Volatile agents and renal transplantation

The fi rst fl ammable halogenated volatile anesthetic gas was methoxyfl urane which was used in Manhattan Project in 1948 during the 2nd World War. It has been withdrawn for use as an anesthetic agent due to the high rate of vasopressin resistant renal failure. Afterwards the attempts to fi nd a new agent continued with the discovery of another fl uoride agent. This agent was Sevofl urane and its conversion to haloalkenes by dehydrofl uorination when it encountered CO2 absorber to produce Compound A: trifl uoro methyl vinyl ether, has shown a new concern in rats [1]. Although nephrotoxicity has not been established in clinical studies; according to the FDA recommendations, sevofl urane can only be used up to 1 h with a fresh gas fl ow of 1L/min. Moreover sevofl urane can be considered more than 1h with a fl ow of >2 L/min. As a result, desfl urane gained popularity because of its structure being a fl uorinated methyl ether and highly stable with sodalime. Desfl urane has almost no metabolism even administered at 7 MAC values, and it has the least solubility among volatile agents. By this way the recovery time is almost 50% of isofl urane [2]. Like isofl urane, causes a dose-dependent increase in heart rate and blood pressure and a decrease in systemic vascular resistance with myocardial depression and peripheral vasodilation. On the other side, coronary vasodilatation also leads to a decrease in cardiac workload. The metabolism in liver is about 0.02%. The most unfavorable property is the stimulation of airway refl exes with irritant odor leading to cough and bronchospasm.


History
The fi rst fl ammable halogenated volatile anesthetic gas was methoxyfl urane which was used in Manhattan Project in 1948 during the 2nd World War. It has been withdrawn for use as an anesthetic agent due to the high rate of vasopressin resistant renal failure. Afterwards the attempts to fi nd a new agent continued with the discovery of another fl uoride agent. This agent was Sevofl urane and its conversion to haloalkenes by dehydrofl uorination when it encountered CO 2 absorber to produce Compound A: trifl uoro methyl vinyl ether, has shown a new concern in rats [1]. Although nephrotoxicity has not been established in clinical studies; according to the FDA recommendations, sevofl urane can only be used up to 1 h with a fresh gas fl ow of 1L/min. Moreover sevofl urane can be considered more than 1h with a fl ow of >2 L/min. As a result, desfl urane gained popularity because of its structure being a fl uorinated methyl ether and highly stable with sodalime. Desfl urane has almost no metabolism even administered at 7 MAC values, and it has the least solubility among volatile agents. By this way the recovery time is almost 50% of isofl urane [2]. Like isofl urane, causes a dose-dependent increase in heart rate and blood pressure and a decrease in systemic vascular resistance with myocardial depression and peripheral vasodilation. On the other side, coronary vasodilatation also leads to a decrease in cardiac workload. The metabolism in liver is about 0.02%. The most unfavorable property is the stimulation of airway refl exes with irritant odor leading to cough and bronchospasm.

Volatile agents and immune response
The infl ammatory response to surgery and changes in cellmediated immunity may lead different results. Based on the current literature, changes in the immune system response were found to be more pronounced after a balanced volatile anesthesia compared to total intravenous anesthesia. It is clear that volatile agents can increase infl ammation and cellular adhesion due to their high doses resulting with hypotension and transient hypoxia. They decrease Th1 phenotype, increase cell-mediated immunity and directly affect immune system by manipulating glucose control. For instance, isofl urane has been shown to inhibit normal insulin production and produce a hyperglycemic response.
The NK cell activity is suppressed by volatile agents [3].
Besides they enhance angiogenesis through hypoxia inducible factor-1 activity. Moreover, volatile anesthetics suppress cell-mediated immunity and promote cancer cell proliferation

Volatile agents-induced renal protection
The fi rst successful renal transplantation was performed between twins in 1954 by Joseph Murray under subarachnoid block with limited monitoring of blood pressure and Electrocardiogram (ECG). The fi rst successful live renal tx was performed by Johny and Mohan Rao in 1971 in India [7].
The graft care requires professionalism during the transplantation. A number of pathological processes play a role in the failure of graft [8]. Ischemia Reperfusion Injury (IRI) can lead to early renal dysfunction which causes acute rejection episodes and graft failure. However, the most obvious cascade is the loss of renal function caused by the immune response and the resulting deepening of hemodynamic instability, which in turn leads to more immune activation with a vicious cycle. The release of vasoactive hormones during hemodynamic instability causes intrarenal vasoconstriction and aggregates intrarenal hypoxia. This may lead to potentialization of acute tubular necrosis and tubular damage in the transplanted kidney. Finally renal ischemia causes depletion of ATP stores, bleb formation and a loss of renal tubular polarity. Cytokines and chemokines released from renal tubular epithelial cells increase renal tubular and endothelial damage. The destruction of the endothelial basement membrane causes vascular leakage and neutrophil migration into the interstitial area.
Since years, ischemia-reperfusion injury during kidney transplantation continues to be an important challenge in maintaining organ function and graft viability. IRI is a process that involves a reperfusion injury in live ischemic tissue and its etiology involves biochemical, cellular, vascular endothelial and tissue-specifi c factors with infl ammation. Renal parenchymal destruction leads to increased graft loss resulting in increased vascular damage and fi brosis. ICAM1 secondary to ischemia, macrophage infl ammatory protein, monocyte chemotactic protein, interferon inducible protein are effective in renal damage. The mechanism of apoptosis occurs with the reduction of granzyme, Fas / Fas ligand, cytotoxic T lymphocyte antigen 4, IL-2. The interaction of cytotoxic T lymphocyte antigen 4 with CD 80/86 and T regulatory activity with MHC II cells disrupts T cell activation. Here, apoptosis triggers this contact-dependent pathway. In addition, cytokine production (IL35, TGF beta, IL 10, IL 8) is also associated with T cell activation. IRI results in tubular damage by inducing infl ammatory cells, which causes the accumulation of T cells in the area of the danger zone or in the reperfusion area. These areas are fi elds of hypovascularization and hypoperfusion where IRI occurs. Upregulation of all these substances causes innate immune response in renal tubular cells and endothelium. Endothelial vasoconstriction and necrosis are the products of prolonged ischemia. Reactive Oxygen Species (ROS) production secondary to reperfusion and dysfunction of the antioxidant system exacerbate tubular cell damage and lead to death. Ongoing hypoxia leads to disruption of mitochondrial function, and apoptosis is triggered, afterwards fi brosis begins. On the other hand, activation of procoagulant pathways in peritubular and glomerular capillaries as a response during reperfusion causes fi brin deposits and plt aggregation. This is accompanied by a decrease in Glomerular Filtration Rate (GFR) due to the reduction of renal perfusion. Again, adhesion of erythrocytes and leukocytes to the vascular endothelium contributes to the obstruction of the renal microvasculature. And ultimately, all these events cause thrombosis in renal vasculature and graft loss.
Activation of toll-like receptors by expression of adhesion molecules, polymorphonuclear cells and neutrophil infi ltration as a result of micvovascular plug and local tissue destruction is also exacerbated. Activation of complement by an alternative pathway also contributes to this situation.
Acute tubular necrosis is responsible for 75% of acute renal injury. These necrotic tissues cause more infl ammation and a vicious cycle with danger signals [9]. Therefore, the such as hypoxia-inducible factor-1a (HIF-1a) and hypoxia inducible factor. Adenosine-producing, ecto-50-nucleotidase (CD73), sphingosine-1-phosphate (S1P) via Sphingosine Kinase (SK) and IL-11 molecules such as transforming growth factor-b1 (TGF-b1) have been identifi ed. The relation between sevofl urane and heat shock proteins including ERK, AKT and TGF-b1 has been revealed. The protection mechanism formed by volatiles in the kidney is formed by different paths from the heart, liver and brain. Volatile agents affect on calcium haemostasis in heart, activate myocardial protection pathways with their immunomodulatory effects. The depletion of ATP stores causes an increase in intracellular free calcium, and it has been shown that volatiles inhibit the IR in the heart by inhibiting the Na-Ca exchanger. Renal protection of volatile anesthetics is based on the inhibition of renal tubular, endothelial and interstitial infl ammation by secretion of cytoprotective and anti-infl ammatory molecules.
Volatile agents interact with the plasma lipid membrane in renal tubular cells and induce TGF-1 production by exogenous phosphoditylserin. Volatiles have antinecrotic, antiinfl ammatory and antipytotic effects in renal tubule cells with SK and S1P signaling and TGF-1-induced CD73 increase. In addition, Toll-like receptor-mediated T-cell immune response occurs. They increase megakaryocyte maturation by inducing IL-11 release and inhibiting endothelial cell death. The regulatory T (T reg) cells protect the kidney from IR damage by suppressing infl ammation damage. Preventing the opening of pores with changes in mitochondrial permeability after ischemia, which causes the release of proapoptotic factors and necrotic cell death, is another advocated mechanism [10]. Volatile agents also suppress natural immunity, by the effects on NK, monocyte, neutrophil and macrophages. They also suppress T lymphocytes of CD4, CD 8 with B lymphocytes. Clinically effective concentrations of volatile agents also reduce the activation of mitogen-activated protein kinases with a reduction in infl ammation and apoptosis [11].

Ideal volatile agent
The inorganic fl uoride amount formed by isofl urane and halothane biodegradation was found to be 3 -5 and 1 -2 μmol/L, respectively. These levels are below the renal toxic threshold however desfl urane is not even metabolised. And compared to intravenous anesthetic agents, volatils decrease plasma creatinine, neutrophil and macrophage migration in kidney, decrease expression of proinfl ammatory and adhesion molecules, decrease necrotic and apoptotic damage [12]. Ham, et al. [13], conducted a study in human kidney cells. A 16 h of 1.25-2.5% isofl urane exposure followed 30 min renal ischemia and 4 h period of reperfusion. In contrast with pentobarbital, there was an increase in the synthesis of IL 11 in 1.2% isofl urane post-conditioning. This proves the cytoprotective effects of isofl urane. In a retrospective study, the records of 200 renal transplant patients were examined [14]. Postoperative creatinine levels of patients treated with Isofl urane (n= 103) and sevofl urane (n= 97) were evaluated at the 1st, 3rd and 6th months. There was no statistically signifi cant difference between the isofl urane and sevofl urane groups in terms of postoperative serum creatinine, urea nitrogen and creatine clearance. The incidence of rejection was 4.9% in the isofl urane group and 9.3% in the sevofl urane group (P= 0.22), although not statistically signifi cant. Postoperative dialysis requirement was also found to be higher in sevofl urane than isofl urane group (8.7% vs 13.4%, respectively). However, in a meta-analysis, the studies between 1995 and 2016 were evaluated and the main outcome was a change in plasma creatinine, urine protein and glucose excretion at 24th and 72nd h [15]. Sevofl urane and isofl urane were compared in terms of nephrotoxic potentials and no statistically signifi cant difference was found in 6 studies.
Researchers have begun to study whether an almost nonmetabolized inhalation agent, such as desfl urane, would be more useful in the IRI. In an exprimental study, in the fi rst 15th minutes of reperfusion, post-conditioning was performed using desfl urane and found protective on both renal function and tissue perfusion [16]. Guye, et al. [17], investigated tubular cell damage in rabbits, with desfl urane preconditioning. Three hours of reperfusion phase was observed following a 45 min bilateral renal ischemia period. The histopathological damage score was found to be the lowest in desfl urane and sham groups. Karadeniz, et al. [18], divided renal transplant donors into two groups: sevofl urane (n= 35 pairs) and desfl urane (n= 30 pairs). Preoperatively and on postoperative 1st and 7th days, GFR, creatine, NGAL, IL-18 levels were analysed. No difference was found between the two groups. In another retrospective study, the effects of sevofl urane (n= 73) and desfl urane (n= 71) were compared at postoperative 1st year [19]. Creatinine, BUN levels and glomerular fi ltration rate didnot differ between groups.
However, in several studies, the opposite results were obtained. The effects of desfl urane and sevofl urane (n= 37 in each group) on hepatic and renal functions were evaluated in live donors undergoing right hepatectomy [20]. In sevofl urane group, there was an increase in BUN and creatine levels at 30th day with a reduction in GFR [20]. In a study comparing IV and inhalation anesthetics, it was shown that mRNA coding for chemokines with ICAM 1 and proinfl ammatory cytokine in the renal cortex was less in the volatile group and renal necrosis was rarely detected after 24 -72h [21]. Another study included renal transplant patients from live donors and desfl urane has been shown to provide better preconditioning of renal IR injury than sevofl urane and isofl urane [22]. In another study comparing the effects of volatile agents on neutrophil migration in reperfused organ, it has been shown that Sevofl urane and Desfl urane reduce the neutrophil transmigration induced by IL-8 expression of CXR1 and CXCR2, which are ELR + receptors [23]. In addition, inhibition of CD11b (17% for sevofl urane and 27% for desfl urane) has been shown to reduce the adherence of neutrophils to the endothelium.
Volatile Anaesthetic Protection of Renal Transplants-1 study aimed to compare the biochemical and clinical effects of propofol vs sevofl urane-based anaesthesiology. Sixty pairs of patients were divided in 3 groups: PROP (donor and recipient received propofol), SEVO (donor and recipient received sevofl urane), and PROSE (propofol for donor and sevofl urane for recipient) [24]. (KIM-1), N-acetyl-b-D-Glucosaminidase (NAG), and hearttype fatty acid binding protein (H-FABP). On the second day KIM-1 was higher in SEVO than PROP. However, the acute rejection rate in the second year was 35% in the PROP group and 5% in the PROSE group. In a murine model, desfl urane was found to be related with higher creatinine levels in comparison with halothane, isofl urane and sevofl urane [25]. This was consistent with renal tubular edema, dilatation, and necrosis in histopathological sampling. According to the results of this study, desfl urane was found to be weaker in renal preservation than other anesthetic agents, however this was an experimental study and it was also stated that clinical trials are needed [25] Conclusion As a result, according to the information obtained from the literature, isofl urane has the most severe effects on hemodynamic variables. It has been shown that sevofl urane has less effect on renal blood fl ow, GFR and urinary output with less stable hemodynamics, including a reduction in mean arterial blood pressure. Moreover the nephrotoxic side-effect of inorganic fl uoride and compound A, which is associated with the defl oration of sevofl urane, is still under discussion and there is no clinical evidence. In renal transplantation the main goal should focus on preserving the kidney and maintain the optimal postoperative renal functions.