Abstract
Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase, an enzyme crucial to cholesterol synthesis. Drugs of this class reduce the risk of coronary heart disease and stroke, in large part through lipid modulation. Emerging evidence indicates that statins have additional modes of action. These actions, which encompass modification of endothelial function, plaque stability, thrombus formation and inflammatory pathways, are widely referred to as 'pleiotropic effects'. These pleiotropic effects indicate that the therapeutic potential of statins might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders or conditions such as transplantation, multiple sclerosis, rheumatoid arthritis and chronic kidney disease. Experimental and clinical data provide evidence to support these broader applications of statins; however, more large-scale trials are needed to clarify the therapeutic benefit.
Key Points
-
Statins reduce the risk of stroke and coronary heart disease by inhibiting cholesterol synthesis
-
Experimental and clinical evidence indicates that statins exert additional beneficial effects via modulation of immune processes
-
Statins improve clinical outcomes in rheumatoid arthritis and heart transplantation, and reduce the number of inflammatory lesions in multiple sclerosis
-
Preliminary data indicate that statins might reduce cardiovascular morbidity and mortality in people with chronic kidney disease or diabetic nephropathy, as well as slowing disease progression
-
There are conflicting data on the relevance of statins to graft and recipient survival following renal transplantation
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
LaRosa JC (2002) What do the statins tell us? Am Heart J 144 (Suppl): S21–S26
LaRosa JC et al. (1999) Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 282: 2340–2346
Athyros VG et al. (2002) Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 18: 220–228
[No authors listed] (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344: 1383–1389
[No authors listed] (1998) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 339: 1349–1357
[No authors listed] (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360: 7–22
Sacks FM et al. (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med 335: 1001–1009
Serruys PW et al. (2002) Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 287: 3215–3522
Shepherd J et al. (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med 333: 1301–1307
Kobashigawa JA et al. (1995) Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333: 621–627
Wenke K et al. (1997) Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 96: 1398–1402
Johnson BA et al. (2003) Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 167: 1271–1278
Katznelson S et al. (1996) The effect of pravastatin on acute rejection after kidney transplantation—a pilot study. Transplantation 61: 1469–1474
Tuncer M et al. (2000) Comparison of the effects of simvastatin and pravastatin on acute rejection episodes in renal transplant patients. Transplant Proc 32: 622–625
Masterson R et al. (2005) Impact of statin treatment on 1-year functional and histologic renal allograft outcome. Transplantation 80: 332–338
Kasiske BL et al. (2001) The effects of lipid-lowering agents on acute renal allograft rejection. Transplantation 72: 223–227
Holdaas H et al. (2003) Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 361: 2024–2031
Sahu K et al. (2001) Effect of lovastatin, an HMG CoA reductase inhibitor, on acute renal allograft rejection. Clin Transplant 15: 173–175
Veillard NR and Mach F (2002) Statins: the new aspirin? Cell Mol Life Sci 59: 1771–1786
Goldstein JL and Brown MS (1990) Regulation of the mevalonate pathway. Nature 343: 425–430
Istvan ES and Deisenhofer J (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292: 1160–1164
Wennerberg K et al. (2005) The Ras superfamily at a glance. J Cell Sci 118: 843–846
Martin G et al. (2001) Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest 107: 1423–1432
Duez H et al. (2001) PPARS in inflammation, atherosclerosis and thrombosis. J Cardiovasc Risk 8: 187–194
Delerive P et al. (1999) Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 274: 32048–32054
Hanada T and Yoshimura A (2002) Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 13: 413–421
Ortego M et al. (1999) Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 147: 253–261
Zelvyte I et al. (2002) Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 45: 147–154
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352: 1685–1695
Ridker PM et al. (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352: 20–28
Kent SM et al. (2003) Effect of atorvastatin and pravastatin on serum C-reactive protein. Am Heart J 145: e8
Bickel C et al. (2002) Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 89: 901–908
Ridker PM (2003) Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 108: 2292–2297
Rezaie-Majd A et al. (2002) Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 22: 1194–1199
Waehre T et al. (2003) Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease. J Am Coll Cardiol 41: 1460–1467
Waehre T et al. (2004) Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors. Circulation 109: 1966–1972
Inoue I et al. (2000) Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of mRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells. Life Sci 67: 863–876
Veillard NR et al. (2005) Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages. Atherosclerosis [doi:10.1016/j.atherosclerosis.2005.10.015]
Nakashima Y et al. (1998) Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 18: 842–851
Chung HK et al. (2002) Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Exp Mol Med 34: 451–461
Rezaie-Majd A et al. (2003) Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 23: 397–403
Leung BP et al. (2003) A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170: 1524–1530
Aktas O et al. (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197: 725–733
Youssef S et al. (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78–84
Walters CE et al. (2002) Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol 168: 4087–4094
Greenwood J et al. (2003) Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17: 905–907
McCarey DW et al. (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363: 2015–2021
Vollmer T et al. (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363: 1607–1608
Abud-Mendoza C et al. (2003) Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus 12: 607–611
Shimizu K et al. (2003) Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 108: 2113–2120
Kwak B et al. (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6: 1399–1402
Weitz-Schmidt G et al. (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7: 687–692
Lentine KL and Brennan DC (2004) Statin use after renal transplantation: a systematic quality review of trial-based evidence. Nephrol Dial Transplant 19: 2378–2386
Aull MJ (2004) Chronic allograft nephropathy: pathogenesis and management of an important posttransplant complication. Prog Transplant 14: 82–88
Johnson DW et al. (1999) In vitro effects of simvastatin on tubulointerstitial cells in a human model of cyclosporin nephrotoxicity. Am J Physiol 276: F467–F475
Rogler G et al. (1995) Effects of fluvastatin on growth of porcine and human vascular smooth muscle cells in vitro. Am J Cardiol 76: 114A–116A
Laufs U et al. (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97: 1129–1135
Hernandez-Perera O et al. (1998) 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 101: 2711–2719
Laufs U (2003) Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol 58: 719–731
Harris KP et al. (1990) Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome. Am J Kidney Dis 15: 16–23
Usui H et al. (2003) HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant 18: 265–272
Wanner C et al. (2000) Impact of dyslipidaemia in renal transplant recipients. Curr Opin Urol 10: 77–80
Remuzzi G et al. (1997) Understanding the nature of renal disease progression. Kidney Int 51: 2–15
Keane WF (2000) The role of lipids in renal disease: future challenges. Kidney Int Suppl 75: S27–S31
Fried LF et al. (2001) Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 59: 260–269
Cantarovich F and Rangoonwala B (2003) Therapeutic effects of angiotensin II inhibition or blockade on the progression of chronic renal disease. Int J Clin Pract 57: 801–822
Zoja C et al. (2002) Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int 61: 1635–1645
Zoja C et al. (2002) How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol 13: 2898–2908
Wilson SH et al. (2003) Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia. Nephrol Dial Transplant 18: 703–709
Christensen M et al. (2006) Simvastatin protection against acute immune-mediated glomerulonephritis in mice. Kidney Int 69: 457–463
Danesh FR et al. (2002) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy. Proc Natl Acad Sci USA 99: 8301–8305
Zeng L et al. (2005) HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB J 19: 1845–1847
Gueler F et al. (2002) Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. J Am Soc Nephrol 13: 2288–2298
Yokota N et al. (2003) Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury. Am J Nephrol 23: 13–17
Sabbatini M et al. (2004) Atorvastatin improves the course of ischemic acute renal failure in aging rats. J Am Soc Nephrol 15: 901–909
Zuk A et al. (2001) Expression of fibronectin splice variants in the postischemic rat kidney. Am J Physiol Renal Physiol 280: F1037–F1053
Xing Z et al. (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101: 311–320
Campese VM et al. (2005) Are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors renoprotective? J Am Soc Nephrol 16 (Suppl 1): S11–S17
Ezekowitz J et al. (2004) The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 44: 1587–1592
Tonelli M et al. (2005) Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol 16: 3748–3754
Vidt DG et al. (2004) Rosuvastatin-induced arrest in progression of renal disease. Cardiology 102: 52–60
Tonelli M et al. (2003) Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 14: 1605–1613
Tonelli M et al. (2005) Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int 68: 237–245
Tonelli M et al. (2005) Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation 112: 171–178
Athyros VG et al. (2004) The effect of statins versus untreated dyslipidaemia 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 57: 728–734
Collins R et al. (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361: 2005–2016
Bianchi S et al. (2003) A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 41: 565–570
McTaggart F (2003) Comparative pharmacology of rosuvastatin. Atheroscler Suppl 4: S9–S14
Scott LJ et al. (2004) Rosuvastatin: a review of its use in the management of dyslipidemia. Am J Cardiovasc Drugs 4: 117–138
Olsson GO (2004) Safety and efficacy of rosuvastatin. Lancet 364: 135
Wolfe SM (2004) Dangers of rosuvastatin identified before and after FDA approval. Lancet 363: 2189–2190
Davidson MH (2004) Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf 3: 547–557
Cohen JS (2004) Should rosuvastatin be withdrawn from the market? Lancet 364: 1579
Brewer HB Jr (2003) Benefit–risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol 92: 23K–29K
Alsheikh-Ali AA et al. (2005) The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation 111: 3051–3057
Wanner C et al. (2004) Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabetes on hemodialysis (4D study): demographic and baseline characteristics. Kidney Blood Press Res 27: 259–266
Fellstrom BC et al. (2003) Why do we need a statin trial in hemodialysis patients? Kidney Int Suppl: S204–S206
Baigent C and Landry M (2003) Study of Heart and Renal Protection (SHARP). Kidney Int Suppl: S207–S210
Eto M et al. (2002) Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 105: 1756–1759
Wassmann S et al. (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37: 1450–1457
Nickenig G et al. (1999) Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 100: 2131–2134
Weisstuch JM and Dworkin LD (1992) Does essential hypertension cause end-stage renal disease? Kidney Int Suppl 36: S33–S37
Zhou MS et al. (2004) Atorvastatin prevents end-organ injury in salt-sensitive hypertension: role of eNOS and oxidant stress. Hypertension 44: 186–190
Glorioso N et al. (1999) Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension 34: 1281–1286
Prasad GV et al. (2003) Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant recipients. Kidney Int 63: 360–364
Lee TM et al. (2002) Effect of pravastatin on proteinuria in patients with well-controlled hypertension. Hypertension 40: 67–73
Lee TM et al. (2005) Add-on and withdrawal effect of pravastatin on proteinuria in hypertensive patients treated with AT receptor blockers. Kidney Int 68: 779–787
Cannon CP et al. (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350: 1495–1504
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Steffens, S., Mach, F. Drug Insight: immunomodulatory effects of statins—potential benefits for renal patients?. Nat Rev Nephrol 2, 378–387 (2006). https://doi.org/10.1038/ncpneph0217
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpneph0217
This article is cited by
-
Statins and pneumonia: data from clinical studies
Réanimation (2013)