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Oxygen Supplementation Supports Energy Production During Hypothermic Machine Perfusion in a Model of Donation After Circulatory Death Donors

Hosgood, Sarah A. PhD1; Nicholson, Michael L. DSc1

doi: 10.1097/TP.0000000000002729

1 Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.

Received 19 March 2019.

Accepted 21 March 2019.

The authors declare no funding or conflicts of interest.

S.A.H. drafted and revised the article. M.L.N. co-drafted and reviewed the article.

Correspondence: Dr. Sarah A. Hosgood, PhD, Department of Surgery, University of Cambridge, Level 9, PO BOX 202, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK. (

Organ preservation has historically relied on the concept that by reducing the temperature to 4°C, cellular metabolism is reduced to approximately 10% of normal.1 Therefore, it is thought that the requirement for oxygen is negligible. While hypothermic preservation is simple and beneficial means of preservation, the environment rapidly alters from an aerobic to anaerobic state. The gradual depletion of adenosine triphosphate (ATP) under these conditions results in cellular injury and necrosis leading to irreversible damage and graft loss. The main source of cellular ATP is mitochondrial oxidative phosphorylation, which is dependent on oxygen as the final electron acceptor.1,2

The increasing utilization of mechanical modes of preservation such as hypothermic machine perfusion (HMP) have been beneficial in improving early graft function particularly for kidneys from donation after circulatory death donors.3 The continual recirculation of cold preservation through the vasculature of the kidney at a low pressure is thought to reduce vasospasm, protect the vascular endothelium by modulation of Kruppel-like factor 2, and upregulation of endothelial nitric oxide synthase signaling pathways.4 It also flushes out metabolites and supports a higher level of metabolism compared to static cold storage techniques. There is some uncertainty whether oxygen is needed during HMP. It may be beneficial in replenishing ATP to provide adequate support even when the metabolic demand is significantly reduced. Nonetheless, excess oxygen during ischemia may exacerbate injury through the production of harmful reactive oxygen species.5 The question remains how much oxygen is required. Under normothermic conditions the kidney cortex has one of the highest resting metabolic rates; therefore, the demand for oxygen is high. Experimental studies have favored the use of 100% concentration of oxygen during HMP.6,7 Cold preservation solutions have the capability of providing adequate tissue oxygenation even without the presence of an oxygen carrier. According to Henry’s law the equilibrium concentration of a dissolved gas is the product of its partial pressure. The solubility of oxygen is temperature dependent and increases at lower temperatures. Therefore, more oxygen can be dissolved in cold perfusion solutions. Several clinically relevant studies have found high concentrations of oxygen to be beneficial.6,7 This has prompted the establishment of two clinical trials, the European-led COPE-Compare study comparing oxygenated HMP with HMP alone of donation after circulatory death kidneys from donors aged above 50 years (ISRCTN32967928)8 and COPE-POMP: “in house” preimplantation-oxygenated HMP reconditioning after cold storage versus cold storage alone in expanded criteria donor kidneys from brain-dead donors (ISRCTN6352508).9 Recruitment has been completed in both studies and the results are awaited.

In this addition of Transplantation Venema et al report the use of a porcine kidney model to compare static cold storage and HMP with either no oxygen or concentrations of either 21% or 100% oxygen.10 An assessment of renal function, oxidative stress, cellular damage, and cellular energy was made during an ex vivo reperfusion phase using normothermic perfusion technology. HMP was superior to cold storage (CS) in improving function and reducing oxidative stress, cellular damage, and necrosis. The addition of oxygen 21% and 100% did not have any additional effect on renal function, oxidative stress, or cellular damage. However, it did support a higher level of metabolism with increased generation of ATP. The results of the study favor the addition of 100% rather than 21% with lower levels of aspartate amino transferase indicating less mitochondrial damage.

This study shows an overwhelming benefit of HMP compared to CS. HMP with or without oxygen showed a reduction in tubular and cellular damage suggesting that the mechanical nature of HMP alone exerts a beneficial effect independent to the addition of oxygen and increased production of ATP. Furthermore, in contrast to other studies, there were no functional differences between the HMP groups. Ex vivo models provide some evidence of the functional status of the kidney. However, the short reperfusion phase limits it value. These models lend themselves better to examine early cellular and molecular changes rather than function. The study is limited by small group sizes and a short follow-up phase. Although ethically acceptable, slaughterhouse retrieved kidneys lack a controlled environment and this is likely to cause the variability within the groups.

In conclusion, this study adds to the body of evidence demonstrating the potential benefit of the addition of oxygen during HMP. There are no other studies comparing different concentration of oxygen during HMP with CS and HMP alone. Combined with the current literature this study supports the use of a high concentration of oxygen during HMP.

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