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Table of Contents
Year : 2012  |  Volume : 15  |  Issue : 4  |  Page : 279-286
Acute kidney injury following cardiac surgery

1 Department of Internal Medicine/Critical Care, Princess Durru-Shehvar Children's and General Hospital, Purani Haveli, Hyderabad, Andhra Pradesh, India
2 Department of Nephrology, Medwin Hospital, Nampally, Hyderabad, Andhra Pradesh, India

Click here for correspondence address and email

Date of Submission25-Dec-2011
Date of Acceptance21-Jun-2012
Date of Web Publication1-Oct-2012


Acute kidney injury (AKI), a recognized complication of cardiac surgery with cardiopulmonary bypass (CPB) is associated with increased morbidity and mortality (15-30%) with approximately 1% of all the affected patients requiring dialysis. Early detection of AKI would enable intervention before occurrence of irreversible injury and might minimize the morbidity and mortality. Recently developed biomarkers of AKI facilitate its earlier discovery and help assessment of its severity and prognosis. In this article, we review the causes of well-known yet inexplicable association between CPB and AKI, the advances in pathophysiologic basis, the diagnostics and the management options.

Keywords: Acute kidney injury, Cardiopulmonary bypass, Management

How to cite this article:
Gude D, Jha R. Acute kidney injury following cardiac surgery. Ann Card Anaesth 2012;15:279-86

How to cite this URL:
Gude D, Jha R. Acute kidney injury following cardiac surgery. Ann Card Anaesth [serial online] 2012 [cited 2022 Dec 7];15:279-86. Available from:

   Introduction Top

Acute Kidney Injury post cardiac surgery (AKI-CS) is associated with substantial morbidity and mortality independent of all other factors. [1] Post-operatively even minimal changes in serum creatinine are associated with a substantial decrease in survival as observed in a study that showed 30 day mortality of up to 32.5% with a rise in serum creatinine of more than 0.5 mg/dl. [2] Various risk factors acting through perturbed blood pressure, inflammation and nephrotoxicity have been identified for AKI-CS that may help us risk stratify patients and manage them with renal protective strategies and drugs.

[Table 1] describes the definitions of AKI according to the Risk-Injury-Failure-Loss-End stage (RIFLE) and Acute Kidney Injury Network (AKIN) criteria. [3],[4]
Table 1: Criteria defining AKI

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[Table 2] summarizes the incidence of AKI-CS across various studies and is about 5-20% with 1-2% of these patients requiring dialysis (AKI-D). [5] In a cohort of 2843 patients who underwent cardiopulmonary bypass (CPB), over a 2-yr period, AKI-CS (rise in serum creatinine >1 mg/dl above baseline) occurred in 7.9% patients, and AKI-D occurred in 0.7% patients. [6] With AKI defined as a 50% or greater rise in serum creatinine from baseline, the incidence of AKI-CS rises to 30%. [7] This study of Chertow et al included 42,773 patients who underwent cardiac surgery with CPB and AKI-D incidence was found to be 1.1%. [7] In another study on 311 pediatric patients AKI occurred in 42% (130 patients) within 3 days after surgery. [8] The type of CPB surgery have a significant influence on AKI. Coronary artery bypass grafting and valvular heart surgery have lower incidences of AKI (2.5% and 2.8%) and AKI-D (1% and 1.7%), whereas combined coronary artery bypass grafting and valvular heart surgery results in a higher incidence of AKI about 4.6% and AKI-D of 3.3%. [9],[10]
Table 2: Various studies depicting incidence of AKI- CS

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The development of AKI-CS is associated with a significant increase in infectious complications, an increase in hospital stay, and greater mortality when compared with patients without AKI-CS. [11] The presence of AKI-D increases the risk of death by 7.9 times in these patients. [7]

AKI-CS has a poor prognosis with the mortality ranging from 10-80% (uncomplicated AKI - 10% AKI with multi-organ failure >50%, AKI requiring renal replacement therapy - 80%). [12],[13] In a study the 30 day mortality was 2.77 and 18.64 fold higher in patients who developed 0 to 0.5 mg/dl and >0.5 mg/dl rise in serum creatinine compared to those who had no change in serum creatinine. [2] In another study of 31,677 patients who underwent cardiac surgery, the mortality of AKI-CS was 0.4% in patients with <30% decline in glomerular filtration rate (GFR) and 5.9% when GFR declined 30% or more but did not require dialysis. [14] In an observational study, the relative risk for death at 1 yr was 4.6 for patients who sustained AKI-CS as compared to those who did not. [15] In patients sustaining AKI-D, about 2/3 rd (64%) might require permanent dialysis. [16] Infections are a major cause (40%) of death in AKI-CS (58.5% in AKI-D). [14],[17] Immune dysregulation, platelet dysfunction, factors related to hemodialysis (hemodynamic instability, catheter-related infections, ventricular ectopy, and visceral ischemia) also considerably contribute towards mortality.

   Risk Factors Top
[Table 3]

Patient-related risk factors like female gender, chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease, renal insufficiency, congestive heart failure, left ventricular (LV) ejection fraction <35%, need for emergent surgery, cardiogenic shock requiring IABP, total circulatory arrest, left main coronary artery disease, etc., are the important factors associated with AKI-CS. The Cleveland Clinic Foundation Acute Renal Failure Scoring takes additional risk factors in to consideration like previous cardiac surgery, emergency surgery, valve surgery only, CABG and valve surgery and pre-operative creatinine 1.2 to 2.1 mg/dl or more. [18]
Table 3: Risk factors for AKI-CS

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Procedure Related
Risk factors pertaining to procedures that increase the likelihood of AKI-CS are the CPB time, aortic-clamp time, On-pump versus off-pump CABG, hemolysis, and hemodilution. [1] Although it is believed that non-pulsatile flow is a risk factor for AKI-CS, better ventricular assist devices that provide continuous flow have reported superior end-organ function. [19]

   Pathogenesis Top

The pathogenesis of AKI can be studied under the following headings:

Volume-Responsive AKI
Volume-responsive AKI, sports absolute or relative reduction in renal perfusion (either global or regional), and increased serum creatinine and blood urea nitrogen without kidney damage. It is often accompanied by oliguria. Initially various locally active adaptive responses permit full reversibility; however, they eventually fail if injury continues. Attempts at restoring renal blood flow (RBF) are partly mediated by an intrinsic myogenic response to changes in renal arterial perfusion pressure, allowing a gradual vasodilatation of the preglomerular arteriole and partly to the tubuloglomerular feed-back (TGF) mechanism. However, ongoing generalized hypotension/hypoperfusion activates the sympathetic nervous system and renin-angiotensin-aldosterone system, and releases vasopressin which results in a heightened sensitivity of the vascular endothelium (and inhibition of vasorelaxation) to these and a number of other vasoconstrictors such as thromboxane, endothelin, and leukotrienes. The vasoconstrictor and vasodilator regulatory systems work harmoniously to maintain RBF and GFR at the expense of increased water and urea resorption under the influence of vasopressin. [20] The GFR autoregulation takes place at the expense of generalized vasoconstriction.

Non-Volume-Responsive AKI
Volume responsive AKI, if not treated in time, eventually results in non-volume-responsive AKI, which is rapidly progressive and characterized by profound reduction in GFR, which may continue and even progress after the return of renal perfusion to baseline. During non-volume responsive AKI, the renal injury progresses through various stages. In the initiation stage, ischemia and/or other insults result in failure of autoregulatory mechanisms and tubular epithelial cell injury with disruption of both apical and basolateral membranes, redistribution of cytoskeletal proteins and defective tight junctions causing transtubular back-leak. [21],[22],[23],[24],[ 25] Extension phase is marked by activation of vascular endothelial cells, resulting in stimulation of the inflammatory, oxidative, and coagulation cascades. [20] Microvascular as well as tubular obstruction develop, leading to a worsening cycle of injury and cell loss. While maintenance phase encompasses the process of proliferation and re-differentiation, the polarity and function are reconstituted in repair phase. [20]

Endothelial Injury
Endothelial cell injury results in blunted NO response to endothelium-dependent vasodilators causing impaired vasorelaxation, diapedesis of polymorphonuclear leukocytes and monocytes, local procoagulant and proaggregant conditions, lipid peroxidation and DNA damage. There is upregulation of the adhesion molecules P-selectin, E-selectin, and adhesion molecule-1 on the surface of the endothelial cells believed to cause trapping of thrombocytes and leukocytes. Consequently microvascular stasis, activation of inflammatory cascade leading to further endothelial injury and alterations of the endothelial permeability barrier via cytokines, proteases, and mediators of oxidant injury occur. [20],[26]

Factors Specific to Cardiac Surgery
Low mean arterial pressure below the limits of auto-regulation during cardiac surgery and/or CPB and impaired auto-regulation due to existing comorbidities such as advanced age, atherosclerosis, chronic hypertension, or chronic kidney disease (CKD), recent myocardial infarctions or severe valvular disease with reduced left ventricular function and reduced renal perfusion play a significant role in causing AKI. Administration of drugs that impact kidney auto-regulation (e.g., ACE inhibitors, angiotensin receptor blockers, and radio contrast agents), may also precipitate AKI-CS. CPB decreases the effective renal perfusion pressure up to 30% by altering the vasomotor tone and exposes the renal parenchyma to reduced oxygen tension and contributes to ischemia-reperfusion injury. [11] The pre-renal state worsens in presence of cardiogenic shock and inotropic support or an intra-aortic balloon pump, and episodes of hypotension.

CPB is known to cause hemolysis due to cardiotomy suction, occlusive roller pumps, turbulent flow in the oxygenator, and blood return through cell savers which results in oxidative stress and renal tubular injury. [27] Free iron released from heme leads to organic and inorganic oxygen radical reactions, lipid peroxidation and the formation of damaging hydroxyl radicals with subsequent tissue damage. [28] Microscopic emboli (<40 μm), both gaseous and particulate matter are also released during CPB which damage capillaries and cause organ dysfunction. [29] The CPB itself provokes a systemic inflammatory response syndrome (SIRS) due to ischemia-reperfusion injury, endotoxemia, operative trauma, non-pulsatile blood flow, and pre-existing left ventricular dysfunction. Inflammatory mediators, such as endotoxin, IL-1b, IL-6, IL-8, and TNF-α, considerably rise during CPB [30] owing to activation of neutrophils and vascular endothelium, elaboration of cytotoxic oxygen-derived free radicals, proteases, cytokines, and chemokines and increased platelet activation, degranulation, and adherence. [31],[32] CPB activates factor XII (Hageman factor) to factor XIIa and also results in the activation of intrinsic coagulation system, the kallikrein system, the fibrinolytic system and complement cascade. [33] Post-operative use of vasoactive agents, hemodynamic instability, nephrotoxic medications, volume depletion, sepsis/SIRS, and the need for mechanical support further govern the degree of AKI. [1]

Staging of patients according to the rise in serum creatinine may quantify the risk of AKI-CS. A study on 29,388 individuals who underwent cardiac surgery showed that the magnitude of creatinine increase, class I (1-24%), class II (25-49%), class III (50-99%), or class IV (≥100%), was associated with greater incidence of CKD (hazard ratios of 2.1, 4.0, 5.8, and 6.6, respectively). It also increased the risk of CKD progression, and mortality. [34] Elevated pre-operative serum creatinine is predictive of the risk for ARF-D (about 10 to 20% in patients with a baseline pre-operative creatinine 2.0 to 4.0 mg/dl and 25 to 28% if >4.0 mg/dl). [1] However, the relationship between GFR and serum creatinine is nonlinear and GFR may decrease by more than 50% from normal before a significant rise in serum creatinine occurs; therefore small changes in creatinine reflect a significant reductions in GFR. [35] Preoperative proteinuria is an independent predictor of adverse outcomes in patients undergoing cardiac surgery and suggests higher risk for AKI. [36] Pre-operative anemia, perioperative RBC transfusions, and post-operative re-exploration are independently and strongly associated with AKI-CS. [37] Anemic patients presenting for cardiac surgery are more susceptible to transfusion-related AKI than non-anemic patients (6.6% versus 3.2%) hence, interventions that reduce perioperative transfusions may protect them against AKI. [38] In a retrospective observational study on 4,836 consecutive patients undergoing cardiac surgery, modification of RIFLE by staging of patients requiring acute renal replacement therapy (RRT) in the failure class-F was shown to improve predictive value. Applying AKIN without correction of serum creatinine for fluid balance may lead to over-diagnosis of AKI (poor positive predictive value). [39] The addition of urine biomarkers like IL-18 and neutrophil gelatin-associated lipocalin (NGAL) improves the prediction of risk of AKI-CS compared to clinical models alone. In a study on patients undergoing cardiac surgery, higher levels of urine IL-18 and urine NGAL were associated with higher odds of AKI (both in pediatic and adult patients). A study quantified that urine IL-18 levels of >100 pg/ml were associated with a higher risk of AKI in the next 24 h. [40] In a study on children undergoing cardiac surgery, IL-6 levels at 2 and 12 hours after CPB and IL-8 levels at 2, 12 and 24 hours were associated with the development of AKI. [41] Elevated urine IL-18 and urine NGAL levels are associated with longer hospital stay, longer intensive care unit stay, duration of mechanical ventilation and higher risk for dialysis or death (in adults). [42],[43] Post-operative serum Cystatin-C (CysC) is also useful to risk-stratify patients for AKI treatment trials. The highest quintile of post-operative CysC predicted stages 1 and 2 AKI and the highest tertile of percent change in CysC independently predicted AKI. Post-operative CysC levels also independently predicted longer duration of ventilation and intensive care unit stay. [44] A study combining matrix metalloproteinase-9 (MMP- 9), N-acetyl-β-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) showed a perfect score in diagnosing AKI-CS. KIM-1 was better than MMP-9 or NAG in the detection of AKI. [45] Urinary α glutathione S-transferase (α-GST) has shown promise as an early marker for renal dysfunction. A study showed that along with pre-operative KIM-1, α-GST predicted the future development of stage 1 and stage 3 AKI. [46] L-FABP (Liver-Fatty Acid-Binding Protein) levels in 21 patients who developed AKI-CS were about 94 and 45 folds at 4 and 12 h after cardiac surgery. Both CPB time and urinary L-FABP were significant independent risk indicators for AKI-CS. [47] Plasma concentrations of free hemoglobin and myoglobin have been shown to be independent predictors of AKI-CS. [48] Increases in urinary hepcidin, a central regulator of iron metabolism, may be associated with greater risk of AKI-CS. [49] A study showed that midkine, a multifunctional heparin-binding protein which promotes migration of neutrophils, macrophages, and neurons significantly increased during surgery in AKI patients and reached peak level during surgery earlier than other urinary biomarkers (NGAL and IL-18). [50]

A noninvasive technology, Near-Infrared Spectroscopy (NIRS) can continuously evaluate regional oximetry and may correlate with renal injury and adverse outcomes after cardiac surgery. In an observation, subjects with low renal oximetry (below 50% for 2 h) had significantly higher post-operative peak creatinine levels by 48 h and a higher incidence of AKI (50% vs. 3.1%) than those with normal renal oximetry (85- 90%). Prolonged low renal NIRS correlated with more ventilator days, greater vasoactive support, elevated lactate levels, decreased systemic oxygen delivery and the overall postoperative course. [51]

   Management Options Top

Risk Stratification and Preventive Strategies
Identification of high-risk patients and correction of the factors leading to pre-renal azotemia such as treatment of volume depletion and congestive heart failure before cardiac surgery, perioperative hydration and the use of hemodynamic monitoring and inotropic agents to optimize cardiac output, intra-operative optimization of CPB flow, perfusion pressure, and oxygen delivery may make a substantial difference in protecting the kidneys. Avoiding medications such as non-steroidal anti-inflammatory drugs and other nephrotoxic agents, and use of newer isosmolar agents (in cases demanding radio contrast imaging) are beneficial in minimizing renal damage. Pre-operative discontinuation of drugs that impair coagulation, minimization of hemodilution, expeditious surgery, and aggressive investigation and treatment of excessive blood loss are some of the management strategies to minimize AKI-CS. Use of intravenous iron or erythropoietin-stimulating agents to treat anemia before surgery, limiting RBC transfusions to units that have been stored for short durations, help combat the renal jeopardy. [37]

CPB Measures
CPB results in hemodilution, decreased blood viscosity and improved regional blood flow. However, a hematocrit <25% has been shown to be associated with an increased risk for renal injury from impaired oxygen delivery to an already hypoxic renal medulla. Ensuring appropriate flow and perfusion pressure and limiting the duration of CPB are of considerable importance but there are no consensus guidelines on optimal CPB measures. While a study pointed that high MAP during CPB may have a significant impact in protecting the brain and abdominal organs, other studies demonstrated that CPB flows and CPB pressures were not related to AKI-CS development. [52],[53] Miniaturized CPB has been known to lower the incidence of AKI when compared with conventional CPB among patients undergoing CABG. Mini-CPB system may minimize the alterations in the hemodynamics, cut-down bleeding and transfusion requirements, decrease systemic inflammatory response, and reduce immediate post-operative renal and intestinal tissue injury. [54],[55]

Surgical Approach
American Heart Association opines that off-pump CABG when compared to the on-pump CABG results in less blood loss and need for transfusion, less myocardial enzyme release up to 24 hours, less early neurocognitive dysfunction, and more importantly less renal insufficiency. [56]

Dopamine in low doses and theophylline, a nonselective adenosine antagonist were tried but no demonstrable effect was seen in controlling the renal jeopardy. [57] Anti inflammatory agents such as pentoxifylline, [58] dexamethasone, [59] were found to have no renoprotective benefit. N-acetylcysteine (N-AC) and a single-chain antibody specific for human C5 (pexelizumab) may hold theoretical promise but till date no study has validated their efficacy. [60],[61] The role of diuretics and mannitol is inconclusive. Theoretically they may wash out the obstructing cellular debris and casts. Mannitol may preserve mitochondrial function by limiting the post-ischemic swelling and free-radical scavenging, loop diuretics improve medullary oxygenation by decreasing energy requirements and by renal vasodilatory properties. A study showed that a cocktail regimen of mannitol, furosemide, and dopamine (2-3 mcg/kg per min) decreased the need for dialysis and resulted in early restoration of renal function. [62] But it is also theorized that in patients with normal renal function, mannitol and furosemide impair the renal oxygen supply/demand relationship by increasing GFR, which increases tubular sodium load and sodium reabsorption. [63] These findings however need further confirmation in larger studies.

Fenoldopam a selective dopaminergic receptor 1 agonist, has shown some benefit in prevention of AKI-CS but the side effect of systemic hypotension may cloud such benefit. [64] Diltiazem is known to reduce urinary excretion of markers of tubule injury (α GST and NAG) although its efficacy in the prevention of renal dysfunction has been inconsistent. [65] Atrial natriuretic peptide (ANP) increases natriuresis by increasing GFR as well as by inhibiting sodium reabsorption by the medullary collecting duct. Anaritide, a 25-amino acid synthetic form of ANP showed some benefit of renoprotection. Recombinant human ANP (rhANP) was used to treat ARF after cardiac surgery in patients who required inotropic support for heart failure. [66] Pre-operative treatment with clonidine (an α-2 agonist) has shown significantly higher creatinine clearances after CPB. [67]

Renal Replacement Strategies
In high risk patients undergoing CPB, prophylactic RRT may be a therapeutic option. Prophylactic hemodialysis showed marked difference in mortality from 30.4% in controls to 4.8% in a study on patients at highest risk for AKI. Post-operative AKI-D was reduced from 34.8% in the control group to 4.8%. [68] Although, the debate continues on the superiority of continuous RRT over intermittent RRT; both the techniques have their benefits depending on the resources and settings. The former is better tolerated in combined acute liver and kidney failure and in acute brain injury, whereas the latter is more practical, flexible and cost-effective. Intermittent RRT removes small solutes such as potassium more efficiently in acute life-threatening conditions. Moreover, it also allow us to discontinue or minimize anticoagulation which reduces the risk of bleeding. The sustained low-efficiency dialysis (SLED) fuses the most of the advantages of both options. [69] A study showed that perioperative prophylactic hemodialysis decreases both operative mortality and morbidity in patients with serum creatinine levels greater than 2.5 mg/dl. [68] Nevertheless, studies are required to recommend universal RRT strategies as preventive measures.

Carbon monoxide (CO) is known to confer renoprotection by exerting anti-inflammatory and anti-apoptotic effects by activation of heat shock protein (HSP-70). In an animal study CO treatment before CPB was associated with evidence of renoprotection, demonstrated fewer histological injuries and decreased CysC concentrations. [70] Increased post-operative glycemic variability and severe hyperglycemia (intraoperative and post operative) were associated with increased risk for adverse outcomes. Remote ischemic preconditioning is believed to prevent AKI-CS. In a study ischemic preconditioning by an automated thigh tourniquet (three 5-min intervals of lower extremity ischemia separated by 5-min intervals of reperfusion) resulted in an absolute risk reduction in AKI (elevation of serum creatinine of ≥0.3 mg/dl within 48h after surgery) of 0.27 and a significantly reduced relative risk of 0.43. [71] Sodium bicarbonate is known to protect from oxidant renal injury, by scavenging of hydroxyl radicals, peroxynitrite and other reactive species and hence may be useful in AKI-CS. [72]

   Conclusion Top

The high morbidity and mortality of AKI-CS, despite RRT and intensive care unit care, emphasize the magnitude of the problem. Adequate management strategies such as identifying high-risk patients, optimizing cardiac output and renal perfusion pressure, off-pump techniques, use of renoprotective agents of proven benefit and avoiding nephrotoxins are of considerable benefit. Biomarkers are beginning to accelerate the diagnostics thus redefining management options. With ever-increasing understanding of CPB-induced inflammation and cell damage, better measures to prevent and treat AKI-CS are likely to emerge in near future.

   Acknowledgements Top

We thank the department of Internal medicine / critical care and nephology for their perpetual support.

   References Top

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Correspondence Address:
Dilip Gude
Intensivist & Research Coordinator, Department of Internal Medicine/Critical Care, Princess Durru-Shehvar Children's and General Hospital, Purani Haveli, Hyderabad, Andhra Pradesh
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Source of Support: Princess Durru-Shehvar Children’s and General Hospital Hyderabad, AP, India, Conflict of Interest: None

DOI: 10.4103/0971-9784.101874

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