Description of the condition
Acute kidney injury (AKI) is a common complication of cardiac surgery with an incidence ranging from 1% to 30% according to the definition used (Conlon 1999; Mariscalco 2011; Ostermann 2000; Thakar 2003). Cardiac surgery-associated AKI (csa-AKI) has been shown to be independently associated with increased morbidity and mortality (Chertow 1997) and a more complicated hospital course. It is associated with longer stay in ICU and increased costs in particular when renal replacement therapy (RRT) is required (Coca 2009; Srisawat 2010; Swaminathan 2007). The use of cardiopulmonary bypass has been identified as an important risk factor for the occurrence of csa-AKI (Bove 2004; Chawla 2012; Lamy 2012), and the morbidity and mortality associated with development of this condition has not changed over the last decade despite significant technological advances in bypass technology (Swaminathan 2007). Further identified risk factors for development of AKI post cardio-pulmonary bypass include pre-existing chronic kidney disease (CKD) (Chertow 1997); older age (Mangano 1998); female gender (Asimakopoulos 2005); reduced left ventricular function (Mistiaen 2009); congestive heart failure (Mangano 1998); diabetes mellitus (Chukwuemeka 2005); peripheral vascular disease (Chukwuemeka 2005); preoperative use of an intra-aortic balloon pump (Bove 2004); need for emergent surgery (Bove 2004); pre-existing anaemia (Karkouti 2009); cardiopulmonary bypass (CPB) time (Bove 2004); duration of cross clamp time (Mistiaen 2009); and requirement of vasopressor support (Arora 2008).
While an overall decrease in renal blood flow has been shown to significantly contribute to the diminished glomerular filtration rate (GFR) observed in ischaemic renal injury, the decrease in renal blood flow alone cannot account for the total reduction in GFR. Renal toxicity is also thought to be mediated by cardiopulmonary bypass triggered activation of bone marrow derived cells, endothelial cells and renal epithelial cells resulting in reactive oxygen species generation and release of inflammatory mediators (Boyle 1997; Chello 2003). The adhesion of such inflammatory cells to activated endothelium in peritubular capillaries of the outer medulla leads to medullary congestion and hypoxic injury to the proximal tubule. Pro-inflammatory cytokines secreted by infiltrating and resident cells contribute to further tissue injury until inflammatory resolution and tubular epithelial proliferation occurs bringing a return to normal tissue function (Devarajan 2006).
Description of the intervention
Statins competitively inhibit the enzyme 3-hydroxy 3-methylglutaryl CoA reductase which catalyses the rate limiting step in cholesterol synthesis (Endo 1976). Since approval for clinical use in 1987 statins have been shown to reduce the progression of atherosclerosis, improve survival and reduce the risks of vascular death, non-fatal myocardial infarction (MI), stroke, and the need for coronary revascularisation across a wide range of cholesterol levels (Baigent 2005).
How the intervention might work
HMG CoA reductase inhibitors (statins) in addition to their lipid lowering actions have been shown to have anti-inflammatory and pleiotropic effects (Haslinger-Löffler 2008). In experimental models of AKI (Gueler 2002; Inman 2005; Yokota 2003), statins have been shown to preserve renal function. Similarly, some studies (Mariscalco 2011) have suggested that statins could reduce postoperative leukocyte and endothelial activation and result in significantly lower postoperative pro-inflammatory serum cytokine levels. There are some evidence that statin administration before percutaneous coronary interventions reduces periprocedural cardiovascular events. However, results are more conflicting when AKI (then called contrast-induced nephropathy) is considered as an outcome (Jo 2008; Ozan 2010; Patti 2008). A recent meta-analysis (Li 2012) supported the use of statins but concluded that their use must be considered in the context of variable patient demographics. In patients undergoing cardiac surgery, results are conflicting and only small randomised control trials (RCT) have been published to date.
Why it is important to do this review
In the absence of a large RCT, current evidence relies on numerous observational trials with conflicting results and a few small RCT's. Although several systematic reviews have evaluated the overall benefits of perioperative statins in cardiac surgery (Liakopoulos 2008; Liakopoulos 2012), none of them have focused on AKI as a primary outcome. We propose a more specific review focusing on AKI with a search strategy as outlined including procedures requiring cardiac bypass, with the exception of cardiac transplantation surgery and correction of congenital cardiac disease. All levels of renal injury will be included. There is a considerable need for effective therapies that prevent AKI in this setting as renal dysfunction after surgery results in significantly increased morbidity compared with those who have maintained normal renal function (Karkouti 2009). In general prevention of renal reperfusion injury after cardiac bypass surgery involves correction of dehydration and minimising nephrotoxins. Therefore the evidence showing that statins help prevent renal injury in this setting will help fill this therapeutic gap. Recent evidence (even amongst those patients not requiring RRT following AKI) suggests that renal injury was associated with increased long-term mortality risk independent of residual renal function, with risk proportionate to the severity of the renal injury (Lafrance 2010). The purpose of this review is to examine the evidence that suggests that statins may prevent AKI in patients undergoing surgery requiring cardiac bypass.