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Effect of inhalational anesthetics on acute kidney injury.

SUMMARY--Acute kidney injury (AKI) is a serious complication associated with increased morbidity and mortality. Total incidence of AKI in hospitalized patients is 1%-5%. As many as 30% of these patients develop AKI in the perioperative period, which is associated with anesthesia and surgery. Despite scientific advances and improved surgery techniques, as well as treatment in intensive care units, no significant decrease in AKI incidence has been achieved. To change this outcome, it is important to identify patients at risk of AKI and prevent its occurrence. Correct selection of anesthetic drugs during general anesthesia, adjusted to the individual needs of patients, also influences the overall outcome of treatment. Nowadays, inhalational anesthetics are not considered nephrotoxic. The more so, inhalational anesthetics have a strong and direct protective effect on many organs through preconditioning and postconditioning. New studies have shown that sevoflurane diminishes ischemia/reperfusion kidney injury and has an anti-inflammatory effect, thus having the potential to reduce the occurrence of AKI. Given the incidence of AKI in the perioperative period, as well as new findings about anesthetics, the issue of anesthetic selection during general anesthesia might be of crucial importance for the final outcome of treatment.

Key words: Acute kidney injury; Anesthesia, general; Anesthetics, inhalation; Sevoflurane; Ischemia; Reperfusion injury


The choice of general anesthesia best suited to the individual patient needs is of great importance, as the correct selection of anesthesia-inducing drugs can prevent unwanted effects on risk-group patients. In addition, it increases the effectiveness of the protective effects of individual anesthetics that have been proven in clinical practice, thus improving the outcome of treatment.

Acute kidney injury (AKI) in the perioperative period is characterized by acute kidney function reduction within 48 hours of surgery. In most cases, the damage is partially reversible, and recovery is expected within several weeks. Unfortunately, function recovery is complete only in 15% of patients. AKI is a serious perioperative period complication accompanied by increased mortality, morbidity and treatment costs. It is accompanied by the development and progression of chronic kidney disease, as well as an increased need for future dialysis, particularly in patients already suffering from disturbances in kidney function.

There are several classifications of AKI, previously known as acute renal failure, of which the most widely used are the Kidney Disease Improving Global Outcomes (KDIGO) and Risk, Injury, Failure and Endstage renal disease (RIFLE) classifications. The main characteristic of AKI is lost kidney function, which can be assessed by measuring serum creatinine levels as a measure of glomerular filtration rates, and by measuring urine output volume (1).

An increase in creatinine occurs only after a decrease in the glomerular filtration rate by more than 50%. Therefore, it is not surprising that even a small serum creatinine increase is associated with increased short-term and long-term mortality, regardless of whether at the time of discharge from the hospital kidney function has partially or fully recovered. Consequently, even a minor creatinine increase needs to be considered seriously, as it represents significant kidney function damage (2-7).

The incidence of AKI in surgery patients depends on the type of surgery. Some types of surgery associated with a high incidence of AKI development are cardiac surgery, abdominal and thoracoabdominal aneurysm surgery, and liver transplantation, while the incidence is significantly lower in general surgery. Despite new findings on AKI and improvements in surgery techniques and treatment in intensive care units, there has been no significant impact on this outcome. Therefore, identifying the risk groups and prevention of AKI occurrence are of extraordinary importance (8,9). The results of risk factor studies are often analyzed according to the type of surgery. In a prospective study of patients undergoing major non-cardiac surgery, Kheterpal et al. found an increased risk of developing AKI in seven risk groups: patients older than 59 years, those with a body mass index greater than 32 kg/m (2), those with chronic obstructive pulmonary disease, liver disease or peripheral vascular occlusive disease, and urgent surgery and high-risk surgery patients (10).

Knowing the preoperative, intraoperative and postoperative risk factors enables the introduction of precautionary measures in each particular perioperative period. Measures are aimed at the prevention of hemodynamic disorders and inflammatory changes, avoiding nephrotoxic drugs, and the prevention of metabolic disorders. In the preoperative period, optimization of the patient's condition is important. During anesthesia, emphasis is on the choice of anesthetics and on hemodynamic optimization, maintaining medium artery pressure (MAP >65 mm Hg), adequate volume compensation and vasoactive drug administration. In the postoperative period, particularly in intensive care units, where patients are administered a large number of drugs, administration of nephrotoxic drugs should be avoided and drug dosage adapted to kidney function.

This review discusses the results of research investigating the use of inhalational anesthetics and their effect on kidney function.

For the time being, modern inhalational anesthetics are basic anesthetic agents, equally used for anesthesia maintenance and for anesthesia induction. Sevoflurane, isoflurane and desflurane are the most frequently administered inhalational anesthetics. The major anesthesiological effect of these gases is unconsciousness as a result of the central nervous system depression. In recent years, their non-anesthesiological characteristics, such as their direct effect on AKI, have been investigated.

Preconditioning and Postconditioning of Inhalational Anesthetics

It is known that the use of inhalational anesthetics ahead of an expected organ ischemia has a protective effect. This phenomenon is called anesthetic preconditioning (11,12). Inhalational anesthetic agents have a neuroprotective effect owing to the activation of adenosine triphosphate (ATP)-dependent potassium channels. Sevoflurane preconditioning for 10 minutes significantly decreases the postoperative release of brain natriuretic peptide, a biochemical marker of myocardial contractile dysfunction. In addition, translocation of protein kinase C isoforms 8 and [pounds sterling] in human myocardium in response to sevoflurane preconditioning has been observed, as well as lower postoperative plasma cystatin C concentrations. This indicates better cardiac and renal function in patients.

The updated American Heart Association Guidelines recommend administering inhalational anesthetics during general anesthesia in non-cardiac surgery in hemodynamically stable patients at high risk of perioperative myocardial ischemia (13).

Administering inhalational anesthetics after completion of ischemic injury protects several organs, including liver, heart and kidney, which is called anesthetic postconditioning (14,15).

These facts open up new possibilities for AKI prevention and treatment.

In the past, administering inhalational anesthetics, particularly sevoflurane, was associated with nephrotoxicity as a result of the production of vinyl halide (compound A) during dehydrofluorination by carbon dioxide absorbers. Compound A has been shown to be nephrotoxic in rats (16). Contrary to this are the results of the research conducted by Bito et al., who measured the impact of sevoflurane and isoflurane on blood urea nitrogen and serum creatinine concentration values, and on urinary excretion of the kidney-specific enzymes. The results of the study did not show any significant effects of compound A production during sevoflurane anesthesia on kidney function (17).

Modulation of Ischemia/Reperfusion Injury and Anti-Inflammatory Effects

The major cause of AKI incidence is inflammatory reaction as a consequence of ischemic/reperfusion injury. Inflammatory response in tubules and endothelium causes breakdown of the endothelial basement membrane and inflammatory migration into the interstitial space. The inflammatory response can be reduced by activation of regulatory T lymphocytes further facilitating the production of anti-inflammatory mediators.

Inhalational anesthetics exert powerful multi-organ protective effects during the perioperative period and powerfully modulate ischemia/reperfusion injury. It has been proven that they activate multiple pathways to synthesize key cytoprotective and anti-inflammatory signaling molecules to attenuate ischemic AKI, as has been detailed by Fukazawa and Lee (18). In ischemia/reperfusion kidney injury, proinflammatory cytokines are produced in dying or injured cells of proximal tubules, while the increasing number of chemokines attracting cytotoxic neutrophils and cytotoxic T lymphocytes additionally contributes to the local inflammatory response.

On the other hand, regulatory T cells produce antiinflammatory mediators, including transforming growth factor (TGF)-fil and interleukin (IL)-IO, and express ectonucleoside triphosphate diphosphohydrolase (CD39) and ecto-5'-nucleotidase (CD73), which convert proinflammatory ATP into cytoprotective adenosine, which produces effects via A2a receptors. Thus, regulatory T cells protect the kidney from ischemic/reperfusion injury.

Inhalational anesthetics decrease nuclear translocation of NF-[KAPPA]B, a key proinflammatory transcription factor (19). Furthermore, inhalational anesthetics produce and promote anti-inflammatory mediators important for renal protection, including TGF-[beta]1 release, CD73 activation, and adenosine generation (20-22).

Serum creatinine and estimated glomerular filtration rate as kidney function markers are insensitive to truly test the efficacy of the protective role of inhalational anesthetics. Recent research has been aimed at an early predictive marker of AKI, i.e. neutrophil gelatinase associated lipocalin (NGAL). A study of sevoflurane effects on renal function in rats after liver transplantation demonstrated significantly reduced NGAL concentrations in the sevoflurane group, as well as smaller epithelial necrosis. In the group anesthetized with sevoflurane, significantly lower serum concentrations of TNF-[alpha], IL-6, and myeloperoxidase were found 2 hours after reperfusion (23).

In parallel with the increase in the number of studies demonstrating the protective role of sevoflurane against the occurrence of AKI, there is also a large number of studies on the protective effects of other anesthetics, such as propofol, with regard to AKI. While some studies point to a stronger protective effect of propofol as compared with sevoflurane relative to the occurrence of AKI (24), others demonstrated that there were no statistically significant differences in the incidence of AKI between the two groups (25,26).


Acute kidney injury in the perioperative period is a serious complication which often has an adverse effect on the course of treatment and outcome in surgical patients.This syndrome manifests with increased laboratory values of creatinine without clinical symptoms of anuria. The results of studies have shown higher mortality rates even in milder forms of AKI. The present-day approach aimed at reducing AKI incidence is based on applying precautionary measures in patients at risk during the perioperative period. AKI needs to be treated in a timely manner in order to ensure maximum kidney function recovery. It is also important to point out the multidisciplinary approach required for such patients, which includes an anesthesiologist, a surgeon, clinical pharmacologist and nephrologist.

The major cause of AKI incidence is inflammatory reaction as a consequence of ischemic/reperfusion injury. Modern inhalational anesthetics, such as sevoflurane and isoflurane, have immunomodulatory renoprotective effects based on the activation of regulatory T lymphocytes promoting the production of anti-inflammatory mediators. Study results confirm that administering inhalational anesthetics in patients at risk of developing AKI is justified.

Given the above, it is concluded that the selection of the type of anesthetic during general anesthesia remains an important clinical issue, and that further research is needed to clarify the protective effect of inhalational anesthetics on the occurrence of AKI.


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M. Miklic Bublic, D. Tonkovic, S. Sakan, A. Misir i D. Bandic Pavlovic

Akutno ostecenje bubrega (AOB) je ozbiljna komplikacija povezana s povisenim pobolom i smrtnoscu. Ukupna incidencija AOB u bolnickih bolesnika iznosi 1%-5%. Cak 30% tih bolesnika su razvili AOB u perioperacijskom razdoblju kao posljedicu anestezije i operacije. Unatoc novim znanstvenim spoznajama i unaprjedenju kirurskih tehnika te lijecenja u jedinicama intenzivne njege, nije postignut znacajniji pomak u smanjenju incidencije AOB. Za promjenu tog ishoda vazno je prepoznavanje rizicne skupine bolesnika te prevencija. Na ukupni ishod lijecenja utjece i pravilan odabir anestetickih sredstava tijekom opce anestezije, koji je najbolje prilagoden individualnim potrebama bolesnika. Danas se smatra da inhalacijski anestetici nisu nefrotoksicni. Dapace, inhalacijski anestetici imaju snazan izravan zastitni ucinak na mnoge organe kroz predkondicioniranje i postkondicioniranje. Nova istrazivanja pokazuju da sevofl uran smanjuje ishemijsko-reperfuzijsku ozljedu bubrega i djeluje protuupalno, zbog cega ima potencijal smanjiti pojavu AOB. S obzirom na incidenciju AOB u perioperacijskom razdoblju i nove spoznaje o anesteticima, pitanje odabira anestetika tijekom opce anestezije moglo bi biti od kljucnog znacenja za sveukupni ishod lijecenja.

Kljucne rijeci: Akutno ostecenje bubrega; Anestezija, opca; Anestetici, inhalacijski; Sevofl uran; Ishemija; Reperfuzijska ozljeda

Martina Miklic Bublic (1), Dinko Tonkovic (1,2), Sanja Sakan (3), Anita Misir (1) and Daniela Bandic Pavlovic (1,2)

(1) University Department of Anesthesiology, Resuscitation and Intensive Care, Zagreb University Hospital Center;

(2) University of Zagreb, School of Medicine, Zagreb; (3) Magdalena Special Hospital, Krapinske Toplice, Croatia

Correspondence to: Martina Miklic Bublic, MD, University Department of Anesthesiology, Resuscitation and Intensive Care, Zagreb University Hospital Center, Kispaticeva 12, HR-10000 Zagreb, Croatia


Received April 8,2016, accepted June 27,2016
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Author:Bublic, Martina Miklic; Tonkovic, Dinko; Sakan, Sanja; Misir, Anita; Pavlovic, Daniela Bandic
Publication:Acta Clinica Croatica
Date:Nov 1, 2016
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