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Transplantation of a human liver following 3 days of ex situ normothermic preservation

Nature Biotechnology volume 40, pages 1610–1616 (2022)Cite this article

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Abstract

Current organ preservation methods provide a narrow window (usually <12 hours) to assess, transport and implant donor grafts for human transplantation. Here we report the transplantation of a human liver discarded by all centers, which could be preserved for several days using ex situ normothermic machine perfusion. The transplanted liver exhibited normal function, with minimal reperfusion injury and the need for only a minimal immunosuppressive regimen. The patient rapidly recovered a normal quality of life without any signs of liver damage, such as rejection or injury to the bile ducts, according to a 1-year follow up. This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure.

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Fig. 1: Donor liver shown on a preoperative CT scan, on the back table and during perfusion.
Fig. 2: Liver performance parameters during ex situ normothermic machine perfusion.
Fig. 3: Liver morphology from before ex situ normothermic machine perfusion (donor liver biopsy) until 6 weeks after liver transplantation.
Fig. 4: Liver performance after liver transplantation.
Fig. 5: Mitotic proliferation, cell size and volumetry before and after transplantation.
Fig. 6: Liver volume, cell count and cell size.

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Data availability

Additional data can be obtained by contacting the correponding author (P.-A.C.). According to local policies, data must remain on controlled access due to patient protection and ethical laws in Switzerland. Any request will be addressed within a 1-month framework after notice.

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Acknowledgements

This research was made possible by the commitment of many colleagues and individuals who contributed to a variety of clinical or research tasks related to the project. Among many others, we would like to thank T. Krones from the Department of Clinical Ethics at University Hospital, Zurich, Switzerland; M. De Oliveira, O. de Rougemont, R. Graf, A. Gupta, B. Humar, P. Ignatavicius, J. P. Jonas, K. Lehmann, L. Mancina, C. E. Oberkofler, H. Petrowsky and F. Roessler from the Department of Surgery & Transplantation, University Hospital, Zurich, Switzerland; R. Schuepbach, D. Spahn and C. Von Deschwanden from the Department of Anesthesiology, University Hospital, Zurich, Switzerland, as well as L. Stursi and the operating room nursing team; R. Schuepbach from the Department of Intensive Care Medicine, University Hospital, Zurich, Switzerland; D. Lenggenhager from the Department of Pathology and Molecular Pathology, University Hospital, Zurich, Switzerland; S. Brugger and N. Mueller from the Department of Infectiology, University Hospital, Zurich, Switzerland, as well as S. Schiess and the entire transplant coordinating team at University Hospital, Zurich, Switzerland; J. Antunes Crisóstomo, C. Hagedorn, F. Huwyler, J. Binz, X. Muller and C. Onder as members of Wyss Zurich Translational Center, ETH Zurich / University of Zurich, Zurich, Switzerland; B. Stieger from the Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland; K. Hübel and T. Mueller from the Department of Nephrology, University Hospital, Zurich, Switzerland; and P. Breiding, M. Eberhard, S. Ghafoor and T. Pfammatter from the Department of Diagnostic and Interventional Radiology, University Hospital, Zurich, Switzerland. Furthermore, we are grateful for the robust support from the hospital leadership: G. Zuend, J. Hodler and P. Giovanoli. A special thanks must go to F. Immer, director of Swisstransplant, who strongly supported this project from its earlier stage. In addition, we recognize the diligent support from the Federal Office of Public Health, which authorized this program. In addition, we would like to thank all members of the international advisory board, consisting of W. Chapman, Washington University School of Medicine; D. Cherqui, Hôpital Paul Brousse; G. Gores, Mayo Clinic; S. Friedman, Mount Sinai Hospital; and P. Muiesan, Università Degli Studi Firenzeor, for their close support. Finally, we would like to dedicate this inaugural case to Hansjoerg Wyss, an entrepreneur, innovator and philanthropist, who supported the project through Wyss Zurich Translational Center, Zurich, Switzerland, and was personally involved in the sequential developments and applications of the machine perfusion, which logically must remain known as the Wyss perfusion machine. Funding: The project was performed and mostly funded under the roof of Wyss Zurich Translational Center, Zurich, Switzerland. Further financial supports were provided by the Helmut Horten, PROMEDICA and Liver and Gastrointestinal Disease Foundations.

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  1. Brian R. Burg

    Present address: Pixium Vision, Paris, France

Authors and Affiliations

  1. Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) and Transplant Center, University Hospital Zurich, Zurich, Switzerland

    Pierre-Alain Clavien, Philipp Dutkowski, Matteo Mueller, Dilmurodjon Eshmuminov, Lucia Bautista Borrego & Richard X. Sousa Da Silva

  2. Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland

    Pierre-Alain Clavien, Matteo Mueller, Dilmurodjon Eshmuminov, Lucia Bautista Borrego, Richard X. Sousa Da Silva, Brian R. Burg, Philipp Rudolf von Rohr, Martin J. Schuler, Dustin Becker, Max Hefti & Mark W. Tibbitt

  3. Department of Pathology and Molecular Pathology, and Institute of Molecular Cancer Research, University of Zurich and University Hospital Zurich, Zurich, Switzerland

    Achim Weber

  4. Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

    Beat Muellhaupt

  5. Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland

    Brian R. Burg, Philipp Rudolf von Rohr, Martin J. Schuler, Dustin Becker, Max Hefti & Mark W. Tibbitt

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Contributions

P.-A.C., P.D., M.M., D.E., L.B.B., R.X.S.D.S., B.B., P.R.V.R., M.J.S., D.B., M.H. and M.W.T. designed the perfusion machine, established the perfusion protocol, performed the perfusion, generated and interpreted the data and wrote the manuscript. P.-A.C. and P.D. performed the transplantation and took care of the donor and the recipient. A.W. interpreted the liver biopsies and wrote the manuscript. B.M. was involved in the management of the donor and recipient.

Corresponding author

Correspondence to Pierre-Alain Clavien.

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Competing interests

ETH (Swiss Federal Institute of Technology in Zurich) and the University of Zurich (D.E., D.B., L.B.B., M.H., M.J.S., P.D., P.R.V.R., B.B. and P.-A.C.) have applied for patents on this new perfusion technology (PCT/EP2017/068506 and PCT/EP2019/051252). Correspondence and requests for materials should be addressed to P.-A.C. We confirm that no other author has any competing interest.

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Extended data

Extended Data Fig. 1 Pressure and vascular resistance of portal vein and hepatic artery during ex situ normothermic perfusion.

a, Portal vein pressure shows a stable course with a mean pressure of 12.2 mmHg. b, Mean hepatic arterial pressure that increases slightly over time, which is related to the loss of initial vasoplegia. c, Portal vein resistance, which remains constant over time with minimal decrease. d, Hepatic artery resistance, which increases overall over time, which is related to the loss of initial vasoplegia.

Extended Data Fig. 2 Tumor biopsy.

a, Histology suggestive of a perivascular epithelioid tumor (PEComa) / epithelioid angiomyolipoma. Scale bar: 250 µm. b, Immunohistochemical reactivity with antibodies against SMA (smooth muscle actin) and HMB45. Scale bars: 250 µm. For reproducibility, all staining was performed with control stains.

Extended Data Fig. 3 Liver histology from prior to ex situ normothermic machine perfusion (donor liver biopsy) until 6 weeks post liver transplantation.

a, HE: mostly preserved tissue architecture with mild nodularity. Scale bars; HE: 500 µm; b, MAS (Masson trichrome): no fibrosis present; GOM: moderate nodular regenerative hyperplasia; CD68: persisting macrophages, also during ex situ normothermic machine perfusion. Scale bars; MAS, GOM: 500 µm; CD68: 250 µm. For reproducibility, all staining was performed with control stains.

Extended Data Table 1 Perfusate preparation
Full size table
Extended Data Table 2 Quantification of liver volume, cell size and cell count
Full size table
Extended Data Table 3 Postoperative course of transaminases
Full size table

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Clavien, PA., Dutkowski, P., Mueller, M. et al. Transplantation of a human liver following 3 days of ex situ normothermic preservation. Nat Biotechnol 40, 1610–1616 (2022). https://doi.org/10.1038/s41587-022-01354-7

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