Liver protection strategies in liver transplantation

Hangzhou, China

Liver protection strategies in liver transplantation

Jun-Jun Jia, Jian-Hui Li, Li Jiang, Bin-Yi Lin, Li Wang, Rong Su, Lin Zhou and Shu-Sen Zheng

Hangzhou, China

BACKGROUND:Liver transplantation is the therapy of choice for patients with end-stage liver diseases. However, the gap between the low availability of organs and high demand is continuously increasing. Innovative strategies for organ protection are necessary to expand donor pool and to achieve better outcomes for liver transplantation. The present review analyzed and compared various strategies of liver protection.

DATA SOURCES:Databases such as PubMed, Embase and Ovid were searched for the literature related to donor liver protection strategies using following key words: “ischemia reperfusion injury“, “graft preservation“, “liver transplantation“, “machine perfusion“ and “conditioning“. Of the 146 studies identifed, only those with cutting edge strategies were analyzed.

RESULTS:A variety of therapeutic approaches were proposed to alleviate graft ischemia/reperfusion injury, which included static cold storage, machine perfusion (hypothermic, normothermic and subnormothermic), manual conditioning (pre, post and remote), and pharmacological conditioning. Evidences from animal experiments and clinical trials suggested that all these strategies could potentially protect liver graft; however, their clinical applications are limited partially due to their own disadvantages.

CONCLUSIONS:There are a plenty of methods suggested to decrease the degree of donor liver transplantation-related injury. However, none of these approaches is perfect in clinical practice. More translational researches (molecular and clinical studies) are needed to improve the techniques in liver graft protection.

(Hepatobiliary Pancreat Dis Int 2015;14：34-42)

ischemia reperfusion injury; liver transplantation; organ protection; conditioning

Introduction

Human liver transplantation (LT) was frst successfully performed by Dr. Starzl in 1963. Following the advances in surgery, the immunosuppressive drugs and refnements in donor liver protection, the outcome of LT has been greatly improved over the years.[1]LT is now a treatment of choice for patients with endstage liver diseases. Although cardiac death donors and living donors (split liver donation) are sources of organs, the gap between the low availability of organs and the high demand is continuously increasing.[1]To improve the liver availability, we need to innovate better preservation techniques. Better understanding of the graft-related injuries such as ischemia/reperfusion (I/R) injury is crucial to fnd a better liver preservation method.

There are three stages between organ donation and reperfusion during transplantation: donor management and organ procurement (pre-preservation), washout and cold preservation, rewarming (preservation) and reperfusion after transplantation (reperfusion). Each stage may injure the graft in different ways. The sum of injuries in each stage infuences the outcomes after transplantation.

The pre-preservation injury may present in the organ or it may be induced before infusion of cold preservation solutions. It is related to the pre-existing diseases and organ procurement. The preservation injury occurs when the donor's blood gets ceased and it continues until the recipient's graft is reperfused. The main type of graft injury in this phase is cold preservation injury, which occurs during the stagnant hypothermia of the graft.[2]Reperfusion of the graft with oxygenized recipient blood may lead to further liver injury. This phenomenon is known as reperfusion injury, which consists of two distinct phases. The early phase occurs within 2 hours after reperfusion and is characterized by activation of immune cells and oxidative stress. The late phase occurs from 6 to48 hours after reperfusion; and it is an infammatory disorder mediated by neutrophils, attracted by chemokines released in the early stage, and attached to the liver by adhesion molecules.[3]

Fig. 1.The common strategies (IPC, SCS, MP and IPostC) work as triggers mainly through detoxifcation of ROS (positive and negative mediators) play a protective role in liver graft. IPC: ischemic preconditioning; SCS: static cold storage; MP: machine perfusion; Pharm: pharmacological conditioning; ROS: reactive oxygen species; IPostC: ischemic post-conditioning.

The mechanisms of injury during each period and the amelioration of injury have attracted intense research. A number of therapeutic strategies have been proposed to alleviate events and protect the graft, which include static cold storage, hypothermic machine perfusion, pharmacological agents, and manual conditioning treatment (Fig. 1). Databases such as PubMed, Embase and Ovid were searched using the following key words:“ischemia reperfusion injury“, “graft preservation“, “liver transplantation“, “machine perfusion“ and “conditioning“; and 146 studies were identifed in total, which included clinical trials, experimental studies and reviews. Only the state-of-the-art donor liver protection strategies required during preservation and reperfusion are analyzed and discussed in this review, with perspectives from preclinical experiment to clinical implementation and future strategies to achieve better outcomes of LT.

Strategies to protect liver graft Static cold storage (SCS)

The main principle to minimize preservation-related injury is to rapidly cool down the graft in order to reduce metabolism and effectively remove blood from vasculature, thus to prevent hypothermia anoxic induced cellswelling and acidosis.

Rinse solutions

Optimizing organ preservation starts with an effective blood washout. Although the University of Wisconsin (UW) cold-storage solution is the most popular washout solution, its high viscosity could result in initial poor perfusion of potential grafts and incomplete distribution of UW between intravascular space and liver parenchyma in the donor livers.[4]Besides, hydroxyethyl starch in UW causes hyper-aggregating effects on erythrocytes, which hampers a complete washout from the liver.[5]A recent study in an animal model showed that histidine-tryptophan-ketoglutarate (HTK) solution with a 1/3 viscosity of UW at 4 ℃ fush followed by UW storage was superior to single use of either UW or HTK solution in hepatic microcirculation. This combination increases the percentage of reperfused sinusoids and reduces sinusoidal leukostasis.[6]Celsior solution (CS) has the similar effciency for portal vein fushing as compared with UW solution.[7]

Cold-storage solution (CSS)

Hypothermia preservation and preservation solution are of major importance to bridge the procurement and transplantation. Evidence shows that hypothermia can reduce the tissue energy demand and extend the safe ischemia period.[8]Nowadays, SCS is the most popularly used technique for clinical organ preservation.[9]For liver graft, the sinusoidal lining cells are more vulnerable for the hypothermia anoxic injury, since this is different from other solid organs, in which the parenchyma cell injury is the main cell type during the cold preservation process.[10]In the liver microcirculation, the hypothermia anoxic injury is refected by loss of sinusoidal lining, rounding of sinusoidal lining cells, and irreversible detachment from hepatocytes.

UW solution is currently used inex vivoliver preservation. The UW solution protects the sinusoidal lining cells by delaying the alteration of energy depletion and lipid peroxidation.[11]It allows preservation of donor livers for up to 12-18 hours in clinical settings and up to 48 hours in laboratory experiments.[12]It contains 12 constituents added empirically based on the assumed counterbalance homeostatic change during the preservation of the liver (Table 1). The exact protection mechanism of UW solution is not fully defned yet. The constituents, which may act through the “summation of protection“, act synergistically or only are effective in combination.

Although UW solution is the gold standard for use in LT, the shortage of intracellular electrolyte composition imposes a markedly different ionic environment onvascular smooth muscle cells.[13]Thus, administration of such solutions can be anticipated to markedly affect vascular tone and fow distribution between and within organs of the body, causing regional inadequate perfusion.[5]A number of new organ preservation solutions or “UW look-a-likes“ such as HTK, CS, Institute Georges Lopez-1 (IGL), Leeds solution (LS), and POLYSOL have been developed. However, these modifcations do not demonstrate a better and longer preservation of donor organs.[14]The main compositions of these solutions are listed in Table 1.

Table 1.Main composition of UW, HTK, CS, IGL, LS and POLYSOL[15-18]

Machine perfusion (MP)

Hypothermic machine perfusion (HMP)

HMP was proposed by Belzer in the early 1960s. It preserves the organ by a constant perfusion through its blood vessels with a machine perfusion solution (MPS), which is initially perfused with Collins solution and later with UW, modifed UW, POLYSOL, HTK or Custodiol-N solution.[19]Results of MP are proved to be positive and even superior to SCS, especially in kidney transplantation.[20]However, the complex nature of this technique, cumbersome in handling equipment, and not-so-clarifed mechanisms have limited its wide usage in the clinical settings. Nowadays, the SCS technique is still the gold standard preservation method. In the era of donor organ shortage, MP is now regaining interest in kidney and liver transplantation centers, since it can better monitor the graft, improve washout of injurious waste products, continuously supply nutrients and oxygen, allow pharmaceutical intervention such as addition of oxygen radical scavengers and eventually, decrease the I/R injury and extend the duration of preservation. MP allows transplantation even in the marginal or cardiac death donors.[21,22]To gain clinical acceptance, the more simplifed technique is the prerequisite. There have no consensus on the optimal MPS or MP settings including optimal pressures and fow velocity, double or single vessel perfusion (retrograde or antegrade; pulsatile or not pulsatile), and settings with or without oxygen.[23]In 2009, the frst prospective liver HMP study of human providing safe and reliable preservation of donor liver was reported.[24]Recently, evidence shows that HMP signifcantly reduces molecular markers of I/R injury including expression of proinfammatory cytokines, adhesion molecules, and migration of leukocytes;[25]but it could simultaneously maintain the endothelial and Kupffer cell injury, leading to the failure of these grafts.[26]Hence, further multicenter trials are still warranted.

Normothermic machine perfusion (NMP) and subnormothermic machine perfusion (SMP)

NMP is another type of machine perfusion, which uses oxygen carrier (for example blood) and provides oxygen and other metabolic substrates under normo-thermic conditions. NMP avoids cold ischemic injury, maintains liver function, monitors the real-time graft function by bile fow production, further improves graft viability, and gains good clinical practicability.[27]The Oxford University had conducted the frst NMP clinical trial and proved that NMP could preserve a functioning liver outside the body for 24 hours. This procedure was performed on two patients so far who were on LT, and both showed excellent recoveries. This technology currently is continually tested in humans at King's College Hospital in London (http://www.ox.ac.uk/media/news_r eleases_for_journalists/130315.html). To avoid the need for oxygen carriers or temperature control, a simplifed MP system named as SMP was validated in a model of LT, and the results showed that the I/R injury damaged livers could be regenerated effectively.[28]

Manual conditioning

Ischemic manual conditioning is one potential strategy to limit the lethal I/R injury. The protective stimulus can be applied before (ischemic pre-conditioning, IPC) or after (ischemic post-conditioning, IPostC) the onset of the sustained episode of lethal ischemia. Furthermore, the protective stimulus can be applied noninvasively by placing a blood-pressure cuff on an upper or lower limb to induce brief episodes of nonlethal I/R (remote ischemic conditioning, RIC) (Fig. 2).

IPC

Fig. 2.The algorithm of strategies to protect the liver graft. P: perfusion; I: ischemia; R: reperfusion. The conditioning treatment could be short period I/R stimulus or pharmacological agents.

In 1986, IPC was frst reported by Murry et al[29]in a canine model, which was done by pre-exposing the heart to a brief period of ischemia and then reperfusion before the actual period of ischemia. It has attracted some particular interests because of the advantage of simplicity and inexpensive cost. There are numerous experimental and clinical studies which demonstrate the strong protective effect of IPC on both histological and functional effects for many organs such as muscle faps,[30]kidneys,[31]lungs,[32]and the liver.[33]

In experimental animal models, IPC of the liver has been shown to alleviate subsequent hepatocellular injury related to I/R, and various circle of intermittent clamping such as three cycles of 15 minutes I/5 minutes R[34]and three cycles of 10 minutes I/5 minutes R[35]before LT were shown to protect I/R injury. Clinically, IPC by clamping of the portal triad has shown some promises in preventing I/R injury of human hepatectomy.[36]There are still controversies on how to do LT. Studies[37,38]showed a signifcant decrease in transaminase levels after IPC (10 minutes I/10 minutes R) of the graft in clinical setting. Further, evidence showed that IPC may induce autophagy in human steatotic liver grafts and reduce rejection in their recipients.[39]Recently, the effectiveness of IPC has been questioned, since a clinical study has showed graft IPC (10 minutes I/10 minutes R) in the living related-donor is not associated with any beneft for the recipient or donor, which may be due to the variability of the individual or insuffcient activation of the protective signal pathway by the selected IPC protocol.[40]Meanwhile, the clinical application of IPC in LT has been limited by the unpredicted ischemic episodes and potential ethical reasons.

IPostC

The terminology of IPostC was proposed by Na et al,[41]who proved that post-conditioning was as effective as pre-conditioning in preventing ventricular fbrillations in cats, and it was then developed in 2003 by Zhao et al,[42]who showed that IPostC signifcantly reduced heart infarct size in a canine model. Recent studies[43,44]have undoubtedly demonstrated that the IPostC is simple to apply and potentially effective to reduce I/R injury in the liver.

Various circles of intermittent clamping such as three cycles of 1 minute R/1 minute I,[45]six cycles of 1 minute R/1 minute I,[44]and two or six cycles of 30 seconds R/30 seconds I[43]showed signifcant protection of liver from I/R injury. Our group also got similar results and proved repetitive short stimulus with more cycles, which were shown to be more effective than a single ischemia. These effects may be mediated through activation of p-AKT expression of the RISK pathway (unpublished data). Until now, there is no clinical trial result published on IPostC.

RIC

Although direct or local IPC does protect the liveragainst I/R injury, its main disadvantages are direct stress to the target organ and mechanical trauma to major vascular structures and in some clinical settings, it is not feasible to perform.[46]Alternatively, the concept of RIC was originally developed by Przyklenk et al in 1993;[47]a brief ischemia of one tissue had been confrmed to confer protection on distant important organs without direct stress to the target organ. As for local conditioning techniques (IPC and IPostC), RIC can be applied before target organ ischemia (remote ischemic pre-conditioning [R-IPC]), after ischemic and before perfusion (remote ischemic per-conditioning [R-IPER], or at the onset of reperfusion (remote ischemic post-conditioning [R-IP-ostC]) (Fig. 2). RIC could provide protection to the heart in children who underwent surgery on cardiopulmonary bypass for congenital heart disease.[48]Apart from the heart, RIC has been shown to ameliorate the I/R injury of the liver, lung, intestine and kidney.[49-51]

Until today, only few experimental studies have investigated the ability of RIC on hepatectomy: focus on either brief hind limb vascular occlusion or infrarenal aortic clamping. 3 cycles of 10 minutes I/10 minutes R in leg with a tourniquet prevented liver I/R in a rabbit model;[48]4 cycles of 10 minutes I/10 minutes R of femoral artery occlusion in rats, showing mitigation of subsequent injury caused by liver I/R;[52]one cycle of 10 minutes I leading to the distant protective effect;[53]and 40 minutes R-IPER by infrarenal aortic clamping before liver I/R signifcantly ameliorating liver I/R injury.[54]However, the effects of RIC on the liver grafts have not yet been reported.

Pharmacological conditioning

Pharmacological conditioning always elicits growing enthusiasm for the potential therapeutic utility in various ischemic episodes due to its practicability and feasibility with a nonischemic, nonhypoxic stimulus to protect against prolonged ischemia.[55]The pharmacological conditioning can be applied either before or after the ischemia episode. Adenosine A2B receptor antagonist MRS1754 is used before[56]and diazoxide is applied after ischemic conditioning,[57]both decrease the I/R injury and increase the survival of graft.

Application of gaseous agent is another novel strategy for attenuating I/R injury in solid organ transplantation. Carbon monoxide (CO) is an endogenous byproduct of heme degradation. Low dose CO treatment prevents cold I/R injury in rat LT,[58]and it ameliorates allograft and xenograft rejection[59]via its cytoprotective effects such as anti-infammatory, anti-apoptotic, anti-proliferation and immunomodulatory role during transplantation.[60]As a novel approach to deliver CO, CO-releasing molecules have shown to protect against rat hepatic I/R injury and attenuate the cold preservation injury.[61]These evidences indicate that CO could be utilized as adjuvant therapeutics in UW solution.[62]Nitric oxide (NO), another gaseous agent, is proved to attenuate cold I/R injury. Livergrafts from wild type donors had milder cold I/R injury compared to those from eNOS-defcient mice.[63]A prospective, blinded, placebo-controlled study indicated that NO inhaling accelerates restoration of liver function following orthotopic LT.[64]

Table 2.Pharmacological agents reported in the last 4 years

Hydrogen sulfde is a physiologic gaseous agent, which has the ability to protect against hepatic I/R injury during hypothermic preservation.[65]Besides, hypothermic reconditioning by gaseous oxygen improves survival after LT in the pig.[66]A plenty of agents are tested to reduce I/R injury of LT (Table 2). They are mostly at the experiment stage, but few are used in clinical practice.

Related conditioning mechanisms

In the conditioning treatments from ischemic conditioning to pharmacological intervention, researchers have proved that all of them could generate protective effects against sustained ischemia in either functional or morphological levels.[45,75]The mechanisms involved in the liver graft I/R injury are complicated (Fig. 1) and reviewed by other authors.[2,18,76]Basically, ischemia followed by reperfusion results in the activation of Kupffer cells and polymorphonucleocytes, these cells release reactive oxygen species (ROSs), cytokines, and adhesion molecules which lead to liver parenchymal damage. Evidences have shown that the ROSs and their related productions are critical in hepatic I/R.[76,77]ROSs are generated early during reperfusion, where the initial cell death triggers an infammatory cascade with activation of tissue macrophages and recruitment of neutrophils, both of which cause cell damage by further ROS release. Alleviating the infammatory response and subsequent detoxifcation of oxygen in the postoperative phase are the main mechanisms of conditioning to exert the protection effects.[76,78]Though there are some differences between local and remote conditioning, RIC plays its role partially through neural mediated protective effect[79]and mainly shares the common mechanisms.[78]Many possible components are associated with the protection effects: enhanced pathways (PI3K/AKT pathways,[80,81]TLR4,[82]and STAT[83]), inhibited pathways (cAMP[68]and NF-κB[84]), upregulated molecules and factors (NO,[85]HIF-1 transcription factor,[86]adenosine,[87]heme oxygenase-1,[52]opioid receptor,[88]nuclear protein high mobility group-box 1,[53]and heat shock protein-72[54]), and downregulated molecules (angiotensin II[89]and CD73[90]). However, the detailed role of these components needs further studies.

Prospective

Decreasing the degree of I/R injury has continuously attracted the researchers for decades. The traditional methods are improved, and new strategies are rapidly rising up such as genetic modulation to achieve better outcomes. However, none of them is perfect in clinical setting. In the future, a multifaceted liver preservation strategy that integrates pharmacological conditionings, manual conditioning, preservation solution, and MP may likely to minimize liver injury and maximize patient outcomes. More translational studies (molecular and clinical studies) are needed to clarify the mechanisms and ultimately to beneft the patients undergoing liver transplantation.

Contributors:ZL and ZSS proposed the study. JJJ and LJH performed the research, wrote the frst draft and contributed equally to this work. JL, LBY, WL and SR collected the data. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding:This work was supported in part by grants from the National Science and Technology Major Project (2012ZX10002-017), Natural Science Foundation of China for Innovative Research Group (81121002), the National Natural Science Foundation of China (81470891), the Qianjiang Talent Program of Zhejiang Province, China (2012R10045), the 863 National High-Technology Research and Development Program of China for young scientists (2015AA020923) and the Scientifc Research Program for the Returned Overseas Chinese Scholars, Ministry of Health, China (491010-G51104).

Ethical approval:Not needed.

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 O'Mahony CA, Goss JA. The future of liver transplantation. Tex Heart Inst J 2012;39:874-875.

2 Zhai Y, Petrowsky H, Hong JC, Busuttil RW, Kupiec-Weglinski JW. Ischaemia-reperfusion injury in liver transplantation--from bench to bedside. Nat Rev Gastroenterol Hepatol 2013; 10:79-89.

3 Klune JR, Tsung A. Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg Clin North Am 2010;90:665-677.

4 Yamauchi JI, Richter S, Vollmar B, Menger MD, Minor T. Warm prefush with streptokinase improves microvascular procurement and tissue integrity in liver graft retrieval from non-heart-beating donors. Transplantation 2000;69:1780-1784.

5 van der Plaats A, 't Hart NA, Morariu AM, Verkerke GJ, Leuvenink HG, Ploeg RJ, et al. Effect of University of Wisconsin organ-preservation solution on haemorheology. Transpl Int 2004;17:227-233.

6 Olschewski P, Hunold G, Eipel C, Neumann U, Schöning W, Schmitz V, et al. Improved microcirculation by low-viscosity histidine- tryptophan-ketoglutarate graft fush and subsequent cold storage in University of Wisconsin solution: results of an orthotopic rat liver transplantation model. Transpl Int 2008;21:1175-1180.

7 Boudjema K, Grandadam S, Compagnon P, Salamé E, Wolf P,Ducerf C, et al. Effcacy and safety of Celsior preservation fuid in liver transplantation: one-year follow up of a prospective, multicenter, non-randomized study. Clin Transplant 2012;26: 199-207.

8 Ryszka F, Dolińska B, Caban A, Ostróżka-Cieślik A, Budziński G, Krzysztofk M, et al. Hepatoprotective effect of prolactin and cysteine contained in perfusion and preservation solutions on porcine liver stored in simple hypothermia. Transplant Proc 2011;43:2882-2886.

9 Guibert EE, Petrenko AY, Balaban CL, Somov AY, Rodriguez JV, Fuller BJ. Organ preservation: current concepts and new strategies for the next decade. Transfus Med Hemother 2011;38:125-142.

10 Cursio R, Gugenheim J. Ischemia-reperfusion injury and ischemic-type biliary lesions following liver transplantation. J Transplant 2012;2012:164329.

11 Quintana AB, Guibert EE, Rodríguez JV. Effect of cold preservation/reperfusion on glycogen content of liver. concise review. Ann Hepatol 2005;4:25-31.

12 van der Plaats A, 't Hart NA, Verkerke GJ, Leuvenink HG, Ploeg RJ, Rakhorst G. Hypothermic machine preservation in liver transplantation revisited: concepts and criteria in the new millennium. Ann Biomed Eng 2004;32:623-631.

13 Eghtesad B, Aucejo F, Fung JJ. Preservation solutions in liver transplantation: what are the options? Liver Transpl 2006;12: 196-198.

14 Faenza A, Catena F, Nardo B, Montalti R, Capocasale E, Busi N, et al. Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study. Transplantation 2001;72:1274-1277.

15 Yagi S, Doorschodt BM, Affy M, Klinge U, Kobayashi E, Uemoto S, et al. Improved preservation and microcirculation with POLYSOL after partial liver transplantation in rats. J Surg Res 2011;167:e375-383.

16 Corps CL, Ahmed I, McKenzie S, Shires M, Potts DJ, Lodge JP. Functional and histological comparison of rat liver preserved in University of Wisconsin solution compared with tissue preserved in a novel solution. Transplant Proc 2010;42:3427-3430.

17 Guarrera JV, Karim NA. Liver preservation: is there anything new yet? Curr Opin Organ Transplant 2008;13:148-154.

18 de Rougemont O, Lehmann K, Clavien PA. Preconditioning, organ preservation, and postconditioning to prevent ischemiareperfusion injury to the liver. Liver Transpl 2009;15:1172-1182.

19 Stegemann J, Hirner A, Rauen U, Minor T. Use of a new modifed HTK solution for machine preservation of marginal liver grafts. J Surg Res 2010;160:155-162.

20 Wight JP, Chilcott JB, Holmes MW, Brewer N. Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systematic review. Clin Transplant 2003;17:293-307.

21 Shigeta T, Matsuno N, Huai-Che H, Obara H, Mizunuma H, Hirano T, et al. A basic consideration for porcine liver preservation using a novel continuous machine perfusion device. Transplant Proc 2012;44:942-945.

22 Shigeta T, Matsuno N, Obara H, Mizunuma H, Kanazawa H, Tanaka H, et al. Functional recovery of donation after cardiac death liver graft by continuous machine perfusion preservation in pigs. Transplant Proc 2012;44:946-947.

23 Vekemans K, Liu Q, Pirenne J, Monbaliu D. Artifcial circulation of the liver: machine perfusion as a preservation method in liver transplantation. Anat Rec (Hoboken) 2008;291:735-740.

24 Guarrera JV, Henry SD, Samstein B, Odeh-Ramadan R, Kinkhabwala M, Goldstein MJ, et al. Hypothermic machine preservation in human liver transplantation: the frst clinical series. Am J Transplant 2010;10:372-381.

25 Henry SD, Nachber E, Tulipan J, Stone J, Bae C, Reznik L, et al. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation. Am J Transplant 2012;12:2477-2486.

26 Fondevila C, Hessheimer AJ, Maathuis MH, Muñoz J, Taurá P, Calatayud D, et al. Hypothermic oxygenated machine perfusion in porcine donation after circulatory determination of death liver transplant. Transplantation 2012;94:22-29.

27 op den Dries S, Karimian N, Sutton ME, Westerkamp AC, Nijsten MW, Gouw AS, et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am J Transplant 2013;13:1327-1335.

28 Berendsen TA, Bruinsma BG, Lee J, D'Andrea V, Liu Q, Izamis ML, et al. A simplifed subnormothermic machine perfusion system restores ischemically damaged liver grafts in a rat model of orthotopic liver transplantation. Transplant Res 2012;1:6.

29 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-1136.

30 Schoen M, Rotter R, Gierer P, Gradl G, Strauss U, Jonas L, et al. Ischemic preconditioning prevents skeletal muscle tissue injury, but not nerve lesion upon tourniquet-induced ischemia. J Trauma 2007;63:788-797.

31 Bonventre JV. Kidney ischemic preconditioning. Curr Opin Nephrol Hypertens 2002;11:43-48.

32 Yildiz G, Demiryürek AT, Gümüşel B, Lippton H. Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: role of adenosine receptors. Eur J Pharmacol 2007;556:144-150.

33 Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under infow occlusion in humans. Ann Surg 2000;232:155-162.

34 Seyama Y, Imamura H, Inagaki Y, Matsuyama Y, Tang W, Makuuchi M, et al. Intermittent clamping is superior to ischemic preconditioning and its effect is more marked with shorter clamping cycles in the rat liver. J Gastroenterol 2013;48:115-124.

35 Currin RT, Peng XX, Lemasters JJ. Ischemic preconditioning of rat livers from non-heart-beating donors decreases parenchymal cell killing and increases graft survival after transplantation. HPB Surg 2012;2012:236406.

36 Desai KK, Dikdan GS, Shareef A, Koneru B. Ischemic preconditioning of the liver: a few perspectives from the bench to bedside translation. Liver Transpl 2008;14:1569-1577.

37 Azoulay D, Del Gaudio M, Andreani P, Ichai P, Sebag M, Adam R, et al. Effects of 10 minutes of ischemic preconditioning of the cadaveric liver on the graft's preservation and function: the ying and the yang. Ann Surg 2005;242:133-139.

38 Amador A, Grande L, Martí J, Deulofeu R, Miquel R, Solá A, et al. Ischemic pre-conditioning in deceased donor liver transplantation: a prospective randomized clinical trial. Am J Transplant 2007;7:2180-2189.

39 Degli Esposti D, Sebagh M, Pham P, Reffas M, Poüs C, Brenner C, et al. Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes. Cell Death Dis 2011;2:e111.

40 Andreani P, Hoti E, de la Serna S, degli Esposti D, Sebagh M, Lemoine A, et al. Ischaemic preconditioning of the graft inadult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance. HPB (Oxford) 2010;12:439-446.

41 Na HS, Kim YI, Yoon YW, Han HC, Nahm SH, Hong SK. Ventricular premature beat-driven intermittent restoration of coronary blood fow reduces the incidence of reperfusioninduced ventricular fbrillation in a cat model of regional ischemia. Am Heart J 1996;132:78-83.

42 Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003;285: H579-588.

43 Wang N, Lu JG, He XL, Li N, Qiao Q, Yin JK, et al. Effects of ischemic postconditioning on reperfusion injury in rat liver grafts after orthotopic liver transplantation. Hepatol Res 2009; 39:382-390.

44 Zeng Z, Huang HF, Chen MQ, Song F, Zhang YJ. Contributions of heme oxygenase-1 in postconditioning-protected ischemia-reperfusion injury in rat liver transplantation. Transplant Proc 2011;43:2517-2523.

45 Lin HC, Lee TK, Tsai CC, Lai IR, Lu KS. Ischemic postconditioning protects liver from ischemia-reperfusion injury by modulating mitochondrial permeability transition. Transplantation 2012;93:265-271.

46 Kanoria S, Jalan R, Davies NA, Seifalian AM, Williams R, Davidson BR. Remote ischaemic preconditioning of the hind limb reduces experimental liver warm ischaemia-reperfusion injury. Br J Surg 2006;93:762-768.

47 Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res 2008;79:377-386.

48 Pavione MA, Carmona F, de Castro M, Carlotti AP. Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial. J Thorac Cardiovasc Surg 2012;144:178-183.

49 Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience 2008;151:1099-1103.

50 Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury--a review. J Surg Res 2008;150:304-330.

51 Eberlin KR, McCormack MC, Nguyen JT, Tatlidede HS, Randolph MA, Austen WG Jr. Ischemic preconditioning of skeletal muscle mitigates remote injury and mortality. J Surg Res 2008;148:24-30.

52 Lai IR, Chang KJ, Chen CF, Tsai HW. Transient limb ischemia induces remote preconditioning in liver among rats: the protective role of heme oxygenase-1. Transplantation 2006;81: 1311-1317.

53 Wang F, Birch SE, He R, Tawadros P, Szaszi K, Kapus A, et al. Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury: the role of High Mobility Group-Box 1. Ann Surg 2010;251:292-299.

54 Czigány Z, Turóczi Z, Bulhardt O, Hegedüs V, Lotz G, Rakonczay Z, et al. Remote ischemic conditioning: short-term effects on rat liver ischemic-reperfusion injury. [Article in Hungarian] Orv Hetil 2012;153:1579-1587.

55 Andreadou I, Iliodromitis EK, Koufaki M, Kremastinos DT. Pharmacological pre- and post- conditioning agents: reperfusion-injury of the heart revisited. Mini Rev Med Chem 2008;8: 952-959.

56 Choukèr A, Ohta A, Martignoni A, Lukashev D, Zacharia LC, Jackson EK, et al. In vivo hypoxic preconditioning protects from warm liver ischemia-reperfusion injury through the adenosine A2B receptor. Transplantation 2012;94:894-902.

57 Tian YS, Rong TZ, Hong YL, Min L, Jian PG. Pharmacological postconditioning with diazoxide attenuates ischemia/reperfusion-induced injury in rat liver. Exp Ther Med 2013;5:1169-1173.

58 Lee LY, Kaizu T, Toyokawa H, Zhang M, Ross M, Stolz DB, et al. Carbon monoxide induces hypothermia tolerance in Kupffer cells and attenuates liver ischemia/reperfusion injury in rats. Liver Transpl 2011;17:1457-1466.

59 Bösch F, Tsui TY. Carbon monoxide, a two-face for the protection of the liver. Curr Pharm Biotechnol 2012;13:803- 812.

60 Amano MT, Camara NO. The immunomodulatory role of carbon monoxide during transplantation. Med Gas Res 2013;3:1.

61 Wei Y, Chen P, de Bruyn M, Zhang W, Bremer E, Helfrich W. Carbon monoxide-releasing molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats. BMC Gastroenterol 2010;10:42.

62 Pizarro MD, Rodriguez JV, Mamprin ME, Fuller BJ, Mann BE, Motterlini R, et al. Protective effects of a carbon monoxidereleasing molecule (CORM-3) during hepatic cold preservation. Cryobiology 2009;58:248-255.

63 Theruvath TP, Zhong Z, Currin RT, Ramshesh VK, Lemasters JJ. Endothelial nitric oxide synthase protects transplanted mouse livers against storage/reperfusion injury: Role of vasodilatory and innate immunity pathways. Transplant Proc 2006;38:3351-3357.

64 Lang JD Jr, Teng X, Chumley P, Crawford JH, Isbell TS, Chacko BK, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest 2007;117:2583-2591.

65 Balaban CL, Rodriguez JV, Guibert EE. Delivery of the bioactive gas hydrogen sulfde during cold preservation of rat liver: effects on hepatic function in an ex vivo model. Artif Organs 2011;35:508-515.

66 Minor T, Koetting M, Koetting M, Kaiser G, Efferz P, Lüer B, et al. Hypothermic reconditioning by gaseous oxygen improves survival after liver transplantation in the pig. Am J Transplant 2011;11:2627-2634.

67 Ye S, Dong J, Han B. Protective effect of reduced glutathione and venous systemic oxygen persuffation on rat steatotic graft following liver transplantation. J Surg Res 2010;158:138-146.

68 Jimenez-Castro MB, Casillas-Ramirez A, Massip-Salcedo M, Elias-Miro M, Serafn A, Rimola A, et al. Cyclic adenosine 3' 5'-monophosphate in rat steatotic liver transplantation. Liver Transpl 2011;17:1099-1110.

69 Pratschke S, Bilzer M, Grützner U, Angele M, Tufman A, Jauch KW, et al. Tacrolimus preconditioning of rat liver allografts impacts glutathione homeostasis and early reperfusion injury. J Surg Res 2012;176:309-316.

70 Ghonem N, Yoshida J, Stolz DB, Humar A, Starzl TE, Murase N, et al. Treprostinil, a prostacyclin analog, ameliorates ischemiareperfusion injury in rat orthotopic liver transplantation. Am J Transplant 2011;11:2508-2516.

71 Wang CF, Wang ZY, Tao SF, Ding J, Sun LJ, Li JY, et al. Preconditioning donor liver with Nodosin perfusion lessens rat isch-emia reperfusion injury via heme oxygenase-1 upregulation. J Gastroenterol Hepatol 2012;27:832-840.

72 Tsai YF, Lin CC, Lee WC, Yu HP. Propofol attenuates ischemic reperfusion-induced formation of lipid peroxides in liver transplant recipients. Transplant Proc 2012;44:376-379.

73 Busuttil RW, Lipshutz GS, Kupiec-Weglinski JW, Ponthieux S, Gjertson DW, Cheadle C, et al. rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study. Am J Transplant 2011;11: 786-797.

74 D'Amico F, Vitale A, Piovan D, Bertacco A, Ramirez Morales R, Chiara Frigo A, et al. Use of N-acetylcysteine during liver procurement: a prospective randomized controlled study. Liver Transpl 2013;19:135-144.

75 Teixeira AR, Molan NT, Kubrusly MS, Bellodi-Privato M, Coelho AM, Leite KR, et al. Postconditioning ameliorates lipid peroxidation in liver ischemia-reperfusion injury in rats. Acta Cir Bras 2009;24:52-56.

76 Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando) 2012;26:103-114.

77 Harrison EM, Sharpe E, Bellamy CO, McNally SJ, Devey L, Garden OJ, et al. Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemiareperfusion injury. Am J Physiol Renal Physiol 2008;295:F397-405.

78 Selzner N, Boehnert M, Selzner M. Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications. Transplant Rev (Orlando) 2012;26:115-124.

78 Heidbreder M, Naumann A, Tempel K, Dominiak P, Dendorfer A. Remote vs. ischaemic preconditioning: the differential role of mitogen-activated protein kinase pathways. Cardiovasc Res 2008;78:108-115.

80 Park SW, Chen SW, Kim M, Brown KM, D'Agati VD, Lee HT. Protection against acute kidney injury via A(1) adenosine receptor-mediated Akt activation reduces liver injury after liver ischemia and reperfusion in mice. J Pharmacol Exp Ther 2010;333:736-747.

81 Cescon M, Carini R, Grazi G, Caraceni P, Alchera E, Gasloli G, et al. Variable activation of phosphoinositide 3-kinase infuences the response of liver grafts to ischemic preconditioning. J Hepatol 2009;50:937-947.

82 Izuishi K, Tsung A, Jeyabalan G, Critchlow ND, Li J, Tracey KJ, et al. Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. J Immunol 2006;176:7154-7158.

83 Shawky HM, Younan SM, Rashed LA, Shoukry H. Effect of recombinant erythropoietin on ischemia-reperfusion-induced apoptosis in rat liver. J Physiol Biochem 2012;68:19-28.

84 Yoshizumi T, Ikeda Y, Kaneda Y, Sueishi K. Ex vivo transfer of nuclear factor-kappaB decoy ameliorates hepatic cold ischemia/reperfusion injury. Transplant Proc 2009;41:1504-1507.

85 Abe Y, Hines I, Zibari G, Grisham MB. Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury. Arch Biochem Biophys 2009;484:232-237.

86 Alchera E, Tacchini L, Imarisio C, Dal Ponte C, De Ponti C, Gammella E, et al. Adenosine-dependent activation of hypoxia-inducible factor-1 induces late preconditioning in liver cells. Hepatology 2008;48:230-239.

87 McCully JD, Toyoda Y, Uematsu M, Stewart RD, Levitsky S. Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion. Am J Physiol Heart Circ Physiol 2001;280:H591-602.

88 Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Mol Cell Biochem 1998;186:3-12.

89 Padrissa-Altés S, Franco-Gou R, Boillot O, Serafín A, Rimola A, Arroyo V, et al. Effect of angiotensin II and bradykinin inhibition in rat reduced-size liver transplantation. Liver Transpl 2009;15:313-320.

90 Lu B, Rajakumar SV, Robson SC, Lee EK, Crikis S, d'Apice AJ, et al. The impact of purinergic signaling on renal ischemiareperfusion injury. Transplantation 2008;86:1707-1712.

Received January 1, 2014

Accepted after revision October 17, 2014

AuthorAffliations:Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health; Department of Hepatobiliary and Pancreatic Surgery, First Affliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Jia JJ, Li JH, Jiang L, Lin BY, Wang L, Su R, Zhou L and Zheng SS)

Shu-Sen Zheng, MD, PhD, FACS, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health; Department of Hepatobiliary and Pancreatic Surgery, First Affliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: +86-571-87236567; Fax: +86-571-87236884; Email: shusenzheng@zju.edu.cn)

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(15)60332-0

Published online January 2, 2015.