An integrated perfusion machine preserves injured human livers for 1 week.
Adenosine Triphosphate
/ metabolism
Alarmins
/ metabolism
Animals
Biomarkers
/ metabolism
Electrolytes
/ metabolism
Glucose
/ metabolism
Hemodynamics
Hemolysis
Humans
Liver
/ injuries
Oxygen
/ metabolism
Oxygen Consumption
Perfusion
/ instrumentation
Portal Vein
/ metabolism
Preservation, Biological
Reperfusion
Swine
Journal
Nature biotechnology
ISSN: 1546-1696
Titre abrégé: Nat Biotechnol
Pays: United States
ID NLM: 9604648
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
23
12
2018
accepted:
18
11
2019
pubmed:
15
1
2020
medline:
10
4
2020
entrez:
15
1
2020
Statut:
ppublish
Résumé
The ability to preserve metabolically active livers ex vivo for 1 week or more could allow repair of poor-quality livers that would otherwise be declined for transplantation. Current approaches for normothermic perfusion can preserve human livers for only 24 h. Here we report a liver perfusion machine that integrates multiple core physiological functions, including automated management of glucose levels and oxygenation, waste-product removal and hematocrit control. We developed the machine in a stepwise fashion using pig livers. Study of multiple ex vivo parameters and early phase reperfusion in vivo demonstrated the viability of pig livers perfused for 1 week without the need for additional blood products or perfusate exchange. We tested the approach on ten injured human livers that had been declined for transplantation by all European centers. After a 7-d perfusion, six of the human livers showed preserved function as indicated by bile production, synthesis of coagulation factors, maintained cellular energy (ATP) and intact liver structure.
Identifiants
pubmed: 31932726
doi: 10.1038/s41587-019-0374-x
pii: 10.1038/s41587-019-0374-x
pmc: PMC7008032
mid: EMS84970
doi:
Substances chimiques
Alarmins
0
Biomarkers
0
Electrolytes
0
Adenosine Triphosphate
8L70Q75FXE
Glucose
IY9XDZ35W2
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
189-198Subventions
Organisme : Swiss National Science Foundation
ID : 137355
Pays : Switzerland
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Références
Giwa, S. et al. The promise of organ and tissue preservation to transform medicine. Nat. Biotechnol. 35, 530–542 (2017).
doi: 10.1038/nbt.3889
de Vries, R. J. et al. Supercooling extends preservation time of human livers. Nat. Biotechnol. 37, 1131–1136 (2019).
doi: 10.1038/s41587-019-0223-y
Buying time for transplants. Nat. Biotechnol. 35, 801 (2017).
Watson, C. J. E. et al. Observations on the ex situ perfusion of livers for transplantation. Am. J. Transplant. 18, 2005–2020 (2018).
doi: 10.1111/ajt.14687
Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018).
doi: 10.1038/s41586-018-0047-9
Eshmuminov, D. et al. Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy. Br. J. Surg. 103, 1768–1782 (2016).
doi: 10.1002/bjs.10290
Schnitzbauer, A. A. et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann. Surg. 255, 405–414 (2012).
doi: 10.1097/SLA.0b013e31824856f5
de Santibanes, E. & Clavien, P. A. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann. Surg. 255, 415–417 (2012).
doi: 10.1097/SLA.0b013e318248577d
Lautt, W. W. In Colloquium Series on Integrated Systems Physiology: from Molecule to Function to Disease (Eds. Granger, D. N. and Granger, J. P.) (San Rafael, 2009).
Berg, J. M, Tymoczko, J. L. & Stryer, L. Biochemistry 5th edn (W. H. Freeman, 2002).
Eshmuminov, D et al. Perfusion settings and additives in liver normothermic machine perfusion with red blood cells as oxygen carrier. A systematic review of human and porcine perfusion protocols. Transplant Int. 31, 956–969 (2018).
doi: 10.1111/tri.13306
Liu, Q. et al. Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 h of normothermic machine perfusion. Liver Transpl. 24, 233–245 (2018).
doi: 10.1002/lt.24972
Baba, A. et al. Microcirculation of the bulbar conjunctiva in the goat implanted with a total artificial heart: effects of pulsatile and nonpulsatile flow. ASAIO J. 50, 321–327 (2004).
doi: 10.1097/01.MAT.0000129320.57362.db
Orime, Y. et al. The role of pulsatility in end-organ microcirculation after cardiogenic shock. ASAIO J. 42, M724–M729 (1996).
doi: 10.1097/00002480-199609000-00083
O’Neil, M. P., Fleming, J. C., Badhwar, A. & Guo, L. R. Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: microcirculatory and systemic effects. Ann. Thorac. Surg. 94, 2046–2053 (2012).
doi: 10.1016/j.athoracsur.2012.05.065
Koning, N. J. et al. Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics. J. Appl. Physiol. 112, 1727–1734 (2012).
doi: 10.1152/japplphysiol.01191.2011
European Association for the Study of the Liver. EASL clinical practice guidelines: liver transplantation. J. Hepatol. 64, 433–485 (2016).
doi: 10.1016/j.jhep.2015.10.006
Attaye, I. et al. The effects of hyperoxia on microvascular endothelial cell proliferation and production of vaso-active substances. Intensive Care Med. Exp. 5, 22 (2017).
doi: 10.1186/s40635-017-0135-4
Dallinger, S. et al. Endothelin-1 contributes to hyperoxia-induced vasoconstriction in the human retina. Invest. Ophthalmol. Vis. Sci. 41, 864–869 (2000).
pubmed: 10711705
pmcid: 10711705
Liu, Q. et al. Ex situ 86-hour liver perfusion: pushing the boundary of organ preservation. Liver Transpl. 24, 557–561 (2018).
doi: 10.1002/lt.25007
Neuhaus, P. & Blumhardt, G. Extracorporeal liver perfusion: applications of an improved model for experimental studies of the liver. Int. J. Artif. Organs 16, 729–739 (1993).
doi: 10.1177/039139889301601010
de Rougemont, O. et al. One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death. Ann. Surg. 250, 674–683 (2009).
doi: 10.1097/SLA.0b013e3181bcb1ee
Saad, H. & Aladawy, M. Temperature management in cardiac surgery. Glob. Cardiol. Sci. Pract. 2013, 44–62 (2013).
doi: 10.5339/gcsp.2013.44
Clavien, P. A., Harvey, P. R. & Strasberg, S. M. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation 53, 957–978 (1992).
doi: 10.1097/00007890-199205000-00001
Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell Metab. 23, 254–263 (2016).
doi: 10.1016/j.cmet.2015.12.009
Selzner, M., Rudiger, H. A., Sindram, D., Madden, J. & Clavien, P. A. Mechanisms of ischemic injury are different in the steatotic and normal rat liver. Hepatology 32, 1280–1288 (2000).
doi: 10.1053/jhep.2000.20528
McCormack, L. et al. Use of severely steatotic grafts in liver transplantation: a matched case-control study. Ann Surg. 246, 940–946 (2007).
doi: 10.1097/SLA.0b013e31815c2a3f
Muller, X et al. Can hypothermic oxygenated perfusion (HOPE) rescue futile DCD liver grafts? HPB 21, 1156–1165 (2019).
doi: 10.1016/j.hpb.2019.01.004
Muller, X. et al. Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results. Ann. Surg. 267, 419–425 (2018).
doi: 10.1097/SLA.0000000000002477
Matton, A. P. M. et al. Biliary bicarbonate, pH, and glucose are suitable biomarkers of biliary viability during ex situ normothermic machine perfusion of human donor livers. Transplantation 103, 1405–1413 (2019).
doi: 10.1097/TP.0000000000002500
Shaked, A., Nunes, F. A., Olthoff, K. M. & Lucey, M. R. Assessment of liver function: pre- and peritransplant evaluation. Clin. Chem. 43, 1539–1545 (1997).
doi: 10.1093/clinchem/43.8.1539
Karangwa, S. A. et al. Production of physiologically relevant quantities of hemostatic proteins during ex situ normothermic machine perfusion of human livers. Liver Transpl. 24, 1298–1302 (2018).
doi: 10.1002/lt.25290
Neves, D. B., Rusi, M. B., Diaz, L. G. & Salvalaggio, P. Primary graft dysfunction of the liver: definitions, diagnostic criteria and risk factors. Einstein 14, 567–572 (2016).
doi: 10.1590/s1679-45082016rw3585
Laing, R. W. et al. Viability testing and transplantation of marginal livers (VITTAL) using normothermic machine perfusion: study protocol for an open-label, non-randomised, prospective, single-arm trial. BMJ Open 7, e017733 (2017).
pubmed: 29183928
pmcid: 29183928
Verhoeven, C. J. et al. Biomarkers to assess graft quality during conventional and machine preservation in liver transplantation. J. Hepatol. 61, 672–684 (2014).
doi: 10.1016/j.jhep.2014.04.031
Linares-Cervantes, I et al. Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts. Am. J. Transplant. 19, 2991–3005 (2019).
doi: 10.1111/ajt.15395
Fedoravicius, A. & Charlton, M. Abnormal liver tests after liver transplantation. Clin. Liver. Dis. 7, 73–79 (2016).
doi: 10.1002/cld.540
Sinturel, F. et al. Diurnal oscillations in liver mass and cell size accompany ribosome assembly cycles. Cell 169, 651–663 (2017).
doi: 10.1016/j.cell.2017.04.015
Dutkowski, P. & Clavien, P. A. Uploading cellular batteries: caring for mitochondria is key. Liver Transpl. 24, 462–464 (2018).
doi: 10.1002/lt.25036
Guicciardi, M. E. & Gores, G. J. Apoptosis: a mechanism of acute and chronic liver injury. Gut 54, 1024–1033 (2005).
doi: 10.1136/gut.2004.053850