C O
URRENTPINIONAcute kidney injury in cardiac surgery
Alan M. Gaffney and Robert N. Sladen
Purpose of review
Acute kidney injury (AKI) is a long-recognized complication of cardiac surgery. It is a commonly
encountered clinical syndrome that, in its most severe form, increases the odds of operative mortality three to eight-fold. The pathogenesis of cardiac surgery-associated acute kidney injury (CSA-AKI) is complex. No single intervention is likely to provide a panacea, and thus, the purpose of this review is to assess the wide breadth of emerging research into potential strategies to prevent, diagnose, and treat CSA-AKI.
Recent findings
Research in the field of CSA-AKI published within the last 18 months adds further layers of knowledge to many previously studied areas. These include its definition (Risk, Injury, Failure, Loss, End-stage kidney disease, Acute Kidney Injury Network, and Kidney Disease: Improving Global Outcomes criteria),
diagnosis (biomarkers and intraoperative renal oximetry), prevention (statin therapy, acetylsalicylic acid,N- acetylcysteine, sodium bicarbonate, off-pump coronary revascularization, goal-directed hemodynamic therapy, and minimizing blood transfusion), and treatment (early initiation of renal replacement therapy).
Summary
Although there has been much high-quality research conducted in this field in recent years, preventing CSA-AKI by avoiding renal insults remains the mainstay of management. Although biomarkers have the potential to diagnose CSA-AKI at an earlier stage, efficacious interventions to treat established CSA-AKI remain elusive.
Keywords
acute kidney injury, cardiac surgery, cardiac surgery-associated acute kidney injury
INTRODUCTION
Acute kidney injury (AKI) is a formidable compli- cation of cardiac surgery. Depending on how it is defined and its severity, the incidence of cardiac surgery-associated AKI (CSA-AKI) varies widely, from 7 to 40% in large patient cohorts undergoing a variety of procedures [1–4]. The incidence of CSA- AKI increases to as high as 50% in groups of patients with known risk factors [5&,6].
As implied above, the wide range of incidence of CSA-AKI depends on its definition. The severity of CSA-AKI ranges from asymptomatic increases in bio- chemical markers of renal injury that are of little clinical consequence, to the requirement for renal replacement therapy (RRT) that has a dramatic impact on ICU and hospital length of stay (LOS), as well as operative mortality [7–9]. At its most severe extreme, new onset CSA-AKI increases the odds of operative mortality three to eight-fold [10,11].
The association between CSA-AKI and poor out- come has been appreciated for many years. Consider- able progress has been made in more accurate definition of the syndrome and greater under- standing of its pathophysiology, and yet the early
detection, prevention, and management CSA-AKI remains a substantial challenge. The assumption remains prevalent that a decrease in the incidence in CSA-AKI will decrease perioperative morbidity and mortality, and that the development of CSA-AKI is modifiable [12]. However, the pathogenesis of peri- operative CSA-AKI may be more closely related to the stage of preoperative chronic kidney disease (CKD) and the severity of perioperative cardiac dysfunction, and may explain the lack of success of so many specific ‘renal’ interventions.
In this review, the focus is on studies published within the last 18 months (January 2013 to August 2014) that provide an update on CSA-AKI. For an
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, USA
Correspondence to Alan M. Gaffney, Assistant Professor of Anesthesi- ology, Associate Medical Director Cardiothoracic ICU, Department of Anesthesiology, MH 5-289, College of Physicians and Surgeons of Columbia University, 630 West 168th St, New York, NY 10032, USA.
Tel: +1 212 305 4090; e-mail: ag2606@cumc.columbia.edu Curr Opin Anesthesiol2015, 28:50–59
DOI:10.1097/ACO.0000000000000154
excellent overall review of perioperative AKI, the reader is referred to the recent article by Mooney et al.[13&].
PATHOPHYSIOLOGY OF CARDIAC SURGERY-ASSOCIATED ACUTE KIDNEY INJURY
It is very unlikely that a single etiologic factor will cause perioperative AKI. Almost inevitably, CSA-AKI is the consequence of multiple, interactive pathways. Patients may be more susceptible to CSA-AKI by virtue of their sex, age, pre-existing cardiac dysfunction, pre-existing CKD, previous cardiac surgery, or comorbidity such as chronic obstructive pulmonary disease or diabetes mellitus [14]. Perioperative administration of nephrotoxic agents, such as radiocontrast dyes, angiotensin- converting enzyme inhibitors, loop diuretics, or aminoglycoside antibiotics, can enhance the likeli- hood of CSA-AKI [14]. These agents seldom act in isolation; it is a truism that the risk of nephro- toxicity is exponentially related to the number of nephrotoxic insults, which includes a milieu of intravascular hypovolemia or hemodynamic insta- bility. Perhaps the greatest influence on renal out- come is the complexity and emergent nature of the cardiac surgical procedure, resulting in the so-called cardiorenal syndrome. These patients are poten- tially subject to a multiplicity of damaging entities.
The most prominent are prolonged duration of cardiopulmonary bypass (CPB) and its contact- activated inflammatory response, and prolonged aortic cross-clamping, with an increased likelihood of cardiac ischemia-reperfusion injury and a low cardiac output syndrome that, in turn, compromises renal blood flow and perfusion pressure. Additional
exacerbating renal insults that inevitably occur with complex or complicated cardiac surgery include post-CPB hemodynamic instability with arrhyth- mias and compromised cardiac function; prolonged hypotension and the requirement for potent vaso- pressors such as norepinephrine in high doses;
and bleeding and administration of multiple blood products.
Cardiopulmonary bypass
When off-pump coronary artery bypass grafting (OPCAB) was introduced, it was postulated that the avoidance of CPB and its inflammatory response might decrease the incidence and severity of CSA-AKI [15].
A systematic review and meta-analysis of 22 randomized controlled trials (4819 patients) suggested that OPCAB may be associated with a lower incidence of CSA-AKI, although without a decrease in the requirement for RRT [16]. As always, definitive conclusions were limited by variability in the definition of AKI and other methodological problems. In contrast, the German OPCAB in Elderly Patients trial detected no difference in the incidence or severity of CSA-AKI by Acute Kidney Injury Network (AKIN) criteria in 1612 patients undergoing OPCAB versus coronary artery bypass grafting (CABG) with CPB [5&]. The CABG Off or On Pump Revascularization Study (CORONARY) inves- tigators randomized 4752 patients in 79 centers in 19 countries to off-pump or on-pump CABG. There was no difference in the primary composite out- come measure of the 30-day rate of death, myo- cardial infarction, stroke, or renal failure requiring dialysis [17]. The same investigators conducted a kidney function substudy of this main study by adding further renal data collection for patients after recruitment had already begun [18]. Data for 2932 patients were analyzed. The risk of CSA-AKI was lower in the OPCAB group compared to the on- pump group (relative risk 0.75–0.89 depending on the definition of AKI used). Interestingly, however, and contrary to the results of many observational studies [19], there was no difference between the groups in the degree of renal injury present at 1 year.
In other words, although OPCABG induced less CSA-AKI, this was not associated with better clinically meaningful or important outcomes. This serves to highlight the importance of confirming (or refuting) the results of observational studies with prospectively collected data from randomized clinical trials (RCTs) [20]. That being said, this is only one RCT, albeit large and multicenter. Ideally, the results of multiple such RCTs, meta-analyzed, would provide the best evidence for any association
KEY POINTS
Considerable progress has been made in more accurate definition of CSA-AKI and greater understanding of its pathophysiology; however, prevention and management of CSA-AKI remains a substantial challenge.
In time, the KDIGO criteria will likely supplant the RIFLE and AKIN criteria, but still do not come close to identifying AKI at the time of renal insult.
Of the many biomarkers currently under investigation, NGAL has emerged as the one most likely to become established for the early diagnosis of AKI.
Early initiation of RRT deserves further attention as a potential intervention to alter the clinical course of CSA-AKI. RCTs are warranted.
or lack of association between CSA-AKI and import- ant clinical outcomes including CKD and mortality.
Hypotension during cardiopulmonary bypass The optimal mean arterial pressure (MAP) to help prevent CSA-AKI during CPB is unknown [21].
Almost all studies that examine MAP during CPB are observational and have attempted to correlate hypotension with adverse neurologic outcome.
Renal outcome studies have demonstrated conflict- ing data [22–24].
Azau et al. [25] recently published results of a single-center randomized controlled study of 300 patients with known risk factors for AKI under- going elective cardiac surgery with normothermic CBP. In the control group, MAP during CPB was targeted to 50–60 mmHg, whereas in the interven- tion group, the target was 75–85 mmHg. The aver- age MAP achieved in the control and intervention groups was 606 and 796 mmHg, respectively.
There was no intergroup difference in CSA-AKI, hospital LOS, or mortality.
Blood transfusion
Khanet al.[26&] examined the putative role of blood transfusion in causing CSA-AKI in 1210 adults undergoing cardiac surgery. Of these, 74% received no red blood cells (RBCs), 17% received two units RBCs or less, and 9% received more than two units RBCs. The authors defined AKI by a doubling of serum creatinine (SCr), but also measured urine interleukin-18 and neutrophil gelatinase-associated lipocalin (NGAL). After adjusting for 12 preopera- tive and surgical variables, the authors concluded that the risk of AKI was highest in patients receiving more than two units RBCs by all three end points.
However, the authors also acknowledged that the study was limited by being observational: there was no set transfusion trigger; the age of RBCs was variable; and a direct causal relationship between RBC transfusion and AKI could not be confirmed.
Contrast-induced nephropathy
A substantial proportion of patients undergo contrast angiography or ventriculography prior to cardiac surgery. The risk of contrast-induced nephropathy (CIN) as a pathway to AKI is related to associated factors such as the type and dose of contrast medium, the patient’s age, degree of underlying CKD, and state of hydration. CIN is induced by a number of path- ways [27], which may explain why no single inter- vention, including intravenous isotonic fluid hydration, sodium bicarbonate, N-acetylcysteine
(NAC), fenoldopam, and statins among others has been shown to prevent CIN [28]. Only intravenous isotonic fluid hydration remains consistently recom- mended in guidelines that attempt to decrease the risk of CIN [28].
An important question is whether extending the time period between angiography and cardiac surgery can decrease the risk of CIN. The 2011 American College of Cardiology Foundation/
American Heart Association Guideline for CABG Surgery states that ‘in patients with pre-existing renal dysfunction, a delay of surgery after coronary angiography may be reasonable until the effect of radiographic contrast material on renal function is assessed’ [29]. This recommendation is based on retrospective, single-center epidemiological studies using multivariable logistic regression showing an increase in the odds ratio of CSA-AKI when surgery was performed less than 5 days after angiography [30–32]. In contrast, O¨ zkaynaket al.[33] found that time to surgery following angiography in a cohort of 573 consecutive patients was not a risk factor for the development of CSA-AKI. Given the dearth of pro- spective randomized studies, the most reasonable approach might be to attempt to evaluate for CIN prior to elective cardiac surgery, but not to delay urgent surgery to allow a longer interval after angiography.
DEFINITIONS, STAGING, AND
EPIDEMIOLOGY OF CARDIAC SURGERY- ASSOCIATED ACUTE KIDNEY INJURY For decades, there was no standard definition or staging system for the diagnosis of AKI and more than 30 different and often arbitrary definitions were used over time [34]. This greatly limited our ability to compare epidemiologic studies or prog- nosticate outcomes. An agreed consensus definition was necessary to improve the consistency of study inclusion and exclusion criteria as well as defined, standardized, clinical end points (Table 1).
In 2004, Bellomoet al.[34] introduced the RIFLE classification, which defined and staged renal failure over 7 days into five classes of increasing severity:
risk, injury, failure, loss of renal function, and end- stage kidney disease (Table 1). The Risk, Injury, and Failure criteria were based upon changes in SCr, estimated (not measured) glomerular filtration rate (eGFR), and/or urine output. This group of investi- gators subsequently formed the AKIN and in 2007 published the so-called AKIN criteria [35] (Table 1).
This made several practical refinements. The chronic criteria (loss and end-stage renal disease) as well as eGFR were discarded, decreasing the classi- fication from five to three stages (AKIN Stages 1, 2,
Table1.ComparisonofRIFLE,AKIN,andKDIGOclassificationsofacutekidneyinjury RIFLE[34]AKIN[35]KDIGO[36]KDIGO/AKIN/RIFLE DefinitionSCr>1.5baselineover7daysSCr>1.5baselineover48hoursSCr>1.5baselineover 7daysUrineoutputcriteria (commontoall threeclassifications) OROR IncreaseinSCrof0.3mg/dlover 48hoursIncreaseinSCrof 0.3mg/dlover48hours Serumcreatinine /RRT/GFRcriteriaClassSCr>1.5baselineStageSCr>1.5baselineStageSCr>1.5baseline<0.5ml/kg/hfor>6hours OROROR RiskGFR>25%10.3mg/dlincrease10.3mg/dlincrease InjurySCr>2baseline2SCr>2baseline2SCr>2baseline<0.5ml/kg/hfor>12hours OR GFR>50% FailureSCr>3baseline3SCr>3baseline3SCr>3baseline<0.3ml/kg/hfor>24hours OROROROR IncreaseinSCrto4.0mg/dl (withanacuteincrease ofatleast0.5mg/dl) IncreaseinSCrto4.0mg/dl (withanacuteincrease ofatleast0.5mg/dl)
IncreaseinSCrto 4.0mg/dlAnuriafor>12hours OROROR GFR>75%InitiationofRRTInitiationofRRT LossRRTrequiredfor>4weeks EndstageRRTrequiredfor>3months AKIN,AcuteKidneyInjuryNetwork;GFR,glomerularfiltrationrate;KDIGO,KidneyDisease:ImprovingGlobalOutcomes;OR,oddsratio;RIFLE,risk,injury,failure,loss,end-stagekidneydisease;RRT,renal replacementtherapy;SCr,serumcreatinineconcentration.
and 3). Information regarding the considerable impact of small increases in SCr on postoperative mortality after cardiothoracic surgery was applied by incorporating an absolute increase in SCr of at least 0.3 mg/dl over 48 hours into the criteria for AKIN Stage 1 [37]. The same group of investigators then formed an organization called Kidney Disease:
Improving Global Outcomes (KDIGO) and in 2013 further refined the AKIN criteria by including RRT and 12 hours of anuria as criteria for Stage 3 AKI [36]
(Table 1). However, while the time to an absolute increase in SCr to at least 0.3 mg/dl remains at 48 hours, the time for SCr to increase by more than 50% from baseline reverts to the 7-day time period used in RIFLE.
The RIFLE and AKIN criteria are now well estab- lished criteria in studies of CSA-AKI [5&,38–40].
However, Sampaio et al. [41] declared the KDIGO criteria to be superior to AKIN and RIFLE with regard to prognostic power. This is also suggested by a single-center observational study in the general ICU population, where the KDIGO criteria demon- strated greater sensitivity to detect AKI and predict in-hospital mortality [42]. Machado et al. [4] used KDIGO criteria in a retrospective analysis of a cohort of 2804 patients and found that even slight changes in renal function are independent predictors of 30-day mortality. These studies suggest that in time the KDIGO criteria will supplant the RIFLE and AKIN criteria, but still do not come close to identi- fying AKI at the time of renal insult.
A number of surgical scoring systems that incorporate SCr have been developed to help predict overall morbidity and mortality in patients under- going cardiac surgery. The most commonly used are the Society of Thoracic Surgeons Score, a risk model used to predict operative morbidity and mortality after adult cardiac surgery. The Euroscore II system for cardiac operative risk evaluation utilizes the eGFR based upon the preoperative SCr.
MONITORING RENAL FUNCTION AND ACUTE KIDNEY INJURY
In order to determine whether AKI has occurred, or is likely to occur, biomarkers and physiological indicators have been studied.
Renal biomarkers
The RIFLE, AKIN, and KDIGO criteria have enor- mously helped in defining and staging AKI. How- ever, they all have important limitations. First, they were not designed for the early diagnosis of peri- operative AKI, given that they are based upon changes in SCr occurring 48 hours to 7 days after
the original insult. Moreover, SCr is affected by age, sex, ethnicity, muscle mass, diet, drugs, and intra- vascular volume loading, independently of renal function [43,44]. Thus, rescue interventions based upon RIFLE, AKIN, or KDIGO criteria may be insti- tuted far too late to ameliorate intraoperative or early perioperative AKI [45]. Second, urine output criteria are notoriously unreliable in predicting AKI, and there is no effort to differentiate prerenal from intrarenal oliguria or ischemic from nephrotoxic kidney injury [46–48]. AKI may occur in the absence of oliguria [49] and oliguria may be the consequence of extrarenal obstruction [50].
These limitations have spurred the search for biomarkers of early AKI that might timely direct intervention that could alter renal outcomes (Table 2) [51&].
The two biomarkers that have shown to be most promising are human NGAL and cystatin C.
NGAL, also known as lipocalin 2, is secreted by injured distal tubule epithelial cells, and enters the urine via tubular back leak. Preclinical studies ident- ified it to be one of the most upregulated genes and proteins very early after AKI, substantially preceding the increase in SCr. In the past few years, there have been a very large number of investigations of the role of NGAL in the early detection of AKI. Haase- Fielitzet al.[52&&] searched MEDLINE, PubMed, and EMBASE for human biomarker studies that included
Table 2. Selection of biomarkers of acute kidney injury that have been clinically investigated
Biomarker Origin in nephron
NGAL Glomerulus, distal tubule,
collecting duct
Cystatin C Glomerulus, proximal tubule
Interleukin-18 Proximal tubule
KIM-1 Proximal tubule
L-FABP Proximal tubule
NAG Proximal tubule, distal tubule
UrineaGST Proximal tubule
UrineBGST Distal tubule
Netrin-1 Proximal tubule
Hepcidin Proximal tubule
Urinary calprotectin Collecting duct
TIMP-2 Proximal tubule
IGFBP7 Proximal tubule
TLR 3 Proximal tubule
b2-microglobulin Glomerulus
aGST,aglutathione S-transferase; IGFBP7, insulin-like growth factor-binding protein 7; KIM-1, kidney injury molecule-1; L-FABP, liver-type fatty acid binding protein; NAG,N-acetyl-b-D-glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2;
TLR 3, Toll-like receptor 3.
NGAL between 2005 and 2013 in cardiac surgery, critical illness, and kidney transplantation. They identified 58 manuscripts on more than 16 500 patients, including over 7000 patients after cardiac surgery. Measurement of NGAL consistently pre- dicted the incidence and severity of AKI, with an impressive area under the receiver operator charac- teristic curve of 0.82–0.83. However, the authors also pointed out a number of limitations, including a lack of specific cutoff values for NGAL.
There have been a number of recent prospective studies that have primarily focused on NGAL in cardiac surgery. Omerika et al. [53] studied 150 patients undergoing cardiovascular surgery and concluded that urinary NGAL predicted postopera- tive AKI 24–48 hours earlier than elevations in SCr that met RIFLE criteria. In a study of 53 patients with aortic stenosis undergoing aortic valve replacement, Kidheret al.[54] found that plasma NGAL measured as early as 3 hours after CPB was a much stronger predictor of AKI and the need for early medical intervention than SCr.
Cystatin C is a low-molecular-weight protein that is rapidly filtered by the glomerulus. When GFR decreases, serum cystatin C levels increase before elevations in SCr. There are a number of studies that suggest that cystatin C may be a useful early predictor of AKI in cardiac surgery patients [6,46,55,56]. In a prospective cohort study, the Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury–AKI Consortium enrolled 1147 adults undergoing cardiac surgery and found that preoperative cystatin C was superior to SCr and eGFR in predicting the risk of postoperative AKI [6]. A similar conclusion was reached in a multi- center, prospective study of 288 children [57]. In contrast, another prospective cohort study con- ducted on 1150 high-risk adult cardiac surgery patients found that cystatin C levels were less sensi- tive than SCr for detection of AKI, but were able to identify which patients were at substantially higher risk for AKI with adverse outcomes [55].
In a prospective study of 616 patients under- going cardiac surgery, Wang et al. [56] found that the level of preoperative serum cystatin C combined with the severity of dipstick proteinuria were accu- rate predictors of the 179 patients who developed postoperative AKI defined by AKIN Stage 1 criteria.
High preoperative cystatin C levels and heavy pro- teinuria were associated with a high incidence of preoperative CKD, hyperuricemia, heart failure, or recent myocardial infarction, indicative of multi- factorial risk factors for postoperative AKI.
There are a number of other biomarkers that have been investigated but very few are clinically used. Often, biomarkers that show promise in small
single-center trials have not yet been subject to larger prospective trials. For example, Meersch et al.[58] decided to study urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), which are both inducers of cell cycle arrest in the mech- anism of AKI. In 50 patients undergoing high-risk cardiac surgery with CPB, they found that elevated TIMP-2 times IGFBP7, that is, [TIMP-2][IGFBP7], detected AKI within 4 hours of CPB compared with 1–3 days for SCr. A decline in [TIMP-2][IGFBP7] was the strongest predictor of renal recovery.
Billingset al.[59] examined the hypothesis that intravascular hemolysis induced during cardiac surgery releases plasma-free hemoglobin that in turn induces heme oxygenase-1. In patients who developed AKI after cardiac surgery, peak-free hemo- globin levels correlated with peak heme oxygenase-1, and heme oxygenase-1 levels increased with duration of CPB and interleukin activation. This biomarker might help identify the pathogenesis of AKI rather than its early detection.
Most clinical scoring systems designed to pre- dict CAS-AKI use SCr to classify CKD and renal risk [60]. Simoniniet al.[61] found that the inclusion of endogenous ouabain, another newer biomarker, improved the predictive ability of the New England Cardiovascular Disease Study Group score predic- tion.
In sum, of the many biomarkers currently under investigation, NGAL has emerged as the one most likely to become established for the early diagnosis of AKI. Its practicability will depend on the develop- ment of an easy-to-use and inexpensive point-of- care kit that could be used in the operating room or ICU.
Renal oximetry
Perioperative optimization of renal tissue oxygen- ation is of paramount importance, especially in the renal medulla, where, because of sluggish blood flow that facilitates urinary concentration, tissue PO2 is less than 10 mmHg [14]. Renal tissue oxygenation could be maintained by support of intravascular volume, hemoglobin concentration, oxygen satur- ation, cardiac output, and renal perfusion pressure.
Choiet al.[62&] conducted a prospective obser- vational study of regional renal oximetry (rSO2) using near-infrared spectroscopy and attempted to correlate it with CSA-AKI by RIFLE criteria. The device was placed on 100 patients undergoing elec- tive cardiac surgery with CPB, with a renal depth of less than 40 mm from the skin, and simultaneous cerebral oximetry. At the time of initiation of CPB, both cerebral and renal rSO2 declined; however,
rSO2, thereafter, trended back toward the baseline.
On separation from CPB, cerebral oximetry readings quickly returned to baseline, whereas rSO2gradually decreased. Patients who developed CSA-AKI appeared to have increased duration of low rSO2
(<55%). Similar to most initial studies, this study raises more questions than it answers – such as, what intervention should be made in response to a given level of rSO2that would alter renal outcome?
[63].
THERAPEUTIC INTERVENTIONS IN ACUTE KIDNEY INJURY
A number of drug therapies have been studied as potential preventive agents for AKI as has the timing of RRT initiation.
Preoperative statin therapy
There is some evidence that stains might prevent AKI, but most of the studies are on animals, or retrospective and inconclusive. Molnar et al. [64&] evaluated the effects of continuing preoperative statins versus discontinuing them for 24 hours in 625 adult patients undergoing elective cardiac surgery operations. There was no difference in AKI defined by a doubling of SCr or requirement for RRT. However, in patients who continued statins until the time of surgery, a battery of renal bio- markers were significantly decreased, including urine interleukin-18, urine and plasma NGAL, and urine kidney injury molecule-1. These findings are supportive of prospective controlled studies to further define the potential renoprotective role of statins.
Preoperative acetylsalicylic acid and preoperative chronic kidney disease
In prior observational studies, preoperative and early postoperative aspirin therapy in cardiac surgery has been associated with decreased overall morbidity, mortality, and CSA-AKI [65–68]. A recent retrospective cohort study suggests that pre- operative acetylsalicylic acid may have a protective effect against AKI in patients with preoperative CKD [69]. The severity of CKD is calculated by the Modi- fication of Diet in Renal Disease algorithm, which classifies it as Stages 1–5 based upon an eGFR of greater than 90, 60–89, 30–59, 15–29, and less than 15 ml/min/1.73 m2, respectively. The greatest benefit of preoperative acetylsalicylic acid in decreasing the incidence and severity of AKI as well as mortality appeared to be in patients with Stages 4 and 5 CKD (eGFR <30 ml/min/1.73 m2). The
authors postulated that this might reflect the anti- inflammatory and antiplatelet effects of acetylsali- cylic acid, but also recognized that a retrospective study cannot establish direct cause and effect. The putative protective role of acetylsalicylic acid thus awaits definition by prospective studies.
N-Acetylcysteine
NAC has been extensively studied as a protective agent in CIN [70], but because the evidence is con- flicting, it is not routinely recommended as a pre- ventive therapy. Because its putative mechanism of renal protection is via its antioxidant properties [71], NAC has also been studied for the possible prevention of CSA-AKI. However, meta-analyses do not confirm a consistent benefit in decreasing the risk of CSA-AKI or other important clinical out- comes [72,73]. A major challenge in analyzing multiple studies is the variability in NAC dose, route of administration, baseline renal function, and type and dose of contrast medium.
Santana-Santos et al. [74] recently published results of a small, single-center RCT of high-dose NAC (150 mg/kg, then 50 mg/kg infusion over 6 hours) in 70 patients with Stage 3 or 4 CKD under- going CABG surgery with or without CPB. The primary end point was AKI defined by AKIN criteria.
The incidence of AKI by AKIN was 29% in patients who received NAC versus 57% in those who did not, although in more than 80% of patients, the severity of AKI was limited to Stage 1. The authors found that NAC constrained an increase in reactive oxidative species (reflected by thiobarbituric-acid-reactive substance levels) and suggested this as a possible mechanism for its protective effect. There was an important interaction with CPB. The incidence of AKI in patients who had CPB and did not receive NAC was 63%, compared with only 8% in patients who received NAC and had OPCAB surgery. These findings emphasize the multifactorial and interac- tive pathogenesis of CSA-AKI.
Sodium bicarbonate
Similar to NAC, sodium bicarbonate has been investigated as a possible preventive agent in CIN, through a similar mechanism of reduction in tubular oxidative stress [75]. Results of trials have been inconsistent, and urinary alkalinization is currently not recommended for the prevention of CIN [76].
Urinary alkalinization has also been evaluated as a possible protective intervention in cardiac surgery.
Turner et al. [77] recently reported the results of a multicenter RCT of sodium bicarbonate versus 0.9%
isotonic saline in patients at high risk for CSA-AKI.
At the planned interim analysis after 123 patients had been enrolled, there was no difference in CSA- AKI; therefore, the study was stopped on the grounds of futility.
Tian et al. [78] performed a meta-analysis of trials of sodium bicarbonate in cardiac surgery that included five RCTs and one prospective observatio- nal cohort study (a total of 1673 patients). There was no difference in the incidence of CSA-AKI.
Early initiation of renal replacement therapy There has been considerable debate on the most favorable timing of RRT after the onset of AKI.
Nephrologists often balk at early intervention because of lack of evidence of benefit, expense, and the potential for complications of therapy.
These include problems associated with vascular access, rapid fluid and electrolyte shifts, hemody- namic instability, and disequilibrium syndromes related to cerebral edema. On the contrary, delayed RRT subjects patients to the many hazards or uremia such as encephalopathy, aspiration, platelet dys- function and bleeding, impaired wound healing, and resistance to infection. The advent of continu- ous renal replacement therapy (CRRT) has obviated many of these concerns by facilitating the early and practical application of RRT while avoiding hemo- dynamic instability in susceptible patients after cardiac surgery.
Liuet al.[79&] conducted a systematic review and meta-analysis of nine retrospective cohort studies and two RCTs of early versus late initiation of CRRT in critically ill patients with CSA-AKI. Most of these investigations were published between 2002 and 2011, and included a total of 841 patients. Analysis of the overall results suggested that early CRRT was associated with shorter ICU LOS and decreased 28-day mortality. Similar meta-analyses, in general, critical care populations, have also indicated a benefit from early initiation of CRRT [80,81]. How- ever, as the authors caution, almost all studies are retrospective and observational, with inconsistent definitions of ‘early’ and ‘late’ CRRT. A definitive answer to this question awaits the conduct of pro- spective RCTs.
CONCLUSION
Given the complex pathogenesis of CSA-AKI, it is unlikely that its incidence can be significantly reduced by any one intervention. Just as a combi- nation of factors working in concert leads to this clinical syndrome, prevention and treatment of CSA-AKI requires a multimodal approach where
both the premorbid condition of the patient and the particular idiosyncrasies of the cardiac surgical procedure itself are taken into account. Timely intervention requires early recognition of potential and actual kidney injury. The research published in the last 18 months reflects the numerous appro- aches being taken to address CSA-AKI. Although there have been few practice-changing articles pub- lished during the period covered by this review, the research that has been cited here is, for the most part, of relatively high quality. It is by studying indicators and interventions in differing settings in differing populations that we can come to a better understanding of their real merit through inclusion in systematic reviews and meta-analyses. The research cited here adds further depth to our under- standing of CSA-AKI and builds upon an enormous fund of existing knowledge.
Acknowledgements None.
Financial support and sponsorship None.
Conflicts of interest None.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
& of special interest
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