Strategies to Restore Adenosine Triphosphate (ATP) Level After More than 20 Hours of Cold Ischemia Time in Human Marginal Kidney Grafts

Abstract

BackgroundThe persisting organ shortage in the field of transplantation recommends the use of marginal kidneys which poorly tolerate ischemic damage. Adenosine triphosphate (ATP) depletion during cold ischemia time (CIT) is considered crucial for graft function. We tested different strategies of kidney perfusion before transplantation in the attempt to improve the technique.Material/MethodsTwenty human discarded kidneys from donors after brain death and with at least 20 hours of CIT were randomized to the following experimental groups (treatment time three-hours at 4°C): a) static cold storage (CS); b) static cold hyperbaric oxygenation (Hyp); c) hypothermic perfusion (PE); d) hypothermic perfusion in hyperbaric oxygenation (PE-Hyp); and e) hypothermic oxygenated perfusion (PE-O2).ResultsHistological results showed that perfusion with or without oxygen did not produce any endothelial damage. A depletion of ATP content following the preservation procedure was observed in CS, PE, and Hyp, while PE-Hyp and PE-O2 were associated with a net increase of ATP content with respect to baseline level. In addition, PE-Hyp was associated with a significant downregulation of endothelial isoform of nitric oxide synthase (eNOS) gene expression and of hypoxia inducible factor-1α (HIF-1α).ConclusionsHyperbaric or normobaric oxygenation with perfusion improves organ metabolic preservation compared to other methods. This approach may prevent the onset of delayed graft function, but clinical trials are needed to confirm this.

The Effect of Preservation Temperature on Liver, Kidney, and Pancreas Tissue ATP in Animal and Preclinical Human Models

“…The metabolic protective effects of HOPE at 4 • C on tissue ATP were also demonstrated in discarded human DBD kidneys subjected to >20 h of cold ischaemia by Ravaioli et al [47] compared to the SCS group, in which the team investigated different oxygenation parameters (hyperbaric and normobaric oxygen). Taking the similarities of kidneys between porcine and humans in terms of size and function into account, ATP resynthesis appears to be possible in grafts challenged by CIT exceeding 8 h, a limit suggested in Buchs et al's study [43].…”

“…In kidneys, there were more studies on HMP compared to other perfusion modalities: Three large animal porcine studies, which researched models with characteristics of different extended criteria donors (e.g., DCD, DBD) [44][45][46] and one preclinical study [47] reporting tissue ATP as one of the primary endpoints between 2010 to 2019 were identified (Table 7). Pre-perfusion ADP:ATP ratios were high, demonstrating effects of reduction in cell metabolism due to cold storage.…”

Beneficial effects of the novel marine oxygen carrier M101 during cold preservation of rat and human pancreas

“…The oxygen supply of the preservation solution is important, and maintenance of the gradient is related to oxygen release by M101. Interestingly, the maintenance of cell respiration in the presence of M101 was not correlated with an increase in ATP, despite increased glucose uptake, which has not been previously shown in the literature . However, a decrease in xanthine/hypoxanthine production (a degradation product of ATP) shows that the ATP pool was less degraded as compared to the control.…”

“…Interestingly, the maintenance of cell respiration in the presence of M101 was not correlated with an increase in ATP, despite increased glucose uptake, which has not been previously shown in the literature. [49][50][51] However, a decrease in xanthine/hypoxanthine production (a degradation product of ATP) shows that the ATP pool was less degraded 37 as compared to the control. Further experiments are necessary to completely understand this effect.…”

Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study

“…Lactate production during normothermic regional perfusion is because of the abdominal organs, while during hypothermic oxygenated perfusion it is because of specific organ justifying the use of HOPE after NRP, although some authors perform only NRP in renal DCD transplant . If the lactate significance is confirmed in clinical trials, HOPE might be a powerful procedure for evaluating organ function as well as for improving organ preservation with increase in ATP production .…”