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Objectives

  • To describe definition and epidemiology of AKI

  • To understand risk factors for AKI and prediction scores

  • To discuss prevention and management of AKI

Introduction

Cardiac surgery-associated acute kidney injury (CSA-AKI) has been recognized as a frequent adverse event following cardiac surgery [1–4]. CSA-AKI has nearly doubled over the past decade [5] and strongly associated with increased morbidity, mortality, and length of hospitalization [1–4, 6]. When AKI occurs in the hospital, the approximate additional costs in health-care expenditures amount to $7,500 [7], making AKI a costly complication and an important target for prevention.

AKI Epidemiology

AKI is thought to develop as a result of extended cardiopulmonary bypass pump times with paralleled hypoperfusion and reduced oxygen saturation delivery to critical organs including the brain and kidneys.

Common definitions for diagnosing AKI in cardiac surgery have included: the Society for Thoracic Surgeons (STS); the Acute Dialysis Quality Initiative Workgroup for risk, injury, failure, loss, and end-stage kidney disease (RIFLE) criteria [8]; and the Acute Kidney Injury Network (AKIN) [9] definition (Table 7.1). In addition, the duration of AKI using the AKIN definition has also been evaluated as a more sensitive and specific measure of AKI severity after general surgery [

Table 7.1 Incidence of AKI following cardiovascular surgery across AKI definitions
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10] and cardiac surgery [2].

In cardiac surgery, even small changes in serum creatinine have been associated with poor survivorship [1] and progression of chronic kidney disease and end-stage renal disease [11]. AKI after cardiac surgery has been associated with more rapid progression to incident chronic kidney disease (CKD), progressive CKD, and renal failure (dialysis or kidney transplant) [11]. This evidence suggests that there is a direct correlation between the degree of acute injury to the kidneys during the perioperative period and long-term progression of worsening renal function.

Others have confirmed this phenomenon in other patient populations demonstrating the increase risk of progression to end-stage renal disease (ESRD) and mortality [12–14]. Therefore, patients developing perioperative AKI are at risk for progressing towards worsening renal function and should be monitored following the perioperative period to prevent unnoticed rapid progression to renal failure.

The Northern New England Cardiovascular Disease Study Group (NNECDSG, www.nnecdsg.org) has reported on the poor survivorship-associated perioperative changes in serum creatinine [1] and longer durations of AKI [15]. The early findings demonstrated that subtle changes in serum creatinine were directly proportional to increased 90-day mortality [1]. The association between AKIN stages of AKI and survival is consistent with the earlier reports of changes in serum creatinine (Fig. 7.1). More recently, NNECDSG AKI researchers and Translational Research Investigating Biomarker End-Points in Acute Kidney Injury (TRIBE-AKI) investigators jointly evaluated the role of the duration of AKI as a marker for AKI severity and demonstrated the proportionality associated with longer durations of AKI and worse survival (Fig. 7.2). Over 18 % of patients developed AKI for 1–2 days, 11 % for 3–6 days, and 9 % for 7 or more days. AKI duration categories were directly proportional to in-hospital dialysis rates (0.2, 0.5, and 7.2 %) as well as 5-year mortality (13.7, 17.5, and 36.9 %, respectively). These figures demonstrate the severe consequences patients face with the development of AKI and moderate or severe AKI.

Fig. 7.1
figure 1

Kaplan-Meier survival graph for cardiac surgery patients by Acute Kidney Injury Network (AKIN) stages: no AKI (blue), AKIN stage 1 (red), AKIN stage 2 (green), and AKIN stage 3 or renal failure (yellow) (Reprinted by permission of Oxford University Press from Brown and Parikh [68])

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Fig. 7.2
figure 2

Kaplan-Meier survival graphs by duration of acute kidney injury after cardiac surgery: no AKI, AKI lasting 1–2 days, AKI lasting 3–6 days, and AKI lasting 7 or more days (Reprinted from Brown et al. [2], copyright 2010, with permission from Elsevier)

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Etiology Risk Factors and Prediction of AKI

AKI is postulated to result from various patient and procedural factors. Patient factors include many of the risk factors used the prediction modeling described previously (age, gender, baseline renal function, heart failure, and diabetes). Preoperative anemia (hemoglobin <14) has also been shown to have an inverse relationship with AKI, whereby each successive drop in hemoglobin under 14 (g/dL) increases the risk of postoperative AKI by 23 % for hemoglobin between 12 and 13.9 (g/dL), by 63 % for hemoglobin 10–11.9 (g/dL), and by 99 % for hemoglobin <10 (g/dL) [16].

Before the patient arrives to the operating room for cardiac surgery, it is most likely the patient has had a recent angiography, or cardiac catheterization. These procedures usually use small amounts of low-osmolar or iso-osmolar contrast; however, sometimes an ad hoc angioplasty (percutaneous coronary intervention, PCI) is performed and stents implanted in the coronary arteries to reestablish or sustain blood flow. During a PCI, larger, and potentially dangerous, volumes of contrast dye are injected to visualize the coronary arteries for the deployment of the devices and stents. It is during this time that patients are likely to develop contrast-induced AKI resulting from acute tubular necrosis and oxidative stress. It has been shown that there is a direct relationship between the dose of contrast and AKI [17, 18]. Others have demonstrated there is direct relationship between the timing of the cardiac catheterization and cardiac surgery, whereby the risk of AKI is higher among patients undergoing cardiac surgery within 24 h of a cardiac catheterization [19–22] with direct ties to the amount of contrast used [19, 20]. In addition, others have reported if the cardiac catheterization was conducted during the same admission as cardiac surgery (including in-patient transfers), the risk of AKI is increased by 54 % [23].

There are several operative factors that should be considered. Cardiopulmonary bypass (pump time) contributes to the development of AKI [1, 16]. Off-pump cardiac surgery has been shown to reduce the incidence of AKI [24, 25]; however, caution should be taken to only incorporate off-pump cardiac surgery as a protective measure against AKI among proficient off-pump surgeons, and the risk-benefit should be weighed against the risk of incomplete revascularization and bleeding [26]. During cardiopulmonary bypass, gaseous or particulate emboli, renal ischemia from hypoperfusion of the kidneys, and myoglobinuria and free hemoglobinuria are proposed causes of AKI [27]. It is thought that the cardiopulmonary bypass pump may result in an imbalance in O2 supply due to low hematocrit and the need for O2 by the kidneys. When the O2 is <260 mL/min/m2, it can increase lactate levels and increase the risk of AKI. O2 delivery can be optimized by coupling the pump flow with the hematocrit [28–30]. To counteract these causes, cardiac surgeons and perfusionists have worked together to improve cardiopulmonary bypass management through temperature and blood pressure management and development of mechanisms and filtering devices to reduce gaseous micro-emboli and optimize O2 delivery through improving the flow rate, hemoglobin levels, and hemodilution [27].

The number of perioperative packed red blood cell (pRBCs) has a direct linear dose-response to the risk of developing AKI. Stored red blood cells have been shown to deteriorate after being frozen and stored for weeks at a lime. It has been demonstrated that these red blood cells develop specula and lose the biconcave disc shape causing inflexibility to travel through the capillaries and result in capillary damage and reduced microcirculation [31]. Others have shown that patients receiving newer blood (pRBC stored for ≤14 days) had significantly better survival and a lower incidence of renal failure than patients receiving pRBC transfusions that was stored for more than 14 days [32]. A similar effect was reported in pediatric cardiac surgery for AKI whereby AKI was reduced by 4.4 % [30].

In Table 7.2, we summarize the various etiologies of factors contributing to cardiac surgery-associated AKI in adults including patient factors, medication, in-hospital and prior procedural risks, as well as cardiac surgery procedural risk factors [1, 2, 28, 33–40].

Table 7.2 Factors of cardiac surgery-associated with acute kidney injury
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Identifying risk factors for AKI and establishing prediction models are necessary to risk-stratify patients before, during, and immediately after cardiac surgery. However, most of the prediction modeling efforts have investigated the ability of patient and procedural risk factors to predict the occurrence of renal failure [41–44]. These models have also performed well for predicting severe AKI using the STS definitional of acute renal failure, defined as a 2.0 mg/dL or twofold increase in serum creatinine or new dialysis [42–45]. Yet, other investigators have developed models in predicting immediate postoperative declines in creatinine clearance (CrCl) or estimate glomerular filtration rate (eGFR) [34, 46, 47]. One example is the NNECDSG’s approach to predict at least a 30 mL/min/m2 drop in eGFR among patients with normal or near-normal renal function (eGFR ≥60) [34]. Recent investigations have incorporated additional perioperative risk factors from the procedure and complications from the procedure as an attempt to improve the prediction of AKI and duration of AKI. There are various risk factors utilized in the prediction modeling for renal failure and AKI. Major similarities among the models include: age, gender, baseline renal function, heart failure, diabetes, use of intra-aortic balloon pump, and duration on cardiopulmonary bypass (Table 7.3) [48]. Other models to predict renal replacement therapy after cardiac surgery include the Cleveland Clinic score [43], Mehta score [42], and Simplified Renal Index score [44] with external validation [45, 49].

Table 7.3 Variables included in the models
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Another approach to predicting the severity of AKI focused on predicting the length of time, or duration, of the acute injury. The duration of AKI was modeled to predict the average projected number of days a patient may sustain AKI and is published as an online risk calculator (http://medicine.yale.edu/intmed/patr/resources/akicalc.aspx). This can be a useful way to determine a patient’s risk and length, or duration, or AKI after cardiac surgery. If the duration is projected to be longer than 3 days, a nephrology consult on admission to the ICU may be helpful in preventing the onset of AKI and minimize the duration.

Novel biomarkers have the ability to improve our prediction of AKI events and provide earlier detection. Several biomarkers have been rigorously investigated including plasma cystatin C, urinary neutrophil gelatinase-associated lipocalin (NGAL), urinary interleukin 18 (IL-18), N-acetyl-B-(D)-glucosaminidase (NAG), alpha-1 microglobulin, albuminuria, and urinary kidney injury molecule 1 (KIM-1) [50–53]. The TRIBE-AKI Consortium released evidence that supports the use of serum creatinine and cystatin C in determining risk of AKI prior to cardiac surgery; this was found to be true among all patients and more so for predicting severe AKI [53]. In cardiac surgery, TRIBE also demonstrated the clinical utility of postoperative kidney biomarkers, including plasma NGAL and urinary IL-18 and NGAL. They reported that urinary IL-18 had superior prediction for AKI over plasma or urinary NGAL [51]. A small study of 103 subjects by Liangos and colleagues reported that KIM-1, NAG, NGAL, and IL-18 significantly predicted AKI at 2 h after cardiopulmonary bypass; however, after adjustment for the preoperative Cleveland Clinic Foundation score for acute renal failure and/or cardiopulmonary bypass time, only KIM-1 remained statistically significant [50]. Albuminuria is a predictive marker for the development of AKI [54–58]. An increase in the ratio between urinary albumin and creatinine has been demonstrated to improve preoperative risk prediction of AKI suggesting the addition of albuminuria to preoperative risk assessment for AKI [57, 59]. KIM-1 and other markers such as L-type fatty acid-binding protein and alpha-1 microglobulin need further large-scale clinical trial investigations.

Prevention and Management of AKI

A systematic review summarized the interventions to prevent AKI that have been evaluated with mixed efficacy in cardiac surgery. Interventions have included antiinflammatory (N-acetylcysteine, glutathione, fenoldopam, aspirin, dexamethasone, methylprednisolone, and leukodepletion), natriuretics/diuretics (nesiritide, A-type natriuretic peptide [ANP], furosemide, urodilatin, and mannitol), vasodilators (prostaglandin E1 [PGE1], diltiazem, dopexamine, dopamine [DA], mannitol, fenoldopam, angiotensin-converting enzyme (ACE) inhibitor, sodium nitroprusside, theophylline, and prostacyclin), operative techniques (mostly off pump), prophylactic continuous venovenous hemodiafiltration or renal replacement therapy, and other strategies (albumin, insulin, clonidine, and volume expansion) [25]. Park and colleagues concluded that most of the prophylactic strategies conducted prior to cardiac surgery were protective against AKI; these included ANP/nesiritide, fenoldopam, and dopamine [25].

Ischemic preconditioning prior to cardiac surgery may be an alternative prophylactic method to reduce AKI. By preconditioning a remote site in the body (arm or leg) to reduced blood flow, reperfusion injury and AKI may be prevented [60, 61]. Zimmerman and colleagues demonstrated in a small single-center randomized trial that ischemic preconditioning resulting in an absolute risk reduction of 0.27 (12 versus 28 AKI events, p = 0.004) and resulted in lower rates of sustained AKI at 2 or more days [61]. It is likely that simple ischemic preconditioning methods could be incorporated at the time of entry to the operating room (OR) and may not only assist in AKI event reduction but also reduce myocardial reperfusion injury.

We have summarized the clinical research that has sought to mitigate AKI in the context of cardiac surgery. Some of these interventions have demonstrated consistency in prevention, while others either need more investigation or the development of new strategies. Most of these efforts have focused around modifying or discontinuing potentially nephrotoxic medication or exposure to nephrotoxins, such as radiocontrast dye. McCoy and colleagues reported on the single-center use of a computerized medication safety tool designed for patients developing AKI. Through the use of this automated intervention tool, 52.6 % of the time potentially nephrotoxic medications were halted or modified within 24 h of an acute increase in serum creatinine qualifying as AKI, a 49 % improvement prior to the intervention [62]. Additional simple and sophisticated process tools should be developed by multidisciplinary teams to study the problem of AKI. When doing so, teams should identify targets for intervention, test those interventions, evaluate their effectiveness, and redesign continually. Such microsystem-level improvement efforts are known as PDSA cycles of change (Plan-Do-Study-Act) [63, 64].

Conclusions

In this chapter, we have discussed the mortality, subsequent health-care costs, utilization, and morbidity that follow subtle changes in serum creatinine known as AKI in the perioperative setting of cardiac surgery. The field has come a long way from 10 years ago where subtle changes in serum creatinine were often ignored to the current volume of research and dedication that has identified and sought solutions for the patient safety issues surrounding cardiac surgery-associated AKI. We provide an algorithm to aid clinical care teams to identify pre- and perioperative modifiable risk factors to minimize the aid in the prevention of cardiac surgery-associated AKI and recommendations for early AKI recognition and follow-up (Fig. 7.3). Majority of the recommendations are based on epidemiologic observations or quality control protocols and require confirmation in interventional trials. In the near future, novel kidney injury biomarkers and risk tools will be available to identify early signs of AKI and acute tubular necrosis and hopefully matched with aggressive tools for medication adjustment and injury-specific interventions to mitigate AKI and its subsequent morbidity and mortality.

Fig. 7.3
figure 3

AKI risk assessment algorithm

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Key Messages

  • AKI is a common adverse event following adult cardiac surgery ranging from 3 to 42 % depending on the definition used.

  • Patients developing AKI are at an increased risk of in-hospital mortality, and those who are discharged face poor long-term survival and risk of end-stage renal failure.

  • Prediction models for both onset and duration of AKI can assist clinical teams in therapeutic and prognostic information.

  • Several modifiable strategies may be effective in preventing the risk of AKI following cardiac surgery.