21. Supplemented oxygenation during hypothermic storage: Friend or foe

Abstract

There is a shortage of donated organs for clinical allo-transplantation with potential recipients dying while on the waiting list. Despite that only a fraction of the donated organs are currently utilized. For example certain organs with prolonged cold ischemia times and organs from expanded criteria donors (ECD) are not routinely utilized. ECD organs may be more sensitive to stressful conditions during preservation and maintenance of the health of these organs during preservation is even more critical and challenging and may require more sophisticated preservation techniques. This has led to substantial interest and investment in improved methods for organ preservation. The lack of oxygen during hypothermic preservation is believed to be detrimental to cellular viability and maybe responsible for priming the organ for damage during normothermic reperfusion (ischemia reperfusion injury). As a consequence, oxygen supply is a major research focus in the field of organ preservation. It has been demonstrated that the simplest and most widely used technique for hypothermic organ preservation, static cold storage can only oxygenate to a maximum depth of a millimeter from the surface of an organ even if the organ preservation solution around the organ is fully saturated with 100% oxygen. In this case, even though the oxygen demand is substantially reduced by hypothermia, it still exceeds the supply by diffusion. Even hypothermic machine perfusion, which has been designed to deliver cold preservation solution into the organ via the circulation, may be incapable of delivering adequate oxygen to an organ during preservation, particularly when the perfusate does not have substantially higher oxygen carrying capacity than water and it is not saturated with a gas containing higher oxygen fraction than air. New and improved methods for oxygen delivery to organs during hypothermic preservation are clearly still needed. A major consideration in the development of such methods is that even though lack of oxygen can be detrimental, high levels of oxygen (hyperoxia) could be equally or more damaging. Emerging literature suggests that negative effects of hyperoxia may be more pronounced under hypothermia because the cellular antioxidant mechanisms in place may not be as effective at lower temperatures. The effects of high or low oxygen may be temperature as well as organ dependent and are currently not well defined. Further research is needed to define the fine balance between oxygen demand and delivery for the organ or tissue of interest at relevant temperatures. In this paper we will present data on the effects of high and low oxygen on pancreas and islet (beta-cell) health at various temperatures ranging from 4C to 37C. Islets are known to be particularly sensitive to oxidative damage as they express lower levels of antioxidant enzymes typically found in other cell types under physiological conditions. Islets are also particularly sensitive to hypoxia because they express very low levels of LDH-alpha and they cannot effectively generate energy anaerobically, which makes them an interesting and challenging model system in the context of oxygen delivery optimization to avoid hypoxia induced damage without resulting to high oxygen toxicity.