Perioperative acute kidney injury: Current knowledge and the role of anaesthesiologists

Abstract

Background

Among the different types of perioperative organ injury, acute kidney injury (AKI) occurs frequently and is consistently associated with increased rates of mortality and mortality. Despite development of many clinical trials to assess perioperative interventions, reliable means to prevent or reverse AKI are still lacking.

Objectives

This narrative review discusses recent literature on modifiable risk factors, current approaches to prevention and potential directions for future research.

Methods

A Pubmed search with the relevant keywords was done for articles published in the last 10 years.

Results

New insights into preoperative identification and optimisation, intraoperative strategies, including the choice of anaesthetic, haemodynamic and fluid management, have been made, with the aim of preventing perioperative AKI.

Conclusion

A patient-centric multidisciplinary approach is essential to protect kidney function of patients going for surgery. Much can be done by anaesthesiologists perioperatively, to reduce the risk of development of AKI, especially in susceptible patients. There is a need for further multicentred trials to enhance the currently generic perioperative recommendations.

Keywords

Acute kidney injury perioperative renal protection

Introduction

Acute Kidney Injury (AKI) is a common complication after surgery, the incidence of which can range from 18-47%.^1,2 AKI has been associated with both short term morbidity and mortality, as well as long term adverse outcomes, including the increased risk for cardiovascular disease such as myocardial infarction, heart failure and stroke, as well as the subsequent progression to Chronic Kidney Disease (CKD).^3–7 Mortality is higher even after complete renal recovery from perioperative AKI.⁸

Mirroring the morbidity and mortality associated with AKI, the related costs are also increased in both the short and long term. Short term costs may be incurred with the additional supportive interventions required for management of AKI. Long term costs related to associated comorbidities, such as cardiovascular disease, CKD or even End Stage Renal Disease, can be significant. A study by Alshaikh et al. in 2017 based in USA revealed that the overall incremental annual index hospitalisation cost associated with AKI after cardiac surgery was $1.01 billion.⁹

Perioperative AKI is a serious complication but often under-appreciated. The aim of this review is to discuss considerations of AKI relevant to the perioperative period. The anaesthesiologist is required to recognise the patients at risk pre-operatively, optimise modifiable risk factors, including correction of anaemia. Intraoperative preventive strategies should be implemented, especially in high-risk patients, to reduce nephrotoxic insults. These include optimisation of haemodynamic parameters, fluid and blood management, avoidance of nephrotoxins.

Definition

Current consensus criteria for AKI diagnosis are based on measured changes in urine output and serum creatinine (SCr). Based on a clinical practice guideline proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) Foundation, AKI is defined as any of the following: increase in SCr by ≥ 0.3 mg/dl (≥26.5 μmol/l) within 48 h; or increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume ≤0.5 mL/kg/h for 6 h⁹ AKI is further staged into three severity stages by the worsening of either SCr changes or reduced urine output.

Pathophysiology

Acute kidney injury is now perceived as a multifaceted systemic disease process involving distant organs, giving rise to perioperative AKI syndromes which have unique pathophysiologies and management. The historical classification of pre-renal, renal and post-renal causes of AKI has provided a convenient but over-simplistic framework. Commonly implicated mechanisms for AKI perioperatively include haemodynamic-induced, damage-associated molecular pattern (DAMP)-induced, nephrotoxicity, inflammation and obstruction.¹⁰

Haemodynamic-induced AKI may result from hypoperfusion (arterial hypotension, left ventricular failure) and high venous pressure (right ventricular failure, intra-abdominal hypertension). Haemodynamic alterations reducing distal organ perfusion, as well as tissue injury from trauma and surgery itself, release various molecules in the class of DAMPs into the circulation to trigger stress response in the kidney, inducing tubular injury.^11,12 Nephrotoxic drugs such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), antibiotics (eg aminoglycosides), intravenous contrast and certain fluids (Hydroxyethyl Starch, saline) may also contribute to AKI. The healing process from surgery and sepsis release inflammatory mediators such as tumour necrosis factor-α as well as activation of circulating immune effector cells that can injure the kidney.¹⁰ Colorectal, urological and gynaecological surgery may directly cause injury to the ureters, and are often associated with urinary retention, which may result in obstruction.

Risk factors

Patient factors

Several patient characteristics are correlated with an increased risk for perioperative AKI and they are often more strongly associated with postoperative mortality than surgical factors. These include age, pre-existing comorbidities such as hypertension, diabetes mellitus, pulmonary disease, active congestive heart failure, peripheral vascular disease, cerebrovascular disease and pre-existing CKD.^13–17 Pre-existing CKD is a significant predictor for postoperative AKI among both cardiac and non-cardiac surgical patients, with rates of AKI requiring dialysis approaching 30% when these patients undergo cardiac surgery, making it the most important risk factor for perioperative AKI in this setting.^14–19 Obesity is a risk factor for AKI in general and perioperatively, being associated with metabolic syndrome and obesity-related glomerulopathy.^20–22 Patients going for emergency surgeries are at increased risk of AKI, which can be further complicated by the presence of sepsis.^13,20,23,24

Surgical factors

Major vascular surgery and cardiac surgery are well-known risk factors for AKI.^12,20,25,26 Procedure-related factors within these surgeries include prolonged aortic cross-clamp and ischaemia time, creation of micro- and macro-emboli, low cardiac output state, use of intra-aortic balloon pump and the multiple damaging elements of cardiopulmonary bypass.^20,26–29 Blood flow across the bypass circuit triggers contact-activated systemic inflammation, activates the renin-angiotensin-aldosterone system, leading to reduction in renal perfusion pressure. It also can cause direct injury to renal epithelium from the free radicals generated when the circuit imposes mechanical damage to the erythrocytes.¹²

Intraperitoneal surgery is an established risk for AKI^13,23 and is associated with raised intra-abdominal pressure, which represents a higher risk of postoperative AKI secondary to reduction in renal perfusion, increase in intrarenal pressure and venous congestion.³⁰ Notably, oliguria due to the transient increase in intra-abdominal pressure during laparoscopy, is not a predictor of postoperative AKI.^1,31,32 Other surgeries associated with higher incidence of AKI include lung resection³³ and transplantation surgery, including that of kidney,³⁴ liver^35,36 and lung.³⁷

Pre-operative identification and stratification

Risk prediction models

The initial step towards the prevention of AKI is to be able to identify patients at risk. The various risk factors previously discussed act as red flags to alert the anaesthetist to the possibility of perioperative AKI. Some of the risk factors can be optimised preoperatively. This has led to the development of risk prediction models, to risk stratify patients, potentially allowing for personalised perioperative interventions. Kheterpal et al.¹³ derived a General Surgery AKI Risk Index, based on 11 separate preoperative risk factors, each being scored and the total score will categorise patients into five risk classes. The incidence of AKI and hazard ratios increase with risk class. Several models have been developed and validated for other surgical specialties, such as orthopaedic³⁸ and cardiac surgeries.³⁹ These models, however, were developed using older definitions of AKI, instead of the currently used KDIGO definition. Further studies to validate risk scores over multiple centres using the currently more accepted KDIGO definition is crucial, and they may be used to inform a multidisciplinary team to guide preoperative counselling, optimisation, informed decision making and allow for longer-term care provision.

Remote ischaemic preconditioning

Remote Ischaemic Preconditioning (RIPC) is an intervention consisting of brief episodes of ischaemia and reperfusion at a remote site before subsequent occurrence of ischaemic insults.¹² Kidney is highly susceptible to ischaemia-reperfusion injury, because of its high metabolic rate and complex vascular anatomy.⁴⁰ The exact underlying mechanisms of RIPC are not fully known but it is speculated to activate several neuronal and humoral signalling pathways, triggering endogenous protection against renal ischaemic damage.^12,41 A typical method is to place a blood pressure cuff around an arm and inflate it up to 50 mmHg above the systolic blood pressure for a 5-min duration to induce ischaemia, after which the cuff is released for reperfusion. These are repeated several times. This simple and uncomplicated method may offer an effective renal protective strategy. Several trials have investigated the effectiveness of RIPC on the kidney, with conflicting results. Zarbock et al.⁴² reported, in a large multicentre, randomised control trial, that RIPC was effective at reducing the incidence of AKI when performed before cardiac surgery in susceptible patients. In a follow-up study, the authors reported that RIPC significantly reduced 3-months prevalence of major adverse kidney events, which included mortality, need for renal replacement therapy and chronic renal dysfunction.⁴³ Ali et al.⁴⁴ and Zimmerman et al.⁴⁵ supported these findings in their randomised controlled trials. These findings were conflicted by ERICCA trial⁴⁶ and RIPHeart study,⁴⁷ which were unable to establish a protective effect of RIPC. It is important to note that in cardiac patients, propofol can interfere and diminish the protective effect of RIPC.^48,49 RIPC, being non-invasive and simple to apply, without association with complications, should be considered as a preventive measure preoperatively especially for patients susceptible to AKI.

Intraoperative strategies

Choice of anaesthetic

Knowledge of the effects of anaesthetic drugs on renal function is fundamental to the delivery of perioperative care optimal to improving renal outcomes after surgery.⁵⁰ It has been suggested that volatile anaesthetics may be renoprotective by modulating ischaemic-reperfusion injury and inflammation.^51,52 Although some volatile anaesthetics attenuate AKI, studies have shown that anaesthesia with propofol is associated with further reduction in incidence and severity of AKI.^53,54 In a study by Nieuwenhuijs Moeke et al., in which patients undergoing living donor kidney transplantation were either anaesthetised with propofol or sevoflurane, the sevoflurane group showed higher urinary AKI biomarkers on the second day after surgery, indicating kidney stress even though there was no significant difference in graft outcome.⁵⁵

A meta-analysis reported a reduction in incidence of perioperative AKI in cardiac surgery in the group of general anaesthesia combined with epidural analgesia.⁵⁶ A retrospective analysis of patients undergoing elective abdominal aortic aneurysm repair showed that those receiving combined epidural and general anaesthesia had a significantly lower dialysis requirements.⁵⁷ However, epidural analgesia has been found to possibly be an independent risk factor for postoperative AKI after major liver surgery. In patients undergoing major hepatectomies, there was substantial difference in AKI incidences among patients who received epidural as compared to those who did not (13.8 vs 5.0%; p = 0.025).⁵⁸ More studies are required to further determine the effects of epidural analgesia on kidney function in various types of surgery.

Use of dexmedetomidine

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, used commonly as a sedative agent in the intensive care unit and is also used as an adjuvant to general anaesthetic. The use of dexmedetomidine, whether intraoperatively or postoperatively in the intensive care unit, has been shown to improve renal function, as evidenced by an increased in creatinine clearance and a decrease in Neutrophil gelatinase-associated lipoprotein (NGAL), which is a novel AKI biomarker.⁵⁹ It is postulated that the mechanism by which dexmedetomidine exerts reno-protective effects is by its sympatholytic, anti-inflammatory and cytoprotective properties.^59,60 It also enhances renal blood flow and promotes diuresis leading to improvement in glomerular filtration rate.⁶¹ Multiple studies have reported reductions in incidence of cardiac surgery-associated AKI in valvular heart surgeries with the use of dexmedetomidine.^61–64 A meta-analysis by Shi and Tie⁶⁵ also reported significantly reduced incidence of AKI in patients after cardiac surgery. Dexmedetomidine failed to significantly decrease postoperative mortality, duration of mechanical ventilator, ICU and hospital length of stay, although decreased trends were observed for them. Dexmedetomidine might be a promising prevention strategy for AKI. More high-quality, multi centred trials will have to verify the beneficial effect of dexmedetomidine before its clinical application.

Haemodynamic management

Strong associations have been reported between intraoperative hypotension and perioperative AKI.^66–68 It is imperative to avoid intraoperative hypotension to maintain organ perfusion. The risk of AKI was increased when Mean Arterial Pressure (MAP) was <60 mmHg for >20 min or <55 mmHg for >10 min, suggesting that duration of hypotension is also a contributory factor to the development of AKI.⁶⁷ Baseline MAP needs to be taken into account when determining the target MAP. A MAP target of >65 mmHg used as part of a goal-directed therapy (GDT) in the FEDORA trial, has shown to have fewer postoperative complications, including AKI, strengthening the associations found between intraoperative hypotension and AKI.⁶⁹ A higher target MAP may be required in patients with hypertension.^9,70

Goal-directed therapy is a strategy to reach target haemodynamic parameters using administration of fluids, inotropes or vasopressors, guided by invasive or non-invasive monitoring techniques. It was proposed that GDT improves microvascular perfusion pressure and cellular oxygenation, while diminishing adverse effects of excess fluids administration.^71–74 It has been suggested that GDT may reduce the risk of AKI.^69,75 A recent meta-analysis by Giglio et al.⁷⁵ reported that GDT improve renal perfusion and oxygenation in high-risk patients undergoing major abdominal and orthopaedic surgery. Kidney disease: Improving global outcomes guidelines state that current evidence is insufficient to conclude that one vasoactive agent is superior to another in preventing AKI.⁹

Fluid Management

Fluid replacement approaches

The initial approach to manage intraoperative hypotension is often fluid therapy, although this should be approached with caution as excess fluid administration is associated with postoperative complications including prolonged duration of mechanical ventilation and poor wound healing.^76,77 Furthermore, several studies have reported that fluid overload is associated with organ oedema which, in turn, has a detrimental effect on renal function.^77–79 With the introduction of Enhanced Recovery after Surgery (ERAS), a model of care to implement strategies in an effort to improve patient outcomes, a more restrictive approach to fluid administration has been proposed to result in fewer postoperative complications (including pulmonary, AKI, sepsis, wound healing) and shorter length of hospital stay.^80–82 Myles et al.⁸³ conducted an international randomised controlled trial (RELIEF) to investigate the outcome of liberal versus restrictive (designed to achieve zero fluid balance during surgery and the 24-h postoperative period) fluid administration in 3000 patients undergoing major abdominal surgery. They found a significantly higher risk of AKI in the restrictive, zero fluid balance group than those in the liberal fluid group (8.6% vs. 5%, p < 0.001). It was hence suggested that a moderately liberal fluid regimen aiming for an overall positive fluid balance of 1–2L at the end of a major surgery should be recommended.⁸⁴

Intraoperative urine output

Urine output is a sensitive parameter to identify AKI and hence is included in the definition of AKI. However, when used intraoperatively, urine output may not reflect volume status or predict development of postoperative AKI. It has been shown that the renal clearance of the infused fluid during surgery is only 10–20% when compared with that in conscious volunteers, attributable to effects of anaesthesia, hypovolemia and release of aldosterone and vasopressin from stress.⁸⁵ A retrospective study⁸⁶ and two prospective randomised studies^87,88 did not find intraoperative oliguria to be predictive of postoperative AKI. Both randomised studies found no association between the amount of intraoperative fluids infused and intraoperative urine output or postoperative AKI.^87,88 Knowing that liberal fluid administration can have undesirable postoperative outcomes, the traditional recommendation of maintaining intraoperative urine output of at least 0.5 mL/kg/h should be reconsidered.⁸⁹

Choice of fluid composition

Composition of the fluid administered may also affect the risk of AKI. Normal Saline (0.9% Sodium Chloride) is associated with hyperchloremic acidosis, renal vasoconstriction and increased risk of AKI.^90–92 The findings from two large-scale trials involving the use of either saline or balanced crystalloids, in both ICU and non-ICU patients, concluded that the use of saline, compared with balanced crystalloids, is associated with increased incidence of major kidney events.^93,94 The use of Hydroxyethyl Starch compared with that of crystalloids, in ICU and septic patients, is associated with increased rate of renal replacement therapy and death.^95,96

Avoidance of nephrotoxic agents

Nephrotoxic drugs are a well-established cause of AKI. Non-Steroidal Anti-Inflammatory Drugs can be administered via various modes perioperatively, including intra-articular injections during orthopaedic procedures. They are commonly incorporated into the multimodal analgesic strategy of ERAS guidelines as opiate-sparing agents.⁸⁰ The routine use of NSAIDs should be reconsidered in patients who have other risk factors of AKI, due to its effects on renal plasma flow and potential to cause interstitial nephritis.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are commonly discontinued 24 h before surgery to avoid intraoperative hypotension and development of AKI, particularly ACEi with its inhibitory effect on the compensatory mechanisms to maintain glomerular filtration rate.⁹⁷

The routine use of gentamicin for surgical prophylaxis during orthopaedic surgery was associated with increased risk of AKI.⁹⁸ Aminoglycosides can cause AKI through processes such as reduction of protein synthesis and mitochondrial dysfunction.²⁰

Contrast-induced AKI is well recognised and when its use is not avoidable, the minimisation of the contrast burden and maintenance of normovolaemia using crystalloid fluid therapy may prevent it.^9,20 There is no evidence for the use of N-acetylcysteine to prevent contrast-associated AKI.⁹⁹

Goldstein et al.¹⁰⁰ analysed and implemented a surveillance system on their electronic health record to screen for the exposure to nephrotoxins, with a subsequent decision matrix, thereby reducing exposure rate and AKI rate. This highlights the potential of vigilance in scrutinising for exposure to nephrotoxins, thereby reducing avoidable harm.

Anaemia and transfusion

Anaemia results in reduced oxygen-carrying capacity, which leads to renal cortical and medullary hypoxia, and the subsequent development of AKI.¹⁰¹ Pre-operative anaemia was found to be strongly associated with the development of AKI in a graded manner.^102,103 Similarly, post-operative reduction in haemoglobin levels also demonstrated a graded increase in the risk of AKI.¹⁰² However, perioperative transfusion of red blood cells also increases the risk of AKI, such that the incidence of AKI in cardiac surgery increases by 10–20% with every unit of transfused blood. This has been attributed to the preservation and storage effect of red blood cells, which in turn promote a pro-inflammatory state and impair oxygen delivery.¹⁰⁴

With both anaemia and transfusion being associated with AKI, it is important to optimise pre-operative haemoglobin levels, as well as adopt measures to reduce surgical bleeding to avoid unnecessary transfusion.

Post-operative recommendations

Postoperative hypotension (systolic blood pressure <90 mmHg) is associated with increased risk of all-cause mortality and myocardial injury.¹⁰⁵ With postoperative hypotension affecting more than 30% of patients and potentially for a longer duration than intraoperative hypotension, it suggests that maintenance of haemodynamic status early postoperatively can be recommended to avoid AKI, especially in high risk patients.

With ERAS protocols advocating multimodal, opioid-sparing approach for postoperative analgesia, the use of NSAIDs should be weighed against risk of AKI in susceptible patients. The reintroduction of ACEi and ARB, with their beneficial effects on cardiovascular and kidney health, should be actively considered postoperatively.

Conclusions

Perioperative AKI is a common complication after surgery and is associated with increased both short-term and long-term morbidity and mortality. Yet it is often under-appreciated despite its significant burden on healthcare resources. There is a need to raise the awareness of this complication to clinicians involved in perioperative care of surgical patients, including anaesthesiologists, whose intraoperative strategies have significant impact on the kidney function. A personalised and multidisciplinary approach is essential to protect kidney function during the perioperative period. Future research should look into modalities for earlier detection of subclinical AKI, allowing for earlier initiation of renal protective measures. There is also potential for further research to enhance the currently generic perioperative recommendations.

Footnotes

Author contributions

JX conceived the study, researched the literature and wrote the first draft of the manuscript. All Authors reviewed, edited the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Availability of data

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Ethical approval

Not applicable.

Informed Consent

Not applicable.

Trial Registration

Not applicable.

ORCID iD

Jieyin Xing

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