University of Groningen
Transplantation of Suboptimal Donor Livers: Exploring the Boundaries van Leeuwen, Otto
DOI:
10.33612/diss.132816502
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2020
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van Leeuwen, O. (2020). Transplantation of Suboptimal Donor Livers: Exploring the Boundaries. University of Groningen. https://doi.org/10.33612/diss.132816502
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1 General introduction and outline of this thesis
Liver transplantation: past and present
Liver transplantation is currently the standard life-saving treatment for patients with end-stage liver disease as well as for selected patients with hepatobiliary malignancies or certain metabolic diseases. The first liver transplant was performed by dr. Thomas Starzl and his team in Denver, Colorado, in 1963.1 Unfortunately, as a result of massive bleeding, the three-years-old recipient died intra-operatively. Problems persisted during the following five transplants, with patient survival no more than 23 days. In 1967, Starzl performed the first successful liver transplant with patient survival exceeding one year.2 Twelve years later, after Calne’s development of cyclosporine and Starzl’s introduction of tacrolimus, liver transplantation steadily progressed towards a standardized treatment with acceptable outcomes.3,4 Nowadays, 1 year graft and patient survival rates of over 90% are seen globally.
The demand for donor livers, however, severely exceeds the number of suitable donor livers available. Until the late 1990’s liver grafts were mainly donated after determination of brain death in the donor (DBD donation). In an attempt to widen the potential donor pool, donation after circulatory death (DCD) was re-introduced.5 In the early phases of this development, excellent results with DCD liver transplantation were achieved. However, by extending the acceptance criteria for DCD livers, the prevalence of biliary complications increased. Post-transplant cholangiopathy (PTC) became the most frequent complication following DCD liver transplantation.6 The largest component of PTCs are the non-anastomotic strictures (NAS) of the bile duct in the presence of a patent hepatic artery. Incidences of NAS have been reported in up to 30% of DCD liver recipients.6
Organ preservation
In the early 1980’s, Belzer’s group developed the University of Wisconsin (UW) preservation solution, which became a standardized fluid used to preserve organs.
During organ procurement, the abdominal compartment is flushed with several liters of ice-cold UW solution, after which the liver is stored in a bag containing UW solution in a box with ice. This static preservation technique, unfortunately, does not sufficiently prevent NAS. As a result, dynamic preservation techniques of donor livers by using machine perfusion is increasingly studied in an attempt to improve outcomes after
(suboptimal) liver transplantation.7-10 Ex situ machine perfusion can be performed at different temperatures and time points. For example, hypothermic machine perfusion (4-12°C) has the potential to reduce ischemia-reperfusion injury, whereas normothermic machine perfusion (37°C) allows viability testing and potential graft treatment.9
Outline of this thesis
This thesis focuses on transplantation of suboptimal donor livers, especially livers donated after circulatory death. Part 1 contains observational studies which aimed to identify the boundaries in transplantation of suboptimal donor livers, and to recognize risk factors that determine these boundaries. Part 2 contains observational, preclinical and clinical studies with a common goal to investigate safe and successful transplantation of suboptimal livers.
Part I: Transplantation of suboptimal donor livers: determining the boundaries
Biliary complications, including NAS, remain the Achilles heel in DCD liver transplantation.6 About half of the patients that develop NAS undergo re- transplantation, with another 25% passing away before a suitable donor liver becomes available.6 Several studies have focused on predicting graft survival after DCD liver transplantation, but the prediction of NAS still remains highly difficult. Known risk factors such as high donor age, prolonged donor warm ischemia times and cold ischemic preservation periods are not present in a significant proportion of NAS cases. Chapter 2 provides a review of literature on biliary complications after liver transplantation.
Although ischemia and subsequent reperfusion injury is a main risk factor for the development of NAS, other mechanisms, such as immune-mediated injury, bile salt toxicity, and insufficient regeneration of the epithelium also play a role in the pathogenesis, and are discussed in this review. Chapter 3 describes a study on the influence of the time between start of cold flushing and the end of liver retrieval on the development of biliary complications after DCD liver transplantation. During liver retrieval, donor livers maintain a temperature of around 15-20°C and therefore
continues to suffer lukewarm ischemia.12 Therefore, it is hypothesized that the duration of this period is a substantial determinant of the development of NAS. Chapter 4 contains a study on the involvement of DCD donor blood composition on the development of biliary complications. In addition to peribiliary gland injury, arteriolonecrosis in the bile duct wall is considered to be one of the prime risk factors for the development of NAS after transplantation.13 We considered that graft flush-out upon procurement, and thereby the severity of the arteriolonecrosis, would be influenced by the cellular composition of donor blood. In chapter 5, it is investigated whether DCD livers can be safely used for patients requiring a re-transplantation.
Part II: Transplantation of suboptimal donor livers: expanding the boundaries
Over the last years, dynamic preservation of donor livers by using machine perfusion is slowly making its way into clinic. The first randomized controlled trials have recently finished with patient accrual, however, study protocols are highly different over the globe and the results of aforementioned trials remain awaited.8 Substantial benefits of end-ischemic hypothermic machine perfusion have been reported, however, viability testing (especially of the biliary tree) remains not possible using this technique.9-11 End- ischemic normothermic machine perfusion has the benefit that it does allow viability testing, but it exposes the organ to an extra hit of ischemia-reperfusion injury and does not mitigate reperfusion injury.8 In the study described in chapter 6, we investigated the effect of dual hypothermic oxygenated machine perfusion (DHOPE) on the development of biliary injury during DCD liver transplantation. Biopsies were taken upon arrival and after reperfusion in DHOPE livers and control livers, to assess the potential benefit of DHOPE. In chapter 7, we describe a study on the safety of prolonged DHOPE, and compared liver function after 2, 6 and 24 hours of DHOPE. Prolonged DHOPE can simplify logistics and may potentially facilitate day-time liver transplantation. In chapter 8, we report the results from a single-arm prospective intervention trial. In this study, end-ischemic dynamic preservation using sequential hypo- and normothermic machine perfusion was applied in an attempt to resuscitate and assess the function of previously discarded human livers, and to subsequently allow safe transplantation. Chapter 9 contains a preclinical study to potentially simplify ischemia-free liver transplantation.14 Rather than portal perfusion via an end-to-side
anastomosed autologous iliac vein graft, we investigated the feasibility of portal venous machine perfusion via the surgically reopened umbilical vein.
Located after chapter 10 are two appendices. Appendix I is a case report using the technique described in Chapter 6. Appendix II contains an editorial in which viability criteria for functional assessment of donor livers are discussed.
References
1. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR.
Homotransplantation of the liver in humans. Surg Gynecol Obstet. 1963;117:659–
676.
2. Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB, et al.
Orthotopic homotransplantation of the human liver. Ann Surg. 1968;168(3):392–
415.
3. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2(8151):1033–1036.
4. Starzl T, Fung J, Venkataramman R, Todo S, Demetris A, Jain A. FK 506 for liver, kidney and pancreas transplantation. The Lancet. 1989;334(8670):1000-1004.
5. Monbaliu D, Pirenne J, Talbot D. Liver transplantation using Donation after Cardiac Death donors. J Hepatol. 2012;56(2):474-485.
6. de Vries Y, von Meijenfeldt F, Porte R. Post-transplant cholangiopathy:
Classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4):1507-1515.
7. Jamieson NV, Sundberg R, Lindell S,et al.Preservation of the canine liver for 24-48 hours using simple cold storage with UW solution. Transplantation 1988;46(4):517-522
8. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018;557:50-56.
9. Schegel A, Muller X, Kalisvaart M, et al. Outcomes of DCD liver transplantation using organs treated by hypothermic machine perfusion before implantation. J Hepatol 2019;70:50-57.
10. De Meijer VE, Fujiyoshi M, Porte RJ. Ex situ machine perfusion strategies in liver transplantation. J Hepatol. 2019;70:203-205.
11. Van Rijn R, Karimian N, Matton APM, et al. Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death. Br J Surg 2017;104:907-917.
12. Villa R, Fondevila C, Erill I, et al. Real-time direct measurement of human liver allograft temperature from recovery to transplantation. Transplantation.
2006;81(3):483-486.
13. Op den Dries S, Westerkamp AC, Karimian N, et al. Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non- anastomotic biliary strictures. J Hepatol 2014;60:1172-1179.
14. He X, Guo Z, Zhao Q et al. The first case of ischemia-free organ transplantation in humans: A proof of concept. Am J Transplant 2017;18(3):737-744.
Part I: Transplantation of suboptimal donor livers:
determining the boundaries
