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

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.

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.

References

  1. Durand, F. et al. Age and liver transplantation. J. Hepatol. 70, 745–758 (2019).

    Article  Google Scholar 

  2. Schlegel, A. et al. The UK DCD Risk Score: a new proposal to define futility in donation-after-circulatory-death liver transplantation. J. Hepatol. 68, 456–464 (2018).

    Article  Google Scholar 

  3. McCormack, L., Dutkowski, P., El-Badry, A. M. & Clavien, P. A. Liver transplantation using fatty livers: always feasible? J. Hepatol. 54, 1055–1062 (2011).

    Article  Google Scholar 

  4. Chen, C. L., Kabiling, C. S. & Concejero, A. M. Why does living donor liver transplantation flourish in Asia? Nat. Rev. Gastroenterol. Hepat. 10, 746–751 (2013).

    Article  Google Scholar 

  5. Dutkowski, P. et al. Evolving trends in machine perfusion for liver transplantation. Gastroenterology 156, 1542–1547 (2019).

    Article  Google Scholar 

  6. Dutkowski, P. et al. First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants an international-matched case analysis. Ann. Surg. 262, 764–771 (2015).

    Article  Google Scholar 

  7. Schlegel, A. et al. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation. J. Hepatol. 70, 50–57 (2019).

    CAS  Article  Google Scholar 

  8. Van Rijn, R. et al. Hypothermic machine perfusion in liver transplantation—a randomized trial. N. Engl. J. Med. 384, 1391–1401 (2021).

    Article  Google Scholar 

  9. Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018).

    CAS  Article  Google Scholar 

  10. Graham, J. A. & Guarrera, J. V. ‘Resuscitation’ of marginal liver allografts for transplantation with machine perfusion technology. J. Hepatol. 61, 418–431 (2014).

    Article  Google Scholar 

  11. Markmann, J. F. et al. Impact of portable normothermic blood-based machine perfusion on outcomes of liver transplant: the OCS Liver PROTECT randomized clinical trial. JAMA Surg. 157, 189–198 (2022).

  12. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situ resuscitation and assessment using combined hypo- and normothermic machine perfusion a prospective clinical trial. Ann. Surg. 270, 906–914 (2019).

    Article  Google Scholar 

  13. Clavien, P. A., Petrowsky, H., DeOliveira, M. L. & Graf, R. Strategies for safer liver surgery and partial liver transplantation. N. Engl. J. Med. 356, 1545–1559 (2007).

    Article  Google Scholar 

  14. Dutkowski, P., Linecker, M., DeOliveira, M. L., Mullhaupt, B. & Clavien, P. A. Challenges to liver transplantation and strategies to improve outcomes. Gastroenterology 148, 307–323 (2015).

    Article  Google Scholar 

  15. Eshmuminov, D. et al. An integrated perfusion machine preserves injured human livers for 1 week. Nat. Biotechnol. 38, 189–198 (2020).

    CAS  Article  Google Scholar 

  16. Mergental, H. et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).

    CAS  Article  Google Scholar 

  17. Mueller, M. et al. Long-term normothermic machine preservation of partial livers: first experience with 21 human hemi-livers. Ann. Surg. 274, 836–842 (2021).

  18. Wisell, J. et al. Glycogen pseudoground glass change in hepatocytes. Am. J. Surg. Pathol. 30, 1085–1090 (2006).

    Article  Google Scholar 

  19. Sang, B. H., Bang, J. Y., Song, J. G. & Hwang, G. S. Hypoalbuminemia within two postoperative days is an independent risk factor for acute kidney injury following living donor liver transplantation: a propensity score analysis of 998 consecutive patients. Crit. Care Med. 43, 2552–2561 (2015).

    CAS  Article  Google Scholar 

  20. Schlegel, A., Kron, P., Graf, R., Clavien, P. A. & Dutkowski, P. Hypothermic oxygenated perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation. Ann. Surg. 260, 931–938 (2014).

    Article  Google Scholar 

  21. Kron, P. et al. Hypothermic oxygenated perfusion: a simple and effective method to modulate the immune response in kidney transplantation. Transplantation 103, e128–e136 (2019).

    CAS  Article  Google Scholar 

  22. Czigany, Z. et al. Ischemia-reperfusion injury in marginal liver grafts and the role of hypothermic machine perfusion: molecular mechanisms and clinical implications. J. Clin. Med. 9, 846 (2020).

    Article  Google Scholar 

  23. Chan, E. Y. et al. Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors. Liver Transpl. 14, 604–610 (2008).

    Article  Google Scholar 

  24. Jay, C. L. et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta-analysis. Ann. Surg. 253, 259–264 (2011).

    Article  Google Scholar 

  25. Kubal, C. et al. Optimization of perioperative conditions to prevent ischemic cholangiopathy in donation after circulatory death donor liver transplantation. Transplantation 100, 1699–1704 (2016).

    CAS  Article  Google Scholar 

  26. Sindram, D., Porte, R. J., Hoffman, M. R., Bentley, R. C. & Clavien, P. A. Synergism between platelets and leukocytes in inducing endothelial cell apoptosis in the cold ischemic rat liver: a Kupffer cell-mediated injury. FASEB J. 15, 1230–1232 (2001).

    CAS  Article  Google Scholar 

  27. Lee, W. Y. & Kubes, P. Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs. J. Hepatol. 48, 504–512 (2008).

    CAS  Article  Google Scholar 

  28. Huang, H. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62, 600–614 (2015).

    CAS  Article  Google Scholar 

  29. Lesurtel, M. et al. Platelet-derived serotonin mediates liver regeneration. Science 312, 104–107 (2006).

    CAS  Article  Google Scholar 

  30. Nocito, A. et al. Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice. Hepatology 45, 369–376 (2007).

    CAS  Article  Google Scholar 

  31. 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).

    CAS  Article  Google Scholar 

  32. Cho, J. Y. et al. The hepatic regeneration power of mild steatotic grafts is not impaired in living-donor liver transplantation. Liver Transpl. 11, 210–217 (2005).

    Article  Google Scholar 

  33. Laing, R. W. et al. The delivery of multipotent adult progenitor cells to extended criteria human donor livers using normothermic machine perfusion. Front. Immunol. 11, 1226 (2020).

  34. Sampaziotis, F. et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 371, 839 (2021).

    CAS  Article  Google Scholar 

  35. Chan, S. C. et al. Validation of graft and standard liver size predictions in right liver living donor liver transplantation. Hepatol. Int. 5, 913–917 (2011).

    Article  Google Scholar 

Download references

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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Authors

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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Nature Biotechnology thanks Charles Lee, Alexandra Shingina and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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
Extended Data Table 2 Quantification of liver volume, cell size and cell count
Extended Data Table 3 Postoperative course of transaminases

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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 (2022). https://doi.org/10.1038/s41587-022-01354-7

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