Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads

Abstract

Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia–reperfusion injury that occurs in the complex route of the graft from “harvest to revascularization”. Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics.

The Role of IGL-2 Preservation Solution on Rat Livers during SCS and HOPE

“…The present research investigates the efficiency of the IGL-2 solution, a modified version of IGL-1, where vasodilatation and antioxidant properties were boosted by increasing five-fold and three-fold the concentration of PEG35 and glutathione, respectively ( Table 1 ). We hypothesized that these boosted properties are the most suitable ones for combining static preservation and dynamic perfusion ([ 32 ], p. 2, [ 33 ]). Moreover, the use of a unique solution for both the static and dynamic preservation solutions could greatly facilitate the logistical hurdles and avoid “interactions” that could be caused by the mixing of the different solutions when static cold storage is combined with HOPE using complete or partial liver grafts, as recently demonstrated by Mabrut et al [ 34 ].…”

End‐ischemic hypothermic oxygenated machine perfusion does not improve renal outcome following liver transplantation from aged donors: A single‐center retrospective report

“…16 These biomolecules may act as damage-associated molecular patterns (DAMPs) and stimulate multiple signaling pathways and cascades, ultimately leading to cell and organ dysfunction. 17 Therefore, we and others hypothesize that renal injury after liver transplantation may be partly driven by alterations occurring in the liver graft. [4][5][6] We have previously shown that grafts of LT recipients developing early AKI reveal distinct proteomic changes, mainly related to the innate immunity response, inflammation, and ongoing neutrophil degranulation, compared to the liver grafts of patients retaining normal renal function after LT. 6 Given the lack of an obvious effect of HOPE on the development of AKI, we speculate that the altered proteome is not influenced by any of the putative protective mechanisms of HOPE, 17 which seem unable to override the multiple metabolic processes apparently steered from the graft.…”

“…17 Therefore, we and others hypothesize that renal injury after liver transplantation may be partly driven by alterations occurring in the liver graft. [4][5][6] We have previously shown that grafts of LT recipients developing early AKI reveal distinct proteomic changes, mainly related to the innate immunity response, inflammation, and ongoing neutrophil degranulation, compared to the liver grafts of patients retaining normal renal function after LT. 6 Given the lack of an obvious effect of HOPE on the development of AKI, we speculate that the altered proteome is not influenced by any of the putative protective mechanisms of HOPE, 17 which seem unable to override the multiple metabolic processes apparently steered from the graft. Most studies using HOPE are performed on ECDs, and a majority report an improvement of the hepatocellular injury and milder transaminase leak in the recipients of HOPE-treated ECD grafts to levels corresponding to standard donors.…”

“…8 Although transaminase leak is a well-established marker of hepatocyte injury, it has been argued that in this particular setting, assessing transaminase levels as a quantitative indicator of graft injury may be misleading. 17 All transaminase leak that occurs during SCS will spill into the recipients of nonperfused grafts, whereas graft machine perfusion may wash out some of the leaked enzymes, thus decreasing the initial transaminase peak in the recipient of a perfused graft. 18 The analysis of the whole cohort of patients could not identify any difference in terms of allograft (dys) function and postreperfusion transaminase leak between livers undergoing HOPE or not.…”

Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases

“…The authors suggested that a high expression of UCP2 lowers the bioavailability of ATP and thereby contributes to low outcomes. Consequently, some studies confirmed that low UCP2 expression and/or activity protects the liver against reperfusion injury [ 97 , 98 , 99 , 100 ]. However, other studies correlated a high expression of UCP2 with hepatic protection [ 101 , 102 , 103 ].…”