International Urology and Nephrology

, Volume 46, Issue 1, pp 27–39 | Cite as

High-density lipoprotein in uremic patients: metabolism, impairment, and therapy

  • Georges Khoueiry
  • Mokhtar Abdallah
  • Faisal Saiful
  • Nidal Abi Rafeh
  • Muhammad Raza
  • Tariq Bhat
  • Suzanne El-Sayegh
  • Kamyar Kalantar-Zadeh
  • James Lafferty
Nephrology - Review


Several studies have shown that HDL has altered antioxidant and anti-inflammatory effects in chronic uremia, either by the reduction in its antioxidant enzymes or by the impairment of their activity. Systemic oxidative stress, which is highly prevalent in chronic kidney disease (CKD) patients, has been shown to decrease antioxidant and anti-inflammatory effects of HDL and even transform it into a pro-oxidant and pro-inflammatory agent. For this reason, we believe that the propensity for accelerated cardiovascular disease in CKD is facilitated by a few key features of this disease, namely, oxidative stress, inflammation, hypertension, and disorders of lipid metabolism. In a nutshell, oxidative stress and inflammation enhance atherosclerosis leading to increased cardiovascular mortality and morbidity in this population. In this detailed review, we highlight the current knowledge on HDL dysfunction and impairment in chronic kidney disease as well as the available therapy.


Atherosclerosis High-density lipoprotein Uremia Chronic kidney disease Lipid metabolism 


  1. 1.
    Schoolwerth AC et al (2006) Chronic kidney disease: a public health problem that needs a public health action plan. Prev Chronic Dis 3(2):A57PubMedCentralPubMedGoogle Scholar
  2. 2.
    Coresh J et al (2003) Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 41(1):1–12PubMedCrossRefGoogle Scholar
  3. 3.
    Ansell BJ et al (2003) Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108(22):2751–2756PubMedCrossRefGoogle Scholar
  4. 4.
    Feroze U et al (2012) Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J Ren Nutr 22(3):317–326PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    McCullough PA (2003) Why is chronic kidney disease the “spoiler” for cardiovascular outcomes? J Am Coll Cardiol 41(5):725–728PubMedCrossRefGoogle Scholar
  6. 6.
    Himmelfarb J et al (2002) The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 62(5):1524–1538PubMedCrossRefGoogle Scholar
  7. 7.
    Hansson GK, Robertson AK, Soderberg-Naucler C (2006) Inflammation and atherosclerosis. Annu Rev Pathol 1:297–329PubMedCrossRefGoogle Scholar
  8. 8.
    Bobryshev YV (2006) Monocyte recruitment and foam cell formation in atherosclerosis. Micron 37(3):208–222PubMedCrossRefGoogle Scholar
  9. 9.
    Shashkin P, Dragulev B, Ley K (2005) Macrophage differentiation to foam cells. Curr Pharm Des 11(23):3061–3072PubMedCrossRefGoogle Scholar
  10. 10.
    Brunini TM et al (2007) Nitric oxide, malnutrition and chronic renal failure. Cardiovasc Hematol Agents Med Chem 5(2):155–161PubMedCrossRefGoogle Scholar
  11. 11.
    Khoueiry G et al (2011) Dietary intake in hemodialysis patients does not reflect a heart healthy diet. J Ren Nutr 21(6):438–447PubMedCrossRefGoogle Scholar
  12. 12.
    Varma R et al (2005) Chronic renal dysfunction as an independent risk factor for the development of cardiovascular disease. Cardiol Rev 13(2):98–107PubMedCrossRefGoogle Scholar
  13. 13.
    Devlin TM Textbook of biochemistry with clinical correlations, 7th edn. Wiley, pp 722–726Google Scholar
  14. 14.
    Vaziri ND, Navab M, Fogelman AM (2010) HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol 6(5):287–296PubMedCrossRefGoogle Scholar
  15. 15.
    Collins AJ et al (2005) Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 45(1 Suppl 1):5–7 (S1–S280)CrossRefGoogle Scholar
  16. 16.
    Stenvinkel P, Alvestrand A (2002) Inflammation in end-stage renal disease: sources, consequences, and therapy. Semin Dial 15(5):329–337PubMedCrossRefGoogle Scholar
  17. 17.
    Vaziri ND (2001) Effect of chronic renal failure on nitric oxide metabolism. Am J Kidney Dis 38(4 Suppl 1):S74–S79PubMedCrossRefGoogle Scholar
  18. 18.
    Vaziri ND (2004) Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol 24(5):469–473PubMedCrossRefGoogle Scholar
  19. 19.
    Vaziri ND et al (1998) Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol 274(4 Pt 2):F642–F649PubMedGoogle Scholar
  20. 20.
    Vaziri ND (2006) Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol 290(2):F262–F272PubMedCrossRefGoogle Scholar
  21. 21.
    Vaziri ND, Moradi H (2006) Mechanisms of dyslipidemia of chronic renal failure. Hemodial Int 10(1):1–7PubMedCrossRefGoogle Scholar
  22. 22.
    Attman PO, Samuelsson O, Alaupovic P (1993) Lipoprotein metabolism and renal failure. Am J Kidney Dis 21(6):573–592PubMedGoogle Scholar
  23. 23.
    Vaziri ND, Deng G, Liang K (1999) Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrol Dial Transpl 14(6):1462–1466CrossRefGoogle Scholar
  24. 24.
    Moradi H et al (2009) Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transpl Res 153(2):77–85Google Scholar
  25. 25.
    Shao B et al (2006) Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high-density lipoprotein. Curr Opin Cardiol 21(4):322–328PubMedCrossRefGoogle Scholar
  26. 26.
    Fielding CJ, Fielding PE (2001) Cellular cholesterol efflux. Biochim Biophys Acta 1533(3):175–189PubMedCrossRefGoogle Scholar
  27. 27.
    Lawn RM et al (1999) The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 104(8):R25–R31PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Oram JF (2000) Tangier disease and ABCA1. Biochim Biophys Acta 1529(1–3):321–330PubMedCrossRefGoogle Scholar
  29. 29.
    Zhao Y, Marcel YL (1996) Serum albumin is a significant intermediate in cholesterol transfer between cells and lipoproteins. Biochemistry 35(22):7174–7180PubMedCrossRefGoogle Scholar
  30. 30.
    Shoji T et al (1992) Impaired metabolism of high density lipoprotein in uremic patients. Kidney Int 41(6):1653–1661PubMedCrossRefGoogle Scholar
  31. 31.
    Vaziri ND, Liang K, Parks JS (2001) Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int 59(6):2192–2196PubMedGoogle Scholar
  32. 32.
    Vaziri ND, Sato T, Liang K (2003) Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis. Kidney Int 63(5):1756–1763PubMedCrossRefGoogle Scholar
  33. 33.
    Liang K, Kim CH, Vaziri ND (2005) 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(3):F539–F544PubMedCrossRefGoogle Scholar
  34. 34.
    Kimura H et al (2001) Cholesteryl ester transfer protein as a protective factor against vascular disease in hemodialysis patients. Am J Kidney Dis 38(1):70–76PubMedCrossRefGoogle Scholar
  35. 35.
    Kimura H et al (2003) Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP levels. Kidney Int 64(5):1829–1837PubMedCrossRefGoogle Scholar
  36. 36.
    Pahl MV et al (2009) Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD). Nephrol Dial Transplant 24(8):2541–2546PubMedCrossRefGoogle Scholar
  37. 37.
    de Sain-van der Velden MG et al (1998) Plasma alpha 2 macroglobulin is increased in nephrotic patients as a result of increased synthesis alone. Kidney Int 54(2):530–535PubMedCrossRefGoogle Scholar
  38. 38.
    Vaziri ND (2003) Molecular mechanisms of lipid disorders in nephrotic syndrome. Kidney Int 63(5):1964–1976PubMedCrossRefGoogle Scholar
  39. 39.
    Klin M et al (1996) Abnormalities in hepatic lipase in chronic renal failure: role of excess parathyroid hormone. J Clin Invest 97(10):2167–2173PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Liang K, Vaziri ND (1997) Down-regulation of hepatic lipase expression in experimental nephrotic syndrome. Kidney Int 51(6):1933–1937PubMedCrossRefGoogle Scholar
  41. 41.
    Sato T, Liang K, Vaziri ND (2003) Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis. Kidney Int 64(5):1780–1786PubMedCrossRefGoogle Scholar
  42. 42.
    Nevin DN et al (1996) Paraoxonase genotypes, lipoprotein lipase activity, and HDL. Arterioscler Thromb Vasc Biol 16(10):1243–1249PubMedCrossRefGoogle Scholar
  43. 43.
    Holzer M et al (2011) Uremia alters HDL composition and function. J Am Soc Nephrol 22(9):1631–1641PubMedCrossRefGoogle Scholar
  44. 44.
    Liang K, Vaziri ND (1999) Down-regulation of hepatic high-density lipoprotein receptor, SR-B1, in nephrotic syndrome. Kidney Int 56(2):621–626PubMedCrossRefGoogle Scholar
  45. 45.
    Van Lenten BJ et al (2006) Understanding changes in high density lipoproteins during the acute phase response. Arterioscler Thromb Vasc Biol 26(8):1687–1688PubMedCrossRefGoogle Scholar
  46. 46.
    Cabana VG et al (1996) HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease. J Lipid Res 37(12):2662–2674PubMedGoogle Scholar
  47. 47.
    Van Lenten BJ et al (1995) Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 96(6):2758–2767PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Artl A et al (2000) Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler Thromb Vasc Biol 20(3):763–772PubMedCrossRefGoogle Scholar
  49. 49.
    Kalantar-Zadeh K et al (2007) HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int 72(9):1149–1156PubMedCrossRefGoogle Scholar
  50. 50.
    Deigner HP, Hermetter A (2008) Oxidized phospholipids: emerging lipid mediators in pathophysiology. Curr Opin Lipidol 19(3):289–294PubMedCrossRefGoogle Scholar
  51. 51.
    Mehta JL et al (2006) Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc Res 69(1):36–45PubMedCrossRefGoogle Scholar
  52. 52.
    Cominacini L et al (2000) Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem 275(17):12633–12638PubMedCrossRefGoogle Scholar
  53. 53.
    Cominacini L et al (2001) The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem 276(17):13750–13755PubMedGoogle Scholar
  54. 54.
    Bowry VW, Stanley KK, Stocker R (1992) High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci USA 89(21):10316–10320PubMedCrossRefGoogle Scholar
  55. 55.
    Ansell BJ, Fonarow GC, Fogelman AM (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18(4):427–434PubMedCrossRefGoogle Scholar
  56. 56.
    Navab M et al (2006) Mechanisms of disease: proatherogenic HDL–an evolving field. Nat Clin Pract Endocrinol Metab 2(9):504–511PubMedCrossRefGoogle Scholar
  57. 57.
    Harper CR, Jacobson TA (2008) Managing dyslipidemia in chronic kidney disease. J Am Coll Cardiol 51(25):2375–2384PubMedCrossRefGoogle Scholar
  58. 58.
    Fellstrom BC et al (2009) Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360(14):1395–1407PubMedCrossRefGoogle Scholar
  59. 59.
    Wanner C et al (2005) Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353(3):238–248PubMedCrossRefGoogle Scholar
  60. 60.
    Ruan XZ, Varghese Z, Moorhead JF (2009) An update on the lipid nephrotoxicity hypothesis. Nat Rev Nephrol 5(12):713–721PubMedCrossRefGoogle Scholar
  61. 61.
    Baigent C et al (2011) 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(9784):2181–2192PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Carlson LA (2005) Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 258(2):94–114PubMedCrossRefGoogle Scholar
  63. 63.
    Nainggolan L, Bethesda M (2011) NIH pulls plug on AIM-HIGH trial with niacin (niacin + statin)
  64. 64.
    Cho KH et al (2009) Niacin ameliorates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure. Am J Physiol Renal Physiol 297(1):F106–F113PubMedCrossRefGoogle Scholar
  65. 65.
    Cho KH et al (2010) Niacin improves renal lipid metabolism and slows progression in chronic kidney disease. Biochim Biophys Acta 1800(1):6–15PubMedCrossRefGoogle Scholar
  66. 66.
    Duval C, Muller M, Kersten S (2007) PPARalpha and dyslipidemia. Biochim Biophys Acta 1771(8):961–971PubMedCrossRefGoogle Scholar
  67. 67.
    Tonelli M et al (2004) Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 66(3):1123–1130PubMedCrossRefGoogle Scholar
  68. 68.
    Tonelli M et al (2004) Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease. Am J Kidney Dis 44(5):832–839PubMedGoogle Scholar
  69. 69.
    Calabresi L et al (2006) Recombinant apolipoprotein A-IMilano for the treatment of cardiovascular diseases. Curr Atheroscler Rep 8(2):163–167PubMedCrossRefGoogle Scholar
  70. 70.
    Belalcazar LM et al (2003) Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Circulation 107(21):2726–2732PubMedCrossRefGoogle Scholar
  71. 71.
    Nissen SE et al (2003) Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290(17):2292–2300PubMedCrossRefGoogle Scholar
  72. 72.
    Vaziri ND et al (2009) 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. Kidney Int 76(4):437–444PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Navab M et al (2010) Structure and function of HDL mimetics. Arterioscler Thromb Vasc Biol 30(2):164–168PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Navab M et al (2005) D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 25(7):1426–1432PubMedCrossRefGoogle Scholar
  75. 75.
    Navab M et al (2004) Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 109(25):3215–3220PubMedCrossRefGoogle Scholar
  76. 76.
    Li X et al (2004) Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 110(12):1701–1705PubMedCrossRefGoogle Scholar
  77. 77.
    Ou J et al (2005) Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet. Circ Res 97(11):1190–1197PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Navab M et al (2006) Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention. Nat Clin Pract Cardiovasc Med 3(10):540–547PubMedCrossRefGoogle Scholar
  79. 79.
    Barter PJ et al (2003) Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 23(2):160–167PubMedCrossRefGoogle Scholar
  80. 80.
    Boekholdt SM, Thompson JF (2003) Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res 44(6):1080–1093PubMedCrossRefGoogle Scholar
  81. 81.
    Le Goff W, Guerin M, Chapman MJ (2004) Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia. Pharmacol Ther 101(1):17–38PubMedCrossRefGoogle Scholar
  82. 82.
    van der Steeg WA et al (2004) Role of CETP inhibitors in the treatment of dyslipidemia. Curr Opin Lipidol 15(6):631–636PubMedCrossRefGoogle Scholar
  83. 83.
    Barter PJ et al (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357(21):2109–2122PubMedCrossRefGoogle Scholar
  84. 84.
    Ishigami M, Yamashita S, Sakai N, Arai T, Hirano K, Hiraoka H, Kameda-Takemura K, Matsuzawa Y (1994) Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency cannot protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J Biochem (Tokyo) 116:257–262Google Scholar
  85. 85.
    Barter PJ (2002) Hugh sinclair lecture: the regulation and remodelling of HDL by plasma factors. Atheroscler Suppl 3(4):39–47PubMedCrossRefGoogle Scholar
  86. 86.
    Nicholls SJ et al (2011) Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 306(19):2099–2109PubMedCrossRefGoogle Scholar
  87. 87.
    Gotto AM Jr, Moon JE (2012) Safety of inhibition of cholesteryl ester transfer protein with anacetrapib: the DEFINE study. Expert Rev Cardiovasc Ther 10(8):955–963PubMedCrossRefGoogle Scholar
  88. 88.
    Schwartz GG et al (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367(22):2089–2099PubMedCrossRefGoogle Scholar
  89. 89.
    Tardif JC et al (2004) Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 110(21):3372–3377PubMedCrossRefGoogle Scholar
  90. 90.
    Keith DS et al (2004) Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 164(6):659–663PubMedCrossRefGoogle Scholar
  91. 91.
    Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32(5 Suppl 3):S112–S119PubMedCrossRefGoogle Scholar
  92. 92.
    Epstein M, Vaziri ND (2012) Statins in the management of dyslipidemia associated with chronic kidney disease. Nat Rev Nephrol 8(4):214–223PubMedCrossRefGoogle Scholar
  93. 93.
    Vaziri ND (2009) Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial 22(6):644–651PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Svensson M et al (2006) N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. Clin J Am Soc Nephrol 1(4):780–786 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Georges Khoueiry
    • 6
  • Mokhtar Abdallah
    • 2
  • Faisal Saiful
    • 1
  • Nidal Abi Rafeh
    • 7
  • Muhammad Raza
    • 2
  • Tariq Bhat
    • 1
  • Suzanne El-Sayegh
    • 3
  • Kamyar Kalantar-Zadeh
    • 4
    • 5
  • James Lafferty
    • 1
  1. 1.Department of CardiologyStaten Island University HospitalStaten IslandUSA
  2. 2.Department of MedicineStaten Island University HospitalStaten IslandUSA
  3. 3.Department of NephrologyStaten Island University HospitalStaten IslandUSA
  4. 4.Division of Nephrology and HypertensionUniversity of California Irvine, School of MedicineOrangeUSA
  5. 5.UCLA School of Public HealthLos AngelesUSA
  6. 6.Department of CardiologyDartmouth-Hitchcock Medical CenterLebanonUSA
  7. 7.Tulane University Heart and Vascular Institute Tulane University School of MedicineNew OrleansUSA

Personalised recommendations