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Perioperative Management of the Patient at High-Risk for Cardiac Surgery-Associated Acute Kidney Injury

  • Benjamin Milne
    Affiliations
    Department of Anaesthetics and Pain Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom

    National Institute of Health Research Academic Clinical Fellow, King's College London, London, United Kingdom
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  • Tom Gilbey
    Affiliations
    Department of Anaesthetics and Pain Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom

    National Institute of Health Research Academic Clinical Fellow, King's College London, London, United Kingdom
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  • Gudrun Kunst
    Correspondence
    Address correspondence to Professor G. Kunst, Department of Anaesthetics & Pain Medicine, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK, SE5 9RS.
    Affiliations
    Department of Anaesthetics and Pain Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom

    School of Cardiovascular Medicine and Metabolic Medicine and Sciences, King's College London, British Heart Foundation Centre of Excellence, Faculty of Life Sciences and Medicine, London, United Kingdom
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Open AccessPublished:August 26, 2022DOI:https://doi.org/10.1053/j.jvca.2022.08.016
      Acute kidney injury (AKI) is one of the most common major complications of cardiac surgery, and is associated with increased morbidity and mortality. Cardiac surgery-associated AKI has a complex, multifactorial etiology, including numerous factors such as primary cardiac dysfunction, hemodynamic derangements of cardiac surgery and cardiopulmonary bypass, and the possibility of a large volume of blood transfusion. There are no truly effective pharmacologic therapies for the management of AKI, and, therefore, anesthesiologists, intensivists, and cardiac surgeons must remain vigilant and attempt to minimize the risk of developing renal dysfunction. This narrative review describes the current state of the scientific literature concerning the specific aspects of cardiac surgery-associated AKI, and presents it in a chronological fashion to aid the perioperative clinician in their approach to this high-risk patient group. The evidence was considered for risk prediction models, preoperative optimization, and the intraoperative and postoperative management of cardiac surgery patients to improve renal outcomes.

      Key Words

      ACUTE KIDNEY INJURY (AKI) is a common major complication of cardiac surgery, with a multifactorial etiology and a high degree of associated morbidity and mortality. Cardiac surgery-associated AKI (CSA-AKI) is pragmatically recognized as an AKI (diagnosed by appropriate criteria) occurring within 1 week of cardiac surgery.
      • Wang Y
      • Bellomo R.
      Cardiac surgery-associated acute kidney injury: Risk factors, pathophysiology and treatment.
      It is a syndrome of acute organ damage and dysfunction, with systemic effects and a major role in adverse outcomes.
      • Massoth C
      • Zarbock A.
      Diagnosis of cardiac surgery-associated acute kidney injury.
      The pathophysiology of CSA-AKI is complex and may arise from singular or accumulated pathogenic insults during the perioperative period (Fig 1). These factors may act in an additive or synergistic fashion, superimposed upon the preexisting health of the renal system and any underlying genetic susceptibility.
      • Stafford-Smith M
      • Li YJ
      • Mathew JP
      • et al.
      Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.
      Fig 1
      Fig 1Factors contributing to the development of cardiac surgery-associated acute kidney injury in the perioperative period. CPB, cardiopulmonary bypass; HF, heart failure; MV, mechanical ventilation; PPC, postoperative pulmonary complications; RAAS, renin-angiotensin-aldosterone system.
      Fig 2
      Fig 2Preoperative management to reduce incidence of cardiac surgery-associated acute kidney injury. ACEi, angiotensin- converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; Hb, hemoglobin; KDIGO, Kidney Disease: Improving Global Outcomes; RRT, renal replacement therapy.
      Fig 3
      Fig 3Intraoperative management to reduce incidence of cardiac surgery-associated acute kidney injury. CPB, cardiopulmonary bypass; Hb, hemoglobin; IV, intravenous; MAP, mean arterial pressure; RRT, renal replacement therapy.
      The incidence of CSA-AKI is 5%-to-42%, with a suggested global median incidence of 22%, although described rates have exceeded 80%.
      • Wang Y
      • Bellomo R.
      Cardiac surgery-associated acute kidney injury: Risk factors, pathophysiology and treatment.
      ,
      • Hu J
      • Chen R
      • Liu S
      • et al.
      Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: A systematic review and meta-analysis.
      ,
      • Priyanka P
      • Zarbock A
      • Izawa J
      • et al.
      The impact of acute kidney injury by serum creatinine or urine output criteria on major adverse kidney events in cardiac surgery patients.
      In a meta-analysis, median pooled short-term and long-term mortality were in the range of 11% and 30%, respectively.
      • Hu J
      • Chen R
      • Liu S
      • et al.
      Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: A systematic review and meta-analysis.
      Cardiac surgery-associated AKI is independently associated with an increased risk of death, which persists even after complete renal recovery.
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      Acute kidney injury after cardiac surgery: Focus on modifiable risk factors.
      • Srivastava V
      • D'Silva C
      • Tang A
      • et al.
      The impact of major perioperative renal insult on long-term renal function and survival after cardiac surgery.
      • Chertow GM
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      • Hammermeister KE
      • et al.
      Independent association between acute renal failure and mortality following cardiac surgery.
      Lower severity injury states are more common, and the requirement for renal replacement therapy (RRT) is 2%-to-6%, with mortality in this subgroup potentially exceeding 50%.
      • Hu J
      • Chen R
      • Liu S
      • et al.
      Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: A systematic review and meta-analysis.
      ,
      • Petäjä L
      • Vaara S
      • Liuhanen S
      • et al.
      Acute kidney injury after cardiac surgery by complete KDIGO criteria predicts increased mortality.
      • Tan SI
      • Brewster DJ
      • Horrigan D
      • et al.
      Pharmacological and non-surgical renal protective strategies for cardiac surgery patients undergoing cardiopulmonary bypass: A systematic review.
      • Howitt SH
      • Grant SW
      • Caiado C
      • et al.
      The KDIGO acute kidney injury guidelines for cardiac surgery patients in critical care: A validation study.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      • O'Neal JB
      • Shaw AD
      • Billings FTt
      Acute kidney injury following cardiac surgery: Current understanding and future directions.
      However, the outcomes also relate to the duration of AKI, with persistent (>48 hours) AKI and transition to acute kidney disease both associated with worse outcomes independent of stage.
      • Choe SH
      • Cho H
      • Bae J
      • et al.
      Severity and duration of acute kidney injury and chronic kidney disease after cardiac surgery.
      Also, CSA-AKI is associated with subsequent chronic kidney disease and cardiovascular events.
      • Hu J
      • Chen R
      • Liu S
      • et al.
      Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: A systematic review and meta-analysis.
      ,
      • Vives M
      • Hernandez A
      • Parramon F
      • et al.
      Acute kidney injury after cardiac surgery: Prevalence, impact and management challenges.
      Given the significant short-term and long-term risks to this complex cohort, there is a tangible need to identify and appropriately manage those patients at high risk for developing CSA-AKI. The intention of the perioperative physician should be to use evidence-based measures to prevent AKI or to mitigate the most significant adverse effects. This narrative review describes the state of the literature with regard to specific perioperative management of the high-risk patient in a chronological fashion, such that it may aid the clinician in their approach. Identification of the high-risk patient and contributing factors are discussed, with appropriate preoptimization strategies based on the best available evidence. Furthermore, the evidence underpinning intraoperative and postoperative management is considered with reference to the shortcomings of the current literature.

      Identifying the High-Risk Patient

      Clinical assessment of established risk factors is the cornerstone of identifying the patient at high risk for developing CSA-AKI, and several risk prediction models have been developed (Table 1).
      • Thakar CV
      • Arrigain S
      • Worley S
      • et al.
      A clinical score to predict acute renal failure after cardiac surgery.
      • Mehta RH
      • Grab JD
      • O'Brien SM
      • et al.
      Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery.
      • Wijeysundera DN
      • Karkouti K
      • Dupuis JY
      • et al.
      Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery.
      • Birnie K
      • Verheyden V
      • Pagano D
      • et al.
      Predictive models for kidney disease: Improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery.
      These are applied readily at the bedside but have focused primarily on identifying RRT requirements.
      Table 1Predictive Models for CSA-AKI
      StudyThakar
      • Thakar CV
      • Arrigain S
      • Worley S
      • et al.
      A clinical score to predict acute renal failure after cardiac surgery.
      (2005) Cleveland Clinic Score
      Mehta
      • Mehta RH
      • Grab JD
      • O'Brien SM
      • et al.
      Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery.
      (2006) Bedside Risk Score
      Wijeysundera
      • Wijeysundera DN
      • Karkouti K
      • Dupuis JY
      • et al.
      Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery.
      (2007) Simplified Renal Index Scoring System
      Birnie
      • Birnie K
      • Verheyden V
      • Pagano D
      • et al.
      Predictive models for kidney disease: Improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery.
      (2014)
      Any StageStage 3
      DerivationOpen-heart surgeryCABG/valve surgeryOn CPBAll cardiac surgery
      CategoryVariables
      CSA-AKI outcomeAny stage---+-
      Stage 3----+
      Requiring RRT+++--
      Patient characteristicsAdults+++++
      Sex+--++
      Age-+-+-
      Ethnicity-+---
      BMI--++
      Smoking---+-
      CardiacHF classification++++-
      Recent MI-+---
      Recent angiogram---++
      Triple vessel disease---+-
      IABP use+-+-+
      Inotrope use----+
      Cardiogenic shock-+--+
      Hypertension---+-
      ComorbidityPulmonary++---
      DM+++++
      PVD---+-
      Anemia---++
      SurgicalPrevious CS+++--
      Emergency surgery+-++-
      Valvular surgery+++++
      CABG surgery+++++
      Other CS+-+++
      RenalSerum Cr++---
      eGFR--+++
      Interpretation of scorePredicts requirement for RRT—divided into 4 arbitrary groups dependent upon score; lowest risk group with 0.4% requiring RRT, and 21.3% in highest risk group.Predicts % risk of requiring RRT—based upon points score (Score range 0 to 83 to predict risk of dialysis 0% to 85%)Divides patients into low, intermediate and high-risk groups depending upon score.Predicts % risk of outcomes (all stage CSA-AKI; stage 3 CSA-AKI)
      Abbreviations: BMI, body mass index; CABG, coronary artery bypass graft; Cr, creatinine; CS, cardiac surgery; CSA-AKI, cardiac surgery-associated acute kidney injury; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HF, heart failure; IABP, intra-aortic balloon pump; MI, myocardial infarction; PVD, peripheral vascular disease; RRT, renal replacement therapy.
      The Cleveland Clinic Score (CCS), derived from 15,838 patients undergoing cardiac surgery at a single center and subsequently validated on 15,839 patients at the same center, demonstrated an area under the receiver operating characteristic curve (AUROC) of 0.82 for the prediction of RRT requirement (95% CI: 0.80-0.85) in the validation set.
      • Thakar CV
      • Arrigain S
      • Worley S
      • et al.
      A clinical score to predict acute renal failure after cardiac surgery.
      This has compared favorably with 2 subsequently developed scores, including Mehta's Bedside Risk Score (derived from a large national registry of 449,524 patients undergoing coronary artery bypass grafting [CABG] and/or valve surgery in >600 centers), and the Simplified Renal Index Scoring Scheme (derived from a cohort of 10,751 patients undergoing on-pump surgery at a single center and validated across 2 centers [n = 9,380 patients]).
      • Mehta RH
      • Grab JD
      • O'Brien SM
      • et al.
      Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery.
      ,
      • Wijeysundera DN
      • Karkouti K
      • Dupuis JY
      • et al.
      Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery.
      These models are universally limited by a lower RRT rate than current data suggest (1.7%, 1.4%, and 1.3%, respectively), and have been derived from cohorts undergoing surgery 15-to-30 years ago, both of which limit wider current applicability.
      The CCS has performed best in comparisons between the models predicting RRT.
      • Candela-Toha A
      • Elías-Martín E
      • Abraira V
      • et al.
      Predicting acute renal failure after cardiac surgery: External validation of two new clinical scores.
      ,
      • Vives M
      • Monedero P
      • Perez-Valdivieso JR
      • et al.
      External validation and comparison of three scores to predict renal replacement therapy after cardiac surgery: A multicenter cohort.
      In a large cohort (n = 12,096 patients) with a more representative RRT requirement (2.1%) and severe AKI incidence (3.9%), the CCS provided the best discriminatory AUROC for both outcomes (0.86 [0.84-0.88] and 0.81 [0.79-0.83], respectively) and the widest applicability.
      • Englberger L
      • Suri RM
      • Li Z
      • et al.
      Validation of clinical scores predicting severe acute kidney injury after cardiac surgery.
      A systematic review has further supported these findings; and, in addition, an analysis of several models for the outcomes of RRT requirement and stage 1, 2, and 3 Kidney Disease: Improving Global Outcomes (KDIGO)-defined AKI found CCS performed best for each outcome (AUROC: 0.84, 0.73, 0.81, and 0.84, respectively).
      • Huen SC
      • Parikh CR.
      Predicting acute kidney injury after cardiac surgery: A systematic review.
      ,
      • Kristovic D
      • Horvatic I
      • Husedzinovic I
      • et al.
      Cardiac surgery-associated acute kidney injury: Risk factors analysis and comparison of prediction models.
      Cardiac surgery-associated AKI not requiring RRT represents most of the disease burden, and a model for ‘all-stage’ CSA-AKI has been developed from 25,992 patients across 2 centers, with validation in 4,862 patients from a third center. The strengths were the use of routinely available data, the inclusion of on-pump and off-pump procedures, the use of KDIGO criteria (albeit only serum creatinine [sCr] criteria), and representative AKI incidences across the sites, all of which increased wider applicability. The AUROC for all-stage AKI was 0.73 (0.72-0.74) with good calibration, which compared favorably with the CCS (0.70 [0.69-0.72]), although the latter was not intended for this purpose and similarly for stage 3 AKI (AUROC 0.79 [0.76-0.81]). However, shortcomings included the absence of urine output (UO) criteria and no correction for intraoperative and postoperative confounders.
      • Birnie K
      • Verheyden V
      • Pagano D
      • et al.
      Predictive models for kidney disease: Improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery.
      The risk assessment should aim to be dynamic, incorporating the wealth of information provided by intraoperative and (early) postoperative events. For example, the addition of 1 intraoperative variable (nadir hematocrit) has been shown to improve the predictive ability of the CCS, albeit in a small single-center study (AUROC 0.72 [0.62-0.82] v 0.78 [0.70-0.87], p = 0.002).
      • Crosina J
      • Lerner J
      • Ho J
      • et al.
      Improving the prediction of cardiac surgery-associated acute kidney injury.
      Scores have been developed incorporating preoperative and intraoperative variables, such as the AKI after cardiac surgery score, although this precludes preoperative use.
      • Aronson S
      • Fontes ML
      • Miao Y
      • et al.
      Risk index for perioperative renal dysfunction/failure: Critical dependence on pulse pressure hypertension.
      ,
      • Palomba H
      • de Castro I
      • Neto AL
      • et al.
      Acute kidney injury prediction following elective cardiac surgery: AKICS score.
      In contrast, a truly dynamic model has been developed, which enables assessment at 3 separate time points (preoperatively, on admission to the intensive care unit [ICU], and 24 hours after ICU admission). The AUROCs for the model at the 3 time points are 0.74, 0.75, and 0.82, respectively, although generalizability is currently limited by the single-center nature.
      • Jiang W
      • Teng J
      • Xu J
      • et al.
      Dynamic predictive scores for cardiac surgery-associated acute kidney injury.
      The use of machine-learning approaches will enable further insight into the importance of certain perioperative variables and potentially generate better-performing predictive models.
      • Thongprayoon C
      • Hansrivijit P
      • Bathini T
      • et al.
      Predicting acute kidney injury after cardiac surgery by machine learning approaches.
      • Rank N
      • Pfahringer B
      • Kempfert J
      • et al.
      Deep-learning-based real-time prediction of acute kidney injury outperforms human predictive performance.
      • Tseng PY
      • Chen YT
      • Wang CH
      • et al.
      Prediction of the development of acute kidney injury following cardiac surgery by machine learning.
      • Lee WC
      • Lee YT
      • Li LC
      • et al.
      The number of comorbidities predicts renal outcomes in patients with stage 3-5 chronic kidney disease.
      One single-center study (n = 671), with a 24% incidence of AKI, produced a model with an AUROC of 0.84 (0.78-0.90), finding that 14 of the 20 most discriminatory variables were intraoperative features.
      • Tseng PY
      • Chen YT
      • Wang CH
      • et al.
      Prediction of the development of acute kidney injury following cardiac surgery by machine learning.
      This demonstrated a major shortcoming of preoperative predictive models; however, they may still be used, considering this limitation.
      Typifying much of the literature concerning CSA-AKI, model development has been beset by the use of different AKI definitions, varying RRT indications, and the idiosyncrasies of the derivation cohort. The CCS is the most useful in predicting RRT-requiring AKI, with an RRT requirement of 21% in the highest risk group.
      • Thakar CV
      • Arrigain S
      • Worley S
      • et al.
      A clinical score to predict acute renal failure after cardiac surgery.
      The CCS predicting RRT or the model identifying patients at risk at any stage AKI can both provide individualized risk estimation at the bedside preoperatively.16,19 Although the addition of intraoperative data to these scores is appealing, wider evidence for their use is lacking.
      Machine-learning approaches will yield new insights, but clinicians will have to determine how to apply this wealth of information to their patients, and usefulness may be limited in the most high-risk patients.
      • Vanmassenhove J
      • Kielstein J
      • Jörres A
      • et al.
      Management of patients at risk of acute kidney injury.
      Finally, in the absence of a widely applicable, dynamic, and well-evidenced prediction model, the perioperative physician can use common factors across several externally validated models as a rudimentary screening tool (Table 2) to supplement other routine risk scores and consider the degree to which they can modify this risk.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      • Shin SR
      • Kim WH
      • Kim DJ
      • et al.
      Prediction and prevention of acute kidney injury after cardiac surgery.
      • Chen SW
      • Chang CH
      • Fan PC
      • et al.
      Comparison of contemporary preoperative risk models at predicting acute kidney injury after isolated coronary artery bypass grafting: A retrospective cohort study.
      Table 2Common Risk Factors Across the Perioperative Spectrum in Predictive Risk Scores
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Perioperative PeriodModifiabilityRisk Factors
      PreoperativeNonmodifiablePatientAge
      Female
      SurgeryType of surgery
      Emergency case
      Partially modifiablePreoperative physiological stateCardiogenic shock
      Intra-aortic balloon pump
      Cardiovascular comorbiditiesCoronary artery disease
      Cardiac failure
      Renal diseaseChronic kidney disease
      Albuminuria
      Cardiovascular diseaseHypertension
      Peripheral vascular disease
      Other diseaseCOPD
      Diabetes mellitus
      IntraoperativePartially modifiableSurgicalCPB time
      Cross-clamp time
      ModifiableBlood managementTransfusion load
      Hemodilution
      PerfusionHypothermia
      Nonpulsatile CPB
      PostoperativeNonmodifiableComplicationsAtheroembolism
      Sepsis
      Partially modifiableComplicationsCardiogenic shock
      ModifiableComplicationsHypotension
      Hypovolemia
      PharmacologyNephrotoxins
      Adapted from Nadim MK, Forni LG, Bihorac A, et al. Cardiac and Vascular Surgery-Associated Acute Kidney Injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group. J Am Heart Assoc. 2018;711:e008834.
      Abbreviations: COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass.

      Diagnosing Acute Kidney Injury (AKI)

      The KDIGO criteria (Table 3), combining sCr and UO threshold values, are recommended in cardiac surgery.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Luo X
      • Jiang L
      • Du B
      • et al.
      A comparison of different diagnostic criteria of acute kidney injury in critically ill patients.
      ,
      • Khwaja A.
      KDIGO clinical practice guidelines for acute kidney injury.
      Although detailed discussion is beyond the scope of this review, the use of these 2 functional markers for diagnosis of CSA-AKI has several limitations. The glomerular filtration rate (GFR) may reduce by 50% before the derangement of sCr occurs.
      • Stevens LA
      • Levey AS.
      Measured GFR as a confirmatory test for estimated GFR.
      Furthermore, after cardiac surgery, both sCr concentration and intravascular volume are unlikely to be in a state of equilibrium, uncoupling these markers from an accurate contemporaneous reflection of renal function.
      • Takaki S
      • Shehabi Y
      • Pickering JW
      • et al.
      Perioperative change in creatinine following cardiac surgery with cardiopulmonary bypass is useful in predicting acute kidney injury: A single-centre retrospective cohort study.
      Contemporaneous fluid balance (FB) should be considered, alongside sCr and UO, to improve the recognition of CSA-AKI.
      • Englberger L
      • Suri RM
      • Li Z
      • et al.
      Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury in patients undergoing cardiac surgery.
      ,
      • Jin J
      • Chang SC
      • Xu S
      • et al.
      Early postoperative serum creatinine adjusted for fluid balance precisely predicts subsequent acute kidney injury after cardiac surgery.
      Table 3KDIGO Classification of Acute Kidney Injury
      • Khwaja A.
      KDIGO clinical practice guidelines for acute kidney injury.
      AKI StageCreatinine CriteriaUrine Output Criteria
      Stage 1Rise in serum creatinine ≥0.3 mg/dL in 48 hours or rise of 1.5-1.9 times from baseline<0.5 mL/kg/h for 6-12 h
      Stage 2Rise in serum creatinine 2.0-2.9 times from baseline<0.5 mL/kg/h for ≥12 h
      Stage 3Rise in serum creatinine 3 times from baseline or increase in serum creatinine to ≥4 mg/dL or initiation of RRT irrespective of serum creatinine<0.3 mL/kg/h for ≥24 h or anuria for ≥12 h
      Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes; RRT, renal replacement therapy.
      In the absence of a singular efficacious therapy for CSA-AKI, prompt recognition of an injury or preinjury state is of increased importance to allow early implementation of preventative (or mitigating) measures. An alternative classification schema has been proposed that incorporates damage criteria, defined by the markers of cellular stress or damage, recognizing the entity of subclinical AKI, defined solely by raised stress and/or damage biomarkers, with normal functional criteria. Numerous urinary and serum biomarkers are available for the diagnosis of subclinical AKI or the prediction of subsequent KDIGO-defined AKI.
      • Ostermann M
      • Zarbock A
      • Goldstein S
      • et al.
      Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: A consensus statement.
      The best-described biomarkers are neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular damage expressed by proximal tubular epithelia and neutrophils and upregulated early after injury, tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP7). The latter 2 are constitutively expressed proteins released early after ischemia-reperfusion injury to produce G1-cell cycle arrest. They usually are measured together, with an increased product of their concentration a sign of incipient damage.
      • Ostermann M
      • Zarbock A
      • Goldstein S
      • et al.
      Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: A consensus statement.
      A point-of-care automated immunoassay test is available for their measurement. The use of novel cellular stress and/ordamage biomarkers, when evidence-based, are discussed at the relative perioperative time points.

      Preoperative Management

      Preoptimization will need to account for acute and chronic pathologies while considering the urgency of surgery. An ABCD kidney health assessment has been proposed as a framework, including AKI history (eg, risk factors, previous AKI), blood pressure (optimize control and identify autoregulatory thresholds), chronic kidney disease and creatinine (establish baseline sCr and perioperative dialysis plan), and drugs and dipstick (optimize medications, plan for medications perioperatively, optimize volume status).
      • Ostermann M
      • Zarbock A
      • Goldstein S
      • et al.
      Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: A consensus statement.
      Emergency surgical patients are likely to arrive in a more compromised physiologic state and will require preoperative and intraoperative optimization. In this scenario, the most renal-protective step prior to surgery is the maintenance of hemodynamic stability and, thus, perfusion and oxygen delivery (DO2) to the kidney. Attempting to establish baseline sCr is important, even if this is unlikely to be in a steady state.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Dialysis patients should dialyze within 24 hours before and after surgery.
      • Ortega-Loubon C
      • Fernández-Molina M
      • Carrascal-Hinojal Y
      • et al.
      Cardiac surgery-associated acute kidney injury.

      Renin-Angiotensin-Aldosterone System Antagonists

      The perioperative use of renin-angiotensin-aldosterone system (RAAS) inhibitors has been debated extensively for improved renal and other outcomes.
      • Milne B
      • Gilbey T
      • Ostermann M
      • et al.
      Pro: We should stop ACE inhibitors early before cardiac surgery to prevent postoperative acute kidney injury.
      ,
      • Tempe DK
      • Con Hasija S.
      Does preoperative discontinuation of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers reduce postoperative acute kidney injury?.
      Increased RAAS activity during cardiopulmonary bypass (CPB) likely plays a prominent role in hypoperfusion-related renal injury, and it has been postulated that RAAS inhibition will be beneficial. Alternatively, and likely representing the prevailing view, RAAS inhibition is associated with an increased risk of perioperative hypotension and reduced renal perfusion pressure (RPP).
      • Zhou H
      • Xie J
      • Zheng Z
      • et al.
      Effect of renin-angiotensin system inhibitors on acute kidney injury among patients undergoing cardiac surgery: A review and meta-analysis.
      There are few randomized controlled trials (RCTs) addressing this question, and many do not have AKI as their primary endpoint. Furthermore, there is marked variation within these studies as to the intervention under investigation, with some examining novel preoperative, or even postoperative, implementation against no antagonism, whereas other studies have compared naïve patients started on RAAS antagonists to those with chronic use, in whom duration of use will have a different impact upon renal vasculature and inflammatory mediator production. Within these differing patterns of use, conflicting evidence has emerged regarding CSA-AKI incidence, early complications, and short-term mortality.
      • Pretorius M
      • Murray KT
      • Yu C
      • et al.
      Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery.
      • Roberts DJ
      • Smith SA
      • Tan Z
      • et al.
      Angiotensin-converting enzyme inhibitor/receptor blocker, diuretic, or nonsteroidal anti-inflammatory drug use after major surgery and acute kidney injury: A case-control study.
      • Arora P
      • Rajagopalam S
      • Ranjan R
      • et al.
      Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery.
      • Yacoub R
      • Patel N
      • Lohr JW
      • et al.
      Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: A meta-analysis of observational studies.
      • Whiting P
      • Morden A
      • Tomlinson LA
      • et al.
      What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis.
      • Billings FTt
      • Balaguer JM
      • C Y
      • et al.
      Comparative effects of angiotensin receptor blockade and ACE inhibition on the fibrinolytic and inflammatory responses to cardiopulmonary bypass.
      • van Diepen S
      • Norris CM
      • Zheng Y
      • et al.
      Comparison of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker management strategies before cardiac surgery: A pilot randomized controlled registry trial.
      • Drenger B
      • Fontes ML
      • Miao Y
      • et al.
      Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: Effects on in-hospital morbidity and mortality.
      • Ding Q
      • Zhang Z
      • Liu H
      • et al.
      Perioperative use of renin-angiotensin system inhibitors and outcomes in patients undergoing cardiac surgery.
      • Vieira De Melo RM
      • Azevedo DC
      • Danziato LN
      • et al.
      Perioperative use of renin-angiotensin system inhibitors and short-term outcomes in patients undergoing cardiac surgery.
      A Cochrane systematic review of perioperative RAAS antagonist use noted the dearth of applicable data relating to CSA-AKI, and only could conclude that they may not be helpful in reducing CSA-AKI.
      • Zou Z
      • Yuan HB
      • Yang B
      • et al.
      Perioperative angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers for preventing mortality and morbidity in adults.
      A further meta-analysis (21 cohort studies and 2 RCTs, n = 76,321) attempted to address the heterogeneity within the evidence. Overall, for all perioperative use, there was a pooled odds ratio (OR) of 1.02 (0.89-1.17), suggesting RAAS antagonism was not associated with CSA-AKI. Most studies examined preoperative use compared with no previous use, finding no significant association for use with CSA-AKI (OR 1.02 [0.88-1.18]). Concerning chronic RAAS antagonism, there was no significant difference in the odds for CSA-AKI when the antagonist was withdrawn preoperatively versus continuation (2 studies, OR 1.12 [0.94-1.33]). Finally, there was no significant association between the type of RAAS antagonism and CSA-AKI (angiotensin converting enzyme inhibitor: OR 1.10 [0.92-1.32]; angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker: OR 0.96 [0.81-1.14]).
      • Zhou H
      • Xie J
      • Zheng Z
      • et al.
      Effect of renin-angiotensin system inhibitors on acute kidney injury among patients undergoing cardiac surgery: A review and meta-analysis.
      In one study, which was included in the meta-analysis, improved renal outcome was found with continuation of RAAS antagonists (OR 0.47 [0.28-0.79]), but there was no significant association between postoperative initiation and CSA-AKI (OR 0.57 [0.24-1.36]).
      • Drenger B
      • Fontes ML
      • Miao Y
      • et al.
      Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: Effects on in-hospital morbidity and mortality.
      The lack of an association with harm differed from another meta-analysis, despite numerous shared studies, and potentially occurred due to the use of adjusted ORs, accounting for hypertension, diabetes, and obesity.
      • Zhou H
      • Xie J
      • Zheng Z
      • et al.
      Effect of renin-angiotensin system inhibitors on acute kidney injury among patients undergoing cardiac surgery: A review and meta-analysis.
      ,
      • Yacoub R
      • Patel N
      • Lohr JW
      • et al.
      Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: A meta-analysis of observational studies.
      This newer meta-analysis reported a high degree of heterogeneity among studies despite the subclassification of different interventions. International guidelines made recommendations to discontinue angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers perioperatively, specifically to prevent AKI.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Lawton JS
      • Tamis-Holland JE
      • Bangalore S
      • et al.
      2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      ,
      • Sousa-Uva M
      • Head SJ
      • Milojevic M
      • et al.
      2017 EACTS Guidelines on perioperative medication in adult cardiac surgery.
      However, this area will require more RCT evidence, and the most appropriate solution currently appears to be an individualized decision based upon the risk-benefit profile for each patient, considering both renal and wider outcomes for perioperative continuation and the optimal timeframe for discontinuation. Preoperative commencement to improve renal outcomes should currently not be considered.

      Diuretics

      In a large, single-center study (n = 12,593), preoperative diuretic use was associated with CSA-AKI after propensity score matching (19% v 14%, p < 0.0001).
      • Bandeali SJ
      • Kayani WT
      • Lee VV
      • et al.
      Association between preoperative diuretic use and in-hospital outcomes after cardiac surgery.
      However, the exact effect of diuretics will depend on volume status, with hypovolemia making the patient much more likely to sustain AKI, whereas renal congestion will be improved by volume unloading.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Mineralocorticoid receptor antagonists, such as spironolactone, have been less examined within the literature and should be continued given the lack of clear concern relating to their use combined with the known beneficial cardiovascular effect, which may be of greater renal benefit.
      • Barba-Navarro R
      • Tapia-Silva M
      • Garza-Garcia C
      • et al.
      The effect of spironolactone on acute kidney injury after cardiac surgery: A randomized, placebo-controlled trial.
      Diuretic use preoperatively should be continued or discontinued, as appropriate to volume status, with the aim of the patient arriving for surgery with an optimal intravascular state.

      Other Drugs

      Non-Steroidal Anti-Inflammatory Drugs

      Nonantiplatelet nonsteroidal anti-inflammatory drugs (NSAIDs) can impair renal autoregulation, and the risk-benefit profile suggests withholding them immediately preoperatively.
      • Ostermann M
      • Kunst G
      • Baker E
      • et al.
      Cardiac Surgery Associated AKI Prevention Strategies and Medical Treatment for CSA-AKI.
      • Kumar AB
      • Suneja M.
      Cardiopulmonary bypass-associated acute kidney injury.
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      Preoperative use of low-dose aspirin (≤300 mg) is associated with a reduced incidence of adverse renal effects with an OR of 0.44 (0.20-0.95) and 0.38 (0.25-0.58) for CSA-AKI with aspirin use in propensity score-matched analyses of 2 observational studies, suggesting any impaired autoregulation is outweighed by the beneficial effect of platelet inhibition.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      ,
      • Cao L
      • Silvestry S
      • Zhao N
      • et al.
      Effects of preoperative aspirin on cardiocerebral and renal complications in non-emergent cardiac surgery patients: A sub-group and cohort study.
      ,
      • Cao L
      • Young N
      • Liu H
      • et al.
      Preoperative aspirin use and outcomes in cardiac surgery patients.

      Antimicrobials

      Numerous antimicrobials exhibit class-based nephrotoxicity.
      • Awdishu L
      • Mehta RL.
      The 6R's of drug induced nephrotoxicity.
      Single preoperative doses of aminoglycosides, such as gentamicin, have been shown to increase the incidence of CSA-AKI (22% in the exposed v 17% in the nonexposed in 1 matched-pair analysis, p = 0.02) and the requirement for RRT (adjusted OR 4.41 [1.83-10.59] for CSA-AKI RRT).
      • Nielsen DV
      • Hjortdal V
      • Larsson H
      • et al.
      Perioperative aminoglycoside treatment is associated with a higher incidence of postoperative dialysis in adult cardiac surgery patients.
      ,
      • Nielsen DV
      • Fedosova M
      • Hjortdal V
      • et al.
      Is single-dose prophylactic gentamicin associated with acute kidney injury in patients undergoing cardiac surgery? A matched-pair analysis.
      Similarly, glycopeptide antibiotics, such as teicoplanin, may likewise increase the risk of CSA-AKI, especially with preexisting dysfunction.
      • Olsson DP
      • Holzmann MJ
      • Sartipy U.
      Antibiotic prophylaxis by teicoplanin and risk of acute kidney injury in cardiac surgery.
      This evidence may underlie the move towards the use of cephalosporins.
      • Engelman DT
      • Ben Ali W
      • Williams JB
      • et al.
      Guidelines for perioperative care in cardiac surgery: Enhanced recovery after surgery society recommendations.
      However, the use of any of these agents, if indicated by organism culture sensitivities for a preexisting infection, is likely to outweigh the risks of nephrotoxicity given the deleterious hemodynamic effects of untreated sepsis.

      Hydroxymethylglutaryl-coenzyme A Reductase Inhibitors (Statins)

      Preoperative statin use is common in cardiac surgical patients, and an appealing mechanism for protective action exists. However, a large RCT (n = 1,922) examining perioperative rosuvastatin found an increased incidence of CSA-AKI within 48 hours in the intervention arm (25 v 19%, p = 0.005), although both AKI as a secondary outcome and the use of rosuvastatin may limit wider applicability.
      • Zheng Z
      • Jayaram R
      • Jiang L
      • et al.
      Perioperative rosuvastatin in cardiac surgery.
      No evidence for reduced CSA-AKI was found for atorvastatin use preoperatively and perioperatively in 2 RCTs and in a large propensity-matched observational study.
      • Park JH
      • Shim JK
      • Song JW
      • et al.
      Effect of atorvastatin on the incidence of acute kidney injury following valvular heart surgery: A randomized, placebo-controlled trial.
      • Billings FTt
      • Hendricks PA
      • Schildcrout JS
      • et al.
      High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: A randomized clinical trial.
      • Park J
      • Lee J-H
      • Kim KA
      • et al.
      Effects of preoperative statin on acute kidney injury after off-pump coronary artery bypass grafting.
      Meta-analysis data have likewise not demonstrated any renal benefit in a Cochrane Database Systematic Review (5 RCTs, n = 467, OR 0.57 [0.30-1.10]) and other meta-analyses, with 1 suggesting that although the class, on the whole, may not provide benefit, rosuvastatin may increase risk.
      • Lewicki M
      • Ng I
      • Schneider AG.
      HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass.
      • He SJ
      • Liu Q
      • Li HQ
      • et al.
      Role of statins in preventing cardiac surgery-associated acute kidney injury: An updated meta-analysis of randomized controlled trials.
      • Xiong B
      • Nie D
      • Cao Y
      • et al.
      Preoperative statin treatment for the prevention of acute kidney injury in patients undergoing cardiac surgery: A meta-analysis of randomised controlled trials.
      • Zhao BC
      • Shen P
      • Liu KX.
      Perioperative statins do not prevent acute kidney injury after cardiac surgery: A meta-analysis of randomized controlled trials.
      Similarly, 2 meta-analyses have demonstrated an increased risk of CSA-AKI with statin use, with an increased (OR 1.26 [1.05-1.52] and relative risk 1.18 [1.01-1.36]).
      • Zhao BC
      • Shen P
      • Liu KX.
      Perioperative statins do not prevent acute kidney injury after cardiac surgery: A meta-analysis of randomized controlled trials.
      ,
      • Wang S
      • Yao H
      • Yu H
      • et al.
      Effect of perioperative statin therapy on renal outcome in patients undergoing cardiac surgery: A meta-analysis of randomized controlled trials.
      A large, retrospective, observational study provided further contention with preoperative use associated with a lower incidence of all-stage CSA-AKI compared with control (31% v 36%, p < 0.001).
      • Tian Y
      • Li X
      • Wang Y
      • et al.
      Association between preoperative statin exposure and acute kidney injury in adult patients undergoing cardiac surgery.
      Currently, there is no renal indication for use, but continuation until surgery is appropriate and further evidence is required.

      Cardiovascular Support

      Levosimendan

      Levosimendan potentially can improve renal function by increasing cardiac output (CO) and independently causing renal arteriolar vasodilation. However, in several studies, an improvement in cardiac parameters did not result in reduced renal dysfunction.
      • Sharma P
      • Malhotra A
      • Gandhi S
      • et al.
      Preoperative levosimendan in ischemic mitral valve repair.
      • Shah B
      • Sharma P
      • Brahmbhatt A
      • et al.
      Study of levosimendan during off-pump coronary artery bypass grafting in patients with LV dysfunction: A double-blind randomized study.
      • Erb J
      • Beutlhauser T
      • Feldheiser A
      • et al.
      Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery.
      One meta-analysis of 13 relatively small studies (n = 1,345) demonstrated a reduction in CSA-AKI (OR 0.51 [0.34-0.76]) and RRT (OR 0.43 [0.25-0.76]).
      • Zhou C
      • Gong J
      • Chen D
      • et al.
      Levosimendan for prevention of acute kidney injury after cardiac surgery: A Meta-analysis of randomized controlled trials.
      However, a further meta-analysis of moderately larger studies (5 studies, n = 1,519) reported no difference in the rate of AKI (OR 0.61 [0.33-1.13]) compared with placebo for isolated CABG, combined procedures, and overall.
      • Zhu J
      • Zhang Y
      • Chen L
      • et al.
      Levosimendan in patients with low cardiac output syndrome undergoing cardiac surgery: A systematic review and meta-analysis.
      Furthermore, a recent pooled analysis of 2 multicenter RCTs of prophylactic use in patients with left ventricular ejection fraction ≤40% (LEVO-CTS and LICORN, n = 1,084), in which one study randomized patients to preoperative infusion and the latter to infusion starting postinduction, found no significant difference in RRT requirement (a secondary outcome). A specific post hoc analysis of LEVO-CTS found no reduction in CSA-AKI with prophylactic use (OR 0.92 [0.66-1.29]).
      • Caruba T
      • Charles-Nelson A
      • Alexander JH
      • et al.
      Prophylactic levosimendan in patients with low ejection fraction undergoing coronary artery bypass grafting: A pooled analysis of two multicentre randomised controlled trials.
      Currently, prophylactic use of levosimendan to improve renal outcomes in cardiac surgery is not an evidence-based recommendation, separate to routine initiation to support the acutely failing myocardium.

      Intra-Aortic Balloon Pump

      Intra-aortic balloon pumps (IABPs) can provide a modest degree of CO augmentation, and one meta-analysis of 17 studies has demonstrated benefit for prophylactic insertion in patients at high risk for CSA-AKI. The use of IABPs was associated with a reduced incidence of AKI in CABG (OR 0.54 [0.36-0.79]) and in off-pump coronary artery bypass (OPCAB) (OR 0.47 [0.27-0.81]).
      • Wang J
      • Yu W
      • Gao M
      • et al.
      Preoperative prophylactic intraaortic balloon pump reduces the incidence of postoperative acute kidney injury and short-term death of high-risk patients undergoing coronary artery bypass grafting: A meta-analysis of 17 studies.
      Appropriate use carries a Grade 2C recommendation in an expert consensus, but accurate placement must be ensured, and concerns can still arise about perfusion to the distal aorta and the renal arteries.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Any potential benefit needs to be interpreted in the context of the risk of insertion, anticoagulation, and use.

      Radiocontrast Exposure

      Emergency surgery patients may have recent significant contrast exposure, which is associated with CSA-AKI and contrast-induced nephropathy. These share numerous contributing factors, including diabetes mellitus, anemia, hemodynamic instability, and intravascular depletion.
      • Persson PB
      • Hansell P
      • Liss P.
      Pathophysiology of contrast medium-induced nephropathy.
      ,
      • Neumann FJ
      • Sousa-Uva M
      • Ahlsson A
      • et al.
      2018 ESC/EACTS Guidelines on myocardial revascularization.
      The postulated mechanisms of contrast-induced nephropathy include an increase in blood viscosity, with attendant effects on medullary perfusion, and direct cytotoxicity to the endothelium and tubular injury, with the mainstay of prophylaxis and management being adequate hydration.
      • Neumann FJ
      • Sousa-Uva M
      • Ahlsson A
      • et al.
      2018 ESC/EACTS Guidelines on myocardial revascularization.
      ,
      • Rear R
      • Bell RM
      • Hausenloy DJ.
      Contrast-induced nephropathy following angiography and cardiac interventions.
      The ability to do so may be influenced by the underlying cardiac pathology. North American guidance advises awaiting a postcontrast renal function assessment prior to proceeding to CABG in patients with known renal dysfunction when possible.
      • Lawton JS
      • Tamis-Holland JE
      • Bangalore S
      • et al.
      2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      This approach will not be appropriate for all patients, and, as the importance of recent contrast administration is disputed, it should be considered in the context of promptly restoring perfusion.
      • McIlroy DR
      • Epi MC
      • Argenziano M
      • et al.
      Acute kidney injury after cardiac surgery: Does the time interval from contrast administration to surgery matter?.

      Preoperative Patient Blood Management

      A large meta-analysis (22 studies, n = 114,277) has provided robust evidence for the association of preoperative anemia with an increased incidence of CSA-AKI (OR 3.13 [2.37-4.12]).
      • Padmanabhan H
      • Siau K
      • Curtis J
      • et al.
      Preoperative anemia and outcomes in cardiovascular surgery: Systematic review and meta-analysis.
      This has been corroborated by numerous studies, including a large multicenter registry study (n = 35,484) with an increasing OR for CSA-AKI with the increasing severity of anemia (all anemia OR 2.41 [1.97-2.95], mild [≤129 g/L for men, 119 g/L for women] anemia OR 2.20 [1.75-2.76], moderate-severe [<111 g/L for men, <110 g/L for women] anemia OR 2.63 [1.96-3.54]).
      • Hazen Y
      • Noordzij PG
      • Gerritse BM
      • et al.
      Preoperative anaemia and outcome after elective cardiac surgery: A Dutch national registry analysis.
      • Oprea AD
      • Del Rio JM
      • Cooter M
      • et al.
      Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: A retrospective observational study.
      • Karkouti K
      • Wijeysundera DN
      • Beattie WS.
      Risk associated with preoperative anemia in cardiac surgery: A multicenter cohort study.
      Tolerance of anemia is influenced by the degree of deviation from the patient's normal value, and so baseline hemoglobin concentration should be measured.
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      The influence of baseline hemoglobin concentration on tolerance of anemia in cardiac surgery.
      A restrictive transfusion policy (hemoglobin ≥75 g/L) was at least noninferior to a liberal policy in moderate-to-high-risk patients in a large (n = 5,243) multicenter study with RRT-requiring CSA-AKI as part of a composite primary outcome.
      • Mazer CD
      • Whitlock RP
      • Fergusson DA
      • et al.
      Restrictive or liberal red-cell transfusion for cardiac surgery.
      This finding has been further supported by a meta-analysis of 13 trials, with a restrictive transfusion threshold not associated with increased CSA-AKI compared with a liberal threshold (risk ratio 0.96 [0.76-1.20]).
      • Shehata N
      • Mistry N
      • da Costa BR
      • et al.
      Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: A meta-analysis.
      The incidence of CSA-AKI is affected significantly by an increased duration of perioperative anemia (assessed as cumulative time below a threshold hemoglobin value), which will influence any decision to correct preoperative anemia.
      • Duque-Sosa P
      • Martínez-Urbistondo D
      • Echarri G
      • et al.
      Perioperative hemoglobin area under the curve is an independent predictor of renal failure after cardiac surgery. Results from a Spanish multicenter retrospective cohort study.
      However, this multicenter study of 966 patients was not sufficient to derive a widely applicable critical threshold for time-weighted hemoglobin, with a likely substantial degree of variability between individuals. Furthermore, a large cohort study (n = 12,388) of patients undergoing surgery on CPB demonstrated that red cell transfusion was associated with a higher incidence of CSA-AKI in patients who were anemic preoperatively (hemoglobin <125 g/L) compared with those who were not (4% v 2%, p < 0.0001).
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      Influence of erythrocyte transfusion on the risk of acute kidney injury after cardiac surgery differs in anemic and nonanemic patients.
      These findings placed emphasis on the early correction of anemia, and this should preferably be done with nontransfusion methods if time allows. The use of erythropoietin and iron therapies is appropriate, although little evidence exists to support their direct role in reducing adverse renal outcomes.
      • Penny-Dimri JC
      • Cochrane AD
      • Perry LA
      • et al.
      Characterising the role of perioperative erythropoietin for preventing acute kidney injury after cardiac surgery: Systematic review and meta-analysis.
      ,
      • Tankard KA
      • Park B
      • Brovman EY
      • et al.
      The impact of preoperative intravenous iron therapy on perioperative outcomes in cardiac surgery: A systematic review.
      Routine preoperative transfusion should be avoided if DO2 is not critically low.
      • Karkouti K
      • Wijeysundera DN
      • Yau TM
      • et al.
      Advance targeted transfusion in anemic cardiac surgical patients for kidney protection: An unblinded randomized pilot clinical trial.
      For a summary of all preoperative measures to reduce incidence of CSA-AKI please see Figure 2.

      Intraoperative Management

      Cardiovascular Management

      Hemodynamic stability is key to reducing the burden of CSA-AKI by maintaining RPP and renal blood flow (RBF).
      • Kellum JA
      • Lameire N
      • Aspelin P
      • et al.
      Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury.
      Autoregulation assists in the maintenance of RBF, supported by a neurohormonal response.
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      ,
      • Lameire N.
      The pathophysiology of acute renal failure.
      On CPB, autoregulation will occur at a much lower threshold value, and maximal RBF is reduced markedly.
      • Slater JM
      • Orszulak TA
      • Cook DJ.
      Distribution and hierarchy of regional blood flow during hypothermic cardiopulmonary bypass.
      ,
      • Boston US
      • Slater JM
      • Orszulak TA
      • et al.
      Hierarchy of regional oxygen delivery during cardiopulmonary bypass.
      Renal perfusion will be affected by numerous intraoperative factors but, most importantly, by perfusion parameters on CPB and by surgical manipulation in ‘off-pump’ surgery. Individualized parameters, whether on-pump or off-pump, should be established by the multidisciplinary operating team.

      Mean Arterial Pressure Target

      Despite some contention, the best available evidence does not support the routine use of higher mean arterial pressure (MAP) (eg, 75-85 mmHg) to reduce CSA-AKI.
      • Azau A
      • Markowicz P
      • Corbeau JJ
      • et al.
      Increasing mean arterial pressure during cardiac surgery does not reduce the rate of postoperative acute kidney injury.
      • Peng K
      • McIlroy DR
      • Bollen BA
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice update for management of acute kidney injury associated with cardiac surgery.
      • Kanji HD
      • Schulze CJ
      • Hervas-Malo M
      • et al.
      Difference between pre-operative and cardiopulmonary bypass mean arterial pressure is independently associated with early cardiac surgery-associated acute kidney injury.
      • Gold JP
      • Charlson ME
      • Williams-Russo P
      • et al.
      Improvement of outcomes after coronary artery bypass. A randomized trial comparing intraoperative high versus low mean arterial pressure.
      One small RCT (n = 300) achieved good separation between the intervention and control arms (MAP 79 ± 6 mmHg v 60 ± 6 mmHg, respectively), but with no difference in CSA-AKI incidence (17% in both groups).
      • Azau A
      • Markowicz P
      • Corbeau JJ
      • et al.
      Increasing mean arterial pressure during cardiac surgery does not reduce the rate of postoperative acute kidney injury.
      A limited meta-analysis of only 3 studies (n = 579) supported this finding.
      • Peng K
      • McIlroy DR
      • Bollen BA
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice update for management of acute kidney injury associated with cardiac surgery.
      Therefore, routinely applying a higher MAP target is not appropriate. However, further study may be warranted as means by which this MAP is achieved, including the use of vasopressors with their attendant effects on regional kidney perfusion and renal microcirculation, which likely supervene in the relationship.
      In an influential, large (n = 33,330), retrospective noncardiac study, a nadir MAP <55 mmHg, and the time below that value, was associated with an increased risk of AKI.
      • 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.
      Equally robust data for CSA-AKI has not been produced to date. One study has shown that the duration of excursion beneath the cerebral autoregulation threshold is associated with the incidence of CSA-AKI; however, this has limited applicability to current clinical practice. The threshold has a high degree of interpatient variability, although a likely lower bound of 50 mmHg exists. This data could be extrapolated to suggest a nadir <50-to-55 mmHg should be avoided, although such an empirical approach would contradict the individualized approach for which the authors are advocating.
      • Ono M
      • Arnaoutakis GJ
      • Fine DM
      • et al.
      Blood pressure excursions below the cerebral autoregulation threshold during cardiac surgery are associated with acute kidney injury.
      One single-center retrospective study (n = 6,523) found that, post-CPB, each 10-minute period of MAP 55-to-64 mmHg and <55 mmHg was associated with an increased incidence of combined KDIGO stage 2 and 3 AKI (OR 1.13 [1.06-1.20] and 1.09 [1.02-1.16], respectively). Similar thresholds exist for RRT requirement (OR 1.12 [1.06-1.18] and 1.13 [1.05-1.23], respectively).
      • Ngu JMC
      • Jabagi H
      • Chung AM
      • et al.
      Defining an intraoperative hypotension threshold in association with de novo renal replacement therapy after cardiac surgery.
      Extrapolating from the best available evidence suggests that avoiding a nadir MAP <50-to-55 mmHg and taking steps to rapidly remedy a MAP below that threshold may be important to avoid adverse renal outcomes (Fig 3). Routine application of a higher target MAP does not appear to improve outcomes. Mitigating post-CPB hypotension may be a more efficacious and amenable measure, although more study is required. This latter finding may reflect the importance of the post-CPB hemodynamic instability and systemic adverse effects of low CO syndrome in this cohort.

      Vasoactive Support

      Vasopressor and inotropic use, depending upon the agent, will have differential effects on systemic hemodynamics and renovascular perfusion. Use must be considered within the context of concomitant volume therapy.
      • Fliser D
      • Laville M
      • Covic A
      • et al.
      A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: Part 1: Definitions, conservative management and contrast-induced nephropathy.
      Pure alpha-adrenergic agonism (eg, phenylephrine) may reduce RBF and cause increased hepatosplanchnic vasoconstriction, potentially reducing UO and creatinine clearance.
      • Grängsjö G
      • Persson E.
      Influence of some vaso-active substances on regional blood flow in the dog kidney. A study on normovolaemic and hypovolaemic dogs.
      ,
      • Morelli A
      • Lange M
      • Ertmer C
      • et al.
      Short-term effects of phenylephrine on systemic and regional hemodynamics in patients with septic shock: A crossover pilot study.
      Mixed agonism with norepinephrine is likely to be preferable.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      Although patients with normal or mildly deranged renal function may have shown an increased incidence of CSA-AKI with norepinephrine use, this does not necessarily amount to causation.
      • Lombardi R
      • Ferreiro A.
      Risk factors profile for acute kidney injury after cardiac surgery is different according to the level of baseline renal function.
      Vasopressin pharmacodynamics depend on receptor subtype activation and agonist concentration, and low-dose V1-receptor agonism can increase UO.
      • Koshimizu TA
      • Nakamura K
      • Egashira N
      • et al.
      Vasopressin V1a and V1b receptors: From molecules to physiological systems.
      ,
      • Eisenman A
      • Armali Z
      • Enat R
      • et al.
      Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure.
      These renal-specific effects all occur within the context of the systemic hemodynamic effects, and although preferential vasopressin use may lead to improvement in traditional markers of AKI, the wider literature in patients with septic shock does not always support this preference.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      ,
      • Patel BM
      • Chittock DR
      • Russell JA
      • et al.
      Beneficial effects of short-term vasopressin infusion during severe septic shock.
      ,
      • Russell JA
      • Walley KR
      • Singer J
      • et al.
      Vasopressin versus norepinephrine infusion in patients with septic shock.
      Similarly, historic preference for ‘renal-dose’ dopamine in cardiac surgical patients is not evidence-based, and 2 small studies have failed to demonstrate a renal protective effect.
      • Lassnigg A
      • Donner E
      • Grubhofer G
      • et al.
      Lack of renoprotective effects of dopamine and furosemide during cardiac surgery.
      ,
      • Woo EB
      • Tang AT
      • el-Gamel A
      • et al.
      Dopamine therapy for patients at risk of renal dysfunction following cardiac surgery: Science or fiction?.
      Inotropic and vasopressor support are associated with an increased risk of CSA-AKI, but this is likely to reflect the underlying systemic hemodynamics and the microcirculatory effects on renal perfusion.
      • Parolari A
      • Pesce LL
      • Pacini D
      • et al.
      Risk factors for perioperative acute kidney injury after adult cardiac surgery: Role of perioperative management.
      There is little evidence to support individual agents, but an approach that supports cardiac function alongside maintenance of vascular tone is appropriate. The prophylactic use of inotropes (with normal hemodynamic parameters) is not required, failing to reduce the incidence of CSA-AKI in one study (14% v 13%, p = 0.82), and inotropes should be commenced when indicated by usual criteria.
      • Franco RA
      • de Almeida JP
      • Landoni G
      • et al.
      Dobutamine-sparing versus dobutamine-to-all strategy in cardiac surgery: A randomized noninferiority trial.

      Perfusion and Mechanical Circulatory Support

      An increasing duration of CPB is associated with increased CSA-AKI but is largely nonmodifiable.
      • Lombardi R
      • Ferreiro A.
      Risk factors profile for acute kidney injury after cardiac surgery is different according to the level of baseline renal function.
      ,
      • Salis S
      • Mazzanti VV
      • Merli G
      • et al.
      Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery.
      • Husain-Syed F
      • Quattrone MG
      • Ferrari F
      • et al.
      Clinical and operative determinants of acute kidney injury after cardiac surgery.
      • Axtell AL
      • Fiedler AG
      • Melnitchouk S
      • et al.
      Correlation of cardiopulmonary bypass duration with acute renal failure after cardiac surgery.
      Decisions regarding perfusion will depend upon patient, surgeon, and operative factors and largely will be nonmodifiable. Furthermore, off-pump surgery is not reliably associated with a reduced incidence of CSA-AKI, with conflicting results from secondary analyses of 2 large RCTs.
      • Garg AX
      • Devereaux PJ
      • Yusuf S
      • et al.
      Kidney function after off-pump or on-pump coronary artery bypass graft surgery: A randomized clinical trial.
      • Deininger S
      • Hoenicka M
      • Müller-Eising K
      • et al.
      Renal function and urinary biomarkers in cardiac bypass surgery: A prospective randomized trial comparing three surgical techniques.
      • Shroyer AL
      • Grover FL
      • Hattler B
      • et al.
      On-pump versus off-pump coronary-artery bypass surgery.
      Long-term renal outcomes are not improved with OPCAB surgery, and surgical decision-making also should be informed by a potentially reduced 5-year survival with off-pump procedures.
      • 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.
      ,
      • Shroyer AL
      • Hattler B
      • Wagner TH
      • et al.
      Five-year outcomes after on-pump and off-pump coronary-artery bypass.
      Multiple strands of research have attempted to mitigate the harms of CPB. Increasing renal oxygenation by increased CPB flow rate (from 2.4-3.0 L/min/m2) has been studied in one small physiologic trial with a concomitant increase in GFR in proportion to the increased renal perfusion.
      • Lannemyr L
      • Bragadottir G
      • Hjärpe A
      • et al.
      Impact of cardiopulmonary bypass flow on renal oxygenation in patients undergoing cardiac operations.
      Further small clinical studies have demonstrated a reduction in CSA-AKI incidence, with prespecified elevated oxygen delivery targets compared with conventional perfusion (DO2 >300 mL/min/m2 15% v 30%, relative risk 0.48 [0.30-0.77]; DO2 >300 mL/min/m2 9% v 24% [p = 0.008]; DO2 >280 mL/min/m2 stage 1 AKI relative risk 0.45 [0.25-0.83]).

      Mukaida H, Matsushita S, Yamamoto T, et al. Oxygen delivery-guided perfusion for the prevention of acute kidney injury: A randomized controlled trial [e-pub ahead of print]. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2021.03.032. Accessed 17th July 2022.

      • Magruder JT
      • Crawford TC
      • Harness HL
      • et al.
      A pilot goal-directed perfusion initiative is associated with less acute kidney injury after cardiac surgery.
      • Ranucci M
      • Johnson I
      • Willcox T
      • et al.
      Goal-directed perfusion to reduce acute kidney injury: A randomized trial.
      However, further study of the clinical relevance is required, particularly to identify the subgroup most likely to benefit. An alternative strategy uses a miniaturized CPB circuit, with one small RCT demonstrating no reduction in AKI incidence (22% v 21%, p = 0.95), although this outcome may relate to the already reduced volume of modern conventional circuits.
      • Benedetto U
      • Luciani R
      • Goracci M
      • et al.
      Miniaturized cardiopulmonary bypass and acute kidney injury in coronary artery bypass graft surgery.
      ,
      • Chew STH
      • Ng RR
      • Liu W
      • et al.
      Miniaturized versus conventional cardiopulmonary bypass and acute kidney injury after cardiac surgery.
      Nonpulsatile flow transmits less mechanical energy to the vascular wall, producing lower levels of endothelial shear stress and vasodilatory substances. This leads to capillary collapse, microcirculatory shunting, and hypoperfusion, which subsequently increase sympathetic activity, causing vasoconstriction and reduced perfusion.
      • Dodonov M
      • Onorati F
      • Luciani GB
      • et al.
      Efficacy of pulsatile flow perfusion in adult cardiac surgery: Hemodynamic energy and vascular reactivity.
      However, laboratory models and data from patients with continuous-flow ventricular assist devices challenged this dogma, with more benefits derived from the primary increase in CO.
      • Dodonov M
      • Onorati F
      • Luciani GB
      • et al.
      Efficacy of pulsatile flow perfusion in adult cardiac surgery: Hemodynamic energy and vascular reactivity.
      • Farid S
      • Povey H
      • Anderson S
      • et al.
      The effect of pulsatile cardiopulmonary bypass on the need for haemofiltration in patients with renal dysfunction undergoing cardiac surgery.
      • Sandner SE
      • Zimpfer D
      • Zrunek P
      • et al.
      Renal function and outcome after continuous flow left ventricular assist device implantation.
      • Mao H
      • Katz N
      • Kim JC
      • et al.
      Implantable left ventricular assist devices and the kidney.
      • Elbers PW
      • Wijbenga J
      • Solinger F
      • et al.
      Direct observation of the human microcirculation during cardiopulmonary bypass: Effects of pulsatile perfusion.
      A retrospective single-center before-and-after study (n = 2,489) showed no difference in AKI incidence (24% [nonpulsatile] v 25% [pulsatile], p = 0.39) and AKI stage between the 2 strategies.
      • Coulson TG
      • McPhilimey E
      • Falter F
      • et al.
      The association between pulsatile cardiopulmonary bypass and acute kidney injury after cardiac surgery: A before-and-after study.
      Furthermore, in a small animal study, the use of IABP to achieve pulsatile perfusion reduced distal aortic pressure and worsened kidney function.
      • Lundemoen S
      • Kvalheim VL
      • Svendsen Ø S
      • et al.
      Intraaortic counterpulsation during cardiopulmonary bypass impairs distal organ perfusion.
      However, pulsatile CPB remains a grade 2D recommendation in expert consensus.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.

      Fluid Management

      Fluid Balance

      Fluid balance (FB) must be carefully managed intraoperatively, as positive FB and hemodilution are associated with increased CSA-AKI, even in patients with normal preoperative renal function.
      • Haase-Fielitz A
      • Haase M
      • Bellomo R
      • et al.
      Perioperative hemodynamic instability and fluid overload are associated with increasing acute kidney injury severity and worse outcome after cardiac surgery.
      ,
      • Lombardi R
      • Ferreiro A
      • Servetto C.
      Renal function after cardiac surgery: Adverse effect of furosemide.
      However, adequate volume status is vital to protect against hypoperfusion and minimize the deleterious effects of vasoactive therapies or anesthetic agents.
      • Silva AE
      • Castiglia YM
      • Módolo NS
      • et al.
      Does the choice of the halogenated anesthetic influence renal function during hemorrhagic shock and resuscitation?.
      Fluid management must avoid both extremes of the volume spectrum (Fig 3). A disproportionate degree of focus is on ensuring renal perfusion via the afferent limb of the system. However, RPP and renal parenchymal function are also influenced by the efferent limb, and venous congestion will result in AKI (Fig 4).
      Fig 4
      Fig 4Pathologies affecting the afferent and efferent limbs of the renovascular system and perioperative management. GDT, goal-directed therapy; LV, left ventricle; PEEP, positive end-expiratory pressure; RV, right ventricle.
      Fig 5
      Fig 5Postoperative management to reduce incidence of cardiac surgery-associated acute kidney injury. AKI; acute kidney injury; CO, cardiac output; CVP, central venous pressure; IGFBP7, insulin-like growth factor binding protein 7; KDIGO, Kidney Disease: Improving Global Outcomes; NGAL, neutrophil gelatinase-associated lipocalin; RV, right ventricle; RRT, renal replacement therapy; T, temperature; TIMP-2, tissue inhibitor of metalloproteinase 2; USS, ultrasound scan.
      A single-center retrospective cohort study (n = 5,127) of patients undergoing surgery on CPB investigated the association of AKI with venous congestion and intraoperative hypotension, reflecting both limbs of the renal system. Cardiac surgery-associated AKI was associated with combined venous congestion (indicated by an increased central venous pressure [CVP]) and intraoperative hypotension, and every 10 min-epoch of venous congestion of more than 11, 15, and 19 mmHg was associated with increasing ORs (1.03 [1.01-1.06], 1.06 [1.03-1.10], and 1.13 [1.06-1.21], respectively) for CSA-AKI.
      • Chen L
      • Hong L
      • Ma A
      • et al.
      Intraoperative venous congestion rather than hypotension is associated with acute adverse kidney events after cardiac surgery: A retrospective cohort study.
      These results confirmed previous findings at similar threshold values for the CVP.
      • Lopez MG
      • Shotwell MS
      • Morse J
      • et al.
      Intraoperative venous congestion and acute kidney injury in cardiac surgery: An observational cohort study.
      ,
      • Jacquet-Lagrèze M
      • Berthod C
      • Schweizer R
      • et al.
      Venous congestion is more accurate than hypotension in predicting acute kidney injury after cardiac surgery.
      Raised CVP can result from excess intravascular volume, systolic and diastolic heart dysfunction, increased vascular resistance, and intrathoracic pressure, and the above studies did not provide sufficient evidence of causation. Venous congestion is associated with reduced RPP and transglomerular pressure gradients, with the potential to induce inflammation, sympathetic response, and increased endothelial permeability.
      • Lopez MG
      • Shotwell MS
      • Morse J
      • et al.
      Intraoperative venous congestion and acute kidney injury in cardiac surgery: An observational cohort study.
      Furthermore, the impact of venous congestion on renal function will be altered by ventricular function, etiology of injury, and acuity.
      • Gambardella I
      • Gaudino M
      • Ronco C
      • et al.
      Congestive kidney failure in cardiac surgery: The relationship between central venous pressure and acute kidney injury.
      In the congested state, volureceptor stimulation may impact autonomic supply to the kidney more than baroreceptor stimulation, and the importance of venous congestion for worsening of renal function has been emphasized in cohort studies.
      • Chen L
      • Hong L
      • Ma A
      • et al.
      Intraoperative venous congestion rather than hypotension is associated with acute adverse kidney events after cardiac surgery: A retrospective cohort study.
      ,
      • Mullens W
      • Abrahams Z
      • Francis GS
      • et al.
      Importance of venous congestion for worsening of renal function in advanced decompensated heart failure.
      However, there is unlikely an absolute critical CVP threshold, and arterial pressure and inflammatory processes intervene for different patients and different intraoperative events. Although further study is required to demonstrate causation or identify an underlying common causative factor, there are some interventions, which may reduce the deleterious impact, including optimizing positive pressure ventilation (PPV) (and avoiding overzealous positive end-expiratory pressure), diuresis (or ultrafiltration), judicious volume management, and optimizing perfusion strategies (Fig 4).
      Intraoperative UO is of unclear significance in predicting postoperative CSA-AKI, with the stress response likely supervening in this relationship.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      ,
      • Parolari A
      • Pesce LL
      • Pacini D
      • et al.
      Risk factors for perioperative acute kidney injury after adult cardiac surgery: Role of perioperative management.
      ,
      • Knos GB
      • Berry AJ
      • Isaacson IJ
      • et al.
      Intraoperative urinary output and postoperative blood urea nitrogen and creatinine levels in patients undergoing aortic reconstructive surgery.
      Although intraprocedural furosemide can reduce venous congestion, 2 retrospective analyses have suggested that its use may increase CSA-AKI.
      • Lassnigg A
      • Donner E
      • Grubhofer G
      • et al.
      Lack of renoprotective effects of dopamine and furosemide during cardiac surgery.
      ,
      • Parolari A
      • Pesce LL
      • Pacini D
      • et al.
      Risk factors for perioperative acute kidney injury after adult cardiac surgery: Role of perioperative management.
      Crucially, the exact effect will relate to volume status, as above. Synthetic recombinant peptides, including atrial and brain natriuretic peptides,have potential physiologic benefits with a number in phase 2 trials, although concerns regarding systemic hypotension and a lack of outcome benefit have tempered enthusiasm.
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      ,
      • Nigwekar SU
      • Navaneethan SD
      • Parikh CR
      • et al.
      Atrial natriuretic peptide for management of acute kidney injury: A systematic review and meta-analysis.
      • Mentzer Jr., RM
      • Oz MC
      • Sladen RN
      • et al.
      Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: The NAPA Trial.
      • Le S
      • Xiao J
      • Li W
      • et al.
      Continuous administration of recombinant human B-type natriuretic peptide can improve heart and renal function in patients after cardiopulmonary bypass surgery.
      Intraoperative ultrafiltration is an alternative method for modulating FB, but in a small single-center RCT, it did not reduce the incidence of CSA-AKI or functional biomarker elevation.
      • Foroughi M
      • Argani H
      • Hassntash SA
      • et al.
      Lack of renal protection of ultrafiltration during cardiac surgery: A randomized clinical trial.
      ,
      • Paugh TA
      • Dickinson TA
      • Martin JR
      • et al.
      Impact of ultrafiltration on kidney injury after cardiac surgery: The Michigan experience.
      There may be a degree of protective effect in the clearance of inflammatory mediators.
      • Matata BM
      • Scawn N
      • Morgan M
      • et al.
      A single-center randomized trial of intraoperative zero-balanced ultrafiltration during cardiopulmonary bypass for patients with impaired kidney function undergoing cardiac surgery.
      Similar to perfusion-based strategies, this intervention may yield benefits for a specific subgroup of patients that need to be identified.
      Optimizing intraoperative FB is the responsibility of the anesthesiologist, cardiac surgeon, and perfusionist, and will be affected by the stage of the cardiac surgical procedure. The use of reproducible volume status assessments, such as echocardiography, is useful. Ultimately, continuation of optimizing the fluid status into the postoperative period is of importance.

      Types of Fluid

      There is a dearth of cardiac surgery-specific evidence; however, a large multicenter RCT, with a large proportion of cardiothoracic patients (49%), found no reduced incidence of AKI with balanced crystalloids compared with saline (10% v 9%, p = 0.77).
      • Young P
      • Bailey M
      • Beasley R
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: The SPLIT randomized clinical trial.
      A study of 600 OPCAB patients randomized to chloride-liberal or chloride-restrictive fluids demonstrated a reduced incidence of stage 1 AKI with chloride-restrictive fluids (5% v 9%, p < 0.05), and there was no incidence of higher-stage AKI.
      • Bhaskaran K
      • Arumugam G
      • Vinay Kumar PV
      A prospective, randomized, comparison study on effect of perioperative use of chloride liberal intravenous fluids versus chloride restricted intravenous fluids on postoperative acute kidney injury in patients undergoing off-pump coronary artery bypass grafting surgeries.
      However, a systematic review and meta-analysis assessing perioperative outcomes in the perioperative or intensive care setting in 21 studies (n = 6,253) suggested a significant association between higher chloride content fluids and unfavorable outcomes, including AKI.
      • Krajewski ML
      • Raghunathan K
      • Paluszkiewicz SM
      • et al.
      Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation.
      Synthetic colloid use is advised against by expert consensus in the context of widespread concern over their usage.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Reinhart K
      • Takala J.
      Hydroxyethyl starches: What do we still know?.
      ,
      • Schortgen F
      • Lacherade JC
      • Bruneel F
      • et al.
      Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study.
      These recommendations underlie the dearth of RCT evidence. Use of hydroxyethyl starch (HES) 130/0.4 as a pump prime and intraoperative fluid therapy in a before-and-after single-center study was associated with twice the odds for the development of CSA-AKI compared with crystalloid use (OR 2.26 [1.40-3.80]).
      • Lagny MG
      • Roediger L
      • Koch JN
      • et al.
      Hydroxyethyl starch 130/0.4 and the risk of acute kidney injury after cardiopulmonary bypass: A single-center retrospective study.
      However, the recent evaluation of modern HES solutions is providing conflicting evidence. In a multicenter, prospective cohort study of 1,058 patients, the use of 6% HES 130/0.4 was not associated with an increased risk of CSA-AKI (OR 1.01 [0.71-1.46]).
      • Vives M
      • Callejas R
      • Duque P
      • et al.
      Modern hydroxyethyl starch and acute kidney injury after cardiac surgery: A prospective multicentre cohort.
      Further small studies have supported this finding.
      • Nagore D
      • Candela A
      • Bürge M
      • et al.
      Hydroxyethyl starch and acute kidney injury in high-risk patients undergoing cardiac surgery: A prospective multicenter study.
      ,
      • Datzmann T
      • Hoenicka M
      • Reinelt H
      • et al.
      Influence of 6% hydroxyethyl starch 130/0.4 versus crystalloid solution on structural renal damage markers after coronary artery bypass grafting: A post hoc subgroup analysis of a prospective trial.
      Currently, there is a widely endorsed preference for balanced crystalloid use (with a grade 1B recommendation in expert consensus).
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      ,
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Modern starch solutions have appealing potential benefits, but there is not robust enough evidence to recommend their use.

      Blood Management

      Red cell transfusion intraoperatively is associated with an increased risk of CSA-AKI, in a dose-dependent fashion in some studies.
      • Husain-Syed F
      • Quattrone MG
      • Ferrari F
      • et al.
      Clinical and operative determinants of acute kidney injury after cardiac surgery.
      ,
      • Khan UA
      • Coca SG
      • Hong K
      • et al.
      Blood transfusions are associated with urinary biomarkers of kidney injury in cardiac surgery.
      • Kindzelski BA
      • Corcoran P
      • Siegenthaler MP
      • et al.
      Postoperative acute kidney injury following intraoperative blood product transfusions during cardiac surgery.
      • Rasmussen SR
      • Kandler K
      • Nielsen RV
      • et al.
      Association between transfusion of blood products and acute kidney injury following cardiac surgery.
      The restrictive use of blood transfusion is recommended (grade 1A) by expert consensus; however, at the same time, adequate DO2 must be ensured.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      A large retrospective analysis (n = 16,790) found the relative risk of CSA-AKI increased by 7% with each percentage decrement in hematocrit, with a marked inflection <24%.
      • Ranucci M
      • Aloisio T
      • Carboni G
      • et al.
      Acute kidney injury and hemodilution during cardiopulmonary bypass: A changing scenario.
      The maintenance of adequate hematocrit by reducing circuit and prime volume and of adequate oxygen delivery reduced CSA-AKI incidence in this study. Further support for this critical figure was demonstrated in another observational study, and severe hemodilution (ie a hematocrit <21%) was associated with an adjusted OR of 2.34 (1.47-3.41) for CSA-AKI requiring RRT (compared with moderate hemodilution). This suggested that below these thresholds, any improved microperfusion from altered blood rheology is negated by poor oxygen delivery to the kidneys.
      • Karkouti K
      • Beattie WS
      • Wijeysundera DN
      • et al.
      Hemodilution during cardiopulmonary bypass is an independent risk factor for acute renal failure in adult cardiac surgery.
      A large RCT demonstrated that a restrictive transfusion trigger (75 g/L, compared with a liberal 95 g/L), from the point of anesthetic induction onwards, is noninferior for a composite outcome (including CSA-AKI requiring dialysis) within 28 days. Although the study was not powered for the individual outcome of CSA-AKI requiring dialysis, there was no significant difference between the groups (restrictive 2.5% v liberal 3.0%) and for all CSA-AKI (34.0% v 33.9%).
      • Mazer CD
      • Whitlock RP
      • Fergusson DA
      • et al.
      Restrictive or liberal red-cell transfusion for cardiac surgery.
      A subsequent meta-analysis of 7 studies (n = 8,886) supported this finding (OR 1.03 [0.92-1.14]).
      • Chen QH
      • Wang HL
      • Liu L
      • et al.
      Effects of restrictive red blood cell transfusion on the prognoses of adult patients undergoing cardiac surgery: A meta-analysis of randomized controlled trials.
      European guidelines emphasize that acceptable intraoperative hematocrit levels depend on the individual risk profile of the patient and the ability to maintain tissue perfusion and oxygenation.
      • Pagano D
      • MIlojevic M
      • Meesters MI
      • et al.
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      ,
      • Kunst G
      • Milojevic M
      • Boer C
      • et al.
      2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery.
      Adjuncts to reduce the requirement for blood transfusion should be considered. Aminocaproic acid may cause a degree of renal tubular dysfunction but is largely safe, with tranexamic acid as an appropriate alternative.
      • Ortega-Loubon C
      • Fernández-Molina M
      • Carrascal-Hinojal Y
      • et al.
      Cardiac surgery-associated acute kidney injury.
      A bundle of patient blood management interventions (eg, preoperative anemia optimization, restrictive thromboelastography-guided transfusion policy, retrograde autologous circuit priming, reduced circuit volume, use of intraoperative cell salvage, and tranexamic acid use) has been shown to reduce the incidence of CSA-AKI in a before-and-after study (7.6% v 5.0%, p = 0.039) with reduced median blood loss (721 mL v 552 mL, p < 0.001) and a reduced red cell transfusion rate (39% v 21%, p < 0.001).
      • Gross I
      • Seifert B
      • Hofmann A
      • et al.
      Patient blood management in cardiac surgery results in fewer transfusions and better outcome.

      Blood Glucose Management

      Patients with chronic hyperglycemia (hemoglobin A1c ≥42 mmol/mol) are at risk of CSA-AKI, even without a formal diagnosis of diabetes mellitus, and a low threshold for close glucose monitoring and control should be considered.
      • Oezkur M
      • Wagner M
      • Weismann D
      • et al.
      Chronic hyperglycemia is associated with acute kidney injury in patients undergoing CABG surgery–a cohort study.
      ,
      • Kocogulları CU
      • Kunt AT
      • Aksoy R
      • et al.
      Hemoglobin A1c levels predicts acute kidney injury after coronary artery bypass surgery in non-diabetic patients.
      In keeping with wider perioperative management trends, moderate glycemic control is preferable to tight control, with a retrospective study of diabetic and/or hyperglycemic patients undergoing isolated CABG reporting lowest CSA-AKI incidence in the moderate glycemic control group (tight ≤126 mg/dL; moderate 127-179 mg/dL; liberal ≥180 mg/dL: 8.9% v 3.5% v 6.2%, respectively, p < 0.001). However, the incidence of preoperative renal failure was not evenly distributed among the groups, tempering this conclusion.
      • Bhamidipati CM
      • LaPar DJ
      • Stukenborg GJ
      • et al.
      Superiority of moderate control of hyperglycemia to tight control in patients undergoing coronary artery bypass grafting.
      ,
      • Lena D
      • Kalfon P
      • Preiser JC
      • et al.
      Glycemic control in the intensive care unit and during the postoperative period.
      A small RCT (N = 189) has demonstrated noninferiority for a moderately liberal (121-180 mg/dL) strategy compared with a strict regimen (90-120 mg/dL) for the incidence of CSA-AKI in the intention-to-treat analysis. Importantly, there were fewer hypoglycemic events and reduced variability in the liberal group (11% v 33%, p < 0.001), and no difference in maximum glucose level.
      • Desai SP
      • Henry LL
      • Holmes SD
      • et al.
      Strict versus liberal target range for perioperative glucose in patients undergoing coronary artery bypass grafting: A prospective randomized controlled trial.
      Taken together, these results suggested that a moderate glycemic target (120-179 mg/dL) is appropriate and readily deliverable intraoperatively. A variable rate insulin infusion should therefore be considered in patients likely to exceed this range.
      • Furnary AP
      • Gao G
      • Grunkemeier GL
      • et al.
      Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.

      Temperature Management

      The decision regarding temperature management during CPB is likely to be informed by numerous factors. Hypothermic perfusion is likely to reduce postoperative kidney injury, as was demonstrated in a recent systematic review and meta-analysis, including 48 trials (n = 6,690).
      • Abbasciano RG
      • Koulouroudias M
      • Chad T
      • et al.
      Role of Hypothermia in Adult Cardiac Surgery Patients: A Systematic Review and Meta-analysis.
      A small RCT and a multicenter observational study found a higher incidence of CSA-AKI, with rewarming to 37°C compared to 34°C, and that duration of rewarming temperature >37°C was an independent predictor of AKI.
      • Boodhwani M
      • Rubens FD
      • Wozny D
      • et al.
      Effects of mild hypothermia and rewarming on renal function after coronary artery bypass grafting.
      ,
      • Newland RF
      • Baker RA
      • Mazzone AL
      • et al.
      Rewarming temperature during cardiopulmonary bypass and acute kidney injury: A multicenter analysis.
      Therefore, hypothermic perfusion, avoidance of hyperthermic perfusion and overzealous rewarming are appropriate techniques to improve renal outcomes, with a consensus backing (grade 2C recommendation to avoid hyperthermia), although there is a dearth of high-quality evidence.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.

      Anesthesia Management

      The potential of different anesthetic agents to mitigate renal dysfunction is an understandable research interest. In one influential RCT, patients underwent preconditioning prior to CPB with either placebo or sevoflurane (2 minimum alveolar concentration), with significantly lower concentrations of plasma cystatin C, a marker of renal dysfunction in the intervention group.
      • Julier K
      • da Silva R
      • Garcia C
      • et al.
      Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: A double-blinded, placebo-controlled, multicenter study.
      ,
      • Kato R
      • Foëx P.
      Myocardial protection by anesthetic agents against ischemia-reperfusion injury: An update for anesthesiologists.
      Animal studies have further supported an in vivo beneficial effect with volatile anesthesia, protecting against renal ischemia-reperfusion injury.
      • Lee HT
      • Ota-Setlik A
      • Fu Y
      • et al.
      Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo.
      Conflicting results have arisen from 2 meta-analyses, with one (10 RCTs, n = 1,600) showing a significantly reduced risk of AKI (relative risk 0.65 [0.43-0.97]) with volatile (sevoflurane) anesthesia. However, many screened studies were excluded from this review due to heterogeneity in methodology and outcomes. Even between the included studies, there was notable heterogeneity, with nonstandardized outcomes and variable administration and/or concentration of volatile agents, reducing the strength of these conclusions.
      • Cai J
      • Xu R
      • Yu X
      • et al.
      Volatile anesthetics in preventing acute kidney injury after cardiac surgery: A systematic review and meta-analysis.
      A further meta-analysis of 7 RCTs and 1 cohort study (n = 2,218) found no risk reduction for the use of sevoflurane, desflurane, or isoflurane.
      • Tan SI
      • Brewster DJ
      • Horrigan D
      • et al.
      Pharmacological and non-surgical renal protective strategies for cardiac surgery patients undergoing cardiopulmonary bypass: A systematic review.
      The renal outcomes of intravenous anesthetic agents are less-extensively studied, but 1 small RCT favorably compared propofol with sevoflurane.
      • Yoo YC
      • Shim JK
      • Song Y
      • et al.
      Anesthetics influence the incidence of acute kidney injury following valvular heart surgery.
      However, a meta-analysis comparing these agents (8 studies) found no reduced incidence of CSA-AKI with volatile agents over propofol (OR 1.25 [0.77-2.03]), although the use of volatile agents still comes with a grade 2C recommendation in an expert consensus.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Bonanni A
      • Signori A
      • Alicino C
      • et al.
      Volatile anesthetics versus propofol for cardiac surgery with cardiopulmonary bypass: Meta-analysis of randomized trials.
      A small single-center RCT studying dexmedetomidine use intraoperatively has demonstrated a significantly lower sCr concentration (compared with dopamine administration), but sole intraoperative use has not been well-studied.
      • Soliman R
      • Hussien M.
      Comparison of the renoprotective effect of dexmedetomidine and dopamine in high-risk renal patients undergoing cardiac surgery: A double-blind randomized study.
      Meta-analysis data (4 RCTs, n = 1,387) are limited in scope and have not supported improved CSA-AKI incidence (15% v 18%; risk ratio 0.71 [0.41-1.21]).
      • Peng K
      • McIlroy DR
      • Bollen BA
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice update for management of acute kidney injury associated with cardiac surgery.
      Currently, little evidence exists to suggest one agent over any others, and, undoubtedly, the nature of use of each agent will have a substantial impact, alongside their class-based mechanisms.

      Remote Ischemic Preconditioning

      Remote ischemic preconditioning (RIPC) is of longstanding interest in reducing poor renal and other outcomes. Interpretation of the current data is complicated by the marked heterogeneity in the methodology of RIPC induction and the outcome of interest.
      • Tan SI
      • Brewster DJ
      • Horrigan D
      • et al.
      Pharmacological and non-surgical renal protective strategies for cardiac surgery patients undergoing cardiopulmonary bypass: A systematic review.
      Two high-quality RCTs have failed to demonstrate benefit in comparison with a sham intervention, with CSA-AKI as a secondary outcome (n = 1,612, 38.3% v 38.0%, p = 0.98) or part of a composite primary outcome (N = 1,403; no difference for composite outcome or CSA-AKI incidence alone [6.1% v 5.1%, p = 0.45]).
      • Hausenloy DJ
      • Candilio L
      • Evans R
      • et al.
      Remote ischemic preconditioning and outcomes of cardiac surgery.
      ,
      • Meybohm P
      • Bein B
      • Brosteanu O
      • et al.
      A multicenter trial of remote ischemic preconditioning for heart surgery.
      These well-conducted studies add substantial weight to the evidence base for no benefit. However, reflecting the vast number of studies, meta-analysis outcomes are diverse. One study of 19 trials of surgery on CPB (n = 5,100) reported a reduction in CSA-AKI (primary outcome, OR 0.84 [0.72-0.98]) but no impact on RRT requirement.
      • Zhang Y
      • Zhang X
      • Chi D
      • et al.
      Remote ischemic preconditioning for prevention of acute kidney injury in patients undergoing on-pump cardiac surgery: A systematic review and meta-analysis.
      However, a similar-sized meta-analysis (21 trials, n = 5,262) found no reduced CSA-AKI incidence (a co-primary outcome), and a Cochrane Database Systematic Review (primary outcome, 28 studies, n = 6,851) found similar, reporting a minimal impact for one AKI criteria alone (Acute Kidney Injury Network: risk ratio 0.76 [0.57-1.0]).
      • Pierce B
      • Bole I
      • Patel V
      • et al.
      Clinical outcomes of remote ischemic preconditioning prior to cardiac surgery: A meta-analysis of randomized controlled trials.
      ,
      • Menting TP
      • Wever KE
      • Ozdemir-van Brunschot DM
      • et al.
      Ischaemic preconditioning for the reduction of renal ischaemia reperfusion injury.
      In contrast, another RCT (the RenalRIPC study) reported reductions in CSA-AKI and major adverse kidney events with RIPC compared with a sham intervention (AKI: 38% v 53%, p = 0.02; major adverse kidney events: 14% v 25%, p = 0.03).
      • Zarbock A
      • Schmidt C
      • Van Aken H
      • et al.
      Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: A randomized clinical trial.
      ,
      • Zarbock A
      • Kellum JA
      • Van Aken H
      • et al.
      Long-term effects of remote ischemic preconditioning on kidney function in high-risk cardiac surgery patients: Follow-up results from the RenalRIP Trial.
      This study demonstrated a reduction in a composite renal outcome in higher-risk patients with improved recovery from CSA-AKI. Subsequent meta-analyses have demonstrated more positive results with the incorporation of this study. An analysis of 79 RCTs (n = 10,814) showed a reduced incidence of CSA-AKI (co-primary outcome) (22% v 24.4%, risk ratio 0.86 [0.77-0.97]).
      • Long YQ
      • Feng XM
      • Shan XS
      • et al.
      Remote ischemic preconditioning reduces acute kidney injury after cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.
      Expert guidance has graded the use of RIPC a 2B recommendation, but further study is required before routine adoption should be considered.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      For a summary of all intraoperative measures to reduce incidence of CSA-AKI please see Figure 3.

      Postoperative Management

      Reevaluating AKI Risk

      Postoperative risk assessment should occur early, and using novel biomarkers can occur within hours of arrival to the ICU, enabling early intervention. Urinary and serum NGAL has both diagnostic and prognostic functions, with demonstrated utility at 2 hours post-CPB and ICU admission before peaking at 6-to-12 hours postoperatively.
      • Haase M
      • Bellomo R
      • Devarajan P
      • et al.
      Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: A systematic review and meta-analysis.
      • 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.
      • Bennett M
      • Dent CL
      • Ma Q
      • et al.
      Urine NGAL predicts severity of acute kidney injury after cardiac surgery: A prospective study.
      • Parikh CR
      • Coca SG
      • Thiessen-Philbrook H
      • et al.
      Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery.
      • Devarajan P.
      Review: Neutrophil gelatinase-associated lipocalin: A troponin-like biomarker for human acute kidney injury.
      The most extensive evidence exists for TIMP-2 × IGFBP7, accounting for both their diagnostic and/or risk stratification abilities and their use to guide intervention—TIMP-2 × IGFBP7 has been shown to be predictive of subsequent KDIGO-defined AKI as early as 1 hour after the commencement of CPB.
      • Mayer T
      • Bolliger D
      • Scholz M
      • et al.
      Urine biomarkers of tubular renal cell damage for the prediction of acute kidney injury after cardiac surgery-a pilot study.
      However, although intraoperative risk assessment is appealing, the most robust evidence exists for early postoperative risk stratification. A comparative study of 400 patients examined 8 perioperative time points, finding a bimodal elevation with peaks intraoperatively (median 0.45 [ng/mL]2/1,000) and 6 hours postoperatively (1.45 [ng/mL]2/1,000), with each 10-fold increase in concentration associated with a 650% increase in odds for stage 2 to 3 AKI (p < 0.001).
      • Cummings JJ
      • Shaw AD
      • Shi J
      • et al.
      Intraoperative prediction of cardiac surgery-associated acute kidney injury using urinary biomarkers of cell cycle arrest.
      Biomarkers TIMP-2 × IGFBP7 have been used to guide intervention in two RCT (PrevAKI and PrevAKI-Multicenter).
      • 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.
      ,
      • Zarbock A
      • Küllmar M
      • Ostermann M
      • et al.
      Prevention of cardiac surgery-associated acute kidney injury by implementing the KDIGO guidelines in high-risk patients identified by biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.
      The former, a single-center RCT (n = 276), demonstrated that a biomarker-guided (implemented if >0.3 [ng/mL]2/1,000 4 hours after CPB) KDIGO-based renal care bundle (Box 1) reduces CSA-AKI (55% v 72%, p = 0.004 for all-stage; 30% v 45%, p = 0.009 for Stage 2-3). In the PrevAKI-Multicenter RCT (12 centers, n = 278) the biomarker-guided intervention reduced incidence of stage 2 to 3 CSA-AKI (14% v 24%, p = 0.034). Alternatively, a before-and-after study of a quality improvement initiative (n = 847) triaged interventions based upon specific thresholds (<0.3 [ng/mL]2/1,000, fast-track recovery; 0.3-2.0 [ng/mL]2/1,000, lower-level interventions; >2.0 [ng/mL]2/1,000, advanced interventions). This reduced stage 2 to 3 CSA-AKI (0.24% v 2.3%, p = 0.02).
      • Engelman DT
      • Crisafi C
      • Germain M
      • et al.
      Using urinary biomarkers to reduce acute kidney injury following cardiac surgery.
      Two meta-analyses have confirmed a reduced incidence of stages 2-to-3 AKI with biomarker-guided bundles (OR 0.55 [0.39-0.79] and risk ratio 0.64 [0.49-0.84]), although the included number of studies is small.
      • Peng K
      • McIlroy DR
      • Bollen BA
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice update for management of acute kidney injury associated with cardiac surgery.
      ,
      • Li Z
      • Tie H
      • Shi R
      • et al.
      Urinary [TIMP-2]·[IGFBP7]-guided implementation of the KDIGO bundle to prevent acute kidney injury: A meta-analysis.
      The expanding evidence base has led to more routine adoption of this biomarker-bundle intervention.
      • Milne B
      • Helyar S
      • Gilbey T
      • et al.
      Adoption of a novel biomarker-guided quality improvement treatment bundle for patients with subclinical acute kidney injury after cardiac surgery: A Royal Brompton Hospital-King's Health Partners Innovation Project.
      ,
      • Couturier C
      • Maillard N
      • Mariat C
      • et al.
      Prevention of cardiac surgery-associated acute kidney injury by risk stratification using (TIMP-2)*(IGFBP7).
      Box 1Renal care bundle elements from PrevAKI (Meersch [2017]
      • 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.
      ) and PrevAKI-Multicenter (Zarbock [2021]
      • Zarbock A
      • Küllmar M
      • Ostermann M
      • et al.
      Prevention of cardiac surgery-associated acute kidney injury by implementing the KDIGO guidelines in high-risk patients identified by biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.
      )
      For patients with TIMP-2 × IGFBP7 ≥0.3 at 4 hours after CPB:

      Avoidance of nephrotoxic agents

      Discontinuation of angiotensin converting enzyme inhibitors/angiotensin receptor blockers for 48 hours after surgery

      Close monitoring of serum creatinine and urine output

      Avoidance of hyperglycemia for 72 hours after surgery

      Consideration of alternatives to radiocontrast agents

      Close hemodynamic monitoring with an optimization protocol
      Numerous biomarkers show promise for the detection of CSA-AKI, including urinary kidney injury molecule-1, urinary L-type fatty acid binding protein, serum interleukin-6 and interleukin-18, and serum and/or urinary cystatin C.
      • Parikh CR
      • Coca SG
      • Thiessen-Philbrook H
      • et al.
      Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery.
      ,
      • Han WK
      • Waikar SS
      • Johnson A
      • et al.
      Urinary biomarkers in the early diagnosis of acute kidney injury.
      • Klein SJ
      • Brandtner AK
      • Lehner GF
      • et al.
      Biomarkers for prediction of renal replacement therapy in acute kidney injury: A systematic review and meta-analysis.
      • Dennen P
      • Altmann C
      • Kaufman J
      • et al.
      Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery.
      However, currently, the evidence is only robust enough to consider use of TIMP-2 × IGFBP7 or NGAL in clinical practice.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Engelman DT
      • Ben Ali W
      • Williams JB
      • et al.
      Guidelines for perioperative care in cardiac surgery: Enhanced recovery after surgery society recommendations.

      Cardiovascular Management

      Goal-Directed Hemodynamic Therapy

      Renal disease must be considered in the context of potential multisystem dysfunction, especially involving the cardiorespiratory system. Cardiorespiratory interactions can impair renal perfusion, but they also permit dynamic indices of cardiovascular function and fluid status, and goal-directed hemodynamic therapy (GDHT) can improve outcomes.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Aya HD
      • Cecconi M
      • Hamilton M
      • et al.
      Goal-directed therapy in cardiac surgery: A systematic review and meta-analysis.
      Evidence of association between vasoactive medication use and poorer renal outcomes should not be mistaken for clear causation.
      • Lombardi R
      • Ferreiro A.
      Risk factors profile for acute kidney injury after cardiac surgery is different according to the level of baseline renal function.
      ,
      • Parolari A
      • Pesce LL
      • Pacini D
      • et al.
      Risk factors for perioperative acute kidney injury after adult cardiac surgery: Role of perioperative management.
      Renal hypoperfusion and hemodynamic instability should be avoided, targeting a normalized cardiac index and balancing the benefits and harms of vasoactive and fluid therapy.
      • Haase-Fielitz A
      • Haase M
      • Bellomo R
      • et al.
      Perioperative hemodynamic instability and fluid overload are associated with increasing acute kidney injury severity and worse outcome after cardiac surgery.
      ,
      • Westaby S.
      Surgery for heart failure: Now something for everyone?.
      Certainly, avoidance of cardiac index <2 L/min/m2 for the first 48 hours should be ensured.
      • Lomivorotov VV
      • Efremov SM
      • Kirov MY
      • et al.
      Low-cardiac-output syndrome after cardiac surgery.
      Hemodynamic optimization was a key intervention in the PrevAKI study KDIGO-based care bundle, which involved invasive CO monitoring and GDHT.
      • 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.
      The PrevAKI study authors conducted an observational study to assess the pretrial penetration of the care bundle elements into routine practice and found that only 53% of patients receive advanced hemodynamic monitoring, suggesting a potential area for the standardization of practice.
      • Küllmar M
      • Weiß R
      • Ostermann M
      • et al.
      A multinational observational study exploring adherence with the Kidney Disease: Improving Global Outcomes recommendations for prevention of acute kidney injury after cardiac surgery.
      This finding has been reinforced in a large before-and-after study of a quality improvement initiative (n = 1,979) after the implementation of a GDHT protocol (designed to maintain cardiac index >2.5L/min/m2 and MAP >65 mmHg), where CSA-AKI was reduced (OR 0.63 [0.43-0.90]). These results should be interpreted in the context of a nonrandomized, open-label study, using the RIFLE (Risk of renal dysfunction; Injury to the kidney; Failure of kidney function; Loss of kidney function; End-stage kidney disease) criteria.
      • Johnston LE
      • Thiele RH
      • Hawkins RB
      • et al.
      Goal-directed resuscitation following cardiac surgery reduces acute kidney injury: A quality initiative pre-post analysis.
      Two further RCTs have found a reduction in the RRT requirement or CSA-AKI incidence (as part of primary and/or secondary composite outcomes) with GDHT but not separate from the composite outcome.
      • Goepfert MS
      • Richter HP
      • Zu Eulenburg C
      • et al.
      Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: A prospective, randomized controlled trial.
      ,
      • Osawa EA
      • Rhodes A
      • Landoni G
      • et al.
      Effect of perioperative goal-directed hemodynamic resuscitation therapy on outcomes following cardiac surgery: A randomized clinical trial and systematic review.
      The key difference from the PrevAKI studies was the absence of targeting of high-risk patients (by biomarker-guided assessment) as an intensive vasoactive and/or fluid therapy algorithm may not benefit the unselected patient cohort.
      Cardiovascular management includes the management of intravascular fluid status to optimize preload and biventricular function, use of vasopressors to maintain MAP, maintenance of sinus rhythm, and consideration of inotropic and mechanical support as required.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      Low CO syndrome is likely to contribute to CSA-AKI, and possible causes need to be considered and promptly corrected (Box 2).
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      ,
      • Landoni G
      • Bove T
      • Crivellari M
      • et al.
      Acute renal failure after isolated CABG surgery: Six years of experience.
      Vasoplegic shock is more common with the use of RAAS antagonists, and requires individualized consideration preoperatively. It may be refractory to standardized GDHT, and treatment with vasopressin compared with norepinephrine has been associated with lower severe AKI incidence and RRT requirement, likely reflecting its action at the renal efferent arterioles, although further study is required.
      • Vives M
      • Hernandez A
      • Parramon F
      • et al.
      Acute kidney injury after cardiac surgery: Prevalence, impact and management challenges.
      ,
      • Hajjar LA
      • Vincent JL
      • Barbosa Gomes Galas FR
      • et al.
      Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial.
      Box 2Causes of Postoperative Low-Cardiac-Output States (Chew [2019]
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      )
      Causes of Low Cardiac Output States

      Ventricular dysfunction

      Hypovolemia

      Prolonged cross clamp time

      Myocardial ischemia

      Cardiac Tamponade

      Hemorrhage

      Levosimendan

      Separate to a role in postoperative circulatory support, research interest has continued into more specific renal protective roles, for example, in ischemia-reperfusion injury.
      • Grossini E
      • Molinari C
      • Pollesello P
      • et al.
      Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs.
      One meta-analysis has found evidence of reduced incidence of CSA-AKI and RRT after perioperative use. However, there was marked heterogeneity among studies, including the timing of initiation, loading dose, and duration.
      • Zhou C
      • Gong J
      • Chen D
      • et al.
      Levosimendan for prevention of acute kidney injury after cardiac surgery: A Meta-analysis of randomized controlled trials.
      There is currently no evidence to support its use over other inotropes for renal outcomes.
      • Guerrero-Orriach JL
      • Malo-Manso A
      • Ramirez-Aliaga M
      • et al.
      Renal and neurologic benefit of levosimendan vs dobutamine in patients with low cardiac output syndrome after cardiac surgery: Clinical trial FIM-BGC-2014-01.

      Mechanical Circulatory Support

      Postcardiotomy cardiogenic shock affects 0.4%-to-3.7% and may require implementation of mechanical circulatory support (MCS; venoarterial extracorporeal membrane oxygenation or ventricular assist device insertion).
      • Lorusso R
      • Raffa GM
      • Alenizy K
      • et al.
      Structured review of post-cardiotomy extracorporeal membrane oxygenation: Part 1-Adult patients.
      Mechanical circulatory support is associated with high AKI incidence (11%-80%), the greatest in venoarterial extracorporeal membrane oxygenation, and with poor prognostic implications. With MCS, the pathophysiologic processes that occur during CPB continue, particularly those relating to the inflammatory, hemolytic, and thrombotic effects of the blood-air and/or membrane interface.
      • Austin D
      • McCanny P
      • Aneman A.
      Post-operative renal failure management in mechanical circulatory support patients.
      Implementation also can cause an ischemia-reperfusion injury and renal hypoperfusion due to poor forward flow.
      • Austin D
      • McCanny P
      • Aneman A.
      Post-operative renal failure management in mechanical circulatory support patients.
      ,
      • Khorsandi M
      • Dougherty S
      • Bouamra O
      • et al.
      Extra-corporeal membrane oxygenation for refractory cardiogenic shock after adult cardiac surgery: A systematic review and meta-analysis.
      Few specific MCS risk factors for CSA-AKI have been identified, but the duration of support is significant. Management to prevent CSA-AKI is largely similar to the non-MCS cohort. However, suspicion of device-related thrombus should be actively investigated and managed. Furthermore, numerous devices are preload-dependent, and management of fluid status becomes even more imperative.
      • Austin D
      • McCanny P
      • Aneman A.
      Post-operative renal failure management in mechanical circulatory support patients.

      Fluid Management

      Excessive positive FB is a risk factor for multiorgan failure, including CSA-AKI.
      • Haase-Fielitz A
      • Haase M
      • Bellomo R
      • et al.
      Perioperative hemodynamic instability and fluid overload are associated with increasing acute kidney injury severity and worse outcome after cardiac surgery.
      ,
      • Shen Y
      • Zhang W
      • Cheng X
      • et al.
      Association between postoperative fluid balance and acute kidney injury in patients after cardiac surgery: A retrospective cohort study.
      • Chau K
      • Schisler T
      • Er L
      • et al.
      Fluid balance, change in serum creatinine and urine output as markers of acute kidney injury post cardiac surgery: An observational study.
      • Stein A
      • de Souza LV
      • Belettini CR
      • et al.
      Fluid overload and changes in serum creatinine after cardiac surgery: Predictors of mortality and longer intensive care stay. A prospective cohort study.
      In a retrospective observational study (n = 3,899), positive FB at 48 hours increased the odds for CSA-AKI in proportion to the degree of positivity (FB: 11-30 mL/kg/48h: OR 1.27 [1.03-1.57], >30 mL/kg/48h: OR 2.04 [1.65-2.52]).
      • Shen Y
      • Zhang W
      • Cheng X
      • et al.
      Association between postoperative fluid balance and acute kidney injury in patients after cardiac surgery: A retrospective cohort study.
      A similar study has shown that positive 24-hour FB is associated with increased CSA-AKI incidence, and persistent 48-hour FB is associated with progressive CSA-AKI, demonstrating the importance of early intervention.
      • Chen X
      • Xu J
      • Li Y
      • et al.
      The effect of postoperative fluid balance on the occurrence and progression of acute kidney injury after cardiac surgery.
      However, negative FB does not necessarily reduce CSA-AKI incidence, and markedly low fluid intake (≤40 mL/kg/48h) increases the odds for CSA-AKI (OR 1.35 [1.07-1.70]) and marked negative FB at 48 hours (eg, ≤-30 mL/kg/48h) increases the likelihood of CSA-AKI progression (OR 7.08, p = 0.031).
      • Shen Y
      • Zhang W
      • Cheng X
      • et al.
      Association between postoperative fluid balance and acute kidney injury in patients after cardiac surgery: A retrospective cohort study.
      ,
      • Chen X
      • Xu J
      • Li Y
      • et al.
      The effect of postoperative fluid balance on the occurrence and progression of acute kidney injury after cardiac surgery.
      Volume status optimization with GDHT as part of the PrevAKI study KDIGO-based care bundle reduced CSA-AKI incidence.
      • 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.
      Goal-directed fluid therapy (GDFT) continues to be much debated. A small (n = 264) prospective observation study of GDFT (aiming to increase stroke volume by 10%) for 8 hours postoperatively reduced CSA-AKI incidence (7% v 20%, p = 0.002), despite no significant difference in the volume of fluid administered between intervention and control arms, emphasizing the importance of personalized intervention.
      • Thomson R
      • Meeran H
      • Valencia O
      • et al.
      Goal-directed therapy after cardiac surgery and the incidence of acute kidney injury.
      However, assessing the fluid therapy element of GDHT algorithms is difficult, and these are, appropriately, being studied increasingly in place of GDFT.
      Optimizing volume status also includes controlled volume unloading to reduce renal venous pressure (if required and guided by reproducible clinical assessment) and improve GFR.
      • Legrand M
      • Mebazaa A
      • Ronco C
      • et al.
      When cardiac failure, kidney dysfunction, and kidney injury intersect in acute conditions: The case of cardiorenal syndrome.
      High postoperative CVP is associated with an increased risk of CSA-AKI (1.11x [1.08-1.13] higher per mmHg increase in mean CVP), reflecting venous congestion.
      • McCoy IE
      • Montez-Rath ME
      • Chertow GM
      • et al.
      Central venous pressure and the risk of diuretic-associated acute kidney injury in patients after cardiac surgery.
      However, the CVP level did not alter the risk ratios for AKI with diuretic use, and other factors likely supervene in the CVP-volume status relationship. Echocardiographic assessment of the right ventricle to identify significant dysfunction in decompensated heart failure patients and, thus, those who would benefit from decongestion, has been effective.
      • Testani JM
      • Khera AV
      • St John Sutton MG
      • et al.
      Effect of right ventricular function and venous congestion on cardiorenal interactions during the treatment of decompensated heart failure.
      A single-center prospective cohort study examined the use of portal and intrarenal Doppler studies to identify venous congestion, finding both to be associated independently with CSA-AKI.
      • Beaubien-Souligny W
      • Benkreira A
      • Robillard P
      • et al.
      Alterations in portal vein flow and intrarenal venous flow are associated with acute kidney injury after cardiac surgery: A prospective observational cohort study.
      Translation of these findings into clinical practice, if warranted by further investigation, will be associated with significant educational requirements and need to account for interoperator variability.
      Individual studies of diuretic use intraoperatively and postoperatively have produced conflicting outcomes for CSA-AKI incidence, with one systematic review failing to show a significant difference but increased rates in large case-control and cohort studies.
      • Roberts DJ
      • Smith SA
      • Tan Z
      • et al.
      Angiotensin-converting enzyme inhibitor/receptor blocker, diuretic, or nonsteroidal anti-inflammatory drug use after major surgery and acute kidney injury: A case-control study.
      ,
      • Parolari A
      • Pesce LL
      • Pacini D
      • et al.
      Risk factors for perioperative acute kidney injury after adult cardiac surgery: Role of perioperative management.
      ,
      • Ho KM
      • Sheridan DJ.
      Meta-analysis of frusemide to prevent or treat acute renal failure.
      ,
      • Patel NN
      • Rogers CA
      • Angelini GD
      • et al.
      Pharmacological therapies for the prevention of acute kidney injury following cardiac surgery: A systematic review.
      The heterogeneity reflected the importance of a targeted approach to fluid management, identifying those patients with an afferent limb deficit (ie, requiring improved CO and increased renal arteriolar pressure) and those with an efferent limb pathology (ie, requiring venous decongestion), Fig 4. Furthermore, furosemide may precipitate temporary hypercreatininemia, even when contributing to improved proximal tubular function due to change and rate of change in intravascular status.
      • Lombardi R
      • Ferreiro A
      • Servetto C.
      Renal function after cardiac surgery: Adverse effect of furosemide.
      ,
      • Mahesh B
      • Yim B
      • Robson D
      • et al.
      Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.
      Alternative options for diuresis include tolvaptan (ie, vasopressin-2 receptor antagonist), which causes free water diuresis with minimal alteration to renal hemodynamics and increased postoperative UO and GFR.
      • Kato TS
      • Nakamura H
      • Murata M
      • et al.
      The effect of tolvaptan on renal excretion of electrolytes and urea nitrogen in patients undergoing coronary artery bypass surgery.
      ,
      • Yamada M
      • Nishi H
      • Sekiya N
      • et al.
      The efficacy of tolvaptan in the perioperative management of chronic kidney disease patients undergoing open-heart surgery.
      The RCT evidence is emerging for use, although the quantity and quality of included studies are low.
      • Chen H
      • Jiang W
      • Li X
      • et al.
      Efficacy of tolvaptan for fluid management after cardiovascular surgery: A systematic review and meta-analysis of randomized control trials.
      Use alongside conventional diuretics can improve FB without worsening creatinine clearance.
      • Nishi H.
      Advent of New perioperative care for fluid management after cardiovascular surgery: A review of current evidence.
      Alternatively, RRT can optimize FB in the absence of other criteria for initiation.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Goldstein S
      • Bagshaw S
      • Cecconi M
      • et al.
      Pharmacological management of fluid overload.
      ,
      • Rosner MH
      • Ostermann M
      • Murugan R
      • et al.
      Indications and management of mechanical fluid removal in critical illness.
      Cardiac surgery-associated AKI occurs at both ends of the volume spectrum, and a readily applicable, reproducible method of identifying patients existing at these extremes would be invaluable. Furthermore, at different time points, patients may occupy different points on the spectrum; for example, requiring fluid resuscitation early postoperatively before requiring ‘deresuscitation’ later. The evidence has suggested that empirical therapy, applied to all, is unlikely to be appropriate, whether that is unwarranted maintenance infusions or unguided diuresis. Aside from advanced imaging and pressure monitoring techniques, novel biomarkers may identify higher-risk patients that will benefit from specific strategies and should be further investigated.

      Respiratory Management

      Late extubation and duration of PPV have been associated with increased CSA-AKI, potentially independent from RPP, but this is not a unanimous finding due to a potentially large number of confounding variables.
      • Camp SL
      • Stamou SC
      • Stiegel RM
      • et al.
      Can timing of tracheal extubation predict improved outcomes after cardiac surgery?.
      • Xie X
      • Wan X
      • Ji X
      • et al.
      Reassessment of acute kidney injury after cardiac surgery: A retrospective study.
      • Heringlake M
      • Nowak Y
      • Schön J
      • et al.
      Postoperative intubation time is associated with acute kidney injury in cardiac surgical patients.
      • Flynn BC
      • He J
      • Richey M
      • et al.
      Early extubation without increased adverse events in high-risk cardiac surgical patients.
      In one study, CSA-AKI incidence was 17% in those extubated within 4 hours compared with 62% if ventilated for ≥16 hours.
      • Heringlake M
      • Nowak Y
      • Schön J
      • et al.
      Postoperative intubation time is associated with acute kidney injury in cardiac surgical patients.
      Separate from mechanical cardiorespiratory interactions, PPV will affect renal function via neurohumoral pathways, reducing RBF and GFR.
      • Marquez JM
      • Douglas ME
      • Downs JB
      • et al.
      Renal function and cardiovascular responses during positive airway pressure.
      When ongoing PPV is required, low tidal volume ventilation (<10 mL/kg) should be employed (grade 1C recommendation) to reduce the production of inflammatory mediators, which may worsen renal dysfunction.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Lellouche F
      • Dionne S
      • Simard S
      • et al.
      High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery.
      ,
      • Serpa Neto A
      • Cardoso SO
      • Manetta JA
      • et al.
      Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: A meta-analysis.
      Spontaneous ventilation is likely to be less deleterious and should be employed early.
      • Koning HM
      • Leusink JA
      • Nas AA
      • et al.
      Renal function following open heart surgery: The influence of postoperative artificial ventilation.

      Blood Management

      Anemia at ICU admission is associated with CSA-AKI, particularly in the context of preoperative anemia, as is postoperative transfusion.
      • Oprea AD
      • Del Rio JM
      • Cooter M
      • et al.
      Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: A retrospective observational study.
      ,
      • Freeland K
      • Hamidian Jahromi A
      • Duvall LM
      • et al.
      Postoperative blood transfusion is an independent predictor of acute kidney injury in cardiac surgery patients.
      In the absence of cardiac surgery-specific evidence, hemoglobin targets should be maintained as per routine critical care, and a level ≥70-to-80 g/L is appropriate.
      • Murphy GJ
      • Pike K
      • Rogers CA
      • et al.
      Liberal or restrictive transfusion after cardiac surgery.
      ,
      • Huang J
      • Firestone S
      • Moffatt-Bruce S
      • et al.
      2021 Clinical practice guidelines for anesthesiologists on patient blood management in cardiac surgery.
      Adjunctive therapies and viscoelastic testing should be employed as with intraoperative care.

      Blood Glucose Management

      The avoidance of hyperglycemia (>150 mg/dL for >3 hours) for 72 hours postoperatively was part of the PrevAKI study renal care bundle that reduced the incidence of stages 2-to-3 CSA-AKI in high-risk patients.
      • 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.
      Observational data from the PrevAKI study authors suggested that in routine practice concerning glycemic control, this standard is only achieved in 41% of patients.
      • Küllmar M
      • Weiß R
      • Ostermann M
      • et al.
      A multinational observational study exploring adherence with the Kidney Disease: Improving Global Outcomes recommendations for prevention of acute kidney injury after cardiac surgery.
      This may reflect general ICU practice favoring moderate control.
      • Finfer S
      • Chittock DR
      • Su SY
      • et al.
      Intensive versus conventional glucose control in critically ill patients.
      Although support for moderate control in CABG patients has been demonstrated, this was from a retrospective observational study in which patients were stratified by glycemic value, and so being in a ‘moderate’ range (127-179 mg/dL) may reflect stable patients (not requiring insulin infusion or on high-dose catecholamines) in whom outcomes are likely to be better.
      • Bhamidipati CM
      • LaPar DJ
      • Stukenborg GJ
      • et al.
      Superiority of moderate control of hyperglycemia to tight control in patients undergoing coronary artery bypass grafting.
      If there are incremental gains to be made from tight control, a strategy that identifies high-risk patients, such as novel biomarkers, would be an appropriate triage tool, but this requires further study. Currently, outside of research conduct, moderate control and the avoidance of glycemic variability should be sought.
      • Lena D
      • Kalfon P
      • Preiser JC
      • et al.
      Glycemic control in the intensive care unit and during the postoperative period.

      Temperature Management

      Temperature >38°C within 3 postoperative days has been identified as an independent risk factor for CSA-AKI, emphasizing the importance of actively managing pyrexia.
      • Xie X
      • Wan X
      • Ji X
      • et al.
      Reassessment of acute kidney injury after cardiac surgery: A retrospective study.
      Rewarming also must be managed closely with the post-CPB rewarming duration with temperature >37°C associated with increased CSA-AKI incidence.
      • Newland RF
      • Baker RA
      • Mazzone AL
      • et al.
      Rewarming temperature during cardiopulmonary bypass and acute kidney injury: A multicenter analysis.

      Drug Management

      RAAS Antagonists

      As previously discussed, one of the few studies to look at the postoperative initiation of RAAS antagonists reported no significant association with CSA-AKI, and perioperative continuation is also of unclear but contended importance.
      • Zhou H
      • Xie J
      • Zheng Z
      • et al.
      Effect of renin-angiotensin system inhibitors on acute kidney injury among patients undergoing cardiac surgery: A review and meta-analysis.
      ,
      • Drenger B
      • Fontes ML
      • Miao Y
      • et al.
      Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: Effects on in-hospital morbidity and mortality.
      However, de novo introduction or reinitiation early postoperatively does not present a favorable risk-benefit profile. Avoidance for 48 hours postoperatively was a part of the PrevAKI study renal care bundle and should be considered strongly.
      • 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.
      ,
      • Zarbock A
      • Küllmar M
      • Ostermann M
      • et al.
      Prevention of cardiac surgery-associated acute kidney injury by implementing the KDIGO guidelines in high-risk patients identified by biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

      Analgesia

      NSAID-mediated inhibition of prostaglandin synthesis is more pronounced after cardiac surgery.
      • Griffin M.
      Con: Nonsteroidal anti-inflammatory drugs should not be routinely administered for postoperative analgesia after cardiac surgery.
      A systematic review has found no increased CSA-AKI incidence in low-risk patients at normal therapeutic doses for a short duration.
      • Acharya M
      • Dunning J.
      Does the use of non-steroidal anti-inflammatory drugs after cardiac surgery increase the risk of renal failure?.
      A subsequent study with longer treatment duration and fewer low-risk patients demonstrated an increased CSA-AKI incidence in the ibuprofen group (RIFLE Risk: 10% v 3%, p = 0.14, RIFLE Injury: 10% v 0%, p = 0.01).
      • Qazi SM
      • Sindby EJ
      • Nørgaard MA.
      Ibuprofen – a safe analgesic during cardiac surgery recovery? A randomized controlled trial.
      However, in this study, the dose of ibuprofen was high (800 mg), and dysfunction may be lessened by reducing the dose or duration. Other NSAIDs have not shown an increased risk of adverse renal outcomes.
      • Nussmeier NA
      • Whelton AA
      • Brown MT
      • et al.
      Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.
      There is likely to be a cohort in whom NSAIDs are deleterious, emphasizing the importance of individualized decision-making, and this will be further informed by more evidence on the analgesic efficacy of an NSAID-based regimen.
      A multimodal analgesic regimen, including dexamethasone, gabapentin, ibuprofen, and paracetamol, had a better analgesic effect than a morphine-based regimen and was associated with a nonsignificant rise in the sCr level in the intervention group of a small RCT.
      • Rafiq S
      • Steinbrüchel DA
      • Wanscher MJ
      • et al.
      Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial.
      Further study with standardized AKI definitions is required. Alternative analgesic provision using a thoracic epidural block has limited evidence for improved renal outcomes, but concerns regarding systemic heparinization likely limit use.
      • Thiele RH
      • Isbell JM
      • Rosner MH.
      AKI associated with cardiac surgery.
      ,
      • Stenger M
      • Fabrin A
      • Schmidt H
      • et al.
      High thoracic epidural analgesia as an adjunct to general anesthesia is associated with better outcome in low-to-moderate risk cardiac surgery patients.
      ,
      • Svircevic V
      • Passier MM
      • Nierich AP
      • et al.
      Epidural analgesia for cardiac surgery.

      Sedation

      Dexmedetomidine has been postulated to improve renal outcomes by blunting sympathetic activity and reducing inflammatory mediator production, improving hemodynamic stability and mitigating ischemia-reperfusion injury.
      • Cho JS
      • Shim JK
      • Soh S
      • et al.
      Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery.
      ,
      • Ueki M
      • Kawasaki T
      • Habe K
      • et al.
      The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass.
      An RCT (n = 200) of perioperative use of dexmedetomidine, starting with an infusion (0.4 µg/kg/h) after induction and continuing for 24 hours after valve surgery, was associated with a reduced incidence of CSA-AKI within 48 hours (14% v 33%, p = 0.002).
      • Cho JS
      • Shim JK
      • Soh S
      • et al.
      Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery.
      A retrospective study of perioperative use (n = 1,134) found no difference in CSA-AKI (a secondary outcome), but had a higher incidence of preoperative dysfunction in the intervention group.
      • Ji F
      • Li Z
      • Nguyen H
      • et al.
      Perioperative dexmedetomidine improves outcomes of cardiac surgery.
      Postbypass infusion was associated with reduced CSA-AKI incidence in a retrospective study (n = 1,133) (26% v 34%, p = 0.009) and in an RCT with a novel biomarker (NGAL) definition for AKI.
      • Ji F
      • Li Z
      • Young JN
      • et al.
      Post-bypass dexmedetomidine use and postoperative acute kidney injury in patients undergoing cardiac surgery with cardiopulmonary bypass.
      ,
      • Balkanay OO
      • Goksedef D
      • Omeroglu SN
      • et al.
      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.
      Meta-analyses have been performed, including different patterns of use with the larger of the 2, including 10 RCTs (n = 1,575), showing that dexmedetomidine reduced CSA-AKI incidence (OR 0.65 [0.45-0.92])
      • Peng K
      • McIlroy DR
      • Bollen BA
      • et al.
      Society of Cardiovascular Anesthesiologists clinical practice update for management of acute kidney injury associated with cardiac surgery.
      ,
      • Liu Y
      • Sheng B
      • Wang S
      • et al.
      Dexmedetomidine prevents acute kidney injury after adult cardiac surgery: A meta-analysis of randomized controlled trials.
      ; its use to improve renal outcomes should be considered with a relatively favorable risk profile.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      Propofol has been much less studied for this outcome, and may have some antiinflammatory and immunomodulatory properties, attenuating ischemia-reperfusion injury and reducing CSA-AKI incidence, but its ubiquity limits the relevance of small studies.
      • Yoo YC
      • Shim JK
      • Song Y
      • et al.
      Anesthetics influence the incidence of acute kidney injury following valvular heart surgery.
      ,
      • Sánchez-Conde P
      • Rodríguez-López JM
      • Nicolás JL
      • et al.
      The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping.
      The hemodynamic compromise associated with greater concentrations of propofol may prove more deleterious than any anti-inflammatory benefits. Furthermore, there has been little evaluation of the use of opioids and benzodiazepines in sedation management, although they are recommended in shock states.
      • Zeymer U
      • Bueno H
      • Granger CB
      • et al.
      Acute Cardiovascular Care Association position statement for the diagnosis and treatment of patients with acute myocardial infarction complicated by cardiogenic shock: A document of the Acute Cardiovascular Care Association of the European Society of Cardiology.

      Other Nephrotoxic Agents

      Avoidance of nephrotoxic agents for 48 hours was included in the PrevAKI study biomarker-bundle intervention, and observational data showed avoidance occurred in 53% of patients, suggesting heterogeneity in clinical practice.
      • 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.
      ,
      • Zarbock A
      • Küllmar M
      • Ostermann M
      • et al.
      Prevention of cardiac surgery-associated acute kidney injury by implementing the KDIGO guidelines in high-risk patients identified by biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.
      ,
      • Küllmar M
      • Weiß R
      • Ostermann M
      • et al.
      A multinational observational study exploring adherence with the Kidney Disease: Improving Global Outcomes recommendations for prevention of acute kidney injury after cardiac surgery.
      However, the nature of the agents being used will be of vital importance, and, for example, the use of a potentially nephrotoxic antimicrobial agent, if indicated by culture sensitivities, is warranted.

      Radiocontrast Agents

      Postoperative avoidance of contrast agents also formed a part of the KDIGO-based care bundle.
      • 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.
      However, if contrast agents are required, for example, in the assessment of acute aortic pathology, this will take precedence.

      Specific Renal Management

      Measurement of sCr (twice-daily) and UO (hourly) should occur as in the PrevAKI study KDIGO-based renal care bundle, a practice that evidence has suggested routinely occurs in only 24% of patients.
      • 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.
      ,
      • Küllmar M
      • Weiß R
      • Ostermann M
      • et al.
      A multinational observational study exploring adherence with the Kidney Disease: Improving Global Outcomes recommendations for prevention of acute kidney injury after cardiac surgery.
      The management of established CSA-AKI was beyond the scope of this review and has been well described elsewhere.
      • Nadim MK
      • Forni LG
      • Bihorac A
      • et al.
      Cardiac and vascular surgery-associated acute kidney injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group.
      ,
      • Chew STH
      • Hwang NC.
      Acute kidney injury after cardiac surgery: A narrative review of the literature.
      Much of the management, as with the strategies reviewed here, will involve measures to mitigate the more serious grades of dysfunction and the more severe complications.
      For a summary of the postoperative management of CSA-AKI please see Figure 5.

      Conclusion

      Cardiac surgery-associated AKI is a major cause of postoperative morbidity and mortality. In the absence of a clear efficacious treatment, clinicians must take steps to prevent the development of renal dysfunction. Perioperative risk factors for the individual patient should be identified, and increasingly detailed risk prediction models are available. Throughout the perioperative period, there are management decisions that can reduce the chance of morbidity, although the evidence base is developed variably. Established renal dysfunction should be managed in accordance with the best available evidence, although a large part of this will not be specific to cardiac surgical patients.

      Conflict of Interest

      Gudrun Kunst has received speaker fees from Liva Nova, Edwards, and BioMerieux.

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