, 2961–2970 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Bowe, B., Xie, Y., Xian, H., Balasubramanian, S. & Al-Aly, Z. Low levels of high-density lipoprotein cholesterol increase the risk of incident kidney disease and its progression. Kidney Int. 89, 886–896 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Nam, K. H. et al. Association between serum high-density lipoprotein cholesterol levels and progression of chronic kidney disease: results from the KNOW-CKD. J. Am. Heart Assoc. 8, e011162 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bardagjy, A. S. & Steinberg, F. M. Relationship between HDL functional characteristics and cardiovascular health and potential impact of dietary patterns: a narrative review. Nutrients 11, 1231 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  35. Vaziri, N. D., Deng, G. & Liang, K. Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrol. Dialysis Transplant. 14, 1462–1466 (1999).

    Article  CAS  Google Scholar 

  36. Calabresi, L. et al. Acquired lecithin:cholesterol acyltransferase deficiency as a major factor in lowering plasma HDL levels in chronic kidney disease. J. Intern. Med. 277, 552–561 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Vaziri, N. D., Liang, K. & Parks, J. S. Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int. 59, 2192–2196 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Moradi, H. et al. Elevated high-density lipoprotein cholesterol and cardiovascular mortality in maintenance hemodialysis patients. Nephrol. Dialysis Transplant. 29, 1554–1562 (2014).

    Article  CAS  Google Scholar 

  39. Rohatgi, A. et al. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 371, 2383–2393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bauer, L. et al. HDL cholesterol efflux capacity and cardiovascular events in patients with chronic kidney disease. J. Am. Coll. Cardiol. 69, 246–247 (2017).

    Article  PubMed  Google Scholar 

  41. Kopecky, C. et al. HDL cholesterol efflux does not predict cardiovascular risk in hemodialysis patients. J. Am. Soc. Nephrol. 28, 769–775 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Chindhy, S. et al. Impaired renal function on cholesterol efflux capacity, hdl particle number, and cardiovascular events. J. Am. Coll. Cardiol. 72, 698–700 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Yamamoto, S. et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J. Am. Coll. Cardiol. 60, 2372–2379 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Gipson, G. T. et al. Impaired delivery of cholesterol effluxed from macrophages to hepatocytes by serum from CKD patients may underlie increased cardiovascular disease risk. Kidney Int. Rep. 5, 199–210 (2020).

    Article  PubMed  Google Scholar 

  45. Binder, V. et al. The myeloperoxidase product hypochlorous acid generates irreversible high-density lipoprotein receptor inhibitors. Arterioscler. Thromb. Vasc. Biol. 33, 1020–1027 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zewinger, S. et al. Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur. Heart J. 38, 1597–1607 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551–1558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Weichhart, T. et al. Serum amyloid A in uremic HDL promotes inflammation. J. Am. Soc. Nephrol. 23, 934–947 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Holzer, M. et al. Uremia alters HDL composition and function. J. Am. Soc. Nephrol. 22, 1631–1641 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shao, B. et al. A cluster of proteins implicated in kidney disease is increased in high-density lipoprotein isolated from hemodialysis subjects. J. Proteome Res. 14, 2792–2806 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moradi, H., Pahl, M. V., Elahimehr, R. & Vaziri, N. D. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl. Res. 153, 77–85 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Tolle, M. et al. High-density lipoprotein loses its anti-inflammatory capacity by accumulation of pro-inflammatory-serum amyloid A. Cardiovasc. Res. 94, 154–162 (2012).

    Article  PubMed  CAS  Google Scholar 

  54. Luo, M. et al. ApoCIII enrichment in HDL impairs HDL-mediated cholesterol efflux capacity. Sci. Rep. 7, 2312 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Jahangiri, A. High-density lipoprotein and the acute phase response. Curr. Opin. Endocrinol. Diabetes Obes. 17, 156–160 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Artl, A., Marsche, G., Lestavel, S., Sattler, W. & Malle, E. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler. Thromb. Vasc. Biol. 20, 763–772 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Schuchardt, M. et al. Dysfunctional high-density lipoprotein activates toll-like receptors via serum amyloid A in vascular smooth muscle cells. Sci. Rep. 9, 3421 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Zewinger, S. et al. Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. Eur. Heart J. 36, 3007–3016 (2015).

    CAS  PubMed  Google Scholar 

  59. Kopecky, C. et al. Quantification of HDL proteins, cardiac events, and mortality in patients with type 2 diabetes on hemodialysis. Clin. J. Am. Soc. Nephrol. 10, 224–231 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Untersteller, K. et al. HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients. J. Lipid Res. 59, 1256–1265 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chan, D. T. et al. Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III. J. Lipid Res. 50, 2524–2531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ooi, E. M., Barrett, P. H., Chan, D. C. & Watts, G. F. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin. Sci. 114, 611–624 (2008).

    Article  CAS  Google Scholar 

  63. Kohan, A. B. Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease. Curr. Opin. Endocrinol. Diabetes Obes. 22, 119–125 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Qu, J., Ko, C. W., Tso, P. & Bhargava, A. Apolipoprotein A-IV: a multifunctional protein involved in protection against atherosclerosis and diabetes. Cells 8, 319 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  65. Goldberg, I. J., Scheraldi, C. A., Yacoub, L. K., Saxena, U. & Bisgaier, C. L. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. J. Biol. Chem. 265, 4266–4272 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Tan, K. C. B. et al. Carbamylated lipoproteins and progression of diabetic kidney disease. Clin. J. Am. Soc. Nephrol. 15, 359–366 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Holzer, M. et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid. Redox Signal. 14, 2337–2346 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Shao, B. et al. Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase. Circul. Res. 114, 1733–1742 (2014).

    Article  CAS  Google Scholar 

  69. Kashyap, S. R. et al. Glycation reduces the stability of ApoAI and increases HDL dysfunction in diet-controlled type 2 diabetes. J. Clin. Endocrinol. Metab. 103, 388–396 (2018).

    Article  PubMed  Google Scholar 

  70. Shao, B., Pennathur, S. & Heinecke, J. W. Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. J. Biol. Chem. 287, 6375–6386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bakillah, A. et al. Plasma nitration of high-density and low-density lipoproteins in chronic kidney disease patients receiving kidney transplants. Med. Inflamm. 2015, 352356 (2015).

    Article  CAS  Google Scholar 

  72. Miyazaki, A. et al. N-homocysteinylation of apolipoprotein A-I impairs the protein’s antioxidant ability but not its cholesterol efflux capacity. Biol. Chem. 395, 641–648 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Speer, T., Zewinger, S. & Fliser, D. Uraemic dyslipidaemia revisited: role of high-density lipoprotein. Nephrol. Dialysis Transplant. 28, 2456–2463 (2013).

    Article  CAS  Google Scholar 

  74. Sun, J. T. et al. Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. Am. J. Physiol. Renal Physiol. 310, F511–F517 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Bancells, C., Sanchez-Quesada, J. L., Birkelund, R., Ordonez-Llanos, J. & Benitez, S. HDL and electronegative LDL exchange anti- and pro-inflammatory properties. J. Lipid Res. 51, 2947–2956 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yao, S. et al. Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway. J. Lipid Res. 58, 164–177 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Gao, X. et al. Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36. Int. J. Mol. Med. 34, 564–572 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Pérez, L. et al. OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells. Lab. Invest. 99, 421–437 (2019).

    Article  PubMed  CAS  Google Scholar 

  79. Sun, J. T. et al. Oxidized HDL, as a novel biomarker for calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells. J. Cardiovasc. Transl. Res. 12, 560–568 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Honda, H. et al. Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients. Atherosclerosis 220, 493–501 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Florens, N. et al. CKD increases carbonylation of HDL and is associated with impaired antiaggregant properties. J. Am. Soc. Nephrol. 31, 1462–1477 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kraus, L. M. & Kraus, A. P. Jr. Carbamoylation of amino acids and proteins in uremia. Kidney Int. Suppl. 78, S102–S107 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, Z. et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat. Med. 13, 1176–1184 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Chang, C. T. et al. PON-1 carbamylation is enhanced in HDL of uremia patients. J. Food Drug. Anal. 27, 542–550 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Koeth, R. A. et al. Protein carbamylation predicts mortality in ESRD. J. Am. Soc. Nephrol. 24, 853–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tsai, M. Y. et al. New automated assay of small dense low-density lipoprotein cholesterol identifies risk of coronary heart disease: the Multi-ethnic Study of Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 34, 196–201 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Shen, H. et al. Small dense low-density lipoprotein cholesterol was associated with future cardiovascular events in chronic kidney disease patients. BMC Nephrol. 17, 143 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Oi, K., Hirano, T., Sakai, S., Kawaguchi, Y. & Hosoya, T. Role of hepatic lipase in intermediate-density lipoprotein and small, dense low-density lipoprotein formation in hemodialysis patients. Kidney Int. Suppl. 71, S227–S228 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Ikewaki, K. et al. Delayed in vivo catabolism of intermediate-density lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 2615–2622 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Pietzsch, J., Lattke, P. & Julius, U. Oxidation of apolipoprotein B-100 in circulating LDL is related to LDL residence time. In vivo insights from stable-isotope studies. Arterioscler. Thromb. Vasc. Biol. 20, E63–E67 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Baigent, C. et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 2181–2192 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shlipak, M. G. et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA 293, 1737–1745 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Chawla, V. et al. Hyperlipidemia and long-term outcomes in nondiabetic chronic kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1582–1587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cholesterol Treatment Trialists’ (CTT) Collaboration. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol. 4, 829–839 (2016).

    Article  CAS  Google Scholar 

  95. Kovesdy, C. P., Anderson, J. E. & Kalantar-Zadeh, K. Inverse association between lipid levels and mortality in men with chronic kidney disease who are not yet on dialysis: effects of case mix and the malnutrition-inflammation-cachexia syndrome. J. Am. Soc. Nephrol. 18, 304–311 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Liu, Y. et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA291, 451–459 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Ruan, X. Z., Varghese, Z. & Moorhead, J. F. An update on the lipid nephrotoxicity hypothesis. Nat. Rev. Nephrol. 5, 713–721 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Delporte, C. et al. Impact of myeloperoxidase-LDL interactions on enzyme activity and subsequent posttranslational oxidative modifications of apoB-100. J. Lipid Res. 55, 747–757 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hamilton, R. T. et al. LDL protein nitration: implication for LDL protein unfolding. Arch. Biochem. Biophys. 479, 1–14 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Moore, K. J. & Freeman, M. W. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler. Thromb. Vasc. Biol. 26, 1702–1711 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Apostolov, E. O. et al. Carbamylated-oxidized LDL: proatherosclerotic effects on endothelial cells and macrophages. J. Atheroscler. Thromb. 20, 878–892 (2013).

    Article  PubMed  Google Scholar 

  102. Podrez, E. A. et al. Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J. Clin. Invest. 105, 1095–1108 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Jay, A. G., Chen, A. N., Paz, M. A., Hung, J. P. & Hamilton, J. A. CD36 binds oxidized low density lipoprotein (LDL) in a mechanism dependent upon fatty acid binding. J. Biol. Chem. 290, 4590–4603 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Le Master, E. et al. Proatherogenic flow increases endothelial stiffness via enhanced CD36-mediated uptake of oxidized low-density lipoproteins. Arterioscler. Thromb.Vasc. Biol. 38, 64–75 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Meisinger, C., Baumert, J., Khuseyinova, N., Loewel, H. & Koenig, W. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation 112, 651–657 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Drozdz, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell. Longev. 2016, 7520231 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Pawlak, K., Mysliwiec, M. & Pawlak, D. Oxidized LDL to autoantibodies against oxLDL ratio - the new biomarker associated with carotid atherosclerosis and cardiovascular complications in dialyzed patients. Atherosclerosis 224, 252–257 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Hou, J. S. et al. Serum malondialdehyde-modified low-density lipoprotein is a risk factor for central arterial stiffness in maintenance hemodialysis patients. Nutrients 12, 2160 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  109. Ok, E., Basnakian, A. G., Apostolov, E. O., Barri, Y. M. & Shah, S. V. Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease. Kidney Int. 68, 173–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Speer, T. et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur. Heart J. 35, 3021–3032 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Apostolov, E. O., Ray, D., Savenka, A. V., Shah, S. V. & Basnakian, A. G. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J. Am. Soc. Nephrol. 21, 1852–1857 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Afshinnia, F. et al. Myeloperoxidase levels and its product 3-chlorotyrosine predict chronic kidney disease severity and associated coronary artery disease. Am. J. Nephrol. 46, 73–81 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Himmelfarb, J., McMenamin, M. E., Loseto, G. & Heinecke, J. W. Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients. Free Radic. Biol. Med. 31, 1163–1169 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Bucala, R. et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc. Natl Acad. Sci. USA 91, 9441–9445 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hodgkinson, C. P., Laxton, R. C., Patel, K. & Ye, S. Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 2275–2281 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Ooi, E. M. et al. Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease. J. Lipid Res. 52, 794–800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Vaziri, N. D. & Liang, K. Down-regulation of VLDL receptor expression in chronic experimental renal failure. Kidney Int. 51, 913–919 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Kim, C. & Vaziri, N. D. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int. 67, 1028–1032 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Koppe, L. et al. Urea impairs beta cell glycolysis and insulin secretion in chronic kidney disease. J. Clin. Invest. 126, 3598–3612 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Koppe, L. et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Spoto, B., Pisano, A. & Zoccali, C. Insulin resistance in chronic kidney disease: a systematic review. Am. J. Physiol. Renal Physiol. 311, F1087–F1108 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Schwartz, G. G. et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J. Am. Coll. Cardiol. 65, 2267–2275 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Matsuura, Y., Kanter, J. E. & Bornfeldt, K. E. Highlighting residual atherosclerotic cardiovascular disease risk. Arterioscler. Thromb. Vasc. Biol. 39, e1–e9 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Soohoo, M. et al. Serum triglycerides and mortality risk across stages of chronic kidney disease in 2 million U.S. veterans. J. Clin. Lipidol. 13, 744–753.e715 (2019).

    Article  PubMed  Google Scholar 

  125. Utermann, G. in The Metabolic and Molecular Bases of Inherited Disease 8th edn (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 2753–2787 (McGraw-Hill, 2001)

  126. Kronenberg, F. et al. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J. Am. Soc. Nephrol. 11, 105–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Hopewell, J. C., Haynes, R. & Baigent, C. The role of lipoprotein (a) in chronic kidney disease. J. Lipid Res. 59, 577–585 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bittner, V. A. et al. Effect of alirocumab on Lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J. Am. Coll. Cardiol. 75, 133–144 (2020).

    Article  CAS  PubMed  Google Scholar 

  129. O’Donoghue, M. L. et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139, 1483–1492 (2019).

    Article  PubMed  CAS  Google Scholar 

  130. Boden, W. E. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Article  PubMed  CAS  Google Scholar 

  131. Albers, J. J. et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J. Am. Coll. Cardiol. 62, 1575–1579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Landray, M. J. et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).

    Article  PubMed  CAS  Google Scholar 

  133. Parish, S. et al. Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study. Circ. Genom. Precis. Med. 11, e001696 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tsimikas, S. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382, 244–255 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04023552 (2021).

  136. Czumaj, A. et al. Alterations of fatty acid profile may contribute to dyslipidemia in chronic kidney disease by influencing hepatocyte metabolism. Int. J. Mol. Sci. 20, 2470 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  137. Khor, B. H. et al. Blood fatty acid status and clinical outcomes in dialysis patients: a systematic review. Nutrients 10, 1353 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  138. Mantovani, A. et al. Association between increased plasma ceramides and chronic kidney disease in patients with and without ischemic heart disease. Diabetes Metab. 47, 101152 (2020).

    Article  PubMed  CAS  Google Scholar 

  139. Schulze, P. C., Drosatos, K. & Goldberg, I. J. Lipid use and misuse by the heart. Circul. Res. 118, 1736–1751 (2016).

    Article  CAS  Google Scholar 

  140. Afshinnia, F. et al. Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians. JCI Insight 4, e130317 (2019).

    Article  PubMed Central  Google Scholar 

  141. Han, S. H. et al. PGC-1α protects from Notch-induced kidney fibrosis development. J. Am. Soc. Nephrol 28, 3312–3322 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ruggiero, C. et al. Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis. Am. J. Physiol. Renal Physiol. 306, F896–F906 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fierro-Fernandez, M. et al. MiR-95p protects from kidney fibrosis by metabolic reprogramming. FASEB J. 34, 410–431 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Arif, E. et al. Mitochondrial biogenesis induced by the beta2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury. Kidney Int. 96, 656–673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jao, T. M. et al. ATF6alpha downregulation of PPARalpha promotes lipotoxicity-induced tubulointerstitial fibrosis. Kidney Int. 95, 577–589 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Price, N. L. et al. Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis. JCI Insight 4, e131102 (2019).

    Article  PubMed Central  Google Scholar 

  147. Chung, K. W. et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab. 30, 784–799.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Xu, S. et al. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis. 6, e1976 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Yamamoto, T. et al. High-fat diet-induced lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in the kidney. J. Am. Soc. Nephrol. 28, 1534–1551 (2017).

    Article  CAS  PubMed  Google Scholar 

  150. Soumura, M. et al. Oleate and eicosapentaenoic acid attenuate palmitate-induced inflammation and apoptosis in renal proximal tubular cell. Biochem. Biophys. Res. Commun. 402, 265–271 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Listenberger, L. L. et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl Acad. Sci. USA 100, 3077–3082 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sieber, J. et al. Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2. Am. J. Pathol. 183, 735–744 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kampe, K., Sieber, J., Orellana, J. M., Mundel, P. & Jehle, A. W. Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. Am. J. Physiol. Renal Physiol. 306, F401–F409 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Wilfling, F. et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev. Cell 24, 384–399 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Ackerman, D. et al. Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Rep. 24, 2596–2605.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Praticò, D. & Dogné, J. M. Vascular biology of eicosanoids and atherogenesis. Expert Rev. Cardiovasc. Ther. 7, 1079–1089 (2009).

    Article  PubMed  Google Scholar 

  157. Chiurchiù, V., Leuti, A. & Maccarrone, M. Bioactive lipids and chronic inflammation: managing the fire within. Front. Immunol. 9, 38 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Joffre, C., Rey, C. & Laye, S. N-3 polyunsaturated fatty acids and the resolution of neuroinflammation. Front. Pharmacol. 10, 1022 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kim, A. S. & Conte, M. S. Specialized pro-resolving lipid mediators in cardiovascular disease, diagnosis, and therapy. Adv. Drug Deliv. Rev. 159, 170–179 (2020).

    Article  CAS  PubMed  Google Scholar 

  160. de Gaetano, M. et al. Specialized pro-resolving lipid mediators: modulation of diabetes-associated cardio-, reno-, and retino-vascular complications. Front. Pharmacol. 9, 1488 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. de Oliveira Otto, M. C. et al. Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the multi-ethnic study of atherosclerosis. J. Am. Heart Assoc. 2, e000506 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Abdelhamid, A. S. et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 3, CD003177 (2020).

    PubMed  Google Scholar 

  163. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Doshi, R. et al. Meta-analysis comparing combined use of eicosapentaenoic acid and statin to statin alone. Am. J. Cardiol. 125, 198–204 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Rimm, E. B. et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American heart association. Circulation 138, e35–e47 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Marklund, M. et al. Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality. Circulation 139, 2422–2436 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shoji, T. et al. Serum n-3 and n-6 polyunsaturated fatty acid profile as an independent predictor of cardiovascular events in hemodialysis patients. Am. J. Kidney Dis. 62, 568–576 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Friedman, A. N. et al. Inverse relationship between long-chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis. Kidney Int. 83, 1130–1135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Khor, B. H. et al. Efficacy of nutritional interventions on inflammatory markers in haemodialysis patients: a systematic review and limited meta-analysis. Nutrients 10, 397 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  170. He, L., Li, M. S., Lin, M., Zhao, T. Y. & Gao, P. Effect of fish oil supplement in maintenance hemodialysis patients: a systematic review and meta-analysis of published randomized controlled trials. Eur. J. Clin. Pharmacol. 72, 129–139 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Saglimbene, V. M. et al. Effects of omega-3 polyunsaturated fatty acid intake in patients with chronic kidney disease: Systematic review and meta-analysis of randomized controlled trials. Clin. Nutr. 39, 358–368 (2020).

    Article  CAS  PubMed  Google Scholar 

  172. Zeng, Z. et al. Omega-3 polyunsaturated fatty acids attenuate fibroblast activation and kidney fibrosis involving MTORC2 signaling suppression. Sci. Rep. 7, 46146 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Malhotra, R. et al. Dietary polyunsaturated fatty acids and incidence of end-stage renal disease in the Southern community cohort study. BMC Nephrol. 17, 152 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Dos Santos, A. L. T. et al. Low linolenic and linoleic acid consumption are associated with chronic kidney disease in patients with type 2 diabetes. PLoS ONE 13, e0195249 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Cardenas, C., Bordiu, E., Bagazgoitia, J. & Calle-Pascual, A. L. Polyunsaturated fatty acid consumption may play a role in the onset and regression of microalbuminuria in well-controlled type 1 and type 2 diabetic people: a 7-year, prospective, population-based, observational multicenter study. Diabetes Care 27, 1454–1457 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Shapiro, H., Theilla, M., Attal-Singer, J. & Singer, P. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat. Rev. Nephrol. 7, 110–121 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Elajami, T. K. et al. Eicosapentaenoic and docosahexaenoic acids attenuate progression of albuminuria in patients with type 2 diabetes mellitus and coronary artery disease. J. Am. Heart Assoc. 6, e004740 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. de Boer, I. H. et al. Effect of Vitamin D and Omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: a randomized clinical trial. JAMA 322, 1899–1909 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 11–50 (2013).

  180. Palmer, S. C. et al. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann. Intern. Med. 157, 263–275 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Hou, W. et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur. Heart J. 34, 1807–1817 (2013).

    Article  CAS  PubMed  Google Scholar 

  182. Rosenson, R. S. et al. HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nat. Rev. Cardiol. 15, 9–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  183. Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 135, 2494–2504 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Gibson, C. M. et al. The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction. Am. Heart J. 208, 81–90 (2019).

    Article  CAS  PubMed  Google Scholar 

  185. Kalim, S. et al. The effects of parenteral amino acid therapy on protein carbamylation in maintenance hemodialysis patients. J. Ren. Nutr. 25, 388–392 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kang, A. & Jardine, M. J. SGLT2 inhibitors may offer benefit beyond diabetes. Nat. Rev. Nephrol. 17, 83–84 (2021).

    Article  CAS  PubMed  Google Scholar 

  187. Packer, M. Role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient overabundance. Circulation 141, 2095–2105 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02364648 (2019).

  189. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03960073 (2021).

  190. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03579693 (2020).

  191. Mach, F. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 41, 111–188 (2020).

    Article  PubMed  Google Scholar 

  192. Bender, D. A. Introduction to Nutrition and Metabolism 5th edn (CRC, 2014).

  193. Gelber, R. P. et al. Association between body mass index and CKD in apparently healthy men. Am. J. Kidney Dis. 46, 871–880 (2005).

    Article  PubMed  Google Scholar 

  194. D’Agati, V. D. et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat. Rev. Nephrol. 12, 453–471 (2016).

    Article  PubMed  CAS  Google Scholar 

  195. Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M. & Gafter, U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J. Lipid Res. 55, 561–572 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Wu, D. et al. Vaccine against PCSK9 improved renal fibrosis by regulating fatty acid beta-oxidation. J. Am. Heart Assoc. 9, e014358 (2020).

    Article  CAS  PubMed  Google Scholar 

  197. Decleves, A. E. et al. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int. 85, 611–623 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Decleves, A. E., Mathew, A. V., Cunard, R. & Sharma, K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J. Am. Soc. Nephrol. 22, 1846–1855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Udi, S. et al. Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD. J. Am. Soc. Nephrol. 28, 3518–3532 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Bakker, P. J. et al. Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation. Kidney Int. 85, 1112–1122 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Yang, P. et al. Inflammatory stress promotes the development of obesity-related chronic kidney disease via CD36 in mice. J. Lipid Res. 58, 1417–1427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the German Research Foundation (DFG) SFB/TRR219 Project-ID 322900939 (S-03, C-04, M-03, M-05), SFB 1382 Project-ID 403224013 (A-04), by the CORONA foundation and by the Interreg V-A EMR program (EURLIPIDS, EMR23). This project also received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn).

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  1. Institute for Molecular Cardiovascular Research, RWTH Aachen University, University Hospital, Aachen, Germany

    Heidi Noels & Joachim Jankowski

  2. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands

    Heidi Noels

  3. Department of Internal Medicine I, RWTH Aachen University, University Hospital, Aachen, Germany

    Michael Lehrke

  4. Nephrology Section, Department of Internal Medicine and Pediatrics, University Hospital, Ghent, Belgium

    Raymond Vanholder

  5. Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht University, Maastricht, Netherlands

    Joachim Jankowski

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Glossary

Uraemic retention solutes

Substances that accumulate in blood of patients with chronic kidney disease owing to reduced kidney clearance.

Mitochondrial overload

A condition in which mitochondria are presented with an excess of substrate, which overwhelms the mitochondrial capacity for fatty acid β-oxidation, reduces free CoA levels and induces the accumulation of excess acetyl-CoA.

Cholesterol efflux capacity

The capacity of HDL to extract cholesterol from macrophages.

Pulse wave velocity

Velocity at which a blood pressure pulse travels through the vessels; used as a clinical measure of arterial stiffness.

Acute phase protein

A component of the acute phase response, which is the initial systemic response of an organism to inflammation and is characterized by an increase or decrease in acute phase proteins in blood.

Residence time

The length of time present in the circulation.

Malnutrition–inflammation–cachexia syndrome

A condition characterized by malnutrition (protein-energy wasting, defined as loss of body protein mass and energy reserves (fat mass)), inflammation and/or oxidative stress; common in chronic diseases such as chronic kidney disease.

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Noels, H., Lehrke, M., Vanholder, R. et al. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations. Nat Rev Nephrol 17, 528–542 (2021). https://doi.org/10.1038/s41581-021-00423-5

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