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.
This review aims to look at the evidence that supports the benefits of perioperative statins in prevention of AKI occurring in hospitalised adults after surgery requiring cardiac bypass. The main objectives are:
- To determine whether statin use is associated with the prevention of development of AKI.
- To determine whether the use of statins is associated with a reduction in in-hospital mortality.
- To determine whether the use of statins is associated with a reduction in the need for renal replacement therapy.
- To determine any adverse effects associated with the use of statins.
Criteria for considering studies for this review
Types of studies
All published randomised controlled trials (RCTs) that compare the use of statin to placebo or standard treatment given pre-operatively to patients having surgery requiring cardiac bypass. The dose, type or duration of statins used are not restricted. Only published trials are included, no abstract presentations will be included. Case reports and non-randomised studies will not be included in the review.
Types of participants
All adult patients (age > 18 years) who undergo surgery requiring cardiac bypass will be included. Trials including paediatric subjects or mixed paediatric and adult populations will be excluded.
- Patients on extracorporeal RRT prior to the initiation of the study.
- Patients undergoing cardiac transplantation or corrective surgery for congenital heart disease.
- Kidney transplant recipients.
Types of interventions
RCT's assessing the use of statin therapy for any given duration and dose prior to surgery requiring cardiac bypass compared to placebo, or no drug therapy or standard clinical care. All statins will be considered for inclusion, with a priori subgroup analysis defined.
Types of outcome measures
The primary outcome is the incidence of AKI after cardiac surgery. AKI will be defined using the AKIN or RIFLE classification wherever provided. The Acute Kidney Injury Network (AKIN) (Mehta 2007) defines three stages of injury (1, 2 and 3) based on increasingly severe reductions of kidney function (Stage 1: increase in serum creatinine ≥ 0.3 mg/dL, or 1.5- to 2-fold increase from baseline; Stage 2: increase in serum creatinine ≥ 150% to 200% from baseline; Stage 3: increase in serum creatinine > 3-fold from baseline, > 300% from baseline, ≥ 4.0 mg/dL, or initiation of RRT regardless of stage). The RIFLE criteria, proposed by the AQDI (Acute Dialysis Quality Initiative) group (Bellomo 2004) defines five levels of AKI (risk, injury, failure, loss and end-stage kidney disease) again based on incremental reductions in kidney function. If AKI is not reported in the context of these criteria, efforts will be made to classify patients according to these criteria. If necessary, authors will be contacted to provide additional data surrounding creatinine and urine output (if available) to enable this conversion.
- Serum creatinine changes during the same hospitalisation
- In-hospital mortality.
- Need for RRT during the same hospitalisation.
- Adverse effects attributed to the intervention (elevated liver enzymes, creatinine kinase levels, rhabdomyolysis or withdrawal of drug)
Search methods for identification of studies
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
The Cochrane Renal Group’s Specialised Register contains studies identified from:
- Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL;
- Weekly searches of MEDLINE OVID SP;
- Handsearching of renal-related journals & the proceedings of major renal conferences;
- Searching of the current year of EMBASE OVID SP;
- Weekly current awareness alerts for selected renal-journals;
- Searches of the International Clinical Trials Register (ICTRP) Search Portal & ClinicalTrials.gov
Studies contained in the Specialised register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies as well as a list of handsearched journals, conference proceedings and current awareness alerts are available in the 'Specialised Register' section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
- Reference lists of nephrology textbooks, review articles and relevant studies.
- Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.
Searching other resources
For completion, assessment of potential trials in progress, or awaiting publication will be sought through searches of ClinicalTrials.gov (www.clinicaltrials.gov). Further potential trials will be assessed through hand-searching reference lists of included trials. Letters seeking information about unpublished or incomplete studies will be sent to investigators known to be involved in those studies.
Data collection and analysis
Selection of studies
Literature search will be performed using a predefined search strategy (see Appendix 1). The titles and abstracts will be screened initially. Studies that potentially contained information relevant to the review will be retained, whereas studies that do not meet the pre-specified criteria will be discarded. All three authors will independently review and select studies from EMBASE, CENTRAL and MEDLINE database. All of the potentially relevant studies will then be uploaded to a reference management software database (Review Manager 5). Each author will then review the full text of the retained articles to assess suitability for inclusion of the study. Reasons for exclusion will be noted. Crosscheck will be performed among all three authors to determine the final eligibility for inclusion. Disagreement will be arbitrated until a consensus is reached.
Data extraction and management
Data will be extracted independently by all three authors using a data extraction form, which will be designed by AS and piloted by all three authors. The information obtained will be cross-checked by each author. Disagreement will be arbitrated until a consensus is reached. Where more than one publication of a study exists, reports will be grouped together and the most complete data set will be included. Any discrepancy between published versions will be highlighted. The following data will be extracted:
- Study design
- Country of the study performed
- Number of centres involved
- Inclusion criteria
- Exclusion criteria
- Total number of included patients in both treatment group and placebo group
- Age, sex, baseline CKD, diabetes, hypertension, chronic statin use, elective or emergency surgery
Interventions and outcomes
- Statin regimen including the type of statins, the dose and duration
- Proportion with AKI
- Proportion requiring RRT
- Mortality rate
- Proportion with adverse events
- Pre and postoperative serum creatinine level
- Any other outcomes collected for the study
- Source of funding
- Any other relevant information
Attempts will be made to retrieve any missing data or information through direct correspondence with the primary author of the relevant study.
Assessment of risk of bias in included studies
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Studies will be labelled “low risk of bias”, “high risk of bias” or “unclear risk of bias” with reasons documented and a “risk of bias summary” will be presented. Studies with high risk of bias will be identified and this will be taken into account in the outcome analysis.
Measures of treatment effect
For dichotomous outcomes (e.g. proportion of AKI, need for RRT, mortality rates and number of adverse events), results will be expressed as risk ratios (RR) with 95% confidence intervals (CI). A RR < 1 favours statin treatment over control. As postoperative serum creatinine is a continuous outcome it will be first converted to standardised units (µmol/L) and the mean difference (MD) with 95% CI will subsequently be used for comparison.
Unit of analysis issues
Studies with non-standard designs, such as cross-over trials and cluster-randomised trials will not be included in this review.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review.
Assessment of heterogeneity
We will assess the heterogeneity between included studies using the Chi² test on N-1 degrees of freedom with an alpha of 0.05 used for statistical significance and with the I² statistic (Higgins 2003). We consider statistical significance in heterogeneity surrounding calculation of the I², although Chi² with alpha < 0.05 will also be considered. Based on the Cochrane Handbook (Higgins 2011), I² of 0% to 40% may not be important, I² of 30% to 60% may represent moderate heterogeneity, I² of 50% to 90% may represent substantial heterogeneity and I² of 75% to 100% may represent considerable heterogeneity. Visual inspection of forest plots will provide added evidence of heterogeneity.
Assessment of reporting biases
In order to detect any publication bias, electronic searching of websites with current clinical trial protocols will be undertaken. Funnel plot analysis (Sterne 2001) is planned to further investigate publication bias if there is sufficient number of included studies. Language bias is minimized by not applying any language restrictions during the search strategy.
The data from the available randomised controlled trials will be pooled using the random effects model (DerSimonian 1986), however the fixed effects model (Egger 1997) will also be undertaken to ensure the robustness of the model and susceptibility to outliers. The random effects model is to be used for the primary analysis as there may be variability in the form, dose and duration of statin therapy used amongst trials of this nature, and some heterogeneity may be expected. Before a pooled data analysis is performed for each outcome of interest, the authors will assess all the relevant studies to determine the eligibility of data comparison. Results will be presented within the narrative if there are not sufficient comparable data available to undertake a pooled analysis for a specific outcome.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity such as those amongst participants, treatments and study quality. Heterogeneity in patients could be related to age, preoperative renal pathology and other risk factors for renal reperfusion injury. Heterogeneity in treatments could be related to prior agent(s) used and the dose, duration and type of statin used. If sufficient studies are identified we will investigate these potential differences.
We will perform sensitivity analyses if there are sufficient studies identified, in order to explore the influence of the following factors on effect size:
- repeating the analysis excluding unpublished studies;
- repeating the analysis taking account of risk of bias, as specified above;
- repeating the analysis excluding any very long or large studies to establish how much they dominate the results;
- repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
- We are grateful to the Cochrane Renal Group for assistance in preparation of this manuscript
- We also wish to thank the team in the Department of Epidemiology and Preventative Medicine at Monash University, particularly Renea Johnston and Rachelle Buchbinder for their help in preparation of this manuscript
- We also thank Adam Clark for assistance with development of the search strategies
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Contributions of authors
- Draft the protocol: ML, AS, IN
- Study selection: ML, AS, IN
- Extract data from studies: ML, AS, IN
- Enter data into RevMan: AS
- Carry out the analysis: ML, AS, IN
- Interpret the analysis: ML
- Draft the final review: ML, AS, IN
- Disagreement resolution: ML, AS, IN
- Update the review: ML
Declarations of interest
Sources of support
- No sources of support supplied
- Dr M Lewicki, Australia.Supported through a Jacquot Research Entry Scholarship, RACP Foundation Australia
- Dr A Schneider, Switzerland.Supported through a MGS-MIPRS Research Scholarship, Monash University Australia