Terms such as acute renal failure, acute kidney disease, acute kidney syndrome, or AKI have been used in the past to describe kidney dysfunction arising from acute conditions. AKI diagnosis and research was plagued by dozens of different and inconsistent definitions. Ultimately, in 2004, the Acute Dialysis Quality Initiative released the RIFLE criteria, which replaced the term “acute renal failure” and introduced the term “AKI” to indicate the reversibility of the acute condition.17 Subsequently, the RIFLE criteria rapidly gained wide acceptance to define AKI. They were based on changes in serum creatinine (sCr) from baseline or urine output. The diagnostic system differentiates 3 severity grades (risk, injury, failure) and 2 outcome classes (loss, end-stage renal disease) (Table 1). At the time of its introduction, the concept of AKI was attractive because it included patients without actual structural kidney damage but with functional impairment. This group of patients may benefit significantly from early therapeutic interventions. Despite strengths of the RIFLE classification, the obvious discrepancy between increases in sCr concentration and decreases in estimated glomerular filtration rate (GFR) remained problematic.18 In 2007, the AKIN suggested a modification of the RIFLE criteria, in an attempt to improve their sensitivity.15 The bar for diagnosing AKI was significantly lowered (for details see Table 1). In 2012, the Acute Kidney Injury Working Group of KDIGO released the latest classification system with the aim of unifying the RIFLE and AKIN criteria.19Figure 1 displays the current AKI diagnosing criteria.
INCIDENCE AND EPIDEMIOLOGY
Until recently, the lack of a standard definition for AKI resulted in large variations in reported incidence and mortality. Therefore, the review focuses on data published after release of the RIFLE criteria in 2004. In the United States, the overall incidence of AKI is estimated at 2147 cases per million population per year.20 This translates to approximately 600,000 AKI patients annually. It can be assumed that 10% to 20% of these patients progress to late-stage CKD, resulting in up to 120,000 cases of CKD in addition to the population at risk for end-stage renal failure.21 The incidence of AKI in hospitalized patients increased continuously from 4.9% in 198322 to 7.2% in 200223 and to 20% in 2012.24 A recent analysis of 19,249 acute care hospitalizations reported an AKI incidence of 22.7% over a 1-year period.24 In critically ill patients, AKI is even more common, and could affect up to 60%.13 A systematic review identified 24 studies including over 71,000 patients in which the RIFLE classification was used to define AKI.25 The overall mortality rate was 18.9% in the “risk” class, 36.1% in the “injury” class, and 46% in the “failure” class compared with 6.9% mortality in patients not suffering from AKI.
Approximately 30%–40% of all cases of AKI cases occur after surgery. The incidence of AKI in surgical patients ranges from 18% to 47%.26–28 Some surgical patient populations deserve special consideration because they are exposed to distinct risk factors inherent to the type of surgery. AKI is most common among cardiac surgery patients, in whom cardiopulmonary bypass (CPB) is used. These patients face a unique combination of renal stressors. Rates of AKI for elective patients are in the range of 15%, with 2% requiring RRT.29 But also in noncardiac surgery, AKI occurred in approximately 1% of those patients with preoperative normal kidney function.30 Certain noncardiac surgery procedures pose a particular high risk:
- gastric bypass surgery for morbid obesity is associated with an 8.5% incidence of AKI31;
- one-third of the patients receiving liver transplant experience postoperative AKI, with 17% requiring RRT32;
- patients with preexisting CKD showed a significantly increased AKI risk than the average 1%.
Patients who develop AKI during the course of surgery demonstrate an 8-fold increased risk for the progression to CKD.21
The development of perioperative AKI is not caused by 1 single factor but is precipitated by a variety of insults. Hypoperfusion and inflammation are the major mechanisms affecting renal function.
Hypovolemia frequently develops in the perioperative period and may reduce the mean arterial pressure (MAP), resulting in renal hypoperfusion. Initially, the kidneys are able to maintain the GFR through activation of the sympathetic nervous system, which includes the excretion of antidiuretic hormone and angiotensin-II. Persistent hypoperfusion precipitates a decrease in GFR secondary to vasoconstriction of both afferent and efferent arterioles. This compensatory effect depends on the autoregulatory capabilities of the kidneys and is reduced in patients with chronic renal impairment.33 Systemic inflammation, a uniform response of the organism to the trauma of surgery, leads to tubular injury causing AKI.34 Tubular damage is caused by microcirculatory dysfunction, better leukocyte migration, and endothelial dysfunction.35
Irrespective of the acute effects of hypoperfusion and inflammation, the patient’s preoperative clinical condition, intraoperative risk factors, and perioperative conditions impact on renal function.
Risk Factors for the Development of AKI
A number of risk factors predispose for AKI. However, patient-related factors are more strongly associated with mortality than the type of surgery (Table 2).
Preoperative Risk Factors.
The ageing society combined with the growing number of comorbidities displays a tremendous burden. Comorbidities (eg, CKD, diabetes mellitus, chronic obstructive pulmonary disease, and cardiovascular disease) are strongly associated with the development of AKI.36–38 The most important patient-related factor is the preoperative level of kidney function. In cardiac surgery, rates of AKI requiring RRT approach 30% in patients with preexisting CKD.36 Older obese female patients are particularly susceptible to developing AKI.39,40 A recent study demonstrated a strong statistical association between body mass index (BMI) and perioperative AKI after cardiac surgery.41 The odds of AKI increased by 26.5% per 5 kg/m2 BMI. The authors claimed that BMI influenced AKI in part by oxidative stress. It is important to take into account that drugs with nephrotoxicity such as angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, aminoglycosides, and nonsteroidal antiinflammatory drugs increase the development of AKI.
Intraoperative Risk Factors.
Cardiac surgery facilitated by CPB has the highest risk followed by general, thoracic, orthopedic, vascular, and urological surgery.42 Patients with sepsis who undergo surgery or those requiring emergency procedures have higher rates of postoperative AKI when compared with elective procedures.37
CPB and aortic cross clamping, ischemia reperfusion injury, low cardiac output, prolonged periods of hypotension, use of vasopressors, and inotropic support are associated with the development of AKI. CPB is associated with systemic inflammatory response, coagulopathy, and embolism. The perioperative risk of AKI increases with longer duration of CPB. Avoiding CPB by off-pump techniques may reduce AKI and long-term renal outcomes.43–46 A recent meta-analysis of 27,806 patients from 22 observational and randomized trials of patients undergoing on-pump versus off-pump cardiac surgical procedures47 observed a 43% risk reduction for AKI associated with off-pump surgery (odds ratio: 0.57, 95% confidence interval [CI], 0.43–0.76), suggesting off-pump coronary artery bypass as a viable alternative for high-risk patients. Prospective studies are warranted to arrive at definitive conclusions. The most important strategy in cardiac surgical patients is the use of risk-predicting models36,39,48 to detect high-risk patients preemptively to allow timely initiation of preventive strategies.
In vascular surgery, factors that prolong the duration of renal ischemia and intraoperative hypotension are key determinants of postoperative AKI. Newer techniques, such as endovascular aneurysm repair, may be superior to conventional approaches preventing AKI development.49 In abdominal surgery, 1 major problem is intraabdominal hypertension. While the transient increase of intraabdominal pressure during laparoscopic surgery with a reduction of urinary output is not predictive for postoperative AKI,50,51 longer periods of elevated intraabdominal pressure resulting from fluid overload with diffuse edema of the intestinal wall frequently cause an abdominal compartment syndrome. The related compression of the renal vasculature induces renal ischemia and the development of AKI.52,53
Prolonged episodes of hypotension decrease renal perfusion and result in AKI in patients with impaired autoregulation.54 A MAP in the range of 60–75 mm Hg was accompanied by improved oxygen saturation and GFR and prevented AKI.55 Moreover, the duration of hypotensive episodes should thus be kept as short as possible.56 To this date, it is not known which vasopressor is most effective in the prevention of AKI. Guidelines recommend to use primarily norepinephrine for restoration of MAP. In an experimental model, it has been demonstrated that norepinephrine effectively increases global and medullary pressure resulting in higher diuresis.57 However, an optimal perfusion pressure for individual patients cannot be specified because the autoregulatory range of renal perfusion is dependent on underlying diseases and premorbid conditions.
Nephrotoxic agents such as antihypertensive drugs (angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers), antibiotics (eg, aminoglycosides), nonsteroidal antiinflammatory drugs, or loop diuretics are well known to induce AKI. Additionally, a significant number of patients are exposed to contrast agents, promoting the development of contrast-induced AKI. The development of contrast-induced AKI depends on factors such as type and dose of contrast agent, underlying CKD, age, or hydration status.58,59
Significant anemia lowers oxygen supply to tissues as a consequence of the reduced oxygen-carrying capacity of the blood. Subsequent renal hypoxia is a contributing factor in the development of AKI. Studies revealed that preoperative anemia with hemoglobin levels <8 mg/dL is associated with an up to 4-fold increased risk of AKI.60,61 Similarly the transfusion of packed red blood cells correlates with AKI,62–64 giving rise to serious concerns about how to manage anemia.
Emerging Role of Damage Markers
SCr and urine output are functional biomarkers changing late during the development of AKI. However, both markers are constrained by limitations. SCr changes only become evident after 50% of the total renal mass is compromised, resulting in late GFR declines. Transient changes will never become evident although damage has occurred. Urine output does not allow an early detection of renal dysfunction, although recent literature shows a significant association of low urine output and adverse outcomes in adults65 and pediatric patients.66 Therefore, current research activities aim to identify new biomarkers, which are released before sCr increases and/or urinary output declines (Figure 2).67–69 Meanwhile, studies have shown that new biomarkers can detect subclinical AKI in the presence of early tubular damage but before the emergence of filtration dysfunction.67,68
The production and release of possible biomarkers of early tubular stress is triggered by surgical trauma, CPB, or other noxious events. Different biomarkers relate to different aspects of kidney function and different mechanisms of injury. They might help to detect AKI earlier in its course, identify the underlying etiology, and even tailor-specific therapeutic interventions. Several issues have to be addressed before these biomarkers can be introduced into daily clinical routine. The most important ones are the lack of sensitivity that is related to the etiological heterogeneity of AKI, and the lack of specificity that seems related to extrarenal causes for fluctuations in serum or urine concentrations of the biomarkers.70 Renal biomarker performance was most promising when well-defined kidney injury, such as exposure to radiocontrast agents or after particular operations, was examined.71 In more heterogeneous populations with variable onset of kidney injury biomarkers perform less well. Recently, Mårtensson and Bellomo72 called for the use of biomarker panels instead of single molecules in addition to clinical risk models to augment the robustness of predicting postoperative AKI.
Neutrophil-gelatinase–associated lipocalin (NGAL), tissue inhibitor of metalloproteinases-2 (TIMP-2), and insulin-like growth factor binding protein 7 (IGFBP7) are promising73 and have been introduced into clinical medicine. NGAL is almost undetectable in the urine of healthy individuals. After ischemic or nephrotoxic insults, a significant increase in plasma and urine occurs, prompting the notion that NGAL is the “troponin” of the kidneys.74 However, the etiology of AKI is multifactorial and not limited to ischemia. Studies investigating the predictive performance of NGAL are controversial, with some judging the performance as near ideal while others considered it useless.75,76 Explanations for the divergent results are poor performance of the gold standard sCr and urine output as well as the timing of biomarker assessment and preexisting comorbidities, because NGAL can predict AKI only in patients with prior normal kidney function.77 Furthermore, a variety of NGAL isoforms are released from different tissues78 and current point of care tests are not able to distinguish between these. Therefore, the clinical utility of NGAL has been challenged.
Cell cycle arrest of renal tubular epithelial cells is involved in the pathogenesis of AKI,79 suggesting that cell cycle arrest–related proteins could aid early AKI detection (Figure 3). The cell cycle consists of 2 phases. The interphase—which is mainly the preparatory phase for DNA synthesis—consists of the gap-1 (G1), synthesis (S), and gap-2 (G2) phase. During the mitotic (M) phase the cell divides. In case of tubular stress, renal tubular epithelial cells arrest in G1 phase to avoid DNA damage during division of cells.80 TIMP-2 and IGFBP7 are released during G1 arrest and are detectable very early during development of AKI.71,73 It appears that TIMP-2 and IGFBP7 predict mortality, renal recovery, and severity of AKI.81
In analogy to the “angina pectoris” concept for myocardial ischemia, the “renal angina” concept was introduced in 2010 to identify patients at high risk for AKI. In contrast to acute coronary syndromes, AKI does not show any visceral symptoms. Therefore, the “renal angina” concept combines comorbidities with clinical conditions and biomarkers. According to this concept, the measurement of damage biomarkers in patients with certain comorbidities and clinical conditions considerably improves the negative predictive value of these markers.82 The combination of TIMP-2*IGFBP7 has recently been recommended for the diagnosis of AKI in an appropriate patient population (intensive care unit patients, age ≥21 years with 1 further risk factor for AKI, after cardiac bypass or other major high-risk surgery or with sepsis).83 Based on current evidence it is important to note that the measurement of biomarkers should be restricted to patients at high risk for the development of AKI, but may not be useful in patients with already established AKI. In these patients, furosemide stress test might be more meaningful.84
OPTIONS TO PREVENT AKI
Despite some progress, the search for strategies to prevent the development of AKI remains in the introductory stage.
Development of successful pharmacological interventions to prevent and manage AKI has been limited. Table 3 provides an overview of the different types and classes of pharmacological agents that have been studied extensively.
Dexmedetomidine, a highly selective α-2 agonist, has been introduced into perioperative practice due to its sedative, analgesic, and anxiolytic effects. Other beneficial effects such as reduced norepinephrine release, improved hemodynamic stability, and balancing of the myocardial oxygen supply/demand ratio could be demonstrated, prompting the presumption of beneficial effects on renal function. Animal studies demonstrated cytoprotection during renal ischemia and inhibition of hypoxemia-induced apoptosis of proximal tubular cells.85 The renoprotective properties of dexmedetomidine were confirmed in recent clinical trials in cardiac surgery, demonstrating a significant reduction of AKI in patients with preoperative normal or mild impairment of kidney function.86–88 In a randomized placebo-controlled trial in 200 patients undergoing valvular heart surgery, the incidence of AKI and a composite of major morbidity end points during the first 48 postoperative hours89 were significantly improved when dexmedetomidine was compared with placebo (14% vs 33%; odds ratio [OR], 0.33; 95% CI, 0.164–0.667; P= .002). The authors concluded that preemptive dexmedetomidine infusion provides sympatholysis, which might be beneficial for preventing AKI. Another trial demonstrated a dose-dependent effect of dexmedetomidine with the lowest increase in NGAL in the group treated with the higher dexmedetomidine dose, suggesting a beneficial effect on structural AKI.90 Use of dexmedetomidine to prevent AKI appears promising, but data remain insufficient to make a clear recommendation.
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are used to primarily reduce cholesterol levels in the prevention of cardiovascular diseases and may reduce the incidence of AKI due to their pleiotropic effects. However, recently published data did not support this hypothesis.91,92 Billings et al92 randomized 615 patients undergoing cardiac surgery to receive atorvastatin or placebo before, during, and after surgery. Among all participants, AKI occurred in 20.8% in the atorvastatin group versus 19.5% in the placebo group (relative risk, 1.06 [95% CI, 0.78–1.46]; P = .75). The study was stopped for futility but the pretreatment of 416 patients with statin may have influenced the outcome. A recent population-based study examined over 200,000 major surgical procedures, and arrived at different conclusions.93 AKI was found in 1.9% of the patients and 0.5% required RRT during the first 14 postoperative days. The 30-day mortality rate was 2.8%. Statin use was associated with a 16% lower odds of postoperative AKI (OR, 0.84), 17% lower odds of RRT (OR, 0.83), and 21% lower odds of mortality (OR, 0.79). The results showed, according to the authors, beneficial effects of perioperative statin use on important renal complications after major surgery. A general recommendation regarding statin use for AKI cannot be made or refuted, because evidence from prospective trials is lacking.16
Sodium bicarbonate was thought to have protective effects on the kidneys through urinary alkalization.94 However, large randomized controlled trials demonstrated no beneficial effects of sodium bicarbonate.95,96
Taken together, apart from dexmedetomidine to date no pharmacologic treatment that has been tested in clinical trials holds promise for the prevention of AKI in perioperative patients.
The KDIGO guidelines propose a bundle of preventive strategies for patients at high risk for the development of AKI. This bundle includes discontinuation and avoidance of nephrotoxic agents, alternatives to radio contrast agents, maintenance of volume status and perfusion pressure, maintenance of normoglycemia, monitoring of sCr and urine output, and functional hemodynamic monitoring.97 Until now it has not been unequivocally proven that implementing the KDIGO bundle improves renal outcomes, but initial evidence has recently been presented. A single-center, randomized controlled clinical trial (PrevAKI) demonstrated that biomarker-guided implementation of the KDIGO guidelines as compared with standard care significantly reduced the occurrence of AKI in cardiac surgery patients (absolute risk reduction, 16.6% [95 CI, 5.5%–27.9%]; P= .004; intervention described in Figure 4).98
As previously mentioned, the application of nephrotoxic agents is associated with AKI. Surgical patients are frequently exposed to contrast agents or antiinflammatory drugs. Avoidance of these agents prevents AKI.
To prevent arterial hypotension and related drops in renal blood flow, intravascular volume status has to be optimized. The choice of intravenous fluids plays an important role in the development of AKI. Frequently, isotonic saline 0.9% is regarded as first-line treatment. However, it contains unphysiologically high amounts of chloride, causing hyperchloremic acidosis and renal vasoconstriction, resulting in a reduced GFR99 and a higher incidence of AKI.100 A chloride restrictive infusion regimen is therefore associated with a significantly reduced incidence of moderate and severe AKI.101 Thus, balanced crystalloid solutions with electrolyte compositions compared with plasma should be preferred for volume resuscitation.
Arterial hypotension is a frequent result of hypovolemia, but also occurs in association with multiple other etiologies. AKI is associated with intraoperative hypotension in a graded fashion.56,102 A large retrospective cohort study of 5127 patients undergoing noncardiac surgery observed AKI when MAP during surgery was <60 mm Hg for more than 20 minutes and <55 mm Hg for more than 10 minutes (adjusted OR, 2.34 [95% CI, 1.35–4.05]).56
Tight glycemic control has been shown to significantly reduce AKI in critically ill patients.103 Subsequently, it has been ruled out in cardiac surgery patients that tight glycemic control is superior to continuous perioperative insulin therapy in terms of AKI incidence and mortality. This has been underlined by several well-conducted clinical trials.104,105
Remote Ischemic Preconditioning
Ischemic preconditioning was first described in animals with myocardial infarction in 1986.106 Subsequently, it could be demonstrated that protective effects of brief periods of ischemia were not locally limited to the organ or tissue receiving the preconditioning stimulus, but were also detectable in remote tissues.107–109 This phenomenon has been termed remote ischemic preconditioning (RIPC). RIPC is an effective and uncomplicated maneuver to trigger the endogenous protection against hypoxic injuries. It consists of transient episodes of sublethal ischemia, followed by reperfusion. The RIPC stimulus is applied to a remote tissue before the subsequent and definitive ischemic injury to the target organ occurs.
Ischemia reperfusion injury is a significant clinical problem, and the kidney is particularly susceptible to it because of its high metabolic rate and complex vascular anatomy.110 Twenty minutes of ischemia have been shown to cause irreversible kidney damage. To protect the kidney against an ischemia reperfusion injury, a RIPC stimulus is applied to a distant organ. Use of the upper limbs as remote tissue is the established method, as skeletal muscle is less susceptible to ischemia reperfusion injury compared with the kidney. Typically, a blood pressure cuff around the upper arm is inflated to a pressure of 30 mm Hg above the systolic blood pressure for a period of 5 minutes. Thereafter the pressure is released for 5 minutes. The inflation/deflation cycle is repeated 3 times. The underlying molecular mechanisms of RIPC are not fully understood, but the definitive protective step in RIPC signaling is the inhibition of opening of the mitochondrial permeability transition pore, which prevents cell death.110
Several clinical trials have been performed to investigate the effects of RIPC on kidney function especially in patients after cardiac surgery. Beneficial effects of RIPC on the occurrence of AKI in the postoperative period could be demonstrated in some randomized controlled trials111,112 whereas others showed no effect.113,114 The results of the trials are hard to compare due to the heterogeneity of the patient population and the use of different end points. However, in this context, it is important to mention that certain anesthetics such as propofol reverse the protective mechanisms of RIPC.115 The use of propofol might be 1 possible explanation for the different study outcomes. In the face of contradictory study results, the fact that RIPC is easy to apply, does not impose additional costs, and is not associated with complications tips the balance in favor of RIPC,114 and RIPC should be considered as part of the preventive management plan for high-risk patients.
Renal Replacement Therapy
In severe AKI, RRT is the only therapeutic option. RRT modalities include intermittent hemodialysis, as well as continuous and intermittent hemofiltration and hemodiafiltration. The ideal mode of RRT, timing of initiation, and duration remain open to investigation. The KDIGO guidelines recommend initiation of RRT when life-threatening fluid accumulation or significant imbalances (eg, acidosis, various electrolyte abnormalities, and uremic pericardial effusion) occur.97 However, most patients develop severe AKI without life-threatening complications and the initiation of RRT primarily remains at the discretion of the intensivist. Starting RRT late during the course of AKI while awaiting life-threatening complications implies the possibility that at that time AKI is already irreversible. On the other hand, early institution of RRT imposes the additional risks and complications of an invasive therapeutic procedure, without being sure that there is sufficient therapeutic benefit.
In the past, several studies have addressed this issue but have not arrived at definitive conclusions, because of different definitions of “early” or “late” initiation of RRT.116 Recently, 2 randomized controlled trials defining AKI via KDIGO criteria have been published.117,118 The Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with AKI (ELAIN) trial compared a (biomarker supported) strategy of initiation of RRT at KDIGO stage 2 versus KDIGO stage 3. The Artificial Kidney Initiation in Kidney Injury (AKIKI) trial compared the initiation at KDIGO stage 3 versus KDIGO stage 3 plus clinical indication. The results of these studies demonstrate that early initiation at a moderate stage (KDIGO 2) improves patients’ outcome while the initiation at a severe stage (KDIGO 3 and KDIGO 3 plus clinical indication) may be too late during AKI development. One could argue that patients with moderate AKI may have recovered without RRT and were unnecessarily exposed to an invasive procedure. However, an approach that addresses only high-risk patients identified by both clinical risk scores and modern biomarkers82,118 allows for early initiation of RRT while at the same time avoiding its unnecessary execution.
The development of AKI is under-recognized but has significant potential consequences for perioperative patient outcomes. The pathophysiology of AKI is complex. Its prevention requires a multimodal approach. Effective preventive strategies rely on the identification of patients at high risk through the use of clinical scoring systems. The early detection of AKI with the use of damage biomarkers is gaining more acceptance and will probably be included in the next AKI guidelines. Drug treatment still does not play a role in the prevention of AKI, and renoprotective interventions remain limited to adherence to the KDIGO guidelines. Initial evidence suggests that RIPC may be effective for the prevention of AKI and can be considered in high-risk patients. If preventive strategies fail, early initiation of RRT at KDIGO stage 2 seems to offer advantages for high-risk patients.
Name: Melanie Meersch, MD.
Contribution: This author helped conduct the literature review and prepare the manuscript.
Name: Christoph Schmidt, MD.
Contribution: This author helped prepare and review the manuscript.
Name: Alexander Zarbock, MD.
Contribution: This author helped design, prepare, and review the manuscript.
This manuscript was handled by: Richard C. Prielipp, MD.
1. Hoste EA, Kellum JA, Katz NM, Rosner MH, Haase M, Ronco C. Epidemiology of acute kidney injury. Contrib Nephrol. 2010;165:1–8.
2. Lewington AJ, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013;84:457–467.
3. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380:756–766.
4. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–1423.
5. Siew ED, Davenport A. The growth of acute kidney injury: a rising tide or just closer attention to detail? Kidney Int. 2015;87:46–61.
6. Aronson S, Blumenthal R. Perioperative renal dysfunction and cardiovascular anesthesia: concerns and controversies. J Cardiothorac Vasc Anesth. 1998;12:567–586.
7. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP. Renal dysfunction and serious infections after open-heart surgery. Kidney Int. 2003;64:239–246.
8. Basile DP, Bonventre JV, Mehta R, et al; ADQI XIII Work GroupProgression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol. 2016;27:687–697.
9. Chawla LS, Amdur RL, Shaw AD, Faselis C, Palant CE, Kimmel PL. Association between AKI and long-term renal and cardiovascular outcomes in United States veterans. Clin J Am Soc Nephrol. 2014;9:448–456.
10. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305.
11. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365–3370.
12. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Complications and costs after high-risk surgery: where should we focus quality improvement initiatives? J Am Coll Surg. 2003;196:671–678.
13. Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: an increasing global concern. Lancet. 2013;382:170–179.
14. Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kidney injury during hospitalization after major surgery. Ann Surg. 2009;249:851–858.
15. Mehta RL, Kellum JA, Shah SV, et al; Acute Kidney Injury NetworkAcute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31.
16. Thakar CV. Perioperative acute kidney injury. Adv Chronic Kidney Dis. 2013;20:67–75.
17. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212.
18. Pickering JW, Endre ZH. GFR shot by RIFLE: errors in staging acute kidney injury. Lancet. 2009;373:1318–1319.
19. Kellum JA, Lamiere N, Aspelin P, Barsoum RS. KDIGO clinical practice guideline for acte kidney injury 2012. Kidney Int Suppl. 2012;2:1–138.
20. Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol. 2007;18:1292–1298.
21. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81:442–448.
22. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74:243–248.
23. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis. 2002;39:930–936.
24. Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35:349–355.
25. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int. 2008;73:538–546.
26. Carmichael P, Carmichael AR. Acute renal failure in the surgical setting. ANZ J Surg. 2003;73:144–153.
27. Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study. Am J Med. 1987;83:65–71.
28. Uchino S, Kellum JA, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) InvestigatorsAcute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–818.
29. Kheterpal S, Tremper KK, Heung M, et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Anesthesiology. 2009;110:505–515.
30. Kheterpal S, Tremper KK, Englesbe MJ, et al. Predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function. Anesthesiology. 2007;107:892–902.
31. Thakar CV, Kharat V, Blanck S, Leonard AC. Acute kidney injury after gastric bypass surgery. Clin J Am Soc Nephrol. 2007;2:426–430.
32. Cabezuelo JB, Ramírez P, Ríos A, et al. Risk factors of acute renal failure after liver transplantation. Kidney Int. 2006;69:1073–1080.
33. Symons JM. Moving beyond supportive care–current status of specific therapies in pediatric acute kidney injury. Pediatr Nephrol. 2014;29:173–181.
34. Prowle JR, Bellomo R. Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation. Semin Nephrol. 2015;35:64–74.
35. Zafrani L, Ince C. Microcirculation in acute and chronic kidney diseases. Am J Kidney Dis. 2015;66:1083–1094.
36. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol. 2005;16:162–168.
37. Kim M, Brady JE, Li G. Variations in the risk of acute kidney injury across intraabdominal surgery procedures. Anesth Analg. 2014;119:1121–1132.
38. Biteker M, Dayan A, Tekkeşin Aİ, et al. Incidence, risk factors, and outcomes of perioperative acute kidney injury in noncardiac and nonvascular surgery. Am J Surg. 2014;207:53–59.
39. Birnie K, Verheyden V, Pagano D, et al; UK AKI in Cardiac Surgery CollaboratorsPredictive models for kidney disease: improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery. Crit Care. 2014;18:606.
40. O’Sullivan KE, Byrne JS, Hudson A, Murphy AM, Sadlier DM, Hurley JP. The effect of obesity on acute kidney injury after cardiac surgery. J Thorac Cardiovasc Surg. 2015;150:1622–1628.
41. Billings FTt, Pretorius M, Schildcrout JS, et al. Obesity and oxidative stress predict AKI after cardiac surgery. J Am Soc Nephrol. 2012;23:1221–1228.
42. Grams ME, Sang Y, Coresh J, et al. Acute kidney injury after major surgery: a retrospective analysis of Veterans Health Administration data. Am J Kidney Dis. 2016;67:872–880.
43. Reents W, Hilker M, Börgermann J, et al. Acute kidney injury after on-pump or off-pump coronary artery bypass grafting in elderly patients. Ann Thorac Surg. 2014;98:9–14.
44. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Comparison of renal outcomes in off-pump versus on-pump coronary artery bypass grafting: a systematic review and meta-analysis of randomized controlled trials. Nephrology. 2015;20:727–735.
45. Lamy A, Devereaux PJ, Prabhakaran D, et al; CORONARY InvestigatorsOff-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012;366:1489–1497.
46. Hynes CF, Colo S, Amdur RL, Chawla LS, Greenberg MD, Trachiotis GD. Long-term effects of off-pump coronary bypass versus conventional coronary bypass grafting on renal function. Innovations (Phila). 2016;11:54–58.
47. Nigwekar SU, Kandula P, Hix JK, Thakar CV. Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies. Am J Kidney Dis. 2009;54:413–423.
48. Mehta RH, Grab JD, O’Brien SM, et al; Society of Thoracic Surgeons National Cardiac Surgery Database InvestigatorsBedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery. Circulation. 2006;114:2208–2216.
49. Wald R, Waikar SS, Liangos O, Pereira BJ, Chertow GM, Jaber BL. Acute renal failure after endovascular vs open repair of abdominal aortic aneurysm. J Vasc Surg. 2006;43:460–466.
50. Nguyen NT, Perez RV, Fleming N, Rivers R, Wolfe BM. Effect of prolonged pneumoperitoneum on intraoperative urine output during laparoscopic gastric bypass. J Am Coll Surg. 2002;195:476–483.
51. Koivusalo AM, Pere P, Valjus M, Scheinin T. Laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum is safe even for high-risk patients. Surg Endosc. 2008;22:61–67.
52. Dalfino L, Tullo L, Donadio I, Malcangi V, Brienza N. Intra-abdominal hypertension and acute renal failure in critically ill patients. Intensive Care Med. 2008;34:707–713.
53. Demarchi AC, de Almeida CT, Ponce D, et al. Intra-abdominal pressure as a predictor of acute kidney injury in postoperative abdominal surgery. Ren Fail. 2014;36:557–561.
54. Dünser MW, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35:1225–1233.
55. Redfors B, Bragadottir G, Sellgren J, Swärd K, Ricksten SE. Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury. Intensive Care Med. 2011;37:60–67.
56. Sun LY, Wijeysundera DN, Tait GA, Beattie WS. Association of intraoperative hypotension with acute kidney injury after elective noncardiac surgery. Anesthesiology. 2015;123:515–523.
57. Di Giantomasso D, Morimatsu H, May CN, Bellomo R. Intrarenal blood flow distribution in hyperdynamic septic shock: effect of norepinephrine. Crit Care Med. 2003;31:2509–2513.
58. Prasad A, Gurm HS. Can our choice of contrast media impact renal and cardiovascular outcomes? Catheter Cardiovasc Interv. 2016;87:710–711.
59. Liu Y, Li H, Chen S, et al. Excessively high hydration volume may not be associated with decreased risk of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with renal insufficiency. J Am Heart Assoc. 2016;5:e003171.
60. Fowler AJ, Ahmad T, Phull MK, Allard S, Gillies MA, Pearse RM. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Br J Surg. 2015;102:1314–1324.
61. Walsh M, Garg AX, Devereaux PJ, Argalious M, Honar H, Sessler DI. The association between perioperative hemoglobin and acute kidney injury in patients having noncardiac surgery. Anesth Analg. 2013;117:924–931.
62. Karkouti K, Stukel TA, Beattie WS, et al. Relationship of erythrocyte transfusion with short- and long-term mortality in a population-based surgical cohort. Anesthesiology. 2012;117:1175–1183.
63. Karkouti K, Grocott HP, Hall R, et al. Interrelationship of preoperative anemia, intraoperative anemia, and red blood cell transfusion as potentially modifiable risk factors for acute kidney injury in cardiac surgery: a historical multicentre cohort study. Can J Anaesth. 2015;62:377–384.
64. Haase M, Bellomo R, Story D, et al. Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury. Nephrol Dial Transplant. 2012;27:153–160.
65. Kellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol. 2015;26:2231–2238.
66. Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL; AWARE Investigators. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med. 2017;376:11–20.
67. Haase M, Devarajan P, Haase-Fielitz A, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57:1752–1761.
68. Nickolas TL, Schmidt-Ott KM, Canetta P, et al. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol. 2012;59:246–255.
69. Heimbürger O, Stenvinkel P, Bárány P. The enigma of decreased creatinine generation in acute kidney injury. Nephrol Dial Transplant. 2012;27:3973–3974.
70. Golden D, Corbett J, Forni LG. Peri-operative renal dysfunction: prevention and management. Anaesthesia. 2016;71Suppl 151–57.
71. Meersch M, Schmidt C, Van Aken H, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS One. 2014;9:e93460.
72. Mårtensson J, Bellomo R. What’s new in perioperative renal dysfunction? Intensive Care Med. 2015;41:514–516.
73. Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.
74. Devarajan P. Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology (Carlton). 2010;15:419–428.
75. Endre ZH, Pickering JW, Walker RJ, et al. Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int. 2011;79:1119–1130.
76. Makris K, Markou N, Evodia E, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin Chem Lab Med. 2009;47:79–82.
77. McIlroy DR, Wagener G, Lee HT. Neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery: the effect of baseline renal function on diagnostic performance. Clin J Am Soc Nephrol. 2010;5:211–219.
78. Cai L, Rubin J, Han W, Venge P, Xu S. The origin of multiple molecular forms in urine of HNL/NGAL. Clin J Am Soc Nephrol. 2010;5:2229–2235.
79. Bihorac A, Kellum JA. Acute kidney injury in 2014: a step towards understanding mechanisms of renal repair. Nat Rev Nephrol. 2015;11:74–75.
80. Witzgall R. Are renal proximal tubular epithelial cells constantly prepared for an emergency? Focus on “the proliferation capacity of the renal proximal tubule involves the bulk of differentiated epithelial cells”. Am J Physiol Cell Physiol. 2008;294:C1–C3.
81. Aregger F, Uehlinger DE, Witowski J, et al. Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury. Kidney Int. 2014;85:909–919.
82. Goldstein SL, Chawla LS. Renal angina. Clin J Am Soc Nephrol. 2010;5:943–949.
83. Vijayan A, Faubel S, Askenazi DJ, et al; American Society of Nephrology Acute Kidney Injury Advisory GroupClinical use of the urine biomarker [TIMP-2] × [IGFBP7] for acute kidney injury risk assessment. Am J Kidney Dis. 2016;68:19–28.
84. Koyner JL, Davison DL, Brasha-Mitchell E, et al. Furosemide stress test and biomarkers for the prediction of AKI severity. J Am Soc Nephrol. 2015;26:2023–2031.
85. Luo C, Yuan D, Yao W, et al. Dexmedetomidine protects against apoptosis induced by hypoxia/reoxygenation through the inhibition of gap junctions in NRK-52E cells. Life Sci. 2015;122:72–77.
86. Ji F, Li Z, Young JN, Yeranossian A, Liu H. Post-bypass dexmedetomidine use and postoperative acute kidney injury in patients undergoing cardiac surgery with cardiopulmonary bypass. PLoS One. 2013;8:e77446.
87. Xue F, Zhang W, Chu HC. Assessing perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery. Kidney Int. 2016;89:1164.
88. Kwiatkowski DM, Axelrod DM, Sutherland SM, Tesoro TM, Krawczeski CD. Dexmedetomidine is associated with lower incidence of acute kidney injury after congenital heart surgery. Pediatr Crit Care Med. 2016;17:128–134.
89. Cho JS, Shim JK, Soh S, Kim MK, Kwak YL. Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery. Kidney Int. 2016;89:693–700.
90. Balkanay OO, Goksedef D, Omeroglu SN, Ipek G. The dose-related effects of dexmedetomidine on renal functions and serum neutrophil gelatinase-associated lipocalin values after coronary artery bypass grafting: a randomized, triple-blind, placebo-controlled study. Interact Cardiovasc Thorac Surg. 2015;20:209–214.
91. Murugan R, Weissfeld L, Yende S, Singbartl K, Angus DC, Kellum JA; Genetic and Inflammatory Markers of Sepsis (GenIMS) Investigators. Association of statin use with risk and outcome of acute kidney injury in community-acquired pneumonia. Clin J Am Soc Nephrol. 2012;7:895–905.
92. Billings FTt, Hendricks PA, Schildcrout JS, et al. High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: a randomized clinical trial. JAMA. 2016;315:877–888.
93. Molnar AO, Coca SG, Devereaux PJ, et al. Statin use associates with a lower incidence of acute kidney injury after major elective surgery. J Am Soc Nephrol. 2011;22:939–946.
94. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1–85.
95. Haase M, Haase-Fielitz A, Plass M, et al. Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial. PLoS Med. 2013;10:e1001426.
96. McGuinness SP, Parke RL, Bellomo R, Van Haren FM, Bailey M. Sodium bicarbonate infusion to reduce cardiac surgery-associated acute kidney injury: a phase II multicenter double-blind randomized controlled trial. Crit Care Med. 2013;41:1599–1607.
97. KDIGO Aw. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138.
98. Meersch M, Schmidt C, Hoffmeier A, et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. 2017 21 Jan [Epub ahead of print].
99. Bullivant EM, Wilcox CS, Welch WJ. Intrarenal vasoconstriction during hyperchloremia: role of thromboxane. Am J Physiol. 1989;256:F152–F157.
100. McCluskey SA, Karkouti K, Wijeysundera D, Minkovich L, Tait G, Beattie WS. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117:412–421.
101. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308:1566–1572.
102. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013;119:507–515.
103. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359–1367.
104. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med. 2007;146:233–243.
105. Bhamidipati CM, LaPar DJ, Stukenborg GJ, et al. Superiority of moderate control of hyperglycemia to tight control in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2011;141:543–551.
106. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.
107. Jensen HA, Loukogeorgakis S, Yannopoulos F, et al. Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation. 2011;123:714–721.
108. Er F, Nia AM, Dopp H, et al. Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial). Circulation. 2012;126:296–303.
109. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury–a review. J Surg Res. 2008;150:304–330.
110. Menting TP, Wever KE, Ozdemir-van Brunschot DM, Van der Vliet DJ, Rovers MM, Warle MC. Ischaemic preconditioning for the reduction of renal ischaemia reperfusion injury. Cochrane Database Syst Rev. 2017;3:CD010777.
111. Zimmerman RF, Ezeanuna PU, Kane JC, et al. Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int. 2011;80:861–867.
112. Zarbock A, Schmidt C, Van Aken H, et al; RenalRIPC InvestigatorsEffect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015;313:2133–2141.
113. Meybohm P, Hasenclever D, Zacharowski K. Remote ischemic preconditioning and cardiac surgery. N Engl J Med. 2016;374:491.
114. Hausenloy DJ, Candilio L, Evans R, et al; ERICCA Trial InvestigatorsRemote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373:1408–1417.
115. Kottenberg E, Thielmann M, Bergmann L, et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012;56:30–38.
116. Wierstra BT, Kadri S, Alomar S, Burbano X, Barrisford GW, Kao RL. The impact of “early” versus “late” initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis. Crit Care. 2016;20:122.
117. Gaudry S, Hajage D, Dreyfuss D. Initiation of renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375:1901–1902.
© 2017 International Anesthesia Research Society
118. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA. 2016;315:2190–2199.