Statins and Cardiac Surgery

Abstract

THE NUMBER OF cardiac surgeries continues to increase every year,1Grover A. Gorman K. Dall T.M. et al.Shortage of cardiothoracic surgeons is likely by 2020.Circulation. 2009; 120: 488-494Crossref PubMed Scopus (137) Google Scholar and while the specialties of cardiac surgery, anesthesia, and critical care advance, residual morbidity and mortality persist.2Morice M.C. Serruys P.W. Kappetein A.P. et al.Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial.Circulation. 2010; 121: 2645-2653Crossref PubMed Scopus (497) Google Scholar Reasons for these outcomes include the comorbidity that accompanies aging and the unique and complex pathophysiologic response to cardiac surgery. Whether conducted on or off bypass, cardiac surgery is associated with some degree of whole-body inflammatory reaction3Rinder C. Cellular inflammatory response and clinical outcome in cardiac surgery.Curr Opin Anaesthesiol. 2006; 19: 65-68Crossref PubMed Scopus (33) Google Scholar, 4Tomic V. Russwurm S. Moller E. et al.Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting.Circulation. 2005; 112: 2912-2920PubMed Google Scholar involving upregulation of circulating hematopoietic cells and stimulation of inflammatory, oxidative, and coagulation cascades. Cytokines and activated cells disseminate, producing distant organ as well as local myocardial damage. Because the body's response to cardiopulmonary bypass is complex, prevention and treatment strategies have been varied and to date have tended to target individual aspects of this diverse reaction, either in terms of the mechanism of injury or the organ affected. Disappointing results are all-too-familiar. However, a novel approach recently has been suggested and involves the adoption of concurrent, heterogenous strategies5Park M. Coca S.G. Nigwekar S.U. et al.Prevention and treatment of acute kidney injury in patients undergoing cardiac surgery: A systematic review.Am J Nephrol. 2010; 31: 408-418Crossref PubMed Scopus (60) Google Scholar to cover the many aspects of the response to cardiopulmonary bypass. Although this is attractive, in reality it is suspected to be clinically challenging.5Park M. Coca S.G. Nigwekar S.U. et al.Prevention and treatment of acute kidney injury in patients undergoing cardiac surgery: A systematic review.Am J Nephrol. 2010; 31: 408-418Crossref PubMed Scopus (60) Google Scholar A more practical solution to this approach would be to search for a single, multidimensional agent, which is much more clinically appropriate and very appealing.A list of the required actions of a monotherapy to reduce adverse outcomes in cardiac surgery would have to address the major pathophysiologic pathways thought to be important, namely endothelial and epithelial dysfunction secondary to ischemia reperfusion, inflammation, reactive oxygen species, neurohormonal activation, and nitric oxide imbalance. Fortuitously, this list has much in common with the therapeutic profile of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which have been in clinical use in cardiovascular disease for many years. Cholesterol is a major component of all cell membranes and as such is well positioned to affect major inter- and intracellular signaling pathways.6Sadowitz B. Basic science review: Statin therapy—Part I: The pleiotropic effects of statins in cardiovascular disease.Vasc Endovascular Surg. 2010; 44: 241-251Crossref PubMed Scopus (122) Google Scholar Indeed, statins have been shown in vitro and in animal studies to modulate the inflammatory response by reducing the release of inflammatory cytokines and chemoattractants,7Yao H.-W. Mao L.-G. Zhu J.-P. Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury.Clin Exp Pharmacol Physiol. 2006; 33: 793-797Crossref PubMed Scopus (60) Google Scholar cell proliferation, and matrix accumulation8Rodriguez-Vita J. Sanchez-Galan E. Santamaria B. et al.Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.PLoS One. 2008; 3: e3959Crossref PubMed Scopus (47) Google Scholar while accelerating re-endothelialization after injury,9van Nieuw Amerongen G.P. Vermeer M.A. Nègre-Aminou P. et al.Simvastatin improves disturbed endothelial barrier function.Circulation. 2000; 102: 2803-2809Crossref PubMed Google Scholar exerting antithrombotic effects,10Gaddam V. Li D.Y. Mehta J.L. Anti-thrombotic effects of atorvastatin—An effect unrelated to lipid lowering.J Cardiovasc Pharmacol Ther. 2002; 7: 247-253Crossref PubMed Scopus (49) Google Scholar and attenuating reperfusion injury.11Chello M. Spadaccio C. Anselmi A. et al.Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft.J Surg Res. 2006; 136: 302-308Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Recently, it has been shown that simvastatin confers endothelial cell barrier protection in vitro. Endothelial disruption was reduced and linked to cytoskeletal protein rearrangement with a marked induction of genes specifically involved in cell signaling and cytoskeletal regulation.12Jacobson J.R. Dudek S.M. Birukov K.G. et al.Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin.Am J Respir Cell Mol Biol. 2004; 30: 662-670Crossref PubMed Scopus (129) Google ScholarStudies in cardiac surgery patients taking statins versus patients not taking statins have confirmed a reduction in circulating C-reactive protein; tumor necrosis factor-α; myeloperoxidase; and the proinflammatory interleukins (IL) 1, 6, and 8, with a concomitant increase in the anti-inflammatory IL-1013Martinez-Comendador J.M. Alvarez J.R. Mosquera I. et al.Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiac surgery.Eur J Cardiothorac Surg. 2009; 36: 998-1005Crossref PubMed Scopus (46) Google Scholar, 14Spadaccio C. Pollari F. Casacalenda A. et al.Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study.J Cardiovasc Pharmacol. 2010; 55: 30-38Crossref PubMed Scopus (68) Google Scholar, 15Liakopoulos O.J. Dorge H. Schmitto J.D. et al.Effects of preoperative statin therapy on cytokines after cardiac surgery.Thorac Cardiovasc Surg. 2006; 54: 250-254Crossref PubMed Scopus (69) Google Scholar, 16Chello M. Spadaccio C. Anselmi A. et al.Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft.J Surg Res. 2006; 136: 302-308Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 17Chello M. Patti G. Candura D. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (196) Google Scholar, 18Morgan C. Zappitelli M. Gill P. Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: A systematic review.Crit Care. 2009; 13: R165Crossref PubMed Scopus (35) Google Scholar in those taking statins. Although the science behind the expectation that statins should confer an advantage in cardiac surgery has been solid, clinical outcome studies have been equivocal to date. Indeed, the study by Martinez-Comendadaor et al,13Martinez-Comendador J.M. Alvarez J.R. Mosquera I. et al.Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiac surgery.Eur J Cardiothorac Surg. 2009; 36: 998-1005Crossref PubMed Scopus (46) Google Scholar which nicely showed that postoperative IL-6 was reduced in statin takers after cardiopulmonary bypass, produced no differences in morbidity and mortality outcomes. The study was small in terms of cardiac surgery (138 patients), was observational, and included mixed surgeries, possibly accounting for the disappointing results.The ultimate goal in testing the theory that statins might ameliorate the response to cardiopulmonary bypass would of course be a large randomized trial; however, there are obvious barriers to this design. Because evidence-based medicine has shown reduced morbidity and improved survival with the long-term use of statins in diverse populations of medical patients19The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study.Lancet. 1994; 344: 1383-1389Abstract PubMed Scopus (4) Google Scholar, 20The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5549) Google Scholar, 21Downs J.R. Clearfield M. Weis S. et al.Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS.JAMA. 1998; 279: 1615-1622Crossref PubMed Scopus (4978) Google Scholar, 22Sever P.S. Dahlof B. Poulter N.R. et al.Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicenter randomized controlled trial.Lancet. 2003; 361: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3328) Google Scholar including those without raised lipid profiles,21Downs J.R. Clearfield M. Weis S. et al.Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS.JAMA. 1998; 279: 1615-1622Crossref PubMed Scopus (4978) Google Scholar the supply of statin-naive patients presenting for cardiac surgery is severely limited. Likewise, there are ethical issues raised by the withdrawal of statins in order to randomize patients to a control group, particularly because it has been shown that acute statin withdrawal is associated with a rebound inflammatory response23Sposito A.C. Carvalho L.S. Cintra R.M. et al.Brasilia Heart Study Group Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal.Atherosclerosis. 2009; 207: 191-194Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 24Li J.-J. Li Y.-S. Chen J. et al.Rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy.Med Hypotheses. 2006; 66: 1199-1204Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar and increased adverse events in medical patients.25Koziolek M.J. Hennig U. Zapf A. et al.Retrospective analysis of long-term lipid apheresis at a single center.Ther Apher Dial. 2010; 14: 143-152Crossref PubMed Scopus (41) Google Scholar, 26Spencer F.A. Allegrone J. Goldberg R.J. et al.Association of statin therapy with outcomes of acute coronary syndromes: The GRACE study.Ann Intern Med. 2004; 140: 857-866Crossref PubMed Scopus (191) Google ScholarThe alternatives to randomized controlled trials are retrospective analyses of large observational databases and meta-analyses of individual controlled trials. Such studies have provided some positive findings in patients on statins undergoing cardiac surgery, including reduced early postoperative mortality.27Collard C.D. Body S.C. Shernan S.K. et al.Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery.J Thorac Cardiovasc Surg. 2006; 132: 392-400Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 28Tabata M. Khalpey Z. Cohn L.H. et al.Effect of preoperative statins in patients without coronary artery disease who undergo cardiac surgery.J Thorac Cardiovasc Surg. 2008; 136: 1510-1513Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 29Takagi H. Kawai N. Umemoto T. Preoperative statin therapy reduces postoperative all-cause mortality in cardiac surgery: A meta-analysis of controlled studies.J Thorac Cardiovasc Surg. 2009; 137: e52-e53Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 30Liakopoulos O.J. Choi Y.H. Haldenwang P.L. et al.Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: A meta-analysis of over 30,000 patients.Eur Heart J. 2008; 29: 1548-1559Crossref PubMed Scopus (220) Google Scholar, 31Huffmeyer J.L. Mauermann W.J. Thiele R.H. et al.Preoperative statin administration is associated with lower mortality and decreased need for postoperative hemodialysis in patients undergoing coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 2009; 23: 468-473Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar However, results for cardiac surgery–associated morbidity have been variable, with stoke rate reduced in 1 series30Liakopoulos O.J. Choi Y.H. Haldenwang P.L. et al.Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: A meta-analysis of over 30,000 patients.Eur Heart J. 2008; 29: 1548-1559Crossref PubMed Scopus (220) Google Scholar but unaffected in others,27Collard C.D. Body S.C. Shernan S.K. et al.Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery.J Thorac Cardiovasc Surg. 2006; 132: 392-400Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 28Tabata M. Khalpey Z. Cohn L.H. et al.Effect of preoperative statins in patients without coronary artery disease who undergo cardiac surgery.J Thorac Cardiovasc Surg. 2008; 136: 1510-1513Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar and renal dysfunction (as defined by acute kidney injury (AKI) or the need for renal replacement therapy) similarly was shown to be both reduced31Huffmeyer J.L. Mauermann W.J. Thiele R.H. et al.Preoperative statin administration is associated with lower mortality and decreased need for postoperative hemodialysis in patients undergoing coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 2009; 23: 468-473Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 32Virani S.S. Nambi V. Polsani V.R. et al.Preoperative statin therapy decreases risk of postoperative renal insufficiency.Cardiovasc Ther. 2010; 28: 80-86Crossref PubMed Scopus (34) Google Scholar and unaffected.26Spencer F.A. Allegrone J. Goldberg R.J. et al.Association of statin therapy with outcomes of acute coronary syndromes: The GRACE study.Ann Intern Med. 2004; 140: 857-866Crossref PubMed Scopus (191) Google ScholarAlthough observational studies and meta-analyses are often thought of as being inferior to randomized controlled trials because of treatment bias in observational studies and the inclusion of inferior studies in meta-analyses,33Takagi H. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: A meta-analysis of 30,000 patients Letter to the editor.Eur Heart J. 2008; 29: 2443Crossref PubMed Scopus (1) Google Scholar there are well-accepted statistical methodologies that can equate observational trials to the robustness of randomized controlled trials.34D'Agostino Jr, R.B. D'Agostino Sr, R.B. Estimating treatment effects using observational data.JAMA. 2007; 297: 314-316Crossref PubMed Scopus (266) Google Scholar In a randomized controlled trial, both the treatment group and the control group would be equal with respect to demographic characteristics that occur before the treatment is administered, in this case a preoperative statin. However, in observational studies, it is likely that patients already on statins differ from those not on statins with respect to a number of characteristics including age and the incidence of comorbid diseases. Thus, the statistical methods in observational studies need to create an equality of demographic characteristics between the statin and nonstatin groups.35Rubin D.B. The design versus the analysis of observational studies for causal effects: Parallels with the design of randomized studies.Stat Med. 2007; 26: 20-36Crossref PubMed Scopus (694) Google Scholar Two statistical approaches often used to achieve this are analysis of covariance and propensity scores. These 2 methods complement each other and generally should be used together rather than choosing between one and the other.34D'Agostino Jr, R.B. D'Agostino Sr, R.B. Estimating treatment effects using observational data.JAMA. 2007; 297: 314-316Crossref PubMed Scopus (266) Google ScholarIn this month's issue of the Journal of Cardiothoracic and Vascular Anesthesia, 2 articles appear that address outcomes in cardiac surgery in patients on preoperative statins.36Allou N. Augustin P. Dufour G. et al.Preoperative statin treatment is associated with reduced postoperative mortality after isolated heart valve surgery in high cardiovascular risk patients.J Cardiothorac Vasc Anesth. 2010; 24: 921-926Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 37Billings F.T. Early postoperative statin therapy is associated with acute kidney injury following cardiac surgery.J Cardiothorac Vasc Anesth. 2010; 24: 913-920Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Both studies use large databases that were created prospectively, one is a routine institutional database36Allou N. Augustin P. Dufour G. et al.Preoperative statin treatment is associated with reduced postoperative mortality after isolated heart valve surgery in high cardiovascular risk patients.J Cardiothorac Vasc Anesth. 2010; 24: 921-926Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar and the other an interrogation of an ongoing clinical trail of postoperative atrial fibrillation.37Billings F.T. Early postoperative statin therapy is associated with acute kidney injury following cardiac surgery.J Cardiothorac Vasc Anesth. 2010; 24: 913-920Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Both studies used analysis of covariance and propensity score methods. The study by Allou et al36Allou N. Augustin P. Dufour G. et al.Preoperative statin treatment is associated with reduced postoperative mortality after isolated heart valve surgery in high cardiovascular risk patients.J Cardiothorac Vasc Anesth. 2010; 24: 921-926Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar limited the patient cohort (430) to high-risk isolated valve surgery and addresses the question of all-cause mortality and adverse postoperative outcomes including myocardial injury, cardiogenic shock, AKI, stroke, and severe sepsis. After propensity scoring and multivariate analysis, preoperative statins were associated with a 58% reduction in all-cause mortality compared with those patients not on statins. There were no differences in the cause of death and postoperative outcomes. Billings37Billings F.T. Early postoperative statin therapy is associated with acute kidney injury following cardiac surgery.J Cardiothorac Vasc Anesth. 2010; 24: 913-920Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar studied 324 patients undergoing coronary artery bypass or valvular heart surgery. Similar to the findings of Allou et al, Billings also determined that the incidence of AKI was no different between preoperative statin users and nonusers, but contrary to the findings of Allou et al, the Billings study revealed no difference with respect to mortality. Interestingly, when statin use during the perioperative period was further interrogated, the results changed. Patients who received a statin on the first postoperative day (regardless of whether they were on preoperative statins or not and termed “early postoperative use”) developed less AKI than those who did not. Of those who were on a statin preoperatively, a number of patients underwent statin withdrawal postoperatively and experienced almost twice the incidence of AKI than those who did not have their statin withdrawn. After multivariate logistic regression modeling and propensity scoring, early statin use remained highly significantly associated with a reduction in AKI; odds ratio (OR) = 0.3, p = 0.005.The results of these 2 studies are in and of themselves interesting. They both add to the body of knowledge of statin use in the perioperative period in cardiac surgery. With respect to mortality, they appeared at first glance to be conflicting; Allou et al36Allou N. Augustin P. Dufour G. et al.Preoperative statin treatment is associated with reduced postoperative mortality after isolated heart valve surgery in high cardiovascular risk patients.J Cardiothorac Vasc Anesth. 2010; 24: 921-926Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar reported a mortality reduction with preoperative statin use, whereas Billings37Billings F.T. Early postoperative statin therapy is associated with acute kidney injury following cardiac surgery.J Cardiothorac Vasc Anesth. 2010; 24: 913-920Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar reported no difference. However, when all patients rather than only high-risk patients were considered in their studies, Allou et al also reported no difference in mortality between preoperative statin users and nonusers.With respect to AKI, the opposite is true; at first glance, both studies were similar. Both reported no difference in AKI between patients who took statins preoperatively and those who did not. However, after further analysis in the Billings study, the results diverged; AKI was reduced when statins were reintroduced in the early (day 1) postoperative period. This now begs the question why? As noted previously, patients on chronic statins experience a reduced inflammatory response to cardiopulmonary bypass as measured by blood levels of cytokines and circulating hematopoietic cells, both of which are thought to be associated intimately with postoperative AKI.38Greilich P.E. Brouse C.F. Rinder H.M. et al.Monocyte activation in on-pump versus off-pump coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 2008; 22: 361-368Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 39Rinder C.S. Fontes M. Mathew J.P. et al.Multicenter Study of Perioperative Ischemia Research Group Neutrophil CD11b upregulation during cardiopulmonary bypass is associated with postoperative renal injury.Ann Thorac Surg. 2003; 75: 899-905Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Furthermore, statins reduce the expression of vascular endothelial barrier damage9van Nieuw Amerongen G.P. Vermeer M.A. Nègre-Aminou P. et al.Simvastatin improves disturbed endothelial barrier function.Circulation. 2000; 102: 2803-2809Crossref PubMed Google Scholar, 11Chello M. Spadaccio C. Anselmi A. et al.Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft.J Surg Res. 2006; 136: 302-308Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; again, vascular endothelial injury and activation are thought to be key steps in the development of AKI.40Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (442) Google Scholar, 41Molitoris B.A. Sutton T.A. Endothelial injury and dysfunction: Role in the extension phase of acute renal failure.Kidney Int. 2004; 66: 496-499Crossref PubMed Scopus (283) Google Scholar So why would preoperative statins not reduce AKI? Perhaps the answer lies in the time course of AKI.40Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (442) Google Scholar, 41Molitoris B.A. Sutton T.A. Endothelial injury and dysfunction: Role in the extension phase of acute renal failure.Kidney Int. 2004; 66: 496-499Crossref PubMed Scopus (283) Google Scholar Most investigators suggest that clinical AKI is the result of multiple insults, and that injury continues to occur after an initiating event. This is termed the “extension phase” of AKI.40Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (442) Google Scholar, 41Molitoris B.A. Sutton T.A. Endothelial injury and dysfunction: Role in the extension phase of acute renal failure.Kidney Int. 2004; 66: 496-499Crossref PubMed Scopus (283) Google Scholar It occurs 1 to 3 days after the initiation phase when the downstream effects of endothelial and tubular cell injury and activation take place.40Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Crossref PubMed Scopus (442) Google Scholar, 41Molitoris B.A. Sutton T.A. Endothelial injury and dysfunction: Role in the extension phase of acute renal failure.Kidney Int. 2004; 66: 496-499Crossref PubMed Scopus (283) Google Scholar During the extension phase, there is upregulation of messenger ribonucleic acid activity and the induction of genes involved in the cytoskeleton of both endothelial cells and tubular cells, resulting in altered barrier function, increased permeability, and cellular apoptosis.42Sutton T.A. Mang H.E. Campos S.B. et al.Injury of the renal microvascular endothelium alters barrier function after ischemia.Am J Physiol Renal Physiol. 2003; 285: F191-F198Crossref PubMed Scopus (259) Google Scholar, 43Basille D.P. Fredrich K. Weihrauch D. et al.Angiostatin and matrix metalloproteinsase expression following ischemic acute renal failure.Am J Physiol Renal Physiol. 2004; 286: F893-F902Crossref PubMed Scopus (112) Google Scholar, 44Kevil C.G. Oshima T. Alexander B. et al.H(2)O(2)-mediated permeability: Role of MAPK and occludin.Am J Physiol Cell Physiol. 2000; 279: C21-C30PubMed Google Scholar, 45Devarajan P. Update on mechanisms of ischemic acute kidney injury.J Am Soc Nephrol. 2006; 17: 1503-1520Crossref PubMed Scopus (788) Google Scholar The stabilization and repair of injured renal cells then begin early in the maintenance phase of AKI (2-4 days after the initiating event). Extrarenal endothelial progenitor cells traffic to and participate in the regeneration of injured cells during this period,46Lagaaij E.L. Cramer-Knijnenburg G.F. van Kemenade F.J. et al.Endothelial cell chimerism after renal transplantation and vascular rejection.Lancet. 2001; 357: 33-37Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 47Gupta S. Verfaillie C. Chmielewski D. et al.A role for extrarenal cells in the regeneration following acute renal failure.Kidney Int. 2002; 62: 1285-1290Crossref PubMed Google Scholar whereas undifferentiated mesenchymal cells from the bone marrow contribute to the formation of new kidney cells, including mesangial cells, tubular epithelial cells, and podocytes.48Morigi M. Imberti B. Zoja C. et al.Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure.J Am Soc Nephrol. 2004; 15: 1794-1804Crossref PubMed Scopus (661) Google Scholar, 49Herrera M.B. Bussolati B. Bruno S. et al.Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury.Int J Mol Med. 2004; 14: 1035-1041PubMed Google ScholarStatins have been shown to increase the number of endothelial progenitor cells in animal models50Matsumura M. Fukuda N. Kobayashi N. et al.Effects of atorvastatin on angiogenesis in hindlimb ischemia and endothelial progenitor cell formation in rats.Atheroscler Thromb. 2009; 16: 319-326Crossref Scopus (53) Google Scholar and patients on chronic statin therapy.51Pirro M. Schillaci G. Romagno P.F. et al.Influence of short-term rosuvastatin therapy on endothelial progenitor cells and endothelial function.Cardiovasc Pharmacol Ther. 2009; 14: 14-21Crossref PubMed Scopus (57) Google Scholar It also has been shown that the numbers of progenitor cells are increased, both pre– and post–cardiopulmonary bypass, in patients taking preoperative statins before cardiac surgery.14Spadaccio C. Pollari F. Casacalenda A. et al.Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study.J Cardiovasc Pharmacol. 2010; 55: 30-38Crossref PubMed Scopus (68) Google Scholar Furthermore, their mobilization, trafficking, homing, adherence, and activity are increased in a statin-rich milieu50Matsumura M. Fukuda N. Kobayashi N. et al.Effects of atorvastatin on angiogenesis in hindlimb ischemia and endothelial progenitor cell formation in rats.Atheroscler Thromb. 2009; 16: 319-326Crossref Scopus (53) Google Scholar as are their differentiation and maturation,52Li X. Han Y. Pang W. et al.AMP-activated protein kinase promotes the differentiation of endothelial progenitor cells.Arterioscler Thromb Vasc Biol. 2008; 28: 1789-1795Crossref PubMed Scopus (98) Google Scholar whereas apoptosis of these cells is downregulated.53Shao H. Tan Y. Eton D. et al.Statin and stromal cell-derived factor-1 additively promote angiogenesis by enhancement of progenitor cells incorporation into new vessels.Stem Cells. 2008; 26: 1376-1384Crossref PubMed Scopus (119) Google ScholarLooking at the timeline of injury, stabilization, and repair in AKI, it may be necessary for statins to be present during the extension and early maintenance phases (1-4 days postoperatively) to exert the