[Frontiers In Bioscience, Landmark, 23, 146-161, January 1, 2018]

Molecular mechanisms of disorders of lipid metabolism in chronic kidney disease

Hamid Moradi1,2, Nosratola D. Vaziri2

1Nephrology Section, Veterans Affairs Medical Center, Long Beach, 5901 E 7th St, Long Beach, CA 90822, 2 University of California, Irvine, 333 City Blvd West, Orange, CA 92868

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Lipid Disorders in CKD: nature and underlying molecular mechanisms
3.1. Dyslipidemia of CKD and ESRD
3.1.1. Alterations in triglyceride and triglyceride-rich lipoprotein metabolism
3.1.2. Alterations in cholesterol and low density lipoprotein metabolism
3.1.3. Alterations in high density lipoprotein metabolism
4. Summary and perspective
5. Acknowledgements
6. References

1. ABSTRACT

Chronic kidney disease (CKD) is a progressive condition marked by protracted kidney damage which over time can lead to end stage renal disease (ESRD). CKD can be categorized into different stages based on the extent of renal damage and degree of renal dysfunction with ESRD requiring renal replacement therapy considered the final stage. It is important to note that CKD in all of its forms is associated with accelerated atherosclerosis, cardiovascular (CV) disease and poor CV outcomes. While a number of factors contribute to the high risk of CV mortality in this patient population, dyslipidemia is considered to be a key player in the pathogenesis of CV disease in CKD. Molecular mechanisms responsible for CKD-associated lipid disorders are unique and greatly influenced by the stage of renal disease, presence and degree of proteinuria and in patients with ESRD, modality of renal replacement therapy. This article provides a detailed overview of the molecular mechanisms which cause dyslipidemia and the nature of lipid disorders associated with CKD and ESRD.

6. REFERENCES

1. USRDS. USRDS, . Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health NIDDK. (2016)

2. C.P. Kovesdy, and K. Kalantar-Zadeh: Enter the dragon: a Chinese epidemic of chronic kidney disease? Lancet. 379, 783-5 (2012)
DOI:10.1016/S0140-6736(12)60115-9

3. L. Zhang, F. Wang, L. Wang, W. Wang, B. Liu, J. Liu, M. Chen, Q. He, Y. Liao, X. Yu, N. Chen, J.E. Zhang, Z. Hu, F. Liu, D. Hong, L. Ma, H. Liu, X. Zhou, J. Chen, L. Pan, W. Chen, W. Wang, X. Li, and H. Wang: Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet. 379, 815-22 (2012)
DOI:10.1016/S0140-6736(12)60033-6

4. R.T. Gansevoort, R. Correa-Rotter, B.R. Hemmelgarn, T.H. Jafar, H.J. Heerspink, J.F. Mann, K. Matsushita, and C.P. Wen: Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 382, 339-52 (2013)
DOI:10.1016/S0140-6736(13)60595-4

5. R. Segura, and A.M. Gotto, Jr.: Lipid and lipoprotein abnormalities in renal disease. Perspect Nephrol Hypertens. 3, 159-200 (1976)

6. P.O. Attman, and P. Alaupovic : Pathogenesis of hyperlipidemia in the nephrotic syndrome. Am J Nephrol. 10, 69-75 (1990)
DOI:10.1159/000168197

7. J.H. Baxter, H.C. Goodman, and R.J. Havel: Serum lipid and lipoprotein alterations in nephrosis. J Clin Invest. 39, 455-65 (1960)
DOI:10.1172/JCI104058

8. N.D. Vaziri: Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol. 290, F262-72 (2006)
DOI:10.1152/ajprenal.00099.2005

9. N.D. Vaziri, H. Moradi: Mechanisms of dyslipidemia of chronic renal failure. Hemodial Int. 10, 1-7 (2006)
DOI:10.1111/j.1542-4758.2006.01168.x

10. G.A. Kaysen: New insights into lipid metabolism in chronic kidney disease. J Ren Nutr. 21, 120-3 (2011)
DOI:10.1053/j.jrn.2010.10.017

11. D. O'Neal, P. Lee, B. Murphy, and J. Best: Low-density lipoprotein particle size distribution in end-stage renal disease treated with hemodialysis or peritoneal dialysis. Am J Kidney Dis. 27 ,84-91 (1996)
DOI:10.1016/S0272-6386(96)90034-7

12. I. Rajman, L. Harper, D. McPake, M.J. Kendall, and D.C. Wheeler: Low-density lipoprotein subfraction profiles in chronic renal failure. Nephrol Dial Transplant. 13, 2281-7 (1998)
DOI:10.1093/ndt/13.9.2281

13. F. Kronenberg, E. Kuen, E. Ritz, R. Junker, P. Konig, G. Kraatz, K. Lhotta, J.F. Mann, G.A. Muller, U. Neyer, W. Riegel, P. Reigler, V. Schwenger, and A. Von Eckardstein: Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol. 11, 105-15 (2000)

14. F. Kronenberg, U. Neyer, K. Lhotta, E. Trenkwalder, M. Auinger, A. Pribasnig, T. Meisl, P. Konig, and H. Dieplinger: . The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up. J Am Soc Nephrol. 10, 1027-36 (1999)

15. K. Jin, B.S. Park, Y.W. Kim, and N.D. Vaziri: Plasma PCSK9 in nephrotic syndrome and in peritoneal dialysis: a cross-sectional study. Am J Kidney Dis. 63, 584-9 (2014)
DOI:10.1053/j.ajkd.2013.10.042

16. N.D. Vaziri: Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int. 90, 41-52 (2016)
DOI:10.1016/j.kint.2016.02.026

17. N.D. Vaziri: HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat Rev Nephrol. 12, 37-47 (2016)
DOI:10.1038/nrneph.2015.180

18. J.C. Webb, D.D. Patel, M.D. Jones, B.L. Knight, and A.K. Soutar: Characterization and tissue-specific expression of the human 'very low density lipoprotein (VLDL) receptor' mRNA. Hum Mol Genet. 3, 531-7 (1994)
DOI:10.1093/hmg/3.4.531

19. S. Takahashi, Y. Kawarabayasi, T. Nakai, J. Sakai, and T. Yamamoto: Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci U S A. 89, 9252-6 (1992)
DOI:10.1073/pnas.89.19.9252

20. C. Wanner, K. Frommherz, and W.H. Horl: Hyperlipoproteinemia in chronic renal failure: pathophysiological and therapeutic aspects. Cardiology. 78, 202-17 (1991)
DOI:10.1159/000174787

21. N.D. Vaziri, and K. Liang: Down-regulation of VLDL receptor expression in chronic experimental renal failure. Kidney Int. 51, 913-9 (1997)
DOI:10.1038/ki.1997.129

22. N.D. Vaziri, and K. Liang: Down-regulation of tissue lipoprotein lipase expression in experimental chronic renal failure. Kidney Int. 50, 1928-35 (1996)
DOI:10.1038/ki.1996.515

23. I.J. Goldberg: Lipoprotein metabolism in normal and uremic patients. Am J Kidney Dis. 21, 87-90 (1993)
DOI:10.1016/S0272-6386(12)80728-1

24. P. Tessari, E. Kiwanuka, R. Barazzoni, G.M. Toffolo, M. Vettore, I. Cortella, E. Manesso, G. Pasqualetto, L. Puricelli, C. Gabelli, and M. Zanetti: Decreased VLDL-Apo B 100 Fractional Synthesis Rate Despite Hypertriglyceridemia in Subjects With Type 2 Diabetes and Nephropathy. J Clin Endocrinol Metab. 100, 4098-105 (2015)
DOI:10.1210/jc.2015-2172

25. B. Stegmayr, T. Olivecrona, and G. Olivecrona: Lipoprotein lipase disturbances induced by uremia and hemodialysis. Semin Dial. 22, 442-4 (2009)
DOI:10.1111/j.1525-139X.2009.00597.x

26. N.D.Vaziri: Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial. 22, 644-51(2009)
DOI:10.1111/j.1525-139X.2009.00661.x

27. N. Parthasarathy, I.J. Goldberg, P. Sivaram, B. Mulloy, D.M. Flory, and W.D. Wagner: Oligosaccharide sequences of endothelial cell surface heparan sulfate proteoglycan with affinity for lipoprotein lipase. J Biol Chem. 269, 22391-6 (1994)

28. S.G. Young, B.S. Davies, L.G. Fong, P. Gin, M.M. Weinstein, A. Bensadoun, and A.P. Beigneux: GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons. Curr Opin Lipidol. 18, 389-96 (2007)
DOI:10.1097/MOL.0b013e3281527914

29. L.G. Fong, S.G. Young, A.P. Beigneux, A. Bensadoun, M. Oberer, H. Jiang, and M. Ploug: GPIHBP1 and Plasma Triglyceride Metabolism. Trends Endocrinol Metab. (2016) 27, 455-69 (2016)

30. Y. Nishizawa, T. Shoji, H. Nishitani, M. Yamakawa, T. Konishi, K. Kawasaki, and H. Morii: Hypertriglyceridemia and lowered apolipoprotein C-II/C-III ratio in uremia: effect of a fibric acid, clinofibrate. Kidney Int. 44, 1352-9 (1993)
DOI:10.1038/ki.1993.388

31. K. Liang, F. Oveisi, and N.D. Vaziri: Role of secondary hyperparathyroidism in the genesis of hypertriglyceridemia and VLDL receptor deficiency in chronic renal failure. Kidney Int. 53, 626-30 (1998)
DOI:10.1046/j.1523-1755.1998.00786.x

32. N.D. Vaziri, X.Q. Wang, and K. Liang: Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure. Am J Physiol. 273, F925-30 (1997)

33. Y. Nishizawa, T. Shoji, T. Kawagishi, and H. Morii: Atherosclerosis in uremia: possible roles of hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int Supple. 62, S90-2 (1997)

34. S.G. Massry, and M. Akmal: Lipid abnormalities, renal failure, and parathyroid hormone. Am J Med. 87, 42N-4N (1989)

35. M. Klin, M. Smogorzewski, Z. Ni, G. Zhang, and S.G. Massry: Abnormalities in hepatic lipase in chronic renal failure: role of excess parathyroid hormone. J Clin Invest. 97, 2167-73 (1996)
DOI:10.1172/JCI118657

36. M. Akmal, S.E. Kasim, A.R. Soliman, and S.G. Massry: Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure. Kidney Int. 37, 854-8 (1990)
DOI:10.1038/ki.1990.58

37. N.D. Vaziri, J. Yuan, Z. Ni, S.B. Nicholas, and K.C. Norris: Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression. Clin Exp Nephrol. 16, 238-43 (2012)
DOI:10.1007/s10157-011-0549-3

38. B. Nasstrom, G. Olivecrona, T. Olivecrona, and B.G. Stegmayr: Lipoprotein lipase during heparin infusion: lower activity in hemodialysis patients. Scand J Clin Lab Invest. 63, 45-53 (2003)
DOI:10.1080/00365510310000484

39. M.K. Chan, J. Persaud, Z. Varghese, and J.F. Moorhead: Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kid Int. 25, 812-8 (1984)
DOI:10.1038/ki.1984.94

40. B. Nasstrom, B.G. Stegmayr, G. Olivecrona, and T. Olivecrona: Lower plasma levels of lipoprotein lipase after infusion of low molecular weight heparin than after administration of conventional heparin indicate more rapid catabolism of the enzyme. Transl Res. 142, 90-9 (2003)
DOI:10.1016/s0022-2143(03)00059-3

41. D. Mahmood, S. Nilsson, G. Olivecrona, and B. Stegmayr: Lipoprotein lipase activity is favoured by peritoneal dialysis compared to hemodialysis. Scand J Clin Lab Invest. 74, 296-300 (2014)
DOI:10.3109/00365513.2014.882016

42. N.D. Vaziri, and H. Moradi: Dual role of circulating angiopoietin-like 4 (ANGPTL4) in promoting hypertriglyceridemia and lowering proteinuria in nephrotic syndrome. Am J Kidney Dis. 64, 495-8 (2014)
DOI:10.1053/j.ajkd.2014.04.016

43. L.C. Clement, C. Mace, M. Del Nogal Avila, C.B. Marshall, and S.S. Chugh: The proteinuria-hypertriglyceridemia connection as a basis for novel therapeutics for nephrotic syndrome. Transl Res. 165, 499-504 (2015)
DOI:10.1016/j.trsl.2014.06.004

44. T. Baranowski, S. Kralisch, A. Bachmann, U. Lossner, J. Kratzsch, M. Bluher, M. Stumvoll, and M. Fasshauer: Serum levels of the adipokine fasting-induced adipose factor/angiopoietin-like protein 4 depend on renal function. Horm Metab Res. 43, 117-20 (2011)
DOI:10.1055/s-0030-1267917

45. L. Lichtenstein, J.F. Berbee, S.J. van Dijk, K.W. van Dijk, A. Bensadoun, I.P. Kema, P.J. Voshol, M. Muller, P.C. Rensen, and S. Kersten: Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake. Arterioscler Thromb Vasc Biol. 27, 2420-7 (2007)
DOI:10.1161/ATVBAHA.107.151894

46. W.K. Sonnenburg, D. Yu, E.C. Lee, W. Xiong, G. Gololobov, B. Key, J. Gay, N. Wilganowski, Y. Hu, S. Zhao, M. Schneider, Z.M. Ding, B.P. Zambrowicz, G. Landes, D.R. Powell, and U. Desai: GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4. J Lipid Res. 50, 2421-9 (2009)
DOI:10.1194/jlr.M900145-JLR200

47. D. Mahmood, E. Makoveichuk, S. Nilsson, G. Olivecrona, and B. Stegmayr: Response of angiopoietin-like proteins 3 and 4 to hemodialysis. Int J Artif Organs. 37, 13-20 (2014)
DOI:10.5301/ijao.5000252

48. J.B. Roullet, B. Lacour, J.P. Yvert, and T. Drueke: Correction by insulin of disturbed TG-rich LP metabolism in rats with chronic renal failure. Am J Physiol. 250, E373-6 (1986)

49. J.B. Roullet, B. Lacour, and T. Drueke: Partial correction of lipid disturbances by insulin in experimental renal failure. Contrib Nephrol. 50, 203-10 (1986)
DOI:10.1159/000413000

50. B. Saffari, J.M. Ong, and P.A. Kern: Regulation of adipose tissue lipoprotein lipase gene expression by thyroid hormone in rats. J Lipid Res. 33, 241-9 (1992)

51. B. Fagher, M. Monti, P. Nilsson-Ehle, and H. Thysell: Reduced thermogenesis in muscle and disturbed lipoprotein metabolism in relation to thyroid function in haemodialysis patients. Scand J Clin Lab Invest. 47, 91-7 (1987)
DOI:10.3109/00365518709168875

52. C. Kim, and N.D. Vaziri: Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int. 67, 1028-32 (2005)
DOI:10.1111/j.1523-1755.2005.00166.x

53. K. Chapman, M. Holmes, and J. Seckl: 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 93, 1139-206 (2013)
DOI:10.1152/physrev.00020.2012

54. M. Li, E. Ellis, H. Johansson, G. Nowak, B. Isaksson, D. Gnocchi, P. Parini, and J. Axelsson: Changes in gluconeogenesis and intracellular lipid accumulation characterize uremic human hepatocytes ex vivo. Am J Physiol Gastrointest Liver Physiol. 310, G952-61(2016)
DOI:10.1152/ajpgi.00379.2015

55. A. Chapagain, P.W. Caton, J. Kieswich, P. Andrikopoulos, N. Nayuni, J.H. Long, S.M. Harwood, S.P. Webster, M.J. Raftery, C. Thiemermann, B.R. Walker, J.R. Seckl, R. Corder, and M.M. Yaqoob: Elevated hepatic 11beta-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia. Proc Natl Acad Sci U S A. 111, 3817-22 (2014)
DOI:10.1073/pnas.1312436111

56. K. Liang, and N.D. Vaziri: Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure. Nephrol Dial Transplant. 12, 1381-6 (1997)
DOI:10.1093/ndt/12.7.1381

57. N.D. Vaziri, T. Sato, and K. Liang: Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis. Kidney Int. 63, 1756-63 (2003)
DOI:10.1046/j.1523-1755.2003.00911.x

58. K. Liang, and N.D. Vaziri: Upregulation of acyl-CoA: cholesterol acyltransferase in chronic renal failure. Am J Physiol Endocrinol Metab. 283, E676-81 (2002)
DOI:10.1152/ajpendo.00364.2001

59. N.D. Vaziri, and K. Liang: ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure. Am J Physiol Renal Physiol. 287, F1038-43 (2004)
DOI:10.1152/ajprenal.00150.2004

60. H. Moradi, J. Yuan, Z. Ni, K. Norris, and N.D. Vaziri: Reverse cholesterol transport pathway in experimental chronic renal failure. Am J Nephrol. 30, 147-54 (2009)
DOI:10.1159/000210020

61. K. Bolzano, F. Krempler, and F. Sandhofer: Hepatic and extrahepatic triglyceride lipase activity in uraemic patients on chronic haemodialysis. Eur J Clin Invest. 8, 289-93 (1978)
DOI:10.1111/j.1365-2362.1978.tb00844.x

62. C.T. Chang, G.J. Wang, C.C. Kuo, J.Y. Hsieh, A.S. Lee, C.M. Chang, C.C. Wang, M.Y. Shen, C.C. Huang, T. Sawamura, C.Y. Yang, N. Stancel, and C.H. Chen: Electronegative Low-density Lipoprotein Increases Coronary Artery Disease Risk in Uremia Patients on Maintenance Hemodialysis. Medicine (Baltimore) 95, e2265 (2016)
DOI:10.1097/MD.0000000000002265

63. S. Tsimikas: A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 69, 692-711 (2017)
DOI:10.1016/j.jacc.2016.11.042

64. S. Tsimikas, E.S. Brilakis, E.R. Miller, J.P. McConnell, R.J. Lennon, K.S. Kornman, J.L. Witztum, and P.B. Berger: Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 353, 46-57 (2005)
DOI:10.1056/NEJMoa043175

65. M. Poon, X. Zhang, K.G. Dunsky, M.B. Taubman, and P.C. Harpel: Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation. 96, 2514-9 (1997)
DOI:10.1161/01.CIR.96.8.2514

66. E. Trenkwalder, A. Gruber, P. Konig, H. Dieplinger, and F. Kronenberg: Increased plasma concentrations of LDL-unbound apo(a) in patients with end-stage renal disease. Kid Int. 52, 1685-92 (1997)
DOI:10.1038/ki.1997.503

67. F. Kronenberg, K. Ikewaki, J.R. Schaefer, P. Konig, and H. Dieplinger: Kinetic studies of atherogenic lipoproteins in hemodialysis patients: do they tell us more about their pathology? Semin Dial. 20, 554-60 (2007)
DOI:10.1111/j.1525-139X.2007.00338.x

68. H.J. Milionis, M.S. Elisaf, A. Tselepis, E. Bairaktari, S.A. Karabina, and K.C. Siamopoulos: Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure. Am J Kidney Dis. 33, 1100-6 (1999)
DOI:10.1016/S0272-6386(99)70147-2

69. K. Kalantar-Zadeh, and V.S. Balakrishnan: The kidney disease wasting: inflammation, oxidative stress, and diet-gene interaction. Hemodial Int. 10, 315-25 (2006)
DOI:10.1111/j.1542-4758.2006.00124.x

70. D.J. Gordon, and B.M. Rifkind: High-density lipoprotein--the clinical implications of recent studies. N Engl J Med. 321, 1311-6 (1989)
DOI:10.1056/NEJM198911093211907

71. P. Barter, A.M. Gotto, J.C. LaRosa, J. Maroni, M. Szarek, S.M. Grundy, J.J. Kastelein, V. Bittner, J.C. Fruchart: HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 357, 1301-10 (2007)
DOI:10.1056/NEJMoa064278

72. T.I. Chang, E. Streja, and H. Moradi: Could high-density lipoprotein cholesterol predict increased cardiovascular risk? Curr Opin Endocrinol Diabetes Obes. 24, 140-7 (2017)
DOI:10.1097/MED.0000000000000318

73. N.D. Vaziri, M. Navab, and A.M. Fogelman: HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol. 6, 287-96 (2010)
DOI:10.1038/nrneph.2010.36

74. M.G. Sorci-Thomas, and M.J. Thomas: Microdomains, Inflammation, and Atherosclerosis. Circ Res. 118, 679-91 (2016) .
DOI:10.1161/CIRCRESAHA.115.306246

75. D.J. Rader: Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 116, 3090-100 (2006)
DOI:10.1172/JCI30163

76. R.S. Rosenson, H.B. Brewer, Jr., W.S. Davidson, Z.A. Fayad, V. Fuster, J. Goldstein, M. Hellerstein, X.C. Jiang, M.C. Phillips, D.J. Rader, A.T. Remaley, G.H. Rothblat, A.R. Tall, and L. Yvan-Charvet: Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 125, 1905-19 (2012)
DOI:10.1161/CIRCULATIONAHA.111.066589

77. A.R. Tall, L. Yvan-Charvet, N. Terasaka, T. Pagler, and N. Wang: HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 7, 365-75 (2008)
DOI:10.1016/j.cmet.2008.03.001

78. A. Ossoli, C. Pavanello, and L. Calabresi: High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis. Endocrinol Metab (Seoul) 31, 223-9 (2016)
DOI:10.3803/EnM.2016.31.2.223

79. H. Moradi, N.D. Vaziri, M.L. Kashyap, H.M. Said, and K. Kalantar-Zadeh: Role of HDL dysfunction in end-stage renal disease: a double-edged sword. J Ren Nutr. 23, 203-6 (2013)
DOI:10.1053/j.jrn.2013.01.022

80. M. van der Stoep, S.J. Korporaal, and M. Van Eck: High-density lipoprotein as a modulator of platelet and coagulation responses. Cardiovasc Res. 103, 362-71 (2014)
DOI:10.1093/cvr/cvu137

81. E.M. deGoma, R.L. deGoma, and D.J. Rader: Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol. 51, 2199-211 (2008)
DOI:10.1016/j.jacc.2008.03.016

82. M. Tolle, A. Pawlak, M. Schuchardt, A. Kawamura, U.J. Tietge, S. Lorkowski, P. Keul, G. Assmann, J. Chun, B. Levkau, M. van der Giet, and J.R. Nofer: HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production. Arterioscler Thromb Vasc Biol. 28, 1542-8 (2008)
DOI:10.1161/ATVBAHA.107.161042

83. C. Mineo, and P.W. Shaul: Novel biological functions of high-density lipoprotein cholesterol. Circ Res. 111, 1079-90 (2012)
DOI:10.1161/CIRCRESAHA.111.258673

84. A.J. Murphy, K.J. Woollard, A. Hoang, N. Mukhamedova, R.A. Stirzaker, S.P. McCormick, A.T. Remaley, D. Sviridov, and J. Chin-Dusting: High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler Thromb Vasc Biol. 28, 2071-7 (2008)
DOI:10.1161/ATVBAHA.108.168690

85. S. Patel, B.A. Di Bartolo, S. Nakhla, A.K. Heather, T.W. Mitchell, W. Jessup, D.S. Celermajer, P.J. Barter, and K.A. Rye: Anti-inflammatory effects of apolipoprotein A-I in the rabbit. Atherosclerosis. 212, 392-7 (2010)
DOI:10.1016/j.atherosclerosis.2010.05.035

86. S.T. Reddy, M. Navab, G.M. Anantharamaiah, and A.M. Fogelman: Apolipoprotein A-I mimetics. Curr Opin Lipidol. 25, 304-8 (2014)
DOI:10.1097/MOL.0000000000000092

87. N.D. Vaziri, H.J. Kim, H. Moradi, F. Farmand, K. Navab, M. Navab, S. Hama, A.M. Fogelman, Y. Quiroz, and B. Rodriguez-Iturbe: melioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice. Nephrol Dial Transplant. 25, 3525-34 (2010)
DOI:10.1093/ndt/gfq274

88. A.S. Shah, L. Tan, J.L. Long, and W.S. Davidson: Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J Lipid Res. 54, 2575-85 (2013)
DOI:10.1194/jlr.R035725

89. N. Prufer, B. Kleuser, and M. van der Giet: The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality. Biol Chem. 396, 573-83 (2015)
DOI:10.1515/hsz-2014-0192

90. R.S. Birjmohun, S.I. van Leuven, J.H. Levels, C. van 't Veer, J.A. Kuivenhoven, J.C. Meijers, M. Levi, J.J. Kastelein, T. van der Poll, and E.S. Stroes: High-density lipoprotein attenuates inflammation and coagulation response on endotoxin challenge in humans. Arterioscler Thromb Vasc Biol. 27, 1153-8 (2007)
DOI:10.1161/ATVBAHA.106.136325

91. K. Kalantar-Zadeh, M.L. Brennan, and S.L. Hazen: Serum myeloperoxidase and mortality in maintenance hemodialysis patients. Am J Kidney Dis. 48, 59-68 (2006)
DOI:10.1053/j.ajkd.2006.03.047

92. K. Kalantar-Zadeh, J.D. Kopple, N. Kamranpour, A.M. Fogelman, and M. Navab: HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int. 72, 1149-56 (2007)
DOI:10.1038/sj.ki.5002491

93. N.D. Vaziri: Lipotoxicity and impaired high density lipoprotein-mediated reverse cholesterol transport in chronic kidney disease. J Ren Nutr. 20, S35-43 (2010)
DOI:10.1053/j.jrn.2010.05.010

94. T. Speer, S. Zewinger, and D. Fliser: Uraemic dyslipidaemia revisited: role of high-density lipoprotein. Nephrol Dial Transplant. 28, 2456-63 (2013)
DOI:10.1093/ndt/gft080

95. H. Moradi, H.M. Said, and N.D. Vaziri: Post-transcriptional nature of uremia-induced downregulation of hepatic apolipoprotein A-I production. Transl Res. 161, 477-85 (2013)
DOI:10.1016/j.trsl.2012.11.001

96. N.D. Vaziri, G. Deng, and K. Liang: Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrol Dial Transplant. 14, 1462-6 (1999)
DOI:10.1093/ndt/14.6.1462

97. M.C. Batista, F.K. Welty, M.R. Diffenderfer, M.J. Sarnak, E.J. Schaefer, S. Lamon-Fava, B.F. Asztalos, G.G. Dolnikowski, M.E. Brousseau, and J.B. Marsh: Apolipoprotein A-I, B-100, and B-48 metabolism in subjects with chronic kidney disease, obesity, and the metabolic syndrome. Metabolisml. 53, 1255-61 (2004)
DOI:10.1016/j.metabol.2004.05.001

98. K. Okubo, K. Ikewaki, S. Sakai, N. Tada, Y. Kawaguchi, and S. Mochizuki: Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study. J Am Soc Nephrol. 15, 1008-15 (2004)
DOI:10.1097/01.ASN.0000117286.85443.7D

99. M. Pruijm, J. Schmidtko, A. Aho, S. Pagano, P. Roux-Lombard, D. Teta, M. Burnier, and N. Vuilleumier: High prevalence of anti-apolipoprotein/A-1 autoantibodies in maintenance hemodialysis and association with dialysis vintage. Ther Apher Dialysis. 16, 588-94 (2012)
DOI:10.1111/j.1744-9987.2012.01102.x

100. B. Shao: Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL. Biochimica et biophysica acta. 1821, 490-501 (2012)
DOI:10.1016/j.bbalip.2011.11.011

101. V. Kon, H. Yang, and S. Fazio: Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein. Arch Med Res. 46, 379-91 (2015)
DOI:10.1016/j.arcmed.2015.05.009

102. N.D. Vaziri, K. Liang, and J.S. Parks: Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int. 59, 2192-6 (2001)
DOI:10.1046/j.1523-1755.2001.00734.x

103. K. Liang, C.H. Kim, and N.D. Vaziri: HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. Am J Physiol Renal Physiol. 288, F539-44 (2005)
DOI:10.1152/ajprenal.00074.2004

104. H. Moradi, S. Ganji, V. Kamanna, M.V. Pahl, and N.D. Vaziri: Increased monocyte adhesion-promoting capacity of plasma in end-stage renal disease - response to antioxidant therapy. Clin nephrol. 74, 273-81 (2010)
DOI:10.5414/CNP74273

105. T. Miida, O. Miyazaki, O. Hanyu, Y. Nakamura, S. Hirayama, I. Narita, F. Gejyo, I. Ei, K. Tasaki, Y. Kohda, T. Ohta, S. Yata, I. Fukamachi, and M. Okada: LCAT-dependent conversion of prebeta1-HDL into alpha-migrating HDL is severely delayed in hemodialysis patients. J Am Soc Nephrol. 14, 732-8 (2003)
DOI:10.1097/01.ASN.0000046962.43220.8A

106. G.F. Guarnieri, M. Moracchiello, L. Campanacci, F. Ursini, L. Ferri, M. Valente, and C. Gregolin: Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia. Kidney Int Suppl. S26-30 (1978)

107. H. Moradi, M.V. Pahl, R. Elahimehr, and N.D. Vaziri: Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl Res. 153, 77-85 (2009)
DOI:10.1016/j.trsl.2008.11.007

108. M.V. Pahl, Z. Ni, L. Sepassi, H. Moradi, and N.D. Vaziri: Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD) Nephrol Dial Transplant. 24, 2541-6 (2009)
DOI:10.1093/ndt/gfp120

109. H. Kimura, R. Miyazaki, S. Suzuki, F. Gejyo, and H. Yoshida: Cholesteryl ester transfer protein as a protective factor against vascular disease in hemodialysis patients. Am J Kidney Dis. 38, 70-6 (2001)
DOI:10.1053/ajkd.2001.25196

110. S. Yamamoto, and V. Kon: Chronic kidney disease induced dysfunction of high density lipoprotein. Clin Exp Nephrol. 18, 251-4 (2014)
DOI:10.1007/s10157-013-0857-x

111. T.F. Dantoine, J. Debord, J.P. Charmes, L. Merle, P. Marquet, G. Lachatre, and C. Leroux-Robert: Decrease of serum paraoxonase activity in chronic renal failure. J Am Soc Nephrol. 9, 2082-8 (1998)

112. C. Kopecky, M. Haidinger, R. Birner-Grunberger, B. Darnhofer, C.C. Kaltenecker, G. Marsche, M. Holzer, T. Weichhart, M. Antlanger, J.J. Kovarik, J. Werzowa, M. Hecking, and M.D. Saemann: Restoration of renal function does not correct impairment of uremic HDL properties. J Am Soc Nephrol. 26, 565-75 (2015)
DOI:10.1681/ASN.2013111219

113. R. Kaseda, K. Jabs, T.E. Hunley, D. Jones, A. Bian, R.M. Allen, K.C. Vickers, P.G. Yancey, M.F. Linton, S. Fazio, and V. Kon: Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism. 64, 263-73 (2015)
DOI:10.1016/j.metabol.2014.10.020

114. R. Shroff, T. Speer, S. Colin, M. Charakida, S. Zewinger, B. Staels, G. Chinetti-Gbaguidi, I. Hettrich, L. Rohrer, F. O'Neill, E. McLoughlin, D. Long, C.M. Shanahan, U. Landmesser, D. Fliser, and J.E. Deanfield: HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. J Am Soc Nephrol. 25, 2658-68 (2014)
DOI:10.1681/ASN.2013111212

115. M. Holzer, G. Schilcher, S. Curcic, M. Trieb, S. Ljubojevic, T. Stojakovic, H. Scharnagl, C.M. Kopecky, A.R. Rosenkranz, A. Heinemann, and G. Marsche: Dialysis Modalities and HDL Composition and Function. J Am Soc Nephrol. 26, 2267-76 (2015)
DOI:10.1681/ASN.2014030309

116. N.D. Vaziri, H. Moradi, M.V. Pahl, A.M. Fogelman, and M. Navab: In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide. Kid Int. 76, 437-44 (2009)
DOI:10.1038/ki.2009.177

117. N.D. Vaziri, K. Navab, P. Gollapudi, H. Moradi, M.V. Pahl, C.H. Barton, A.M. Fogelman, and M. Navab: Salutary effects of hemodialysis on low-density lipoprotein proinflammatory and high-density lipoprotein anti-inflammatory properties in patient with end-stage renal disease. J Natl Med Assoc. 103, 524-33 (2011)
DOI:10.1016/S0027-9684(15)30368-0

118. S. Yamamoto, P.G. Yancey, T.A. Ikizler, W.G. Jerome, R. Kaseda, B. Cox, A. Bian, A. Shintani, A.B. Fogo, M.F. Linton, S. Fazio, and V. Kon: Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. . J Am Coll Cardiol. 60, 2372-9 (2012)
DOI:10.1016/j.jacc.2012.09.013

119. T. Weichhart, C. Kopecky, M. Kubicek, M. Haidinger, D. Doller, K. Katholnig, C. Suarna, P. Eller, M. Tolle, C. Gerner, G.J. Zlabinger, M. van der Giet, W.H. Horl, R. Stocker, and M.D. Saemann: Serum amyloid A in uremic HDL promotes inflammation. J Am Soc Nephrol. 23, 934-47 (2012)
DOI:10.1681/ASN.2011070668

120. H. Honda, M. Ueda, S. Kojima, S. Mashiba, T. Michihata, K. Takahashi, K. Shishido, and T. Akizawa: Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients. Atherosclerosis. 220, 493-501 (2012)
DOI:10.1016/j.atherosclerosis.2011.10.038

121. S. Zewinger, T. Speer, M.E. Kleber, H. Scharnagl, R. Woitas, P.M. Lepper, K. Pfahler, S. Seiler, G.H. Heine, W. Marz, G. Silbernagel, and D. Fliser: HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J Am Soc Nephrol. 25, 1073-82 (2014)
DOI:10.1681/ASN.2013050482

122. H. Moradi, E. Streja, M.L. Kashyap, N.D. Vaziri, G.C. Fonarow, and K. Kalantar-Zadeh:. Elevated high-density lipoprotein cholesterol and cardiovascular mortality in maintenance hemodialysis patients. Nephrol Dial Transplant. 29, 1554-62 (2014)
DOI:10.1093/ndt/gfu022

123. B. Bowe, Y. Xie, H. Xian, S. Balasubramanian, and Z. Al-Aly: Low levels of high-density lipoprotein cholesterol increase the risk of incident kidney disease and its progression. Kid Int. 89, 886-96 (2016)
DOI:10.1016/j.kint.2015.12.034

124. C. Kopecky, B. Genser, C. Drechsler, V. Krane, C.C. Kaltenecker, M. Hengstschlager, W. Marz, C. Wanner, M.D. Saemann, and T. Weichhart: Quantification of HDL proteins, cardiac events, and mortality in patients with type 2 diabetes on hemodialysis. Clin J Am Soc Nephrol. 10, 224-31 (2015)
DOI:10.2215/CJN.06560714

125. M. Holzer, R. Birner-Gruenberger, T. Stojakovic, D. El-Gamal, V. Binder, C. Wadsack, A. Heinemann, and G. Marsche: Uremia alters HDL composition and function. J Am Soc Nephrol. 22, 1631-41 (2011)
DOI:10.1681/ASN.2010111144

126. A. Rohatgi, A. Khera, J.D. Berry, E.G. Givens, C.R. Ayers, K.E. Wedin, I.J. Neeland, I.S. Yuhanna, D.R. Rader, J.A. de Lemos and P.W. Shaul. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 371, 2383-93 (2014)

127. L. Bauer, S. Kern, K.S. Rogacev, I.E. Emrich, A. Zawada, D. Fliser, A. Heinemann, G.H. Heine and G. Marsche. HDL Cholesterol Efflux Capacity and Cardiovascular Events in Patients With Chronic Kidney Disease. J Am Coll Cardiol. 69, 246-247 (2017)

128. C. Kopecky, S. Ebtehaj, B. Genser, C. Drechsler, V. Krane, M. Antlanger, J.J. Kovarik, C.C. Kaltenecker, M. Parvizi, C. Wanner, T. Weichhart, M.D. Saemann and U.J. Tietge. HDL Cholesterol Efflux Does Not Predict Cardiovascular Risk in Hemodialysis Patients. J Am Soc Nephrol. 28, 769-775 (2017)

129. W. Annema, A. Dikkers, J.F. de Boer, R.P. Dullaart, J.S. Sanders, S.J. Bakker and U.J. Tietge. HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients. J Am Soc Nephrol. 27, 595-603 (2016)

Key Words: Chronic kidney disease, Dyslipidemia, End Stage Renal Disease, Lipid Metabolism, Cardiovascular Disease, Lipoprotein, Hemodialysis, Review

Send correspondence to: Nosratola Vaziri, 333 City Blvd West, Suite 400, Orange, CA, Tel: 714-456-5142, Fax: 714-456-6142, E-mail: ndvaziri@uci.edu