REVIEW URRENT C OPINION
Changing paradigms in organ preservation and resuscitation Fadwa Ali, Anahita Dua, and David C. Cronin
Purpose of review Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. Recent findings Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPSTM- XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. Summary Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs. Keywords ex-vivo machine perfusion, organ preservation solution, organ transplantation
INTRODUCTION
EX-VIVO MACHINE PERFUSION
Organ transplantation is the definitive life-saving treatment for patients with end-stage organ failure. Broader application of transplantation is primarily limited by an insufficient number of donor organs. Innovations in organ resuscitation and dynamic perfusion are being developed to improve the function of standard criteria deceased donor organs, extend organ preservation time, and increase the total number of organs available for transplantation by improving the quality and function of organs currently discarded. The purpose of this review is to update the reader to recent progress in the last 2 years in organ preservation and resuscitation. The progress in ex-vivo machine-based perfusion and preservation, advances in organ preservation solutions, and the clinical applicability of these new techniques to the transplantation of different organs will be discussed.
The most common and widely used method of organ preservation is hypothermic static storage. Donor organs are rapidly exsanguinated, cooled by flushing with cold preservative solution, and stored under hypothermic conditions until implantation. Although this method is simple and affordable, organs preserved under these conditions are subject to a series of cellular, metabolic, and anatomic injuries due to warm ischemia (before
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Division of Transplantation, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Correspondence to David C. Cronin, MD, PhD, MHCM, FACS, Division of Transplantation, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite 5700, Milwaukee, WI 53226, USA. Tel: +1 414 955 6920; e-mail: [email protected] Curr Opin Organ Transplant 2015, 20:152–158 DOI:10.1097/MOT.0000000000000180 Volume 20 Number 2 April 2015
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Changing paradigms in organ preservation and resuscitation Ali et al.
KIDNEY
KEY POINTS Machine perfusion allows ex-vivo organ resuscitation, reconditioning, and assessment of graft function. Ex-vivo machine perfusion can improve function of organs previously considered unsuitable for transplantation. Adding antiapoptotic agents to preservation solutions can potentially reduce ischemic injury and improve organ preservation.
preservation), cold ischemia (during preservation and storage), rewarming injury (during transplantation), and reperfusion injury [1]. The organ dysfunction associated with hypothermic static storage limits the utility of expanded criteria donor organs [2 ,3]. Dynamic organ preservation has once again been investigated as a means to improve organ function before and after transplantation and allow for use of organs previously not considered. In its simplest form, machine preservation consists of organ perfusion (flow based or pressure based, continuous, or pulsatile) with a variety of solutions, under conditions that support or retard cellular activity [2 ]. Advantages of machine perfusion are dependent upon the preservation environment, but all appear to improve the microvasculature patency and integrity, prolong preservation time, and afford a variable opportunity for organ resuscitation and physiologic monitoring. Hypothermic perfusion, similar to static cold storage, decreases metabolic demand in an effort to preserve cellular energy resources and decrease accumulation of toxic metabolites. Machine preservation at near-normothermic or normothermic, aerobic conditions allows assessment of organ metabolic function. In addition, this active metabolic state can allow for organ reconditioning or resuscitation, improved evaluation of function, and viability prior to implantation and graft modifications (cellular transfection). Under both hypothermic and normothermic conditions, various biochemical markers and perfusion parameters are being evaluated to help determine the function of the graft prior to implantation [2 ,3]. The main disadvantages of machine perfusion are the costs of the pump technology, preservation solutions and personnel, and the logistics of the pump availability, portability and dissemination of technology and skill. Different companies are now marketing portable devices for ex-vivo machine perfusion. &&
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Deceased donor kidneys are now stratified according to the kidney donor profile index (KDPI) [4]. Accordingly, kidneys with increasing KDPI are associated with an increased risk of primary and delayed graft dysfunction and shorter graft survival. Expanded use of kidneys with high KDPI or donors after circulatory arrest may benefit from machine perfusion. Several studies have now shown that hypothermic machine perfusion of kidneys results in reduced rates of delayed graft function and improved graft survival when compared with static hypothermic storage especially in expanded criteria donors, donors older than 65 years, and donors after circulatory death [2 ,3,5]. Other studies have also shown that machine perfusion of kidneys can extend preservation time [6]. Furthermore, the viability of these high-risk allografts can be assessed with perfusate biomarkers and perfusion parameters. For example, vascular resistance of kidneys during machine perfusion has been correlated with delayed graft function [2 ,7]. &&
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LIVER Although machine perfusion has gained increasing utility in the clinical practice of kidney transplant, its use has been very limited in liver transplantation. Machine perfusion of the liver was first attempted by Belzer and Starzl in the 1960s as reviewed by Monbaliu and Brassil [8]. Although it was successful, machine perfusion was abandoned because of its troublesome logistics and the emergence of static cold storage as a simple alternative that met the preservation needs at the time. Improved survival and increased application of liver transplantation as a therapy have increased the demand for donor livers far beyond the supply. Consequently, livers previously not considered for transplantation have now been used with caution and risk. These extended criteria donor livers include liver grafts procured from donation after circulatory death (DCD), grafts with more than 30% steatosis, grafts from older donors, and livers with metabolic dysfunction [1,8]. These liver grafts do not tolerate cold ischemia well and are associated with a significant increase of primary nonfunction and recipient death [8]. Consequently, there has been a reemergence in hepatic machine perfusion as a means to improve preservation of DCD livers, resuscitate organs damaged by ischemia, and assess viability of grafts. Machine perfusion of the liver graft is challenging due to its unique anatomy and physiology specifically, the competition between hepatic artery and portal vein inflow, the sensitivity of hepatic endothelial cells to high perfusion pressures,
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and the activation of Kupffer cells upon reperfusion [3,8]. A human clinical trial comparing hypothermic machine perfusion to static cold storage among a matched group of adult liver transplant recipients showed reduction in early allograft dysfunction (5 versus 25%, respectively; P ¼ 0.08) [9]. In addition, perfusate markers of hepatocellular injury including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were significantly lower with hypothermic machine perfusion [9]. Early results of ex-vivo oxygenated normothermic machine perfusion of livers discarded for transplantation has demonstrated maintenance of liver function with minimal injury [10]. Sutton et al. [11] studied the role of bile production as a parameter of liver graft viability during ex-vivo machine perfusion of extended criteria livers demonstrating that low bile production is associated with hepatic necrosis and venous congestion. Measuring biomarkers of hepatocellular injury and organ function during ex-vivo machine perfusion may prove useful in determining the suitability of extended criteria donor livers for transplantation. A critical factor of reperfusion injury is microcirculatory failure, associated with insufficient energy supply, impaired adenosine triphosphate regeneration, and incomplete recovery of hepatocellular excretory function [12,13]. Resuscitation of mitochondria offers a potential avenue to mitigate ischemic reperfusion injury (IRI) because of its central role in energy production, the generation of reactive oxygen species, and the initiation of apoptosis and necrosis. Hong et al. [14] have proposed a novel organ resuscitation therapy of regulated hepatic reperfusion (RHR) to modulate IRI during the critical period of organ revascularization. The strategy aims to nurture ischemic hepatocytes by providing a substrateenriched, leukocyte-depleted, oxygen-saturated perfusate in a pressure, temperature, and flow-controlled milieu in order for compromised cells to withstand reperfusion insult of warm blood during liver revascularization (Fig. 1). In a swine model, RHR mitigated IRI, provided intraoperative postreperfusion hemodynamic stability, facilitated recovery of hepatocellular function, and improved survival after prolonged periods of warm ischemia [14]. Ongoing research work is underway to investigate the utility of RHR in liver transplantation using DCD grafts in a swine model. This novel strategy may have direct applicability to clinical liver surgery and transplantation of marginal grafts.
PANCREAS The role of machine perfusion in pancreas preservation remains unexplored. The main goal of 154
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ongoing research on machine perfusion of the pancreas is to increase islet cell yield [2 ,3]. Some studies suggested applying kidney perfusion pumps to pancreas grafts, particularly during simultaneous kidney and pancreas transplantation [2 ]. However, the pancreas has a unique physiologic low flow and pressure environment, and machine perfusion under standard pressures can damage the pancreatic vascular endothelium and, subsequently, result in graft thrombosis upon reperfusion [3]. In one small human study (n ¼ 4), low-flow machine perfusion of the pancreas resulted in better islet cell yield when compared with static cold storage [15]. &&
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LUNG Currently, 15–25% of lungs from multiorgan donors are deemed unsuitable or suboptimal for transplantation because of donor risk factors including advanced age, smoking history, or donors after cardiac death [16]. Consequently, a 10–20% annual mortality rate exists among candidates for lung transplant [17 ]. Ex-vivo lung perfusion represents a promising method allowing increased preservation and reconditioning of suboptimal grafts for transplantation potentially increasing the number of procedures for lung transplant by 15–30% [18 ]. Steen et al. developed the first functional ex-vivo lung perfusion circuit for clinical use overcoming prior shortcomings of circuit-induced injury of the endothelial cells, increased vascular resistance and pulmonary edema [19]. Their success resulted in performing the first human lung transplant using a DCD lung preserved with machine perfusion in 2000 [19]. They were also able to recondition an initially unacceptable lung using ex-vivo machine perfusion and successfully transplant it in 2005 [20]. Cypel et al. [16] in Toronto treated lungs considered high risk for transplantation (pulmonary edema and/or PaO2 : FiO2 < 300) to 4 h normothermic exvivo machine perfusion and transplanted them if their physiologic function remained stable. When compared with transplantation of conventionally selected lungs, there was no statistically significant difference in graft dysfunction within 72 h, 30-day mortality, or duration of mechanical ventilation [16]. An integrated and portable Organ Care System (OCS) lung (TransMedics, Andover, Massachusetts, USA) is a commercially manufactured ex-vivo lung perfusion system designed to allow reconditioning of marginal lungs [21 ]. It allows ventilation and perfusion of the donor lungs under physiologic conditions. The OCS offers the chance for continuous alveoli recruitment and bronchoscopy while lungs are ventilated on the machine [21 ]. In 2011, TransMedics sponsored an ongoing, &
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Changing paradigms in organ preservation and resuscitation Ali et al.
Jugular vein
Heat exchanger
Oxygenator heat exchanger Liver Leukocyte filter
Portal vein Splenic vein
Centrifugal pump
Hepatic perfusion solution
Roller pump
FIGURE 1. Regulated hepatic reperfusion (RHR) and splenojugularvenovenous bypass circuits. An extracorporeal centrifugal pump recirculates the animal’s splanchnic venous blood to the heart through a splenojugularvenovenous bypass (direction of blood flow – white arrows) to avoid congestion of the splanchnic circulation during total portal occlusion. During RHR, an amount of the animal’s splanchnic venous blood is diverted through a Y-connector from the centrifugal pump and mixed with hepatic perfusion solution (H solution) in a 4 : 1 dilution ratio (perfusate). Another extracorporeal roller pump recirculates the perfusate through a pediatric oxygenator-heat exchanger and leukoreduction filter before perfusion of the liver through the portal vein (direction of perfusate flow – black arrows). The roller pump regulates the reperfusion pressure (8–12 mmHg) and the oxygenator-heat exchanger maintains the perfusate oxygen saturation (to 100%) and temperature (30–328C). Adapted from [14] and [37 ]. &&
prospective, randomized, multicenter trial: International randomized study of the TransMedics Organ Care System (OCS Lung) for lung preservation and transplantation (INSPIRE) to compare OCS lung to standard cold storage [2 ,21 ]. Using the same system (OCS), Mohite et al. [21 ] demonstrated successful preservation, resuscitation, and transplantation of lungs from donation after cardiac death. Recently, the US Food and Drug Administration approved XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA) with STEEN solution (XVIVO Perfusion, Gotenborg Sweden) as a device for preserving donated lungs that do not initially meet the standard criteria for lung transplantation but may be transplantable if there is more time to observe and evaluate the organ’s function to determine whether the lung is viable for transplantation [22]. &&
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HEART Machine perfusion for heart transplantation represents a tremendous opportunity to expand the type and number of heart donors used for transplantation and resuscitate dysfunctional heart allografts prior to implantation. Currently, significant limits on warm donor ischemia and cold storage ischemia exist because of recipient mortality secondary to graft failure [18 ]. Owing to the limited number of useable donor hearts, the limitations on cold static storage and the mortality associated with graft failure, perfusion preservation of the heart has advanced from a research interest to a clinical tool with the goal of prolonged preservation and resuscitation with improved transplant survival. Biomarkers of myocardial injury (including pH, lactate, troponins) can be measured during machine perfusion [3,18 ]. In addition, ex-vivo cardiac imaging with MRI or angiography can be performed to
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assess function, anatomy, and viability [18 ]. Animal experiments of machine perfusion of the heart showed reduction in tissue lactate accumulation and myocardial necrosis, and better preservation of the left ventricular function when compared with static cold storage [18 ,23]. TransMedics’ OCS is a portable device for perfusion and assessment of the heart allograft [2 ]. A multicenter, randomized study of Organ Care system cardiac for preservation of donated hearts for eventual transplantation (PROCEEDII) was initiated in the USA and Europe [24]. Early results with OCS normothermic ex-vivo allograft blood perfusion in adult clinical orthotopic heart transplantation demonstrated better outcomes after transplantation with regard to recipient survival, incidence of primary graft dysfunction, and incidence of acute rejection [25 ]. In addition, OCS has demonstrated successful preservation and assessment and transplantation of three DCD heart allografts [26], whereas a group from Heidelberg, Germany has described the use of ex-vivo angiography to assess the viability of a suboptimal donor heart in the OCS [27]. &&
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ORGAN PRESERVATION SOLUTIONS Graft survival of many organs remains limited by time, temperature, and the health status of the organ prior to preservation. Anoxia associated with hypothermic static storage triggers a biological cascade resulting in cellular apoptosis and production of toxic metabolites upon tissue reperfusion [28 ]. One goal of preservative solutions is to limit ischemic damage during cold ischemia and minimize reperfusion injury by targeting the biochemical changes that occur during these processes. At present, there is no consensus regarding the most optimal preservation solution for hypothermic static storage or machine perfusion. Consequently, this is an area of active research and development. The most commonly used cold preservative solution is ViaSpan [University of Wisconsin (UW) solution, DuPont Pharma, Bad Homburg, Germany]. It is a high-potassium, low-sodium solution that contains hydroxyethyl starch, adenosine, and raffinose. Although it yields improved preservation and outcomes, compared with Euro-Collins solution, ViaSpan has disadvantages that include its high viscosity, which may impede microvascular flushing, the need for filter to prevent crystal formation, microvascular disturbances due to particle formation, and hyperkalemic cardiac arrest on reperfusion [28 ]. Alternatives to ViaSpan (UW solution) include Custodiol-histidine–tryptophan–ketoglutarate (HTK; Essential Pharma, Ewing, New Jersey, USA) solution and the Celsior solution (SangStat Medical, &
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Fremont, California, USA). Custodiol-HTK solution (Essential Pharma) is a low-potassium, low-viscosity crystalloid and does not require filtering. Celsior solution is a high-sodium, low-potassium solution that incorporates mannitol and lactobionate to decrease cellular edema [28 ]. Pulmonary-specific preservation solutions include Perfadex (XVIVO Perfusion Inc.), a dextran-containing, lightly buffered, low-potassium electrolyte solution [29 ]. In a recent meta analysis encompassing 15 trials and 3584 kidney transplants, the use of UW, HTK, or Celsior solution resulted in no difference in the incidence of delayed graft function among kidney transplant recipients [30]. Two meta analyses of donor liver preservation found no difference in the incidence of graft nonfunction, delayed graft function, or patient survival between the use of UW and Celsior solutions [31], or graft function when comparing HTK and UW solutions [32]. In pancreas preservation, most studies found no change in outcome between the use of UW and HTK solutions for preservation [33]. However, some studies showed increased risk of graft thrombosis, pancreatitis, and graft loss with HTK preservation especially with prolonged cold ischemia [34,35]. In cardiac preservation, UW solution was found superior to Celsior regarding graft survival [29 ]. Perfadex remains the preferred solution for lung transplantation. Its use has been associated with an improved PaO2 : FiO2 ratio and shorter duration of mechanical ventilation [29 ]. With better understanding of the pathophysiology of ischemia-induced programmed cell death, there has been a growing interest in adding agents to preservation solutions that target the biochemical processes leading to apoptosis. Caspase activity is increased in liver grafts during cold preservation and several studies have shown that caspase inhibitors can attenuate the ischemia/reperfusion-induced apoptosis [36]. However, caspase inhibition can be detrimental by promoting inflammation by blocking the noninflammatory apoptotic pathway [36]. Targeting intracellular biochemical processes that result in apoptosis or necrosis is an interesting area research that could potentially improve organ preservation and minimize ischemia-related injuries. &
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CONCLUSION The increasing shortage of donor organs has led to increased use of donor organs previously deemed suboptimal. Hypothermic static cold storage is limited in its ability to effectively preserve marginal allografts, prolong storage times, or assess organ function prior to implantation. Hypothermic Volume 20 Number 2 April 2015
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Changing paradigms in organ preservation and resuscitation Ali et al.
machine perfusion has demonstrated improved kidney graft function and survival, especially among expanded criteria donors. Machine perfusion is demonstrating exciting and promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. The availability of portable machine perfusion devices will expand the use of machine perfusion. The role of machine perfusion in standard criteria donors needs further study of cost–effectiveness and indication for use. Ex-vivo machine perfusion also allows a window between procurement and transplantation wherein organs can be resuscitated or reconditioned using various agents in the perfusate, gene, and stem cell therapies. The functionality of grafts could also be assessed using perfusate biochemical markers, perfusion parameters, and ex-vivo imaging. Regarding organ preservation solutions, there is no consensus among physicians about the optimal preservation solutions. Targeting intracellular biochemical processes that result in apoptosis or necrosis by adding antiapoptotic agents to preservation solutions is an interesting research area that could potentially improve organ preservation and minimize ischemia-related injuries. This is an exciting time wherein machine-based, ex-vivo organ preservation under metabolically active conditions can provide for evaluation, resuscitation, and intervention before implantation. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Vogel T, Brockmann JG, Friend PJ. Ex-vivo normo thermic liver perfusion. Curr Opin Organ Transplant 2010; 15:167–172. 2. Van Raemdonck D, Neyrinck A, Rega F, et al. Machine perfusion in organ && transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells? Curr Opin Organ Transplant 2013; 18:24–33. This study summarizes the current experience with ex-vivo machine perfusion. 3. Balfoussia D, Yerrakalva D, Hamaoui K, Papalois V. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant 2012; 10:87–100. 4. Organ Procurement and Transplantation Network (OPTN). A Guide to Calculating and Interpreting the Kidney Donor Profile Index (KDPI). 2014. http://optn.transplant.hrsa.gov/ContentDocuments/Guide_to_Calculating_ Interpreting_KDPI.pdf. Accessed 16 February 2015. 5. Gallinat A, Moers C, Smits JM, et al. Machine perfusion versus static cold storage in expanded criteria donor kidney transplantation: 3-year follow-up data. Transpl Int 2013; 26:E52–E53.
6. Brook NR, Waller JR, Nicholson ML. Non heart-beating kidney donation: current practice and future developments. Kidney Int 2003; 63:1516– 1529. 7. Jochmans I, Moers C, Ploeg R, Pirenne J. To perfuse or not to perfuse kidneys donated after cardiac death. Am J Transplant 2011; 11:409–410. 8. Monbaliu D, Brassil J. Machine perfusion of the liver: past, present and future. Curr Opin Organ Transplant 2010; 15:160–166. 9. Op den Dries S, Karimian N, Sutton ME, et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am J Transplant 2013; 13:1327–1335. 10. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am J Transplant 2010; 10:372–381. 11. Sutton ME, Op den Dries S, Karimian N, et al. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One 2014; 9:e110642. 12. Goto M, Kawano S, Yoshihara H, et al. Hepatic tissue oxygenation as a predictive indicator of ischemia-reperfusion liver injury. Hepatology 1992; 15:432–437. 13. Kamiike W, Nakahara M, Nakao K, et al. Correlation between cellular ATP level and bile excretion in the rat liver. Transplantation 1985; 39:50–55. 14. Hong JC, Koroleff D, Xia V, et al. Regulated hepatic reperfusion mitigates ischemia and reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model. J Am Coll Surg 2012; 214:505–515. 15. Leeser DB, Bingaman AW, Poliakova L, et al. Pulsatile pump perfusion of pancreata before human islet cell isolation. Transplant Proc 2004; 36:1050– 1051. 16. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364:1431–1440. 17. Andreasson AS, Dark JH, Fisher AJ. Ex vivo lung perfusion in clinical lung & transplantation – state of the art. Eur J Cardiothoracic Surg 2014; 46:779– 788. This article summarizes the clinical experience with ex-vivo lung perfusion. 18. Ciubotaru A, Haverich A. Ex vivo approach to treat failing organs: expanding && the limits. Eur Surg Res 2015; 54:64–74. This article discusses in detail the potential benefits of ex-vivo organ resuscitation, imaging, and treatment. 19. Steen S, Sjo¨berg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet 2001; 357:825–829. 20. Ingemansson R, Eyjolfsson A, Mared L, et al. Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg 2009; 87:255–260. 21. Mohite P, Sabashnikov A, Garcia Saez D, et al. Utilization of the Organ Care && System Lung for the assessment of lungs form a donor after cardiac death (DCD) before bilateral transplantation. Perfusion 2014; 29:1–4. This Letter to the Editor describes the first human clinical use of the OCS lung in transplantation of lungs from DCD. 22. U.S. Food and Drug Administration. FDA approves donor lung preservation device that may result in more lung transplants. 2014. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm409488.htm. Accessed 16 February 2015. 23. Rosenbaum DH, Peltz M, DiMaio JM, et al. Perfusion preservation versus static preservation for cardiac transplantation: effects on myocardial function and metabolism. J Heart Lung Transplant 2008; 27:93–99. 24. ClinicalTrials.gov. Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation (PROCEEDII). First received March 3, 2009; last updated July 29, 2013. https://www. clinicaltrials.gov/ct2/show/NCT00855712?term=TransMedics&rank=2. Accessed 16 February 2015. 25. Koerner MM, Ghodsizad A, Schulz U, et al. Normothermicexvivo allograft && blood perfusion in clinical heart transplantation. Heart Surg Forum 2014; 17:E141–E145. This study describes the first human clinical use of the OCS heart for ex-vivo resuscitation and subsequent transplantation. 26. The Transmedics Organ Care System (OCSTM) Heart Technology was Used to Perform the World’s First Series of Adult Human Heart Transplants from Donors after Circulatory Death (DCD Donors) at St Vincent’s Hospital in Sydney, Australia. 2014. Andover, Massachusetts, USA; 24 October 2014. http://www.transmedics.com/wt/page/pr_1414117691. Accessed 16 February 2015. 27. Ghodsizad A, Bordel V, Ungerer M, et al. Ex vivo coronary angiography of a donor heart in the organ care system. Heart Surg Forum 2012; 15:E161– E163. 28. Parsons RF, Guarrera JV. Preservation solutions for static cold storage of & abdominal allografts: which is best? Curr Opin Organ Transplant 2014; 19:100–107. This review article summarizes the clinical experience with the different preservation solution for abdominal allografts. 29. Latchana N, Peck JR, Whitson B, Black SM. Preservation solutions for cardiac & and pulmonary donor grafts: a review of the current literature. J Thorac Dis 2014; 6:1143–1149. This review article summarizes the clinical experience with the different preservation solutions for thoracic allografts.
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Organ preservation and procurement 30. O’Callaghan JM, Knight SR, Morgan RD, Morris PJ. Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. Am J Transplant 2012; 12:896–906. 31. O’Callaghan JM, Morgan RD, Knight SR, Morris PJ. The effect of preservation solutions for storage of liver allografts on transplant outcomes: a systematic review and meta-analysis. Ann Surg 2014; 260:46–55. 32. Zuluaga GLL, Agudelo RES, Tobon JJZ. Preservation solutions for liver transplantation in adults: Celsior versus Custodiol: a systematic review and meta-analysis with an indirect comparison of randomized trials. Transplant Proc 2013; 45:25–32. 33. Schneeberger S, Biebl M, Steurer W, et al. A prospective randomized multicenter trial comparing histidine tryptophane-ketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation. Transpl Int 2009; 22:217–224.
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34. Alonso D, Dunn TB, Rigley T, et al. Increased pancreatitis in allografts flushed with histidine–tryptophan–ketoglutarate solution: a cautionary tale. Am J Transplant 2008; 8:1942–1945. 35. Stewart ZA, Cameron AM, Singer AL, et al. Histidine–tryptophan–ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation. Am J Transplant 2009; 9:217–221. 36. Cursio R. Caspase inhibition in liver transplantation: from basic science to clinical studies. HPB (Oxford) 2010; 12:1–3. 37. Zhai Y, Petrowsky H, Hong JC, et al. Ischaemia-reperfusioninjury in liver transplantation – from bench to bedside. Nat Rev Gastroenterol Hepatol 2013; 10:79–89. Comprehensive review of ischemia reperfusion injury in a large animal liver transplant model.
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Changing paradigms in organ preservation and resuscitation Fadwa Ali, Anahita Dua, and David C. Cronin
Purpose of review Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. Recent findings Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPSTM- XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. Summary Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs. Keywords ex-vivo machine perfusion, organ preservation solution, organ transplantation
INTRODUCTION
EX-VIVO MACHINE PERFUSION
Organ transplantation is the definitive life-saving treatment for patients with end-stage organ failure. Broader application of transplantation is primarily limited by an insufficient number of donor organs. Innovations in organ resuscitation and dynamic perfusion are being developed to improve the function of standard criteria deceased donor organs, extend organ preservation time, and increase the total number of organs available for transplantation by improving the quality and function of organs currently discarded. The purpose of this review is to update the reader to recent progress in the last 2 years in organ preservation and resuscitation. The progress in ex-vivo machine-based perfusion and preservation, advances in organ preservation solutions, and the clinical applicability of these new techniques to the transplantation of different organs will be discussed.
The most common and widely used method of organ preservation is hypothermic static storage. Donor organs are rapidly exsanguinated, cooled by flushing with cold preservative solution, and stored under hypothermic conditions until implantation. Although this method is simple and affordable, organs preserved under these conditions are subject to a series of cellular, metabolic, and anatomic injuries due to warm ischemia (before
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Division of Transplantation, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Correspondence to David C. Cronin, MD, PhD, MHCM, FACS, Division of Transplantation, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite 5700, Milwaukee, WI 53226, USA. Tel: +1 414 955 6920; e-mail: [email protected] Curr Opin Organ Transplant 2015, 20:152–158 DOI:10.1097/MOT.0000000000000180 Volume 20 Number 2 April 2015
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Changing paradigms in organ preservation and resuscitation Ali et al.
KIDNEY
KEY POINTS Machine perfusion allows ex-vivo organ resuscitation, reconditioning, and assessment of graft function. Ex-vivo machine perfusion can improve function of organs previously considered unsuitable for transplantation. Adding antiapoptotic agents to preservation solutions can potentially reduce ischemic injury and improve organ preservation.
preservation), cold ischemia (during preservation and storage), rewarming injury (during transplantation), and reperfusion injury [1]. The organ dysfunction associated with hypothermic static storage limits the utility of expanded criteria donor organs [2 ,3]. Dynamic organ preservation has once again been investigated as a means to improve organ function before and after transplantation and allow for use of organs previously not considered. In its simplest form, machine preservation consists of organ perfusion (flow based or pressure based, continuous, or pulsatile) with a variety of solutions, under conditions that support or retard cellular activity [2 ]. Advantages of machine perfusion are dependent upon the preservation environment, but all appear to improve the microvasculature patency and integrity, prolong preservation time, and afford a variable opportunity for organ resuscitation and physiologic monitoring. Hypothermic perfusion, similar to static cold storage, decreases metabolic demand in an effort to preserve cellular energy resources and decrease accumulation of toxic metabolites. Machine preservation at near-normothermic or normothermic, aerobic conditions allows assessment of organ metabolic function. In addition, this active metabolic state can allow for organ reconditioning or resuscitation, improved evaluation of function, and viability prior to implantation and graft modifications (cellular transfection). Under both hypothermic and normothermic conditions, various biochemical markers and perfusion parameters are being evaluated to help determine the function of the graft prior to implantation [2 ,3]. The main disadvantages of machine perfusion are the costs of the pump technology, preservation solutions and personnel, and the logistics of the pump availability, portability and dissemination of technology and skill. Different companies are now marketing portable devices for ex-vivo machine perfusion. &&
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Deceased donor kidneys are now stratified according to the kidney donor profile index (KDPI) [4]. Accordingly, kidneys with increasing KDPI are associated with an increased risk of primary and delayed graft dysfunction and shorter graft survival. Expanded use of kidneys with high KDPI or donors after circulatory arrest may benefit from machine perfusion. Several studies have now shown that hypothermic machine perfusion of kidneys results in reduced rates of delayed graft function and improved graft survival when compared with static hypothermic storage especially in expanded criteria donors, donors older than 65 years, and donors after circulatory death [2 ,3,5]. Other studies have also shown that machine perfusion of kidneys can extend preservation time [6]. Furthermore, the viability of these high-risk allografts can be assessed with perfusate biomarkers and perfusion parameters. For example, vascular resistance of kidneys during machine perfusion has been correlated with delayed graft function [2 ,7]. &&
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LIVER Although machine perfusion has gained increasing utility in the clinical practice of kidney transplant, its use has been very limited in liver transplantation. Machine perfusion of the liver was first attempted by Belzer and Starzl in the 1960s as reviewed by Monbaliu and Brassil [8]. Although it was successful, machine perfusion was abandoned because of its troublesome logistics and the emergence of static cold storage as a simple alternative that met the preservation needs at the time. Improved survival and increased application of liver transplantation as a therapy have increased the demand for donor livers far beyond the supply. Consequently, livers previously not considered for transplantation have now been used with caution and risk. These extended criteria donor livers include liver grafts procured from donation after circulatory death (DCD), grafts with more than 30% steatosis, grafts from older donors, and livers with metabolic dysfunction [1,8]. These liver grafts do not tolerate cold ischemia well and are associated with a significant increase of primary nonfunction and recipient death [8]. Consequently, there has been a reemergence in hepatic machine perfusion as a means to improve preservation of DCD livers, resuscitate organs damaged by ischemia, and assess viability of grafts. Machine perfusion of the liver graft is challenging due to its unique anatomy and physiology specifically, the competition between hepatic artery and portal vein inflow, the sensitivity of hepatic endothelial cells to high perfusion pressures,
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and the activation of Kupffer cells upon reperfusion [3,8]. A human clinical trial comparing hypothermic machine perfusion to static cold storage among a matched group of adult liver transplant recipients showed reduction in early allograft dysfunction (5 versus 25%, respectively; P ¼ 0.08) [9]. In addition, perfusate markers of hepatocellular injury including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were significantly lower with hypothermic machine perfusion [9]. Early results of ex-vivo oxygenated normothermic machine perfusion of livers discarded for transplantation has demonstrated maintenance of liver function with minimal injury [10]. Sutton et al. [11] studied the role of bile production as a parameter of liver graft viability during ex-vivo machine perfusion of extended criteria livers demonstrating that low bile production is associated with hepatic necrosis and venous congestion. Measuring biomarkers of hepatocellular injury and organ function during ex-vivo machine perfusion may prove useful in determining the suitability of extended criteria donor livers for transplantation. A critical factor of reperfusion injury is microcirculatory failure, associated with insufficient energy supply, impaired adenosine triphosphate regeneration, and incomplete recovery of hepatocellular excretory function [12,13]. Resuscitation of mitochondria offers a potential avenue to mitigate ischemic reperfusion injury (IRI) because of its central role in energy production, the generation of reactive oxygen species, and the initiation of apoptosis and necrosis. Hong et al. [14] have proposed a novel organ resuscitation therapy of regulated hepatic reperfusion (RHR) to modulate IRI during the critical period of organ revascularization. The strategy aims to nurture ischemic hepatocytes by providing a substrateenriched, leukocyte-depleted, oxygen-saturated perfusate in a pressure, temperature, and flow-controlled milieu in order for compromised cells to withstand reperfusion insult of warm blood during liver revascularization (Fig. 1). In a swine model, RHR mitigated IRI, provided intraoperative postreperfusion hemodynamic stability, facilitated recovery of hepatocellular function, and improved survival after prolonged periods of warm ischemia [14]. Ongoing research work is underway to investigate the utility of RHR in liver transplantation using DCD grafts in a swine model. This novel strategy may have direct applicability to clinical liver surgery and transplantation of marginal grafts.
PANCREAS The role of machine perfusion in pancreas preservation remains unexplored. The main goal of 154
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ongoing research on machine perfusion of the pancreas is to increase islet cell yield [2 ,3]. Some studies suggested applying kidney perfusion pumps to pancreas grafts, particularly during simultaneous kidney and pancreas transplantation [2 ]. However, the pancreas has a unique physiologic low flow and pressure environment, and machine perfusion under standard pressures can damage the pancreatic vascular endothelium and, subsequently, result in graft thrombosis upon reperfusion [3]. In one small human study (n ¼ 4), low-flow machine perfusion of the pancreas resulted in better islet cell yield when compared with static cold storage [15]. &&
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LUNG Currently, 15–25% of lungs from multiorgan donors are deemed unsuitable or suboptimal for transplantation because of donor risk factors including advanced age, smoking history, or donors after cardiac death [16]. Consequently, a 10–20% annual mortality rate exists among candidates for lung transplant [17 ]. Ex-vivo lung perfusion represents a promising method allowing increased preservation and reconditioning of suboptimal grafts for transplantation potentially increasing the number of procedures for lung transplant by 15–30% [18 ]. Steen et al. developed the first functional ex-vivo lung perfusion circuit for clinical use overcoming prior shortcomings of circuit-induced injury of the endothelial cells, increased vascular resistance and pulmonary edema [19]. Their success resulted in performing the first human lung transplant using a DCD lung preserved with machine perfusion in 2000 [19]. They were also able to recondition an initially unacceptable lung using ex-vivo machine perfusion and successfully transplant it in 2005 [20]. Cypel et al. [16] in Toronto treated lungs considered high risk for transplantation (pulmonary edema and/or PaO2 : FiO2 < 300) to 4 h normothermic exvivo machine perfusion and transplanted them if their physiologic function remained stable. When compared with transplantation of conventionally selected lungs, there was no statistically significant difference in graft dysfunction within 72 h, 30-day mortality, or duration of mechanical ventilation [16]. An integrated and portable Organ Care System (OCS) lung (TransMedics, Andover, Massachusetts, USA) is a commercially manufactured ex-vivo lung perfusion system designed to allow reconditioning of marginal lungs [21 ]. It allows ventilation and perfusion of the donor lungs under physiologic conditions. The OCS offers the chance for continuous alveoli recruitment and bronchoscopy while lungs are ventilated on the machine [21 ]. In 2011, TransMedics sponsored an ongoing, &
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Changing paradigms in organ preservation and resuscitation Ali et al.
Jugular vein
Heat exchanger
Oxygenator heat exchanger Liver Leukocyte filter
Portal vein Splenic vein
Centrifugal pump
Hepatic perfusion solution
Roller pump
FIGURE 1. Regulated hepatic reperfusion (RHR) and splenojugularvenovenous bypass circuits. An extracorporeal centrifugal pump recirculates the animal’s splanchnic venous blood to the heart through a splenojugularvenovenous bypass (direction of blood flow – white arrows) to avoid congestion of the splanchnic circulation during total portal occlusion. During RHR, an amount of the animal’s splanchnic venous blood is diverted through a Y-connector from the centrifugal pump and mixed with hepatic perfusion solution (H solution) in a 4 : 1 dilution ratio (perfusate). Another extracorporeal roller pump recirculates the perfusate through a pediatric oxygenator-heat exchanger and leukoreduction filter before perfusion of the liver through the portal vein (direction of perfusate flow – black arrows). The roller pump regulates the reperfusion pressure (8–12 mmHg) and the oxygenator-heat exchanger maintains the perfusate oxygen saturation (to 100%) and temperature (30–328C). Adapted from [14] and [37 ]. &&
prospective, randomized, multicenter trial: International randomized study of the TransMedics Organ Care System (OCS Lung) for lung preservation and transplantation (INSPIRE) to compare OCS lung to standard cold storage [2 ,21 ]. Using the same system (OCS), Mohite et al. [21 ] demonstrated successful preservation, resuscitation, and transplantation of lungs from donation after cardiac death. Recently, the US Food and Drug Administration approved XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA) with STEEN solution (XVIVO Perfusion, Gotenborg Sweden) as a device for preserving donated lungs that do not initially meet the standard criteria for lung transplantation but may be transplantable if there is more time to observe and evaluate the organ’s function to determine whether the lung is viable for transplantation [22]. &&
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HEART Machine perfusion for heart transplantation represents a tremendous opportunity to expand the type and number of heart donors used for transplantation and resuscitate dysfunctional heart allografts prior to implantation. Currently, significant limits on warm donor ischemia and cold storage ischemia exist because of recipient mortality secondary to graft failure [18 ]. Owing to the limited number of useable donor hearts, the limitations on cold static storage and the mortality associated with graft failure, perfusion preservation of the heart has advanced from a research interest to a clinical tool with the goal of prolonged preservation and resuscitation with improved transplant survival. Biomarkers of myocardial injury (including pH, lactate, troponins) can be measured during machine perfusion [3,18 ]. In addition, ex-vivo cardiac imaging with MRI or angiography can be performed to
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assess function, anatomy, and viability [18 ]. Animal experiments of machine perfusion of the heart showed reduction in tissue lactate accumulation and myocardial necrosis, and better preservation of the left ventricular function when compared with static cold storage [18 ,23]. TransMedics’ OCS is a portable device for perfusion and assessment of the heart allograft [2 ]. A multicenter, randomized study of Organ Care system cardiac for preservation of donated hearts for eventual transplantation (PROCEEDII) was initiated in the USA and Europe [24]. Early results with OCS normothermic ex-vivo allograft blood perfusion in adult clinical orthotopic heart transplantation demonstrated better outcomes after transplantation with regard to recipient survival, incidence of primary graft dysfunction, and incidence of acute rejection [25 ]. In addition, OCS has demonstrated successful preservation and assessment and transplantation of three DCD heart allografts [26], whereas a group from Heidelberg, Germany has described the use of ex-vivo angiography to assess the viability of a suboptimal donor heart in the OCS [27]. &&
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ORGAN PRESERVATION SOLUTIONS Graft survival of many organs remains limited by time, temperature, and the health status of the organ prior to preservation. Anoxia associated with hypothermic static storage triggers a biological cascade resulting in cellular apoptosis and production of toxic metabolites upon tissue reperfusion [28 ]. One goal of preservative solutions is to limit ischemic damage during cold ischemia and minimize reperfusion injury by targeting the biochemical changes that occur during these processes. At present, there is no consensus regarding the most optimal preservation solution for hypothermic static storage or machine perfusion. Consequently, this is an area of active research and development. The most commonly used cold preservative solution is ViaSpan [University of Wisconsin (UW) solution, DuPont Pharma, Bad Homburg, Germany]. It is a high-potassium, low-sodium solution that contains hydroxyethyl starch, adenosine, and raffinose. Although it yields improved preservation and outcomes, compared with Euro-Collins solution, ViaSpan has disadvantages that include its high viscosity, which may impede microvascular flushing, the need for filter to prevent crystal formation, microvascular disturbances due to particle formation, and hyperkalemic cardiac arrest on reperfusion [28 ]. Alternatives to ViaSpan (UW solution) include Custodiol-histidine–tryptophan–ketoglutarate (HTK; Essential Pharma, Ewing, New Jersey, USA) solution and the Celsior solution (SangStat Medical, &
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Fremont, California, USA). Custodiol-HTK solution (Essential Pharma) is a low-potassium, low-viscosity crystalloid and does not require filtering. Celsior solution is a high-sodium, low-potassium solution that incorporates mannitol and lactobionate to decrease cellular edema [28 ]. Pulmonary-specific preservation solutions include Perfadex (XVIVO Perfusion Inc.), a dextran-containing, lightly buffered, low-potassium electrolyte solution [29 ]. In a recent meta analysis encompassing 15 trials and 3584 kidney transplants, the use of UW, HTK, or Celsior solution resulted in no difference in the incidence of delayed graft function among kidney transplant recipients [30]. Two meta analyses of donor liver preservation found no difference in the incidence of graft nonfunction, delayed graft function, or patient survival between the use of UW and Celsior solutions [31], or graft function when comparing HTK and UW solutions [32]. In pancreas preservation, most studies found no change in outcome between the use of UW and HTK solutions for preservation [33]. However, some studies showed increased risk of graft thrombosis, pancreatitis, and graft loss with HTK preservation especially with prolonged cold ischemia [34,35]. In cardiac preservation, UW solution was found superior to Celsior regarding graft survival [29 ]. Perfadex remains the preferred solution for lung transplantation. Its use has been associated with an improved PaO2 : FiO2 ratio and shorter duration of mechanical ventilation [29 ]. With better understanding of the pathophysiology of ischemia-induced programmed cell death, there has been a growing interest in adding agents to preservation solutions that target the biochemical processes leading to apoptosis. Caspase activity is increased in liver grafts during cold preservation and several studies have shown that caspase inhibitors can attenuate the ischemia/reperfusion-induced apoptosis [36]. However, caspase inhibition can be detrimental by promoting inflammation by blocking the noninflammatory apoptotic pathway [36]. Targeting intracellular biochemical processes that result in apoptosis or necrosis is an interesting area research that could potentially improve organ preservation and minimize ischemia-related injuries. &
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CONCLUSION The increasing shortage of donor organs has led to increased use of donor organs previously deemed suboptimal. Hypothermic static cold storage is limited in its ability to effectively preserve marginal allografts, prolong storage times, or assess organ function prior to implantation. Hypothermic Volume 20 Number 2 April 2015
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Changing paradigms in organ preservation and resuscitation Ali et al.
machine perfusion has demonstrated improved kidney graft function and survival, especially among expanded criteria donors. Machine perfusion is demonstrating exciting and promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. The availability of portable machine perfusion devices will expand the use of machine perfusion. The role of machine perfusion in standard criteria donors needs further study of cost–effectiveness and indication for use. Ex-vivo machine perfusion also allows a window between procurement and transplantation wherein organs can be resuscitated or reconditioned using various agents in the perfusate, gene, and stem cell therapies. The functionality of grafts could also be assessed using perfusate biochemical markers, perfusion parameters, and ex-vivo imaging. Regarding organ preservation solutions, there is no consensus among physicians about the optimal preservation solutions. Targeting intracellular biochemical processes that result in apoptosis or necrosis by adding antiapoptotic agents to preservation solutions is an interesting research area that could potentially improve organ preservation and minimize ischemia-related injuries. This is an exciting time wherein machine-based, ex-vivo organ preservation under metabolically active conditions can provide for evaluation, resuscitation, and intervention before implantation. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Vogel T, Brockmann JG, Friend PJ. Ex-vivo normo thermic liver perfusion. Curr Opin Organ Transplant 2010; 15:167–172. 2. Van Raemdonck D, Neyrinck A, Rega F, et al. Machine perfusion in organ && transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells? Curr Opin Organ Transplant 2013; 18:24–33. This study summarizes the current experience with ex-vivo machine perfusion. 3. Balfoussia D, Yerrakalva D, Hamaoui K, Papalois V. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant 2012; 10:87–100. 4. Organ Procurement and Transplantation Network (OPTN). A Guide to Calculating and Interpreting the Kidney Donor Profile Index (KDPI). 2014. http://optn.transplant.hrsa.gov/ContentDocuments/Guide_to_Calculating_ Interpreting_KDPI.pdf. Accessed 16 February 2015. 5. Gallinat A, Moers C, Smits JM, et al. Machine perfusion versus static cold storage in expanded criteria donor kidney transplantation: 3-year follow-up data. Transpl Int 2013; 26:E52–E53.
6. Brook NR, Waller JR, Nicholson ML. Non heart-beating kidney donation: current practice and future developments. Kidney Int 2003; 63:1516– 1529. 7. Jochmans I, Moers C, Ploeg R, Pirenne J. To perfuse or not to perfuse kidneys donated after cardiac death. Am J Transplant 2011; 11:409–410. 8. Monbaliu D, Brassil J. Machine perfusion of the liver: past, present and future. Curr Opin Organ Transplant 2010; 15:160–166. 9. Op den Dries S, Karimian N, Sutton ME, et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am J Transplant 2013; 13:1327–1335. 10. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am J Transplant 2010; 10:372–381. 11. Sutton ME, Op den Dries S, Karimian N, et al. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One 2014; 9:e110642. 12. Goto M, Kawano S, Yoshihara H, et al. Hepatic tissue oxygenation as a predictive indicator of ischemia-reperfusion liver injury. Hepatology 1992; 15:432–437. 13. Kamiike W, Nakahara M, Nakao K, et al. Correlation between cellular ATP level and bile excretion in the rat liver. Transplantation 1985; 39:50–55. 14. Hong JC, Koroleff D, Xia V, et al. Regulated hepatic reperfusion mitigates ischemia and reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model. J Am Coll Surg 2012; 214:505–515. 15. Leeser DB, Bingaman AW, Poliakova L, et al. Pulsatile pump perfusion of pancreata before human islet cell isolation. Transplant Proc 2004; 36:1050– 1051. 16. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364:1431–1440. 17. Andreasson AS, Dark JH, Fisher AJ. Ex vivo lung perfusion in clinical lung & transplantation – state of the art. Eur J Cardiothoracic Surg 2014; 46:779– 788. This article summarizes the clinical experience with ex-vivo lung perfusion. 18. Ciubotaru A, Haverich A. Ex vivo approach to treat failing organs: expanding && the limits. Eur Surg Res 2015; 54:64–74. This article discusses in detail the potential benefits of ex-vivo organ resuscitation, imaging, and treatment. 19. Steen S, Sjo¨berg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet 2001; 357:825–829. 20. Ingemansson R, Eyjolfsson A, Mared L, et al. Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg 2009; 87:255–260. 21. Mohite P, Sabashnikov A, Garcia Saez D, et al. Utilization of the Organ Care && System Lung for the assessment of lungs form a donor after cardiac death (DCD) before bilateral transplantation. Perfusion 2014; 29:1–4. This Letter to the Editor describes the first human clinical use of the OCS lung in transplantation of lungs from DCD. 22. U.S. Food and Drug Administration. FDA approves donor lung preservation device that may result in more lung transplants. 2014. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm409488.htm. Accessed 16 February 2015. 23. Rosenbaum DH, Peltz M, DiMaio JM, et al. Perfusion preservation versus static preservation for cardiac transplantation: effects on myocardial function and metabolism. J Heart Lung Transplant 2008; 27:93–99. 24. ClinicalTrials.gov. Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation (PROCEEDII). First received March 3, 2009; last updated July 29, 2013. https://www. clinicaltrials.gov/ct2/show/NCT00855712?term=TransMedics&rank=2. Accessed 16 February 2015. 25. Koerner MM, Ghodsizad A, Schulz U, et al. Normothermicexvivo allograft && blood perfusion in clinical heart transplantation. Heart Surg Forum 2014; 17:E141–E145. This study describes the first human clinical use of the OCS heart for ex-vivo resuscitation and subsequent transplantation. 26. The Transmedics Organ Care System (OCSTM) Heart Technology was Used to Perform the World’s First Series of Adult Human Heart Transplants from Donors after Circulatory Death (DCD Donors) at St Vincent’s Hospital in Sydney, Australia. 2014. Andover, Massachusetts, USA; 24 October 2014. http://www.transmedics.com/wt/page/pr_1414117691. Accessed 16 February 2015. 27. Ghodsizad A, Bordel V, Ungerer M, et al. Ex vivo coronary angiography of a donor heart in the organ care system. Heart Surg Forum 2012; 15:E161– E163. 28. Parsons RF, Guarrera JV. Preservation solutions for static cold storage of & abdominal allografts: which is best? Curr Opin Organ Transplant 2014; 19:100–107. This review article summarizes the clinical experience with the different preservation solution for abdominal allografts. 29. Latchana N, Peck JR, Whitson B, Black SM. Preservation solutions for cardiac & and pulmonary donor grafts: a review of the current literature. J Thorac Dis 2014; 6:1143–1149. This review article summarizes the clinical experience with the different preservation solutions for thoracic allografts.
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Organ preservation and procurement 30. O’Callaghan JM, Knight SR, Morgan RD, Morris PJ. Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. Am J Transplant 2012; 12:896–906. 31. O’Callaghan JM, Morgan RD, Knight SR, Morris PJ. The effect of preservation solutions for storage of liver allografts on transplant outcomes: a systematic review and meta-analysis. Ann Surg 2014; 260:46–55. 32. Zuluaga GLL, Agudelo RES, Tobon JJZ. Preservation solutions for liver transplantation in adults: Celsior versus Custodiol: a systematic review and meta-analysis with an indirect comparison of randomized trials. Transplant Proc 2013; 45:25–32. 33. Schneeberger S, Biebl M, Steurer W, et al. A prospective randomized multicenter trial comparing histidine tryptophane-ketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation. Transpl Int 2009; 22:217–224.
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34. Alonso D, Dunn TB, Rigley T, et al. Increased pancreatitis in allografts flushed with histidine–tryptophan–ketoglutarate solution: a cautionary tale. Am J Transplant 2008; 8:1942–1945. 35. Stewart ZA, Cameron AM, Singer AL, et al. Histidine–tryptophan–ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation. Am J Transplant 2009; 9:217–221. 36. Cursio R. Caspase inhibition in liver transplantation: from basic science to clinical studies. HPB (Oxford) 2010; 12:1–3. 37. Zhai Y, Petrowsky H, Hong JC, et al. Ischaemia-reperfusioninjury in liver transplantation – from bench to bedside. Nat Rev Gastroenterol Hepatol 2013; 10:79–89. Comprehensive review of ischemia reperfusion injury in a large animal liver transplant model.
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