The renoprotective properties of xenon and argon in kidney transplantation

Chronic kidney disease is recognised worldwide as a major public health burden. The severity of disease is categorised into five stages and progressive renal impairment may ultimately lead to the development of end-stage renal disease, and the permanent loss of kidney function.1 As a mainstream therapeutic option, kidney transplantation has drastically transformed the quality of health for patients suffering from end-stage renal failure.2 The demand for transplantation continues to rise because of an increase in the prevalence of renal failure and advances in medical care protocols. However, the number of donor organs available is far below the growing need of the patients on the waiting list. The crisis in organ supply challenges the transplant community to maximise and rationalise the use of organs from all potential available donors. Donation after circulatory death is used to describe the retrieval of organ grafts following death confirmed by circulatory failure,3 whereas donation after the confirmation of death using neurological criteria is referred to as donation after brain death4 and currently remains the most important source of organs. Recently, the expanded criteria donor (ECD) category has been introduced, and the ECD donor organ is normally associated with previous medical complications or very advanced ages. The donor characteristics that define an ECD kidney include age at least 60 years, or age 50 to 59 years and two of the following: cerebrovascular accident as the cause of death, preexisting hypertension, or terminal serum creatinine greater than 1.5 mg dl−1.5 Renal transplantation from living kidney donors is still relatively marginal in most European countries. Harmful outcomes for living kidney donors are limited and the living kidney donation may be considered as safe because graft injury is minimal prior to the organ retrieval. In the donor organ after cardiac arrest, hypoperfusion and ischaemia have a considerable effect on organ viability.6 Marginal donor grafts may have suboptimal quality because of injuries inflicted by severe hypoperfusion and vigorous inflammatory response during cardiac arrest or brain death.7–9 Also, they may have increased vulnerability to ischaemia–reperfusion injury and shorter long-term survival.10,11 Optimisation of the preservation of these grafts would maintain the organ quality to the best standard prior to engraftment and would probably increase the number of available organs. Despite the continuous progress in immunosuppressive and supportive therapy, improvements in graft survival have reached a plateau and no further improvement has been evident over the last decade. The majority of grafts develop chronic allograft failure, which remains a major impediment to long-term graft survival.12 Early graft injuries related to the condition of the donor, the preservation of the organ, or ischaemia–reperfusion injury and frequent episodes of acute immune rejection appear to be particularly associated with chronic graft failure. Therefore, strategies for better protection of grafts are urgently needed and better adaptation of preservation protocols is mandatory. This Editorial summarises present argon research and organ protection, particularly in the transplant kidney, together with research on another noble gas, xenon, from the third Argon-Organprotection-Network III meeting held in London on Monday 30th November and Tuesday 1st December 2015. Xenon as a renoprotectant in kidney transplantation Xenon is a colourless, odourless, tasteless and chemically nonreactive gas that occurs in the earth's atmosphere in extremely low concentration.13 Xenon is chemically inert because its outer electron orbitals are completely filled.14 Contrary to its chemical properties, xenon has been found to be very active biologically. Xenon is an anaesthetic agent and, when inhaled, anaesthesia rapidly ensues.15,16 Recently, it has become clear that xenon treatment protects tissues from injury. Evidence of its protective effects in the heart17 and brain18 has spawned interest in renal injury as the new area for the potential organoprotective application of xenon, as the kidney is exceedingly vulnerable to ischaemia–reperfusion injury. Ma et al.19, for the first time, showed that preconditioning with 70% xenon led to significant functional recovery and prolonged survival in the kidney after unilateral severe warm ischaemia–reperfusion injury in mice. Later on, the same group showed the renoprotective effects of xenon against ischaemia–reperfusion injury in the rodent transplant model, and demonstrated that when given either to donors (pretreatment) or to recipients (posttreatment), graft survival was prolonged.20 Xenon treatment has been shown to protect against delayed graft function in Lewis-to-Lewis isografts,20 to protect against acute renal rejection associated with ischaemia–reperfusion injury in Brown Norway-to-Lewis allografts,21 and to protect against chronic allograft nephropathy associated with ischaemia–reperfusion injury in Fischer-to-Lewis allografts.22 In an ex-vivo preserving study,23 the kidney was perfused and kept with ice-cold Soltran preservation solution that had been saturated with 75% xenon. The morphological structure of the ex-vivo rat kidney was well preserved in xenon-containing Soltran solution when compared with that of the control. Xenon shows promise as an effective option in the protection of the graft kidney and this encourages further investigation into other noble gases such as argon in the same setting. Argon as renoprotectant in kidney transplantation Experiments with argon in models of traumatic brain injury and cerebral ischaemia suggest that it too, is neuroprotective.24 The neuro and cardioprotective properties of argon have been extensively reviewed by Hollig et al.25 and Coburn et al.26 Argon and xenon may possibly share some joint features during further signalling, such as Extracellular signal–regulated kinase (ERK)1/2 and B-cell lymphoma-2 signalling, which plays a role in signal transduction by argon.25,26 The relatively high availability of argon in the atmosphere makes it a more cost-effective and a clinically relevant therapeutic option compared with xenon. Zhao et al.27 have shown the neuroprotective mechanisms of argon through activation of the transcription factor NF-E2-related factor 2, which could up-regulate the expression of many antioxidant enzymes under oxidative stress.28 In addition, argon exposure induced activation of the Phosphoinositide 3-kinase (PI-3K) and ERK1/2 pathway, leading to up-regulation of Phosphorylation of mammalian target of rapamycin and NF-E2-related factor 2. Expression of down-stream antioxidative effectors, such as NAD(P)H dehydrogenase (quinone) 1 and superoxide dismutase 1, leads to suppression of reactive oxygen species production in the brain cortex after hypoxic ischaemia. Consequently, neuronal cell death and inflammation were inhibited and brain infarction volume was reduced. Consistent with this study, argon has been demonstrated to enhance ERK 1/2 activity in microglia and also influence ERK 1/2 signalling in astrocytes and neurons in vitro.29 In another study, Zhao et al.30 demonstrated that argon, when combined with hypothermia (35°C and 33°C), protected the neonatal rat brain more effectively against ischaemic brain injury. PI-3K/protein kinase B pathway activation, up-regulation of Heme oxygenase 1 was shown to mediate the beneficial effects of the combined treatment. These findings indicate that the combination of argon and hypothermia confers more effective neuroprotection against a hypoxia-ischaemia insult in neonatal rats. Ulbrich et al.31 conducted a study in the rat retina model of ischaemia–reperfusion injury. Argon treatment attenuated apoptosis by preservation of mitochondrial membrane potential, reducing oxidative stress. Importantly, inhibition of Toll-like receptor (TLR)-2 and 4 attenuated the protective effect mediated by argon. This study, for the first time, demonstrated the critical role of TLR-2 and TLR-4 in mediating the protective effects of argon. Later studies also strengthened these findings.32 Argon treatment markedly reduced TLR-2 and TLR-4 receptor expression. ERK1/2 and TLR signalling inhibitors abolished the cytoprotective effects of argon. In another study in the same model,33 argon treatment protected against retinal ganglion cell death induced by ischaemia–reperfusion injury, through an ERK-1/2-dependent regulation of heme oxygenase 1; ischaemia and reperfusion injuries and subsequent neuronal apoptosis were reduced. In the setting of kidney transplantation, however, there is insufficient evidence for the protective effects of argon in either pretreatment or/and posttreatment. Irani et al.34 demonstrated that a cold-storage solution saturated with argon could limit ischaemia–reperfusion injury following cold ischaemia. Creatinine clearance was significantly higher and urinary albumin significantly lower in the argon treated groups after transplantation. In the porcine model of renal transplantation, Faure et al.35 demonstrated that saturation of the preserving solution with argon improved early functional recovery, graft quality and survival. On the contrary, Jochman's group showed that postconditioning with xenon or argon did not improve function of a graft exposed to severe kidney ischaemia–reperfusion injury in a pig model of kidney transplantation. Interestingly, Martens et al.36 recently studied the effect of argon on the lung but showed argon ventilation during prolong ex-vivo lung perfusion had no impact on the measured physiological variables of the graft. The lack of current studies fuels significant debate regarding the exact mechanism of action of argon in reducing apoptosis and inflammation. Argon, like xenon, is able to limit intrinsic apoptosis stimulated by toxins. Argon inhibited several manifestations of apoptosis, including Δψm dissipation and caspase-3 activation.37 It is likely that argon down-regulates a variety of distinct apoptosis and inflammatory pathways and enhances the expression of antiapoptotic and antioxidative stress markers. Future prospects Argon has already demonstrated several features of an ideal organoprotectant, but more data are needed to evaluate its potential place in an organ preservation protocol. Argon is well tolerated and has no record of toxicity. Argon exposure was effective in promoting neuronal and renal cell survival after hypoxia and reducing experimental ischaemic injury in rat kidneys. Given that argon is relatively inexpensive compared with xenon, if it can be shown to be just as protective in the kidney, it could be a more economically viable treatment, with greater promise for future clinical use. Cellular studies directed at argon protection against ischaemia–reperfusion injuries could be beneficial for all organs and not only for the kidney Acknowledgements related to this article Assistance with the Editorial: the main statements of the third Argon-Organprotection-Network (AON) meeting held in London on Monday 30th November and Tuesday 1st December 2015 are included in this Editorial. The Argon Organo-Protective Network (AON) group members: Nicolas Bruder, APHM, France; Matthieu Chalopin, ALSI, France; Fabrice Chretien, Institut Pasteur, France; Mark Coburn, RWTH Aachen, Germany; Patrice Codogno, INEM, France; Géraldine Farjot, ALSI, France; Michael Fries, St Vincenz Krankenhaus, Germany; Ulrich Goebel, Uniklinik Freiburg, Germany; Ira Katz, ALSI, France; Oliver Kepp, Gustave Roussy Cancer Campus, France; Guido Kroemer, Gustave Roussy Cancer Campus, France; Marc Lemaire, ALSI, France; Daqing Ma, ICL, UK; Patrick Pierre Michel, ICM, France; Arne Neyrinck, KU Leuven, Belgium; Steffen Rex, KU Leuven, Belgium; Nikki Robertson, UCL, UK; Rolf Rossaint, RWTH Aachen, Germany; Franck Verdonk, Institut Pasteur, France; Hailin Zhao, ICL, UK. Financial support and sponsorship: the participants of the AON meeting received travel funds from Air Liquide Santé’ International. Conflicts of interest: none. Comment from the Editor: this article was checked and accepted by the Editors, but was not sent for external peer-review. RR is an Associate Editor of the European Journal of Anaesthesiology.