Effectiveness of pure argon for renal transplant preservation in a preclinical pig model of heterotopic autotransplantation

Abstract

BackgroundIn kidney transplantation, the conditions of organ preservation following removal influence function recovery. Current static preservation procedures are generally based on immersion in a cold-storage solution used under atmospheric air (approximately 78 kPa N2, 21 kPa O2, 1 kPa Ar). Research on static cold-preservation solutions has stalled, and modifying the gas composition of the storage medium for improving preservation was considered. Organoprotective strategies successfully used noble gases and we addressed here the effects of argon and xenon on graft preservation in an established preclinical pig model of autotransplantation.MethodsThe preservation solution Celsior saturated with pure argon (Argon-Celsior) or xenon (Xenon-Celsior) at atmospheric pressure was tested versus Celsior saturated with atmospheric air (Air-Celsior). The left kidney was removed, and Air-Celsior (n = 8 pigs), Argon-Celsior (n = 8) or Xenon-Celsior (n = 6) was used at 4 °C to flush and store the transplant for 30 h, a duration that induced ischemic injury in our model when Air-Celsior was used. Heterotopic autotransplantation and contralateral nephrectomy were performed. Animals were followed for 21 days.ResultsThe use of Argon-Celsior vs. Air-Celsior: (1) improved function recovery as monitored via creatinine clearance, the fraction of excreted sodium and tubulopathy duration; (2) enabled diuresis recovery 2–3 days earlier; (3) improved survival (7/8 vs. 3/8 pigs survived at postoperative day-21); (4) decreased tubular necrosis, interstitial fibrosis, apoptosis and inflammation, and preserved tissue structures as observed after the natural death/euthanasia; (5) stimulated plasma antioxidant defences during the days following transplantation as shown by monitoring the “reduced ascorbic acid/thiobarbituric acid reactive substances” ratio and Hsp27 expression; (6) limited the inflammatory response as shown by expression of TNF-alpha, IL1-beta and IL6 as observed after the natural death/euthanasia. Conversely, Xenon-Celsior was detrimental, no animal surviving by day-8 in a context where functional recovery, renal tissue properties and the antioxidant and inflammation responses were significantly altered. Thus, the positive effects of argon were not attributable to the noble gases as a group.ConclusionsThe saturation of Celsior with argon improved early functional recovery, graft quality and survival. Manipulating the gas composition of a preservation medium constitutes therefore a promising approach to improve preservation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0795-y) contains supplementary material, which is available to authorized users.

Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation

“…Although some investigators have shown decreased infarct volumes and improved cardiac and neural function with xenon after cardiac and cerebral IRI in pigs, others were unable to confirm these protective qualities. Furthermore, porcine kidneys have recently been observed to show an improvement with argon but not xenon reconditioning.…”

“…A meta‐analysis confirmed that inhalation of xenon attenuated IRI and prolonged survival in rodent models of renal IRI and renal transplantation. Saturation of organ preservation solutions with argon had renoprotective effects in transplant models. However, the results from large‐animal models have been disappointing, stressing the importance of performing well designed large‐animal studies before considering clinical trials.…”

A porcine ex vivo lung perfusion model with maximal argon exposure to attenuate ischemia-reperfusion injury

“…And in addition, the perfusate was saturated with Ar via the gas exchanger to expose both the epithelial and the endothelial side of the alveolar membrane during EVLP. This kind of Ar-saturated perfusion solution has also been tested in experimental kidney perfusion leading to improved graft function after transplantation 1213…”

“…During EVLP, ventilating the donor lung prior to transplantation, in normothermic conditions with inhalational therapy is feasible 1617. Also, the perfusion solution on EVLP could be saturated with an Ar mixture, as demonstrated with success in experimental perfusion of kidneys preceding transplantation 1213. Replacing nitrogen (N 2 ) with Ar in the gas mixture for the ventilator and for the gas exchanger in the EVLP system, results in a dual exposure of the pulmonary graft to Ar, on both the endothelial and epithelial sides (“postconditioning”).…”

A Review of Anesthetic Effects on Renal Function: Potential Organ Protection

“…In a recent study, researchers stored porcine kidneys in the preservation solution Celsior, which was saturated with argon or xenon. Argon-Celsior showed promise in renal transplant preservation by improving early functional recovery, graft quality, and survival, in comparison to Xenon-Celsior [30]. …”