We found that preoperative statin therapy was not associated with a reduced prevalence of postoperative AKI, postoperative dialysis, or hospital mortality. The role of statin therapy in the reduction of CPB-induced AKI was postulated based on a number of factors including the finding that statin therapy was associated with a reduction in the incidence of contrast nephropathy in a large retrospective trial,25,26 a condition that shares similar pathologic mechanisms of injury as those caused by CPB. In addition, 2 large retrospective studies demonstrated an association between preoperative statin therapy and a reduction in postoperative mortality in patients undergoing cardiac surgery.14,15
Statins, in addition to their low-density lipoprotein-decreasing effect, have been shown to improve endothelial function by decreasing superoxide formation, upregulating the expression of nitric oxide synthase, and inhibiting the expression of angiotensin II and endothelin.27–29 Pretreatment with statins in patients undergoing cardiac surgery significantly reduced the systemic inflammatory response to CPB as evidenced by reduced cytokine release and neutrophil adhesion to the venous endothelium.17 Atherosclerosis of the ascending aorta, through an increase in renal embolus burden, has been shown to be an important predictor of renal dysfunction after cardiac surgery,30 and statins decrease the thrombogenic response to plaque rupture by reducing platelet aggregation and promoting fibrinolysis through enhanced tissue plasminogen activator synthesis.16,17,27 These pleiotropic effects of statins would plausibly reduce CPB-induced AKI through reduction in ischemia-reperfusion injury, systemic inflammatory response, and a reduction in renal emboli through plaque stabilization.
Statin therapy is interrupted during and immediately after surgery because it is currently available only in oral formulation. One possible explanation for the lack of renoprotective effect of statins in our study is that the serum concentrations of statins are reduced because of hemodilution from CPB. Indeed, Verma et al.27 demonstrated an attenuation in cell injury with pravastatin only above certain serum concentrations (10 μM). Other drugs with renoprotective effects demonstrated outside of cardiac surgery failed to show renoprotective properties in patients undergoing cardiac surgery. For example, N-acetylcysteine showed a reduction of contrast-induced nephropathy in patients undergoing coronary angiography31 but failed to reduce the incidence of AKI in high-risk patients undergoing on-pump CABG surgery.
Our study results support the findings of others who reported that preoperative statin therapy is not associated with a reduction in postoperative AKI.32,33 Huffmyer et al.32 demonstrated a lack of association between preoperative statins and acute renal failure in patients undergoing on-pump CABG surgery. However, they found, unlike our results, a reduction in hospital mortality and renal replacement therapy in patients receiving preoperative statins. This difference in the study results might be explained by their inclusion of patients undergoing CABG surgery with CPB and not patients undergoing valvular surgery as in our study. Moreover, their different definition of acute renal failure (reduction of eGFR of >50%) excluded patients with risk of renal dysfunction (according to the RIFLE criteria) from their analysis. Most importantly, preoperative risk factors such as diabetes mellitus, preoperative left ventricular ejection fraction, and other preoperative medications (β-blockers, calcium channel blockers, aspirin, and angiotensin-converting enzyme inhibitors) known to influence the incidence of AKI were not included in their analysis, which may have confounded their results. Huffmyer et al.32 found no reduction in mortality in the subset of patients requiring renal replacement therapy who received preoperative statins. This finding, in addition to the lack of association between preoperative statin use and acute renal failure in their report, makes a renal-specific benefit of statins unlikely. Indeed, the authors explain the need for renal replacement therapy after CABG as a possible marker of patient systemic injury.
Our study results contrast with other trials that have shown an association between preoperative statin therapy and a reduction in hospital mortality in patients undergoing cardiac surgery with CPB.14,15,33 In our study, there was no consistent protocol for resumption of statin drugs after surgery. It may be that any potential protective effects of statin therapy on mortality are reduced by the delayed postoperative reinstitution of statins in some patients. The deleterious effects of postoperative statin withdrawal on mortality have been reported.34,35 Another explanation, albeit speculative, may be that preoperative statin use is a marker of better overall preoperative health care. Ali and Buth,36 in a retrospective report of 2886 patients undergoing cardiac surgery with CPB, showed similar mortality findings to this report: a lack of association between preoperative statin and in-hospital mortality.
Our risk-adjusted model identified several variables associated with an increased risk for postoperative AKI. Several of these variables such as preoperative renal insufficiency, heart failure, reduced left ventricular function, and emergency surgery have been identified in a validated scoring system for predicting acute renal failure after cardiac surgery.37 Red blood cell transfusion was also found to be associated with an increased risk for postoperative AKI, which is consistent with other studies.2,9,38 The association between a prolonged CPB time and postoperative AKI in our study has also been reported.8,9
Our study has several limitations. In this retrospective cohort study design, the specific formulation, dose, and duration for preoperative statin therapy were not considered. Kourliouros et al.39 recently reported a dose-related effect of statins on atrial fibrillation incidence after cardiac surgery. In their study, high-dose statins had the greatest preventative effect, whereas low-dose statins did not influence postoperative atrial fibrillation, suggesting that the pleiotropic effects of statins may also be dose related. We used serum creatinine as a surrogate for renal function in this study; calculated creatinine clearance has been shown to be more sensitive in the estimation of renal reserve and the need for renal replacement therapy in the postoperative period.40
This study did not show a statistically significant difference in any of the 3 outcomes of AKI, postoperative dialysis, or hospital mortality. These findings could either be because statin therapy truly does not affect the frequency of these outcomes or because the sample size of this study was not large enough to detect a difference between the 2 groups. A post hoc sample size calculation suggests that approximately 27,000 patients per group would be necessary to exclude a type II error in assessing the effects of statin therapy on the frequency of AKI. Furthermore, 15,000 patients per group would be needed to find a reduction in the frequency of postoperative dialysis or hospital mortality with statin versus no statin therapy. Even if found to have a beneficial effect on renal outcomes and mortality after cardiac surgery with a larger patient population, the magnitude of renoprotection by statins is likely to be low.
Although statins' pleiotropic effects offered a biologically plausible mechanism for a potential renoprotective effect in cardiac surgical patients, preoperative statin therapy was not associated with a reduction in the incidence of AKI, postoperative dialysis, or hospital mortality in patients undergoing cardiac surgery.
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