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肝移植前对供肝实施低温机械灌注的随机试验
Hypothermic Machine Perfusion in Liver Transplantation — A Randomized Trial


Rianne van Rijn ... 其他 • 2021.04.15

低温机械灌注护肝技术突破,扩大肝移植供者范围

 

刘连新

中国科学技术大学附属第一医院(安徽省立医院)肝胆外科

 

作为治疗终末期肝病唯一的有效手段,肝移植目前面临的主要难题是器官短缺。心脏死亡器官捐献(DCD),甚至扩大标准供者(ECD)可以增加供肝来源,但器官质量和利用率的问题也随之而来。机械灌注(machine perfusion,MP)是一种新的器官保存技术和理念,可以克服传统静态冷保存器官的诸多问题,对供肝进行灌注、保存、评估甚至修复,进而改善肝移植疗效。机械灌注目前根据工作温度主要分为3类:常温机械灌注(NMP)、低温机械灌注(HMP)和亚低温机械灌注(SNMP)。

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摘要


背景

移植来自心脏死亡供者的肝脏与非吻合口胆道狭窄的风险增加相关。对供肝实施低温氧合机械灌注有可能降低胆道并发症的发生率,但来自前瞻性对照研究的数据有限。

 

方法

在此项多中心、对照试验中,我们将移植来自心脏死亡供者的肝脏的患者随机分组,两组分别接受低温氧合机械灌注后的供肝(机械灌注组)或常规静态冷保存后的供肝(对照组)。主要终点是移植后6个月内的非吻合口胆道狭窄发生率。次要终点包括其他移植物相关并发症和一般并发症。

 

结果

共计160例患者被纳入试验,其中78人接受了机械灌注供肝,78人接受了静态冷保存供肝(本试验中有4例患者未接受肝移植)。机械灌注组6%的患者和对照组18%的患者发生了非吻合口胆道狭窄(风险比,0.36;95%置信区间[CI],0.14~0.94;P=0.03)。机械灌注组12%的受者和对照组27%的受者发生了再灌注后综合征(风险比,0.43;95% CI,0.20~0.91)。26%的机械灌注供肝和40%的对照供肝发生了早期同种异体移植物功能障碍(风险比,0.61;95% CI,0.39~0.96)。机械灌注后因非吻合口胆道狭窄接受治疗的累积次数与对照组相比减少近3/4。两组的不良事件发生率相似。

 

结论

移植来自心脏死亡供者的肝脏时,与常规静态冷保存供肝相比,低温氧合机械灌注供肝可降低移植后非吻合口胆道狭窄的风险(由Fonds NutsOhra资助,DHOPE-DCD在ClinicalTrials.gov注册号为NCT02584283)。





作者信息

Rianne van Rijn, M.D., Ph.D., Ivo J. Schurink, B.Sc., Yvonne de Vries, M.D., Ph.D., Aad P. van den Berg, M.D., Ph.D., Miriam Cortes Cerisuelo, M.D., Ph.D., Sarwa Darwish Murad, M.D., Ph.D., Joris I. Erdmann, M.D, Ph.D., Nicholas Gilbo, M.D., Ph.D., Robbert J. de Haas, M.D., Ph.D., Nigel Heaton, M.D., Ph.D., Bart van Hoek, M.D., Ph.D., Volkert A.L. Huurman, M.D., Ph.D., Ina Jochmans, M.D., Ph.D., Otto B. van Leeuwen, Ph.D., Vincent E. de Meijer, M.D., Ph.D., Diethard Monbaliu, M.D., Ph.D., Wojciech G. Polak, M.D., Ph.D., Jules J.G. Slangen, M.D., Roberto I. Troisi, M.D., Ph.D., Aude Vanlander, M.D., Ph.D., Jeroen de Jonge, M.D., Ph.D., and Robert J. Porte, M.D., Ph.D. for the DHOPE-DCD Trial Investigators*
From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden — all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) — both in Belgium. Address reprint requests to Dr. Porte at the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, P.O. Box 30.001, 9700RB Groningen, the Netherlands, or at r.j.porte@umcg.nl. *A complete list of collaborators and their roles in the DHOPE-DCD trial is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. de Vries Y, von Meijenfeldt FA, Porte RJ. Post-transplant cholangiopathy: classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis 2018;1864:1507-1515.

2. O’Neill S, Roebuck A, Khoo E, Wigmore SJ, Harrison EM. A meta-analysis and meta-regression of outcomes including biliary complications in donation after cardiac death liver transplantation. Transpl Int 2014;27:1159-1174.

3. Foley DP, Fernandez LA, Leverson G, et al. Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and long-term outcomes from a single center. Ann Surg 2011;253:817-825.

4. Tullius SG, Rabb H. Improving the supply and quality of deceased-donor organs for transplantation. N Engl J Med 2018;378:1920-1929.

5. Summers DM, Counter C, Johnson RJ, Murphy PG, Neuberger JM, Bradley JA. Is the increase in DCD organ donors in the United Kingdom contributing to a decline in DBD donors? Transplantation 2010;90:1506-1510.

6. Dutkowski P, Guarrera JV, de Jonge J, Martins PN, Porte RJ, Clavien PA. Evolving trends in machine perfusion for liver transplantation. Gastroenterology 2019;156:1542-1547.

7. Xu J, Buchwald JE, Martins PN. Review of current machine perfusion therapeutics for organ preservation. Transplantation 2020;104:1792-1703.

8. Lüer B, Koetting M, Efferz P, Minor T. Role of oxygen during hypothermic machine perfusion preservation of the liver. Transpl Int 2010;23:944-950.

9. Monbaliu D, Brassil J. Machine perfusion of the liver: past, present and future. Curr Opin Organ Transplant 2010;15:160-166.

10. Dutkowski P, Furrer K, Tian Y, Graf R, Clavien PA. Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor. Ann Surg 2006;244:968-976.

11. de Rougemont O, Breitenstein S, Leskosek B, et al. One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death. Ann Surg 2009;250:674-683.

12. Schlegel A, Kron P, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation. Ann Surg 2014;260:931-937.

13. 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.

14. Dutkowski P, Schlegel A, de Oliveira M, Müllhaupt B, Neff F, Clavien PA. HOPE for human liver grafts obtained from donors after cardiac death. J Hepatol 2014;60:765-772.

15. 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.

16. van Rijn R, van Leeuwen OB, Matton APM, et al. Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers. Liver Transpl 2018;24:655-664.

17. van Rijn R, van den Berg AP, Erdmann JI, et al. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol 2019;19:40-46.

18. Buis CI, Verdonk RC, Van der Jagt EJ, et al. Nonanastomotic biliary strictures after liver transplantation. 1. Radiological features and risk factors for early vs. late presentation. Liver Transpl 2007;13:708-718.

19. Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987;19:Suppl 3:54-55.

20. Hilmi I, Horton CN, Planinsic RM, et al. The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation. Liver Transpl 2008;14:504-508.

21. Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010;16:943-949.

22. Abt P, Crawford M, Desai N, Markmann J, Olthoff K, Shaked A. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:1659-1663.

23. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010;97:744-753.

24. Croome KP, McAlister V, Adams P, Marotta P, Wall W, Hernandez-Alejandro R. Endoscopic management of biliary complications following liver transplantation after donation from cardiac death donors. Can J Gastroenterol 2012;26:607-610.

25. Meurisse N, Vanden Bussche S, Jochmans I, et al. Outcomes of liver transplantations using donations after circulatory death: a single-center experience. Transplant Proc 2012;44:2868-2873.

26. Taner CB, Bulatao IG, Perry DK, et al. Asystole to cross-clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. Transpl Int 2012;25:838-846.

27. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-790.

28. Patrono D, Romagnoli R. Postreperfusion syndrome, hyperkalemia and machine perfusion in liver transplantation. Transl Gastroenterol Hepatol 2019;4:68-68.

29. Burlage LC, Hessels L, van Rijn R, et al. Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers. Am J Transplant 2019;19:1061-1071.

30. Selzner M, Goldaracena N, Echeverri J, et al. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: first North American results. Liver Transpl 2016;22:1501-1508.

31. Bral M, Gala-Lopez B, Bigam D, et al. Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: results of a clinical trial. Am J Transplant 2017;17:1071-1080.

32. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018;557:50-56.

33. Muller X, Schlegel A, Kron P, et al. Novel real-time prediction of liver graft function during hypothermic oxygenated machine perfusion before liver transplantation. Ann Surg 2019;270:783-790.

34. de Vries Y, Matton APM, Nijsten MWN, et al. Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution. Am J Transplant 2019;19:1202-1211.

35. Boteon YL, Laing RW, Schlegel A, et al. The impact on the bioenergetic status and oxidative-mediated tissue injury of a combined protocol of hypothermic and normothermic machine perfusion using an acellular haemoglobin-based oxygen carrier: the cold-to-warm machine perfusion of the liver. PLoS One 2019;14(10):e0224066-e0224066.

36. van Leeuwen OB, de Vries Y, Fujiyoshi M, et al. Transplantation of high-risk donor livers after ex situ resuscitation and assessment using combined hypo- and normothermic machine perfusion: aprospective clinical trial. Ann Surg 2019;270:906-914.

37. Jay CL, Lyuksemburg V, Kang R, et al. The increased costs of donation after cardiac death liver transplantation: caveat emptor. Ann Surg 2010;251:743-748.

38. van der Hilst CS, Ijtsma AJ, Bottema JT, et al. The price of donation after cardiac death in liver transplantation: a prospective cost-effectiveness study. Transpl Int 2013;26:411-418.

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