Skip to main content

Advertisement

Log in

HMG-CoA reductase inhibitors and the kidney

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) have been shown to reduce serum cholesterol and cardiovascular morbidity and mortality. The mechanisms of these beneficial effects are reviewed. Altered inflammatory responses and improved endothelial function mediated by statins are thought to be, in part, responsible for the reduction in cardiovascular events. It has not been well established whether statins confer similar benefits to the kidney. In this review, we critically consider the available data whereby dyslipidemia mediates renal dysfunction by modulating the inflammatory response to diverse cytokines. We also review the emerging database suggesting that statins may modulate renal dysfunction by altering the response of the kidney to dyslipidemia, particularly in patients with end-stage renal disease (ESRD) and post-kidney transplant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003, 41:I–IV, S1–S91.

  2. Anavekar NS, McMurray JJV, Velazquez EJ, et al.: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004, 351:1285–1295.

    Article  PubMed  CAS  Google Scholar 

  3. Go AS, Chertow GM, Fan D, et al.: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004, 351:1296–1305. Among 1,120,295 adults followed between 1996 and 2000 at Kaiser Permanente of Northern California, an independent, graded association was observed between estimated GFR and risk for death, cardiovascular events, and hospitalization.

    Article  PubMed  CAS  Google Scholar 

  4. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM: The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002, 62:1524–1538.

    Article  PubMed  CAS  Google Scholar 

  5. Campese VM, Bianchi S, Bigazzi R: Association between hyperlipidemia and microalbuminuria in essential hypertension. Kidney Int Suppl 1999, 71:S10-S13.

    Article  PubMed  CAS  Google Scholar 

  6. Takemura T, Yoshioka K, Aya N, et al.: Apolipoproteins and lipoprotein receptors in glomeruli in human kidney diseases. Kidney Int 1993, 43:918–927.

    PubMed  CAS  Google Scholar 

  7. Rovin BH, Tan LC: LDL stimulates mesangial fibronectin production and chemoattractant expression. Kidney Int 1993, 43:218–225.

    PubMed  CAS  Google Scholar 

  8. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al.: Effect of statins versus untreated dyslipidemia on renal function in patients with coronary heart disease: a subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study. J Clin Pathol 2004, 57:728–734.

    Article  PubMed  CAS  Google Scholar 

  9. Keane WF, O’Donnell MP, Kasiske BL, Kim Y: Oxidative modification of low-density lipoproteins by mesangial cells. J Am Soc Nephrol 1993, 4:187–194.

    PubMed  CAS  Google Scholar 

  10. Chen HC, Guh JY, Shin SJ, Lai YH: Pravastatins suppress superoxide and fibronectin production of glomerular mesangial cells induced by oxidized-LDL and high glucose. Atherosclerosis 2002, 160:141–146.

    Article  PubMed  CAS  Google Scholar 

  11. Vrtovsnik F, Couette S, Prie D, et al.: Lovastatin-induced inhibition of renal epithelial tubular cell proliferation involves a p21ras activated, AP-1-dependent pathway. Kidney Int 1997, 52:1016–1027.

    Article  PubMed  CAS  Google Scholar 

  12. Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–1135.

    PubMed  CAS  Google Scholar 

  13. Dichtl W, Dulak J, Frick M, et al.: HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003, 23:58–63.

    Article  PubMed  CAS  Google Scholar 

  14. Yoshimura A, Nemoto T, Sugenoya Y, et al.: Effect of simvastatin on proliferative nephritis and cell-cycle protein expression. Kidney Int Suppl 1999, 71:S84-S87.

    Article  PubMed  CAS  Google Scholar 

  15. Yamashita T, Kawashima S, Miwa Y, et al.: A 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor reduces hypertensive nephrosclerosis in stroke-prone spontaneously hypertensive rats. J Hypertens 2002, 20:2465–2473.

    Article  PubMed  CAS  Google Scholar 

  16. Park YS, Guijarro C, Kim Y, et al.: Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats. Am J Kidney Dis 1998, 31:190–194.

    PubMed  CAS  Google Scholar 

  17. Zhou M-S, Jaimes E, Raij L: In salt-sensitive hypertension, statins protect end-organ injury via increased NO production and decreased reative oxygen species. Am J Hypertens 2004, 17:18A.

    Article  Google Scholar 

  18. Ridker PM, Rifai N, Pfeffer MA, et al.: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999, 100:230–235.

    PubMed  CAS  Google Scholar 

  19. Diaz MN, Frei B, Vita JA, Keaney JF Jr: Antioxidants and atherosclerotic heart disease. N Engl J Med 1997, 337:408–416.

    Article  PubMed  CAS  Google Scholar 

  20. Mason JC: Statins and their role in vascular protection. Clin Sci (Lond) 2003, 105:251–266.

    Article  CAS  Google Scholar 

  21. Balk EM, Lau J, Goudas LC, et al.: Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med 2003, 139:670–682.

    PubMed  CAS  Google Scholar 

  22. Zelvyte I, Dominaitiene R, Crisby M, Janciauskiene S: Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 2002, 45:147–154.

    Article  PubMed  CAS  Google Scholar 

  23. Ridker PM, Rifai N, Pfeffer MA, et al.: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998, 98:839–844.

    PubMed  CAS  Google Scholar 

  24. Vamvakopoulos JE, Green C: HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection. BMC Cardiovasc Dis 2003, 3:6.

    Article  Google Scholar 

  25. Ortego M, Bustos C, Hernandez-Presa MA, et al.: Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 1999, 147:253–261.

    Article  PubMed  CAS  Google Scholar 

  26. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al.: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998, 101:2711–2719.

    Article  PubMed  CAS  Google Scholar 

  27. Wolfrum S, Jensen KS, Liao JK: Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003, 23:729–736.

    Article  PubMed  CAS  Google Scholar 

  28. Stokes KY, Cooper D, Tailor A, Granger DN: Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide. Free Radic Biol Med 2002, 33:1026–1036.

    Article  PubMed  CAS  Google Scholar 

  29. Pfeilschifter J: Nitric oxide triggers the expression of proinflammatory and protective gene products in mesangial cells and the inflamed glomerulus. Nephrol Dial Transplant 2002, 17:347–348.

    Article  PubMed  CAS  Google Scholar 

  30. Blantz RC, Munger K: Role of nitric oxide in inflammatory conditions. Nephron 2002, 90:373–378.

    Article  PubMed  Google Scholar 

  31. Yoshida M, Sawada T, Ishii H, et al.: HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol 2001, 21:1165–1171.

    PubMed  CAS  Google Scholar 

  32. Frenette PS: Locking a leukocyte integrin with statins. N Engl J Med 2001, 345:1419–1421.

    Article  PubMed  CAS  Google Scholar 

  33. Sukhova GK, Williams JK, Libby P: Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol 2002, 22:1452–1458.

    Article  PubMed  CAS  Google Scholar 

  34. O’Driscoll G, Green D, Taylor RR: Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997, 95:1126–1131.

    PubMed  CAS  Google Scholar 

  35. Jialal I, Stein D, Balis D, et al.: Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001, 103:1933–1935.

    PubMed  CAS  Google Scholar 

  36. Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004, 291:1071–1080.

    Article  PubMed  CAS  Google Scholar 

  37. Manttari M, Tiula E, Alikoski T, Manninen V: Effects of hypertension and dyslipidemia on the decline in renal function. Hypertension 1995, 26:670–675.

    PubMed  CAS  Google Scholar 

  38. Schaeffner ES, Kurth T, Curhan GC, et al.: Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 2003, 14:2084–2091.

    PubMed  CAS  Google Scholar 

  39. Fried LF, Orchard TJ, Kasiske BL: Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001, 59:260–269.

    Article  PubMed  CAS  Google Scholar 

  40. Chang JW, Yang WS, Min WK, et al.: Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002, 39:1213–1217.

    Article  PubMed  CAS  Google Scholar 

  41. Bianchi S, Bigazzi R, Caiazza A, Campese VM: A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003, 41:565–570. A controlled open-label study showing that atorvastatin reduced proteinuria and the rate of progression of kidney disease in 56 patients with CKD, proteinuria, and hypercholesterolemia.

    Article  PubMed  CAS  Google Scholar 

  42. Tonelli M, Moye L, Sacks FM, et al.: Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003, 14:1605–1613.

    Article  PubMed  CAS  Google Scholar 

  43. Seliger SL, Weiss NS, Gillen DL, et al.: HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002, 61:297–304.

    Article  PubMed  CAS  Google Scholar 

  44. van den Akker JM, Bredie SJ, Diepenveen SH, et al.: Atorvastatin and simvastatin in patients on hemodialysis: effects on lipoproteins, C-reactive protein and in vivo oxidized LDL. J Nephrol 2003, 16:238–244.

    Article  PubMed  Google Scholar 

  45. Wanner C, Krane V, Ruf G, et al.: Atorvastatin lowers LDL but not risk of CV events in diabetics with ESRD. 37th Annual Meeting of the American Society of Nephrology, St. Louis, MO 2004.

  46. Isoniemi H, Nurminen M, Tikkanen MJ, et al.: Risk factors predicting chronic rejection of renal allografts. Transplantation 1994, 57:68–72.

    Article  PubMed  CAS  Google Scholar 

  47. Chakrabarti R, Engleman EG: Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation. J Biol Chem 1991, 266:12216–12222.

    PubMed  CAS  Google Scholar 

  48. Kobashigawa JA, Katznelson S, Laks H, et al.: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995, 333:621–627.

    Article  PubMed  CAS  Google Scholar 

  49. Katznelson S, Wilkinson AH, Kobashigawa JA, et al.: The effect of pravastatin on acute rejection after kidney transplantation —a pilot study. Transplantation 1996, 61:1469–14674.

    Article  PubMed  CAS  Google Scholar 

  50. Kasiske BL, Heim-Duthoy KL, Singer GG, et al.: The effects of lipid-lowering agents on acute renal allograft rejection. Transplantation 2001, 72:223–227.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campese, V.M., Hadaya, B. & Chiu, J. HMG-CoA reductase inhibitors and the kidney. Current Science Inc 7, 337–342 (2005). https://doi.org/10.1007/s11906-005-0066-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-005-0066-4

Keywords

Navigation