An integrated perfusion machine preserves injured human livers for 1 week

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Abstract

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.

Abstract

Livers are stored long term in a sophisticated perfusion system.

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A randomized trial of normothermic preservation in liver transplantation

John Karani, Hynek Mergental, M. Zeeshan Akhtar … (2018)

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

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The promise of organ and tissue preservation to transform medicine

Sebastian Giwa, Jedediah K Lewis, Luis Alvarez … (2017)

The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.

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Observations on the ex situ perfusion of livers for transplantation

Christopher Watson, Vasilis Kosmoliaptsis, Caitlin Pley … (2018)

Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.

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Author and article information

Contributors

Pierre-Alain Clavien:

ORCID: http://orcid.org/0000-0002-9916-7905

clavien@access.uzh.ch

Journal

Journal ID (nlm-ta): Nat Biotechnol

Journal ID (iso-abbrev): Nat. Biotechnol

Title: Nature Biotechnology

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1087-0156

ISSN (Electronic): 1546-1696

Publication date (Electronic): 13 January 2020

Publication date (Print): 2020

Volume: 38

Issue: 2

Pages: 189-198

Affiliations

[1 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, , University Hospital Zurich, ; Zurich, Switzerland

[2 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Wyss Zurich, , ETH Zurich and University of Zurich, ; Zurich, Switzerland

[3 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, Transport Processes and Reactions Laboratory, Department of Mechanical and Process Engineering, , ETH Zurich, ; Zurich, Switzerland

[4 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, Institute for Dynamic Systems and Control, Department of Mechanical and Process Engineering, , ETH Zurich, ; Zurich, Switzerland

[5 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Department of Pathology and Molecular Pathology, and Institute of Molecular Cancer Research (IMCR), , University Zurich and University Hospital Zurich, ; Zurich, Switzerland

Author information

Dilmurodjon Eshmuminov http://orcid.org/0000-0002-9575-7094

Lucia Bautista Borrego http://orcid.org/0000-0001-7709-8024

Max Hefti http://orcid.org/0000-0001-8038-4099

Achim Weber http://orcid.org/0000-0003-0073-3637

Pierre-Alain Clavien http://orcid.org/0000-0002-9916-7905

Article

Publisher ID: 374

DOI: 10.1038/s41587-019-0374-x

PMC ID: 7008032

PubMed ID: 31932726

SO-VID: 9ec490a4-a8b7-4ed0-8647-628048146285

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 23 December 2018

Date accepted : 18 November 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100008307, Promedica Stiftung;

Funded by: The study was funded by a grant from Wyss Zurich, Helmut Horten Foundation, PROMEDICA Foundation, and the Liver and Gastrointestinal foundation (LGID). We gratefully acknowledge this financial support.

Funded by: A.W. was supported by Swiss National Science Foundation (320030_182764/1).

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ScienceOpen disciplines: Biotechnology

Keywords: medical research,translational research,liver diseases,biotechnology

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ScienceOpen disciplines: Biotechnology

Keywords: medical research, translational research, liver diseases, biotechnology

An integrated perfusion machine preserves injured human livers for 1 week

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Most cited references 35

A randomized trial of normothermic preservation in liver transplantation

The promise of organ and tissue preservation to transform medicine

Observations on the ex situ perfusion of livers for transplantation

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