Cardiac Surgery–Associated Acute Kidney Injury

Abstract

AKI is a common and serious complication of cardiac surgery that has a significant impact on patient morbidity and mortality. The Kidney Disease Improving Global Outcomes definition of AKI is widely used to classify and identify AKI associated with cardiac surgery (cardiac surgery–associated AKI [CSA-AKI]) on the basis of changes in serum creatinine and/or urine output. There are various preoperative, intraoperative, and postoperative risk factors for the development of CSA-AKI which should be recognized and addressed as early as possible to expedite its diagnosis, reduce its occurrence, and prevent or ameliorate its devastating complications. Crucial issues are the inaccuracy of serum creatinine as a surrogate parameter of kidney function in the perioperative setting of cardiothoracic surgery and the necessity to discover more representative markers of the pathophysiology of AKI. However, except for the tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ratio, other diagnostic biomarkers with an acceptable sensitivity and specificity are still lacking. This article provides a comprehensive review of various aspects of CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, prevention, and treatment management.

Introduction

Cardiac surgery is a significant risk factor for AKI, affecting 5%–43% of patients and leading to increased mortality, extended hospital stays, and substantial health care costs.^1–9 Even patients with full kidney function recovery experience a heightened risk of CKD and mortality in the following years. ^9–11 The pathogenesis of cardiac surgery–associated AKI (CSA-AKI) is multifaceted, involving reduced renal blood flow, dislodged emboli obstructing renal arteries, and detrimental effects from cardiopulmonary bypass (CPB) (ischemia, hemolysis, inflammation, oxidative stress).^12,13 In addition, medications used during and after surgery can contribute to kidney injury. Collectively, these factors lead to renal dysfunction and characteristic electrolyte imbalances associated with CSA-AKI.

Current diagnostic methods for CSA-AKI have limitations, hindering early intervention and individualized patient management. Researchers are actively pursuing novel strategies for earlier and more precise diagnosis, including identifying the specific etiology of AKI in each patient. In addition, efforts are underway to develop methods for assessing complete recovery potential and predicting long-term outcomes. Furthermore, the possibility of preemptive diagnosis, allowing intervention before AKI onset, is being investigated alongside personalized risk stratification and management strategies tailored to individual patient profiles.

This review highlights the limitations of current CSA-AKI diagnosis using established criteria and provides insights into ongoing diagnostic advancements, encompassing early and etiologic diagnosis, evaluation of renal recovery potential, and prognosis. We further explore the potential of preemptive diagnosis to prevent AKI within the framework of personalized risk stratification and management strategies. Therefore, we conducted a targeted literature search on PubMed identified high-quality observational studies, randomized controlled trials, systematic reviews, and meta-analyses exploring the link between cardiac surgery and AKI. We focused on AKI, ARF, and cardiac surgery as search terms. This review prioritizes robust studies while acknowledging limitations in comprehensively covering all literature.

Diagnosis, Epidemiology, and Economic Consequences

Cardiac surgery poses a significant risk for AKI, with incidence varying from 19% to 29% depending on the specific procedure. This complication carries substantial clinical and economic burdens. Standard criteria for AKI diagnosis, including Kidney Disease Improving Global Outcomes (KDIGO), risk, injury, failure, loss of kidney function, and ESKD, and AKI Network (Table 1) may be unreliable after cardiac surgery because of the influence of fluid resuscitation on diagnostic markers.^14–17 While KDIGO demonstrates promise, further research is necessary to identify the optimal diagnostic criteria for this patient population.^18,19

Table 1.

Different criteria for the diagnosis of cardiac surgery–associated AKI

Classification Systems of AKI	SCr	Urine Output
RIFLE
Risk	• SCr increased by 1.5× • eGFR decreased by >25% within 7 d	• <0.5 ml/kg per hour for 6 h
Injury	• SCr increased by 2.0× • eGFR decreased by >50%	• <0.5 ml/kg per hour for 12 h
Failure	• SCr increased by 3.0× • SCr ≥4 mg/dl with acute rise ≥0.5 mg/dl • eGFR decreased by >75%	• <0.3 ml/kg per hour for ≥24 h • Anuria for ≥12 h
Loss	• Complete loss of kidney function >4 wk
ESKD	• Complete loss of kidney function >3 mo
AKIN
Stage 1	• SCr increased >0.3 mg/dl • SCr increased by 1.5× to 2.0×	• <0.5 ml/kg per hour for >6 h
Stage 2	• SCr increased by >2.0× to 3.0×	• <0.5 ml/kg per hour for >12 h
Stage 3	• SCr increased by >3.0× • SCr ≥4 mg/dl with acute rise ≥0.5 mg/dl	• <0.3 ml/kg per hour for 24 h • Anuria for 12 h
KDIGO
Stage 1	• SCr increased >0.3 mg/dl • SCr increased by 1.5× to 1.9×	• <0.5 ml/kg per hour for 6–12 h
Stage 2	• SCr increased by >2.0× to 2.9×	• <0.5 ml/kg per hour for ≥12 h
Stage 3	• SCr increased by >3.0× • SCr ≥4 mg/dl (≥353.6 µmol/L) • Initiation of RRT	• <0.3 ml/kg per hour for ≥24 h • Anuria for ≥12 h

AKIN, AKI network; d, days; h, hour; KDIQO, Kidney Disease Improving Global Outcomes; kg, kilogram; mg, milligram; µmol, micromole; ml, milliliter; RIFLE, risk, injury, failure, loss of kidney function, and ESKD; SCr, serum creatinine.

AKI can occur in nearly one in five patients after cardiac surgery. However, there are significant differences in AKI severity and surgical procedure, with the lowest and highest incidence being coronary artery bypass graft (CABG) surgery (19%) versus valve surgery (27.5%) or aortic surgery (29%).^20,21 Furthermore, a significant geographic disparity exists, with the highest incidence rates observed in Asia and the lowest in Europe.^20,21 The presence of AKI postsurgery is associated with prolonged stays in intensive care units and overall hospitals. In-hospital mortality rates reach 10.7%, with long-term mortality climbing to 30%.^22,23 Early recovery of kidney function improves long-term outcomes; however, even complete recovery elevates the risk of CKD and mortality for years after surgery.^9–11,24,25 The economic effect is significant, with hospitalizations exceeding $26,000 without the need for RRT and surpassing $69,000 with RRT. This translates to a national cost of nearly $1 billion annually in the United States.²⁶

Pathophysiology

CSA-AKI presents a significant challenge because of its complex and multifaceted etiology. Understanding the diverse insults occurring throughout a patient's surgical journey (Figure 1) is paramount for developing effective preventive and therapeutic strategies.

Figure 1.

Major pathogenic mechanisms of AKI associated with cardiac surgery based on ref. 9. The major pathogenic mechanisms of AKI can be attributed to various factors associated with major surgery, sepsis, or global hypoperfusion. In all scenarios, changes in systemic and glomerular hemodynamics, triggered by factors such as inflammation, anesthesia, volume changes, and myocardial depression, can lead to an initial decline in GFR, which may be reversible. In addition to hemodynamic changes, both sepsis and surgical tissue injury result in the release of DAMPs and PAMPs. These molecular patterns are recognized by TLRs, leading to the release of proinflammatory mediators such as various ILs (IL-1, IL-2, IL-6, etc.), TGFβ, TNF, IFNγ, and chemokines. Antimicrobial drugs used to treat infections may also contribute to kidney injury. DAMPs and PAMPs, along with specific immune responses and other inflammatory mediators, lead to the recruitment of inflammatory cells into the renal tubules. These toxins and mediators may act directly on the endothelium or be filtered in the glomerulus, causing tubular cell, endothelial, and microcirculatory injury. Severe damage can result in persistent clinical AKI that is refractory to systemic hemodynamic correction. Critical illness factors such as fluid overload and abdominal compartment syndrome can further contribute to AKI by increasing tubular pressure and decreasing glomerular perfusion. In the context of global hypoperfusion, AKI can also occur because of low cardiac output and systemic perfusion caused by factors such as hemorrhage, hypovolemia, acute heart failure, or cardiac arrest. Hemodynamic changes can lead to a reversible decline in GFR, while the direct effects of ischemia and reperfusion, along with DAMPs and other inflammatory mediators, can lead to persistent AKI. The ongoing inflammatory nature of renal injury after the initial insult may lead to persistent injury even after systemic perfusion is restored and may be associated with a second systemic vasodilatory response, as commonly seen after resuscitated cardiac arrest. (The influence of nephrotoxic drugs has been omitted for clarity.) DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor.

Renal hypoperfusion, particularly within the oxygen-avid medullary region, lies at the heart of CSA-AKI pathogenesis.¹² CPB significantly amplifies this risk by introducing suboptimal flow rates and pressures, nonpulsatile perfusion, hemodilution, and the potential for emboli formation and rewarming.^27–30 Furthermore, low cardiac output and hypotension further compromise perfusion by activating vasoconstrictive pathway.^{12,15,31–33} Venous congestion and bleeding during surgery add to the problem of inadequate oxygen delivery.^34–36

The crucial role of oxygen supply imbalance during CPB cannot be overstated. Reduced hemoglobin concentration and the inherent hemodilution of this technique decrease the blood's oxygen-carrying capacity, potentially leading to AKI. Research by Ranucci et al. suggests that the nadir of oxygen supply during CPB, with a critical threshold of <272 ml/min per m², is the most accurate predictor of CSA-AKI.³⁷ While moderate hemodilution (hematocrit >25%) is considered acceptable, both extreme hemodilution and transfusions are associated with increased AKI and dialysis risk.³⁸ Cholesterol embolization, more likely after preoperative procedures or during surgery itself, can further worsen ischemia and trigger inflammation.³⁹ Ischemia–reperfusion injury adds another layer of complexity to the pathogenesis of CSA-AKI. This injury is characterized by mitochondrial dysfunction, increased production of harmful molecules (reactive oxygen species), and promotion of inflammation and oxidative stress.^40,41

Cardiac surgery triggers systemic inflammation due to CPB, ischemia–reperfusion, and oxidative stress. This cascade involving the immune system and endothelium can lead to tubular damage and AKI.⁴² CPB circuit materials themselves can worsen inflammation.^26,43–46 Tissue hypoxia and endothelial damage from inadequate blood flow further contribute.^47,48 The inflammatory response disrupts renal oxygen delivery and promotes AKI, while free iron released from hemolysis during CPB fuels further oxidative stress.^49–52

Several factors beyond the core insult of hypoperfusion can exacerbate CSA-AKI risk. Cardiac surgery patients are often exposed to nephrotoxic medications like antibiotics and NSAIDs.⁵³ Medications influencing hemodynamics, such as angiotensin-converting enzyme inhibitors and ARBs, can also contribute.⁵⁴ Hemodynamic changes during surgery trigger neurohormonal adaptations that can lead to reduced renal perfusion and increased AKI risk.^54,55 Septic embolism in infective endocarditis patients poses an additional threat.⁵⁶ Finally, while evidence remains inconclusive, genetic polymorphisms may influence susceptibility to CSA-AKI.^57–59

Prevention and Treatment of CSA-AKI

Identifying Patients at High Risk for CSA-AKI, Risk Prediction Models, Prehabilitation

Early identification of at-risk patients is crucial for preventing CSA-AKI. Established risk factors include demographics (age, sex) and preexisting conditions (CKD, diabetes, etc.) (Table 2). Optimizing these comorbidities preoperatively is essential, although they are nonmodifiable.^60,61

Table 2.

Risk factors for cardiac surgery associated AKI

Patient-related factors
• Advanced age  • Cardiogenic shock (requiring IABP)  • COPD  • Congestive heart failure  • Diabetes mellitus	• Female sex  • Left ventricular ejection fraction <35%  • Left main coronary artery disease  • Need for emergency surgery  • Peripheral vascular disease  • Preexisting CKD  • Previous cardiac surgery
Procedure-related factors
• CPB time  • Cross-clamp time  • Hemodilution	• Hemolysis  • On-pump versus off-pump  • Pulsatile versus nonpulsatile perfusion
Preoperative factors
• Advanced age  • COPD  • Diabetes mellitus  • Female sex  • Heart failure  • Left main coronary artery disease  • Liver disease	• Low cardiac output states or hypotension (cardiogenic shock from acute myocardial infarction, mechanical complications of myocardial infarction)  • Nephrotoxins  • Peripheral vascular disease  • Renal dysfunction
Intraoperative factors
• CPB duration >100–120 min  • CPB non-pulsatile, low-flow, low-pressure perfusion  • Deep hypothermic circulatory arrest  • Embolism  • Hemodilution	• Hemolysis and hemoglobinuria from prolonged duration of CPB  • Hypothermic CPB  • Type of surgery (valvular, valvular and coronary, emergency and redo surgery)  • Venous congestion
Postoperative factors
• Atheroembolism  • Hypotension  • Intense vasoconstriction  • Nephrotoxins	• Low cardiac output (decreased contractility, hypovolemia and absent atrioventricular synchrony in hypertrophied hearts)  • Sepsis  • Venous congestion

COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass; IABP, intra-aortic balloon pump.

Clinical and surgical risk factors have been integrated into prediction models like the Cleveland Clinic Score (Table 3).^62–64 These models accurately predict severe AKI, but a key limitation is their reliance on static data, which may not capture the dynamic nature of surgery's effect on AKI. Future models incorporating real-time data like hemodynamics and evolving kidney biomarkers hold promise for more comprehensive AKI prediction across all stages.^65,66

Table 3.

Different clinical prediction models for cardiac surgery–associated AKI

Variables of the Cleveland Clinic Score64	Variables of the Mehta Score62	Variables of the Simplified Renal Index63
Test cohort: n=15,838 Validation cohort: n=15,839	Test cohort: n=449,524 Validation cohort: n=86,009	Test cohort: n=10,751 Validation cohort 1: n=2566 Validation cohort 2: n=6814
AUC test cohort: 0.81 (95% CI 0.78 to 0.83) AUC validation cohort: 0.82 (95% CI 0.80 to 0.85)	—	AUC test cohort: 0.81 (95% CI 0.78–0.84) AUC validation cohort 1: 0.79 (95% CI, 0.72–0.84) AUC validation cohort 2: 0.78 (95% CI, 0.74–0.81)
Include variables (points)
Female sex (1)	Age 55 or older (0–10)	Preoperative GFR (1–2)
Congestive heart failure (1)	Non-White race (2)	Diabetes requiring medications (1)
Left ventricular ejection fraction <35% (1)	Preoperative SCr (5–40)	Left ventricular ejection fraction ≤40% (1)
Preoperative intra-aortic ballon pump (2)	New York Heart Association class 4 heart failure (3)	Previous cardiac surgery (1)
COPD (1)	Diabetes treated with oral medications (2)	Preoperative intra-aortic ballon pump (1)
Insulin-dependent diabetes (1)	Insulin-dependent diabetes (5)	Nonelective surgery (1)
Previous cardiac surgery (1)	COPD (3)	Type of surgery (1)
Emergency surgery (1)	Recent myocardial infarction (3)
Type of surgery (0–2)	Previous cardiac surgery (3)
Preoperative SCr (0–5)	Cardiogenic shock (7)
	Type of surgery (0–7)
Score range: 0–17	Score range: 0–85	Score range: 0–8

The numbers in parentheses indicate the number of possible points. AUC, area under the curve; CI, confidence interval; COPD, chronic obstructive pulmonary disease; SCr, serum creatinine.

Prehabilitation programs aim to improve patient resilience and reduce complications after cardiac surgery. These programs, recommended to start at least 4 weeks preoperatively, have shown benefits in reducing hospital stay and pulmonary complications.^67,68 However, further research is needed to determine their effect on preventing CSA-AKI. ^69,70

The KDIGO Bundle of Care

The 2012 guidelines from KDIGO suggest various supportive measures to prevent and treat AKI. These measures include discontinuing nephrotoxins, optimizing fluid status and hemodynamics, using functional hemodynamic monitoring, regularly monitoring serum creatinine and urine output, and avoiding hyperglycemia, among other recommendations.⁷¹

Perioperative Medications, Nephrotoxins

Certain medications can significantly increase the risk of AKI, particularly in vulnerable populations. When administering antibiotics, including aminoglycosides and vancomycin, individualized dosing regimens and meticulous monitoring are essential.^71,72 For patients with preexisting conditions, cautious use of NSAIDs and exploration of alternative analgesics are crucial to prevent compromising renal function.^73,74 Delaying surgery by at least 48 hours after contrast media administration is generally recommended to reduce renal damage.^75–78 While the perioperative management of angiotensin-converting enzyme inhibitors and ARBs remains under investigation, discontinuing them 24 hours presurgery, as per the Acute Disease Quality Initiative (ADQI)/Perioperative Quality Initiative and KDIGO bundle recommendations, and potentially extending withdrawal for 48 hours postsurgery, may further reduce the risk of AKI.^79–84

Glucose Homeostasis

Perioperative hyperglycemia is associated with increased mortality, morbidity, and a heightened risk of AKI in cardiac surgery patients.⁸⁵ While initial investigations suggested potential benefits of strict glycemic control (80–110 mg/dl) through intensive insulin therapy, subsequent studies have challenged this strategy.⁸⁵ Current evidence reveals that maintaining moderate blood sugar levels below 150 mg/dl, without resorting to aggressive insulin interventions, provides a safer and more effective approach in this patient population.⁸⁶

Intravenous Fluids and Diuretics

Cardiac surgery disrupts fluid balance, affecting renal perfusion and potentially leading to AKI. Both excess and insufficient fluid pose risks, contributing to endothelial damage, edema, and AKI. Recent research suggests a positive fluid balance increases AKI risk, with higher mortality, cardiovascular complications, and longer hospital stays in patients receiving liberal fluid strategies.^2,87–90 Fluid choice also influences AKI development. Hydroxyethyl starch is discouraged in high-risk patients because of its increased AKI risk.^91–93 Balanced crystalloid solutions such as Ringer's lactate show a lower AKI risk compared with 0.9% saline because of potential chloride-induced complications.⁹⁴ Consensus guidelines recommend balanced crystalloids over saline for resuscitation.^83,91–93 The Albumin in Cardiac Surgery trial found no significant difference in AKI between Ringer's acetate and 4% albumin, but albumin might increase bleeding and other complications, limiting its use.⁹⁵

While diuretics are commonly used, loop diuretics can decrease creatinine clearance and aldosterone antagonists may increase AKI risk; hence, their use for AKI prevention is not recommended.^71,96,97 Mannitol, used in CPB priming, showed no significant improvement in renal function and is currently not recommended for this purpose.^98–100

Inotropic and Vasopressor Support, Target of Mean Arterial Pressure

Cardiac surgery disrupts hemodynamics, potentially leading to AKI through impaired renal perfusion and ischemia. While some studies link intraoperative hypotension to AKI risk, others reveal no clear benefit of targeting higher BP during surgery.^1,101–107

Inotropic and vasopressor medications (NE, vasopressin, dopamine, angiotensin II [AT2]) aim to improve kidney perfusion and BP during low cardiac output and hypotension. While vasopressin initially showed promise for vasoplegic shock, the ADQI group recommends NE as the first-line choice because of limited supporting evidence.^70,108,109 Dobutamine, however, has shown effectiveness in preventing AKI when included in the KDIGO care bundle, as demonstrated by PREV-AKI studies.^83,84

Vasoplegia during bypass surgery requires increased vasopressors and fluids, worsens kidney perfusion, and increases AKI risk.¹¹⁰ Recent studies suggest AT2 may be a promising treatment for both vasoplegic shock and AKI in specific patient groups. Postoperative hyperreninemia, linked to higher AKI risk, might be mitigated by AT2's potential to reduce renin and NE needs while preserving aldosterone, unlike NE.^111–114 While further research is needed, AT2's potential to lessen AKI, especially in patients with vasoplegia and a history of renin–angiotensin blockade, warrants exploration to improve outcomes.

Hemodynamic Monitoring and Improvement

Two large trials investigated the KDIGO bundle for AKI prevention in high-risk cardiac surgery patients. Both studies used continuous cardiac output monitoring and optimized mean arterial pressure and cardiac index.^83,84 Compared with standard care, the bundle significantly reduced severe AKI (stages 2 and 3) in the single-center trial but only showed this benefit for severe AKI in the multicenter trial. The study used an algorithmic approach to optimize hemodynamics, aiming to maintain mean arterial pressure above 65 mm Hg and cardiac index above 2.5 L/min per m². This involved fluid management and dobutamine administration to achieve these targets, consequently leading to increased fluid and dobutamine use in the intervention group.

Biomarker-Guided Implementation of Nephroprotective Care Bundles

Early detection of subtle kidney changes (subclinical AKI) is crucial for timely intervention in cardiac surgery (Figure 2). The ADQI group proposed a new AKI definition integrating functional and damage markers to enable early detection and potentially prevent long-term complications.^115–117 Several promising biomarkers have emerged, with different roles (Table 4). Clinical trials like PrevAKI-1 and PrevAKI-2 demonstrated that the KDIGO care bundle, guided by biomarkers like (tissue inhibitor of metalloproteinase-2)×(insulin-like growth factor binding protein 7), significantly reduced AKI rates in high-risk patients.^{83,84,118,119} In addition, the TRIBE-AKI study suggests that including specific biomarkers (IL-18 and neutrophil gelatinase–associated lipocalin) alongside clinical factors can further improve AKI prediction. ¹²⁰

Figure 2.

Stages of AKI potentially subject to diagnosis. Figure based on ref. 252.

Table 4.

Biomarkers in cardiac surgery–associated AKI

Marker	Description/Origin in Nephron	Advantages	Disadvantages	Examples of Studies
Cystatin C	• Cysteine proteinase inhibitor • Glomerulus, proximal tubule	• Levels are not affected by sex or muscle mass	• Studies present conflicting findings regarding the predictive value of cystatin C for CSA-AKI when compared with SCr121,122	• In a prospective cohort study involving 72 patients, urinary cystatin C emerged as a predictive marker for AKI after cardiac surgery121
TIMP-2, IGFBP7	• Urinary biomarkers of cell cycle arrest • Proximal tubule	• Urinary measurement of the product of (TIMP-2) and (IGFBP7) demonstrates superior diagnostic performance in stratifying AKI risk compared to standard clinical assessment	• TIMP-2, with its ability to promote cellular proliferation, demonstrates strong expression in renal cell carcinoma123 • Elevation in levels may be nonspecific and could result from filtration with impaired proximal tubular reabsorption rather than in situ renal tubular damage	• The product of (TIMP-2) and (IGFBP7) proved to be a predictor for AKI in a study comprising 51 children undergoing CPB124 • TIMP-2 and IGFBP7 outperforms existing methods for predicting moderate to severe AKI in 522 patients with sepsis, shock, major surgery, and trauma125 • A meta-analysis (n=1619) validates the efficacy of TIMP-2×IGFBP7 for CSA-AKI prediction with a cutoff of 0.3 (ng/ml)2/1000 (sensitivity: 0.89, specificity: 0.48, diagnostic odds ratio: 8.33)126 • Using TIMP-2 and IGFBP7, as opposed to the normal KDIGO care bundle, significantly reduced AKI severity, postoperative creatinine increase, and the length of ICU and hospital stay83,84,118,119
Dickkopf-3	• Modulator of tubulointerstitial fibrosis (marker of ongoing tubular stress)	• DKK3 is the only validated biomarker for CSA-AKI that can measure risk before injury occurs • Likely exhibits independent expression for the severity of CKD	• Dickkopf 3 levels undergo changes not exclusive to CSA-AKI; increased levels are also observed in other forms of AKI; moreover, it is not considered a marker for the early diagnosis of CSA-AKI	• Preoperative urine levels of DKK3 identified high-risk patients and predicted postoperative AKI (probability cutoff of 0.31, sensitivity 76.0%, specificity 79.1%, positive likelihood ratio 3.64, and negative likelihood ratio 0.30)127 • High preoperative levels were associated with significantly reduced long-term kidney function, reflecting the AKI-to-CKD transition127,128
NGAL	• Serum and urinary marker of tubular damage129,130 • Glomerulus, distal tubule, collecting duct	• Levels exhibit a rapid increase after renal ischemia–reperfusion injury • Demonstrates high diagnostic value in CSA-AKI, particularly in patients with normal baseline renal function	• Alterations in NGAL levels are not confined to AKI; they can also be influenced by age, anemia, cancer, CKD, and inflammatory conditions • NGAL is suggested to have a potential renoprotective role in ischemic injury	• The TRIBE study demonstrated that measuring urinary and plasma NGAL concentrations enhanced the prediction of CSA-AKI risk120,131
KIM-1	• Transmembrane glycoprotein • Urinary marker of tubular damage	• High sensitivity and specificity	• Pediatric studies yield conflicting results regarding the predictive value for AKI132,133	• The predictive value of NGAL for CSA-AKI is considered moderately accurate in some studies, while others suggest no predictive value132,133 • Children who developed AKI after CPB showed an increased urinary KIM-1 level
L-FABP	• Small cytoplasmic protein • Urinary marker of tubular damage	• Urinary L-FABP levels serve as predictors for adverse outcomes, including the need for RRT or the composite endpoint of death or RRT134	• Increased urinary L-FABP levels can also be observed in CKD135	• L-FABP levels moderately predict CSA-AKI133 • Urinary L-FABP level was increased in children who developed AKI after CPB
IL-18	• Pro-inflammatory cytokine • Proximal tubule	• Levels increase after ischemia–reperfusion injury136	• IL-18 levels likely rise specifically in intrinsic AKI, as opposed to prerenal AKI137	• Early predictive marker for CSA-AKI138,139 • A prospective study showed that urinary IL-18 level was increased in 20 patients who developed AKI after cardiac surgery
ROBO4	• Transmembrane receptor expressed in endothelial cells • Marker for endothelial dysfunction	• Shows transient elevation after cardiac surgery (in contrast to NGAL, which remains elevated at 24 h post-surgery)	• ROBO4 expression is not limited to the kidney because it is also observed in hematopoietic stem cells140	• Elevated ROBO4 served as an early predictor for AKI after CPB in a study of 32 patients, correlating with positive NGAL at 2 h after surgery141
Semaphorin 3A	• Expressed in the developing glomerulus, podocytes, and collecting ducts142	• Early urinary semaphorin 3A levels are linked to clinical outcomes such as the need for RRT and hospital length of stay143	• The existing evidence necessitates validation in a larger study because the current data stem from a small, single-center study only	• A post hoc analysis revealed that urinary semaphorin 3A predicted AKI at 2 h after CPB143
Netrin 1	• Marker of tubular injury	• Preclinical studies indicate its early appearance in urine (within 1–3 h) after AKI, correlating with the duration and severity of AKI and the length of hospital stay144	• Netrin 1 levels can also experience elevation in CKD	• Identified as an early predictor for AKI after CPB, with levels peaking at 6 h after CPB in a study of 26 patients144
CCL-14	• Released from tubular epithelial cells as an inductor of chemotaxis and monocyte–macrophage recruitment in response to renal injury	• Provides diagnostic insights into the expected severity and progression of the disease • Differentiates patients with persistent AKI from those experiencing renal recovery, with performance unaffected by chronic comorbidities and CKD	• Not a marker for early diagnosis of CSA-AKI	• Proven to predict persistent AKI and the need for RRT in a patient cohort with stage 2–3 CSA-AKI145,146

CCL-14, C-C-motif chemokine ligand 14; CPB, cardiopulmonary bypass; CSA-AKI, cardiac surgery–associated AKI; DKK3, Dickkopf-3; ICU, intensive care unit; IGFBP7, insulin-like growth factor-binding protein 7; KDIGO, Kidney Disease Improving Global Outcomes; KIM-1, kidney injury molecule 1; L-FABP, liver fatty acid-binding protein; NAG, N-acetyl-β-d-glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; ROBO4, roundabout guidance receptor 4; SCr, serum creatinine; TIMP-2, tissue inhibitor of metalloproteinases-2.

Intraoperative and Postoperative Strategies

Pharmacological Interventions

Dexmedetomidine, an α2-adrenergic receptor agonist, a drug with potential nephroprotective effects, has shown mixed results across studies, and some trials have raised concerns regarding potential side effects.^147–151 Further investigation is needed to clarify its role in this context. Atrial natriuretic peptide was able to reduce the need for RRT at low doses and to decrease the 30-day mortality and occurrence of AKI, whereas high doses potentially cause adverse events.^151,152 Similarly, levosimendan, a calcium-sensitive inotropic vasodilator with antioxidant, anti-inflammatory, and antiapoptotic properties, requires further exploration to determine its efficacy in preventing AKI despite its potential benefits.^63,168–170 While statins offer established benefits in other cardiovascular contexts, their role in preventing AKI after cardiac surgery remains unclear, with conflicting results reported across studies. ^153–160 Urinary alkalinization with sodium bicarbonate administration demonstrated no overall benefit in preventing AKI in the general cardiac surgery population, but further research is warranted to determine its potential utility in specific patient subgroups.¹⁶¹ The use of sodium–glucose cotransporter type 2 inhibitors seems safe for patients undergoing cardiac surgery, but additional research is necessary to evaluate their potential role in preventing AKI. Importantly, presurgical discontinuation of sodium–glucose cotransporter type 2 inhibitor is recommended to avoid the risk of euglycemic ketoacidosis, as highlighted by recent studies.^162,163 While corticosteroids aim to control inflammation, large trials found no overall protection against AKI.^164–166 However, a post hoc analysis of the Dexamethasone for Cardiac Surgery trial suggests dexamethasone may reduce the need for kidney dialysis in patients with advanced CKD.¹⁶⁷ Albumin, a protein with potential benefits for kidney health, possesses properties such as binding toxins, scavenging free radicals, and maintaining capillary membrane function. A single study investigating albumin administration in patients with low levels before off-pump heart surgery reported increased intraoperative urine output and a reduced risk of postoperative kidney injury. However, a separate retrospective study failed to find long-term benefits.^168,169

A comprehensive investigation of various pharmacological agents, including those previously discussed, has yielded no definitive candidate for preventing CSA-AKI. The limitations of prior studies, characterized by both small sample sizes and substantial methodological heterogeneity, necessitate further research to identify effective pharmacologic strategies.^{150,151,170,171}

CPB

Despite initial evidence suggesting off-pump CABG might reduce AKI risk, large RCTs (CORONARY and ROOBY trial) showed no significant difference in preventing AKI compared with on-pump surgery.^172–176 While off-pump offered benefits like reduced bleeding and respiratory complications, it also carried an increased risk of early revascularization and lower graft patency. The ROOBY trial further demonstrated no survival or renoprotective effects, even showing a higher rate of cardiac death with off-pump surgery. While factors like CPB duration and techniques affect kidney injury, evidence suggests the overall effect of CPB on AKI might be limited, as supported by the HEPCON trial.¹⁷⁷

Goal-Directed Oxygen Delivery on CPB

Recent trials investigated the use of goal-directed oxygen (GDO) during CPB to reduce AKI after cardiac surgery. In the Goal-Directed Perfusion Trial, maintaining oxygen delivery above 280 ml/min per m² during CPB compared with standard methods lowered the incidence of mild AKI (AKI Network stage 1).¹⁷⁸ Similarly, another study found a higher AKI rate (by KDIGO criteria) in patients not receiving GDO.^179,180 Subgroup analysis of both trials suggest individualized oxygen delivery based on factors like hematocrit, and body size might be more effective than relying on body surface area alone.

GDO aligns with recommendations from European Association for CardioThoracic Surgery/European Association of Cardiothoracic Anesthesiology/European Board of Cardiovascular Perfusion to maintain adequate renal perfusion during CPB by adjusting pump flow based on oxygen content.¹⁸¹ Studies by Ranucci et al. and Mukaida et al. reported a significant decrease in AKI (approximately 50%) with GDO compared with standard techniques, supporting its potential to prevent AKI despite limitations in sample size and protocol variations.^178,179 A recent meta-analysis further strengthens this evidence.¹⁵⁰

CPB Rewarming Temperature

Studies investigating rewarming strategies and temperature management on AKI development after cardiac surgery suggest normothermia may be crucial. A two-part study showed a higher AKI incidence in patients rewarmed to 37°C compared with 34°C.¹⁸² In addition, another trial found no benefit to sustained mild hypothermia (34°C) in preventing AKI. Furthermore, a large multicenter registry linked hyperthermic perfusion exceeding 37°C to a heightened risk of AKI. These findings suggest maintaining normothermia throughout the perioperative period, including rewarming and surgery, might be critical for AKI prevention.¹⁸³

Anemia and Transfusion of Packed Red Blood Cells

Studies link anemia, blood transfusions, and increased risk of AKI in cardiac surgery patients.^184–187 A large study found the combined effect of both significantly increases AKI risk compared with either alone, highlighting the need for a cautious transfusion approach.¹⁸⁸ Research suggests restrictive transfusion strategies (maintaining a hematocrit of 24% or higher) are equally effective as liberal strategies in managing complications, supported by large trials and meta-analyses.^23,189–191 Current guidelines recommend packed red blood cell transfusion only if hemoglobin falls below 6 g/dl, suggesting an acceptable hematocrit of 21%–24% with sufficient oxygen delivery.^192,193

RRT

While definitive guidelines for RRT initiation in CSA-AKI are lacking, current best practices advocate reserving its use for refractory electrolyte, acid base, or volume management issues that resist medical intervention.^194,195 Recent studies suggest that early initiation in the absence of such critical imbalances may even be detrimental, potentially increasing hypotensive episodes and hypophosphatemia.¹⁹⁶ In addition, data from the STARRT-AKI trial indicate a higher likelihood of long-term RRT dependence in AKI-RRT survivors who received early intervention compared with those on delayed RRT strategies.¹⁹⁷ Consequently, meticulous perioperative monitoring is crucial to identify high-risk patients and determine the necessity for RRT based on specific, refractory clinical indications.¹⁹⁸ When RRT is warranted, both intermittent and continuous modalities are viable options for patients with CSA-AKI. Notably, continuous RRT is often preferred for hemodynamically unstable individuals because of its gentler approach, characterized by slower fluid removal, osmotic shifts, and electrolyte changes, minimizing the effect on cellular membrane potentials compared with intermittent hemodialysis.^194,195

Removal of Cytokines and Hemolysis Products

Despite efforts to remove inflammatory products through extracorporeal cytokine removal with Cytosorb filters during cardiac surgery, studies have not shown significant benefits.^199,200 The technology has limited ability to remove cell-free hemoglobin and offers minimal improvement in patient outcomes.^201,202 In addition, its use is restricted to specific scenarios involving extracorporeal circulation. While further research might be warranted, current evidence does not support its routine use in cardiac surgery.^203,204

Risk Stratification with Doppler Sonography

Renal ultrasound with Doppler interrogation of blood flow emerges as a valuable tool for identifying and stratifying patients at risk for CSA-AKI.

Arterial Assessment

Elevated renal artery resistance index measured by Doppler ultrasound independently predicts a heightened risk of AKI after CABG surgery. Furthermore, intraparenchymal renal resistive index variation derived from renal artery resistance index demonstrates potential for early detection of AKI. ^205,206

Venous Assessment

Doppler ultrasound surpasses central venous pressure in its ability to assess renal congestion in cardiac surgery patients. Unlike central venous pressure, which is susceptible to external factors, ultrasound directly evaluates organ vein waveforms. Normal renal veins exhibit continuous flow, while abnormal patterns (biphasic or monophasic) are associated with an increased risk of AKI and mortality.^207–209 Similarly, atypical hepatic vein flow and a higher velocity–time integral ratio in hepatic veins are linked to AKI development.^210,211 In addition, abnormal portal vein flow patterns, indicated by a significant difference in diastolic and systolic flow rates, serve as an independent predictor when combined with the pattern of intrarenal vein flow.²¹²

Electronic Alerts

Electronic alerts within laboratory programs are gaining traction for early AKI detection.²¹³ Recognizing changes in serum creatinine, these alerts prompt physician notification and facilitate earlier nephrology consultations. Studies report improved patient outcomes after implementation, suggesting potential benefits for both hospitalization and postdischarge follow-up.

Novel Concepts for Prevention and Treatment of CSA-AKI

Renal Functional Reserve

Renal functional reserve (RFR) reflects the kidneys' ability to adapt to stress by increasing the GFR. This reserve protects against AKI until depleted, leading to a decline in GFR and increased risk.^15,214–216 The RFR test, measuring the difference in GFR at rest and after stimulation, offers a more sensitive assessment of kidney function compared with traditional methods like creatinine levels.^217–220 A study by Husain-Syed et al. demonstrated that patients with lower preoperative RFR, assessed using a protein load test, were more likely to experience a transient rise in postsurgery creatinine even if it returned to baseline.²²¹

Noninvasive Urine Oximetry: A Novel Approach for Real-Time Kidney Monitoring in Cardiac Surgery

Noninvasive urine oximetry is a promising new technique for assessing kidney health in cardiac surgery patients. It continuously measures a marker of kidney oxygenation (urinary PO₂), providing real-time insights into function.²²² Studies have shown lower urinary PO₂ to be linked to a higher risk of AKI, suggesting its potential as an early warning system. This technology allows for real-time monitoring of kidney oxygen delivery, enabling timely interventions to potentially reduce the risk of AKI after cardiac surgery.^223,224

Haptoglobin Administration and Iron Chelation Therapy

Haptoglobin therapy shows promise in preventing AKI by binding and neutralizing free hemoglobin, as demonstrated in animal models.^225–227 Human haptoglobin, currently available only in Japan, has demonstrated the potential to reduce the incidence of CSA-AKI when administered intraoperatively to patients with macrohemoglobinuria during CPB.²²⁸

Hepcidin, an iron-regulating hormone, is being investigated for its potential to prevent AKI through its protective effects on tubular cells.²²⁹ While animal studies suggest its benefit, clinical trials are limited. ^230,231 An ongoing randomized, double-blind, placebo-controlled trial, DEFEAT-AKI (ClinicalTrials.gov NCT04633889) is evaluating the effectiveness of deferoxamine, an iron chelator, in preventing AKI after cardiac surgery.

Nitric Oxide

Several studies show promise for nitric oxide administration in reducing the incidence and severity of AKI after cardiac surgery by potentially protecting the kidneys from hemolysis-related damage.^232,233 However, further research is needed to fully understand its mechanisms and optimize clinical use.

Acetaminophen

Acetaminophen's anti-inflammatory and antioxidant properties may protect against hemolysis-induced kidney injury by preventing harmful iron conversion in cell-free hemoglobin.^234,235 Animal studies and observational data suggest a potential link between acetaminophen use and reduced AKI risk in cardiac surgery patients.^234,236,237 Further clinical trials are needed to confirm its efficacy.

Ravulizumab

C5 inhibitors, such as ravulizumab, are being investigated to target complement activation and potentially prevent AKI in high-risk cardiac surgery patients with CKD. The ongoing ARTEMIS trial (ClinicalTrials.gov NCT04633889) is evaluating ravulizumab's effectiveness in reducing the incidence of major adverse kidney events after surgery.²³⁸ If successful, this approach could offer a new therapeutic strategy for this vulnerable population.

Nicotinamide Adenine Dinucleotide

Nicotinamide (NAM) adenine dinucleotide, ubiquitous in living organisms, plays a pivotal role in cellular energy metabolism and signaling pathways.²³⁹ Early-stage studies suggest that NAM or NAM riboside, precursors to the essential molecule NAM adenine dinucleotide, might help mitigate AKI risk in cardiac surgery patients.²⁴⁰ Ongoing trials, including one specifically designed for cardiac surgery patients (ClinicalTrials.gov NCT04750616), are evaluating their efficacy.

Remote Ischemic Preconditioning

Remote ischemic preconditioning (RIPC), a technique mimicking brief periods of blood flow restriction and restoration in a limb to protect organs, has shown conflicting results in preventing AKI after cardiac surgery. While a small study found benefit, larger trials did not.^241–243 The interaction between RIPC and specific anesthetics like propofol further complicates the picture.^244–247 More research is needed to determine whether RIPC can benefit specific patient groups or surgical settings.

Teprasiran

A phase 2 clinical trial investigated teprasiran, a novel small interfering RNA, for its efficacy in reducing AKI in high-risk cardiac surgery patients. Teprasiran demonstrated a significant decrease in the incidence, severity, and duration of early AKI compared with placebo in a phase 2 trial.²⁴⁸ These promising findings led to a subsequent phase 3 trial (NCT03510897) designed with a primary endpoint of major adverse kidney events at 90 days. However, this larger trial was terminated early because of the intervention failing to meet its efficacy outcome.

Summary of Guidelines and Recommendations

Established professional societies have developed comprehensive guidelines to mitigate CSA-AKI.^150,249 These guidelines prioritize intraoperative strategies such as avoiding hyperthermic CPB perfusion and implementing targeted oxygen delivery (class 1 recommendation). The KDIGO bundle is recommended as a class 2a intervention for high-risk patients. This bundle emphasizes volume optimization, minimizing nephrotoxin exposure, and maintaining blood glucose control. Fenoldopam may be considered for select patients without hypotension (class 2b), while perioperative use of dopamine and mannitol is discouraged (class 3). Similar recommendations advocating for optimal hemodynamic management during bypass and judicious avoidance of nephrotoxic medications are endorsed by other leading societies.^160,250

The KDIGO bundle demonstrates promise in reducing CSA-AKI severity. Studies like the multicenter, randomized controlled trial PrevAKI report a significant 10% reduction in moderate-to-severe AKI with bundle adherence.^83,97 However, a meta-analysis suggests the bundle's effect might be limited to more severe AKI stages (2 or 3), and concerningly, adherence rates remain low, ranging from 5% to 65%.^150,250,251

AKI associated with cardiac surgery is a common and significant complication of cardiac surgery, increasing not only the perioperative but also the short-term and long-term mortality and morbidity. Addressing the risk of CSA-AKI requires a multifaceted approach that encompasses both hemodynamic optimization and supportive measures. The joint guidelines from European Association for CardioThoracic Surgery, European Association of Cardiothoracic Anaesthesiology and Intensive Care, and European Board of Cardiovascular Perfusion; the Society of Cardiovascular Anesthesiologists's practical strategies; and the KDIGO bundle of care offer valuable frameworks for CSA-AKI prevention and treatment. However, continued efforts are needed to improve adherence to these guidelines and strategies, and further research is crucial to identify additional effective interventions for optimizing CSA-AKI prevention.

Supplementary Material

kidney360-5-909-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A517.

Funding

None.

Author Contributions

Conceptualization: Carolin Herzog, Florian G. Scurt.

Data curation: Florian G. Scurt.

Project administration: Florian G. Scurt.

Supervision: Katrin Bose.

Validation: Christos Chatzikyrkou, Carolin Herzog, Florian G. Scurt.

Visualization: Katrin Bose, Florian G. Scurt.

Writing – original draft: Florian G. Scurt.

Writing – review & editing: Katrin Bose, Christos Chatzikyrkou, Carolin Herzog, Peter R. Mertens.