Challenges and Opportunities in Normothermic Liver Perfusion: A Standard Research Review from an Indian Perspective
Keywords:
Normothermic Liver Perfusion, Liver Transplantation, Organ Preservation, Challenges, Opportunities
Abstract
Liver transplantation is the only definitive treatment for end-stage liver disease and acute liver failure; however, the shortage of viable donor organs remains a critical challenge. Conventional static cold storage (SCS), while widely used, is associated with ischemia-reperfusion injury, leading to suboptimal graft function. Normothermic liver perfusion (NLP) has emerged as an advanced preservation technique that mimics physiological conditions, thereby reducing cellular injury, extending preservation times, and improving organ viability. Studies have demonstrated that NLP enhances graft recovery, facilitates viability assessment, and increases the utilization of marginal donor livers. Despite these advantages, the implementation of NLP in India is hindered by high costs, infrastructure limitations, and the need for specialized expertise. However, with increased investment in healthcare, research collaborations, and regulatory support, NLP could revolutionize liver transplantation in India by improving transplant outcomes and expanding the donor pool. This review explores the clinical benefits, challenges, and potential pathways for integrating NLP into India’s organ transplantation framework, highlighting the need for strategic policy interventions, cost-effective solutions, and workforce training to enable widespread adoption.
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References
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8. Sutton ME, op den Dries S, Karimian N, et al. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One. 2014;9(11): e110642. doi: 10.1371/journal.pone.0110642.
9. Watson CJ, Kosmoliaptsis V, Pley C, et al. Observations on the ex-situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-2020. doi:10.1111/ajt.14830.
10. Mergental H, Laing RW, Kirkham AJ, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. 2020;11(1):2939. doi:10.1038/s41467-020-16555-9.
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12. Schlegel A, Kalisvaart M, Scalera I, et al. The UK DCD Risk Score: a new proposal to define futility in donation-after-circulatory-death liver transplantation. J Hepatol. 2018;68(3):456-464. doi: 10.1016/j.jhep.2017.10.027.
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14. Dutkowski P, Guarrera JV, De Jonge J, et al. Evolving trends in machine perfusion for liver transplantation. Gastroenterology. 2019;156(6):1542-1547. doi: 10.1053/j.gastro.2018.12.034.
15. Brüggenwirth IMA, de Meijer VE, Porte RJ, Martins PN. Viability criteria assessment during liver machine perfusion. Nat Biotechnol. 2020;38(11):1260-1262.
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17. Goldaracena N, Spetzler VN, Echeverri J, Kaths JM, Barbas AS, Louis KS, et al. Inducing hepatitis C virus resistance after pig liver transplantation—a proof of concept of liver graft modification using warm ex vivo perfusion. Am J Transplant. 2017;17(4):970-978.
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20. Brockmann J, Reddy S, Coussios C, Pigott D, Guirgis M, Mergental H, et al. Normothermic perfusion: a new paradigm for organ preservation. Ann Surg. 2009;250(1):1-6.
21. Jamieson RW, Zilvetti M, Roy D, Hughes D, Coussios CC, Friend PJ. Hepatic steatosis and normothermic perfusion—preliminary experiments in a porcine model. Transplantation. 2011;92(3):289-295.
22. Tolboom H, Pouw RE, Izamis ML, Milwid JM, Yeh H, Uygun K, et al. Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. Transplantation. 2009;87(2):170-177.
23. Rigo F, Navarro-Tableros V, De Stefano N, Calleri A, Romagnoli R. Ex vivo normothermic hypoxic rat liver perfusion model: an experimental setting for organ recondition and pharmacological intervention. Methods Mol Biol. 2021;2269:139-150.
24. Lau NS, Khosravi M, Eshmuminov D, Schuler MJ, Becker D, Graf R, et al. Long-term ex situ normothermic perfusion of human split livers for more than 1 week. Nat Commun. 2023;14(1):4755.
25. Krendl FJ, Oberhuber R, Singh J, Fodor M, Resch T, Maglione M, et al. Normothermic liver machine perfusion at a large European center—real life insights following 238 applications. HPB (Oxford). 2024;26(Suppl 1):S202.
26. Rezania V, Marsh RE, Coombe D, Tuszynski JA. A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model. arXiv preprint arXiv:1111.1228. 2011.
27. Lukeš V, Jiřík M, Jonášová A, Rohan E, Bublík O, Cimrman R. Numerical simulation of liver perfusion: from CT scans to FE model. arXiv preprint arXiv:1412.6412. 2014.
28. Kotsiliti E. Long-term normothermic liver perfusion. Nat Rev Gastroenterol Hepatol. 2023;20(11):694.
29. Watson CJ, Kosmoliaptsis V, Pley C, Randle LV, Fear C, Crick K, et al. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-20.
30. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-6.
31. van Leeuwen OB, de Vries Y, Fujiyoshi M, Nijsten MW, de Boer MT, Schurink IJ, 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. 2019;270(5):906-14.
32. Minor T, Efferz P, Fox M, Wohlschlaeger J, Luer B. Controlled oxygenated rewarming of cold stored livers prior to transplantation: first clinical application of a new concept. Transplantation. 2021;105(1):e4-e5.
33. Shroff S. Organ donation and transplantation in India: legal aspects and solutions to enhance organ donation. J Pract Cardiovasc Sci. 2021;7(1):14-9.
34. Dhanasekaran R, Nair S, Devarbhavi H. Management of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2018;8(3):281-6.
35. Jha PK, Pandey A, Kumar S. Challenges and opportunities of normothermic machine perfusion in liver transplantation in India. Indian J Transplant. 2020;14(2):95-9.
36. Singh M, Sharma S, Aggarwal S. Ethical issues in liver transplantation: use of marginal donors. J Clin Exp Hepatol. 2019;9(2):216-23.
37. Kumar V, Gupta S, Sharma S. Initial experience with normothermic machine perfusion in liver transplantation in India. Indian J Gastroenterol. 2022;41(1):55-60.
38. Sharma S, Kumar V, Gupta S. Development of cost-effective machine perfusion systems for liver transplantation in India. Transplant Proc. 2021;53(3):1031-5.
39. Selzner M, Goldaracena N, Echeverri J, Kaths JM, Linares I, Selzner N, et al. Normothermic ex vivo liver perfusion using an acellular solution for transplantation of a steatotic graft. Liver Transpl. 2016;22(3):333-343.
40. Watson CJ, Kosmoliaptsis V, Pley C, Randle LV, Fear C, Crick K, et al. Observations on the ex-situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-2020.
41. Mergental H, Laing RW, Kirkham AJ, Perera MT, Boteon YL, Attard J, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. 2020;11(1):2939.
42. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-56.
43. Ghinolfi D, Pezzati D, Rreka E, De Simone P. Normothermic machine perfusion in liver transplantation: current status and perspectives. World J Gastroenterol. 2020;26(13):1557-1568.
2. Jeddou H, Tzedakis S, Chaouch MA, Sulpice L, Samson M, Boudjema K. Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review. Liver Int. 2025;45(2): e16244. doi:10.1111/liv.16244.
3. Hessheimer AJ, Coll E, Torres F, et al. Normothermic regional perfusion versus super rapid recovery in controlled donation after circulatory death liver transplantation. J Hepatol. 2019;70(4):658-665. doi: 10.1016/j.jhep.2018.12.020.
4. Mergental H, Laing RW, Kirkham AJ, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion: the VITTAL (Viability Testing and Transplantation of Marginal Livers) trial outcomes. Nat Commun. 2020;11(1):2939. doi:10.1038/s41467-020-16555-9.
5. Clavien PA, Dutkowski P, Mueller M, et al. Transplantation of a human liver following 3 days of ex situ normothermic preservation. Nat Biotechnol. 2022;40(12):1610-1616. doi:10.1038/s41587-022-01336-1.
6. 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(4):1071-1080. doi:10.1111/ajt.14049.
7. 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(11):1501-1508. doi:10.1002/lt.24499.
8. Sutton ME, op den Dries S, Karimian N, et al. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One. 2014;9(11): e110642. doi: 10.1371/journal.pone.0110642.
9. Watson CJ, Kosmoliaptsis V, Pley C, et al. Observations on the ex-situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-2020. doi:10.1111/ajt.14830.
10. Mergental H, Laing RW, Kirkham AJ, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. 2020;11(1):2939. doi:10.1038/s41467-020-16555-9.
11. De Vries Y, Matton APM, Nijsten MWN, et al. Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death. Am J Transplant. 2019;19(4):1202-1211. doi:10.1111/ajt.15177.
12. Schlegel A, Kalisvaart M, Scalera I, et al. The UK DCD Risk Score: a new proposal to define futility in donation-after-circulatory-death liver transplantation. J Hepatol. 2018;68(3):456-464. doi: 10.1016/j.jhep.2017.10.027.
13. Laing RW, Scalera I, Isaac J, et al. Liver transplantation using grafts from donors after circulatory death: A propensity-matched study from a single centre. Am J Transplant. 2016;16(6):1795-1804. doi:10.1111/ajt.13680.
14. Dutkowski P, Guarrera JV, De Jonge J, et al. Evolving trends in machine perfusion for liver transplantation. Gastroenterology. 2019;156(6):1542-1547. doi: 10.1053/j.gastro.2018.12.034.
15. Brüggenwirth IMA, de Meijer VE, Porte RJ, Martins PN. Viability criteria assessment during liver machine perfusion. Nat Biotechnol. 2020;38(11):1260-1262.
16. Spetzler VN, Goldaracena N, Selzner N, Selzner M. Early clinical results using normothermic machine liver preservation. Curr Transpl Rep. 2015;2(1):74-80.
17. Goldaracena N, Spetzler VN, Echeverri J, Kaths JM, Barbas AS, Louis KS, et al. Inducing hepatitis C virus resistance after pig liver transplantation—a proof of concept of liver graft modification using warm ex vivo perfusion. Am J Transplant. 2017;17(4):970-978.
18. Ravikumar R, Jassem W, Mergental H, Heaton N, Mirza D, Perera MT, et al. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial. Am J Transplant. 2016;16(6):1779-1787.
19. Laing RW, Bhogal RH, Wallace L, Boteon YL, Neil DA, Smith A, et al. The use of an acellular oxygen carrier in a human liver model of normothermic machine perfusion. Transplantation. 2017;101(11):2746-2756.
20. Brockmann J, Reddy S, Coussios C, Pigott D, Guirgis M, Mergental H, et al. Normothermic perfusion: a new paradigm for organ preservation. Ann Surg. 2009;250(1):1-6.
21. Jamieson RW, Zilvetti M, Roy D, Hughes D, Coussios CC, Friend PJ. Hepatic steatosis and normothermic perfusion—preliminary experiments in a porcine model. Transplantation. 2011;92(3):289-295.
22. Tolboom H, Pouw RE, Izamis ML, Milwid JM, Yeh H, Uygun K, et al. Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. Transplantation. 2009;87(2):170-177.
23. Rigo F, Navarro-Tableros V, De Stefano N, Calleri A, Romagnoli R. Ex vivo normothermic hypoxic rat liver perfusion model: an experimental setting for organ recondition and pharmacological intervention. Methods Mol Biol. 2021;2269:139-150.
24. Lau NS, Khosravi M, Eshmuminov D, Schuler MJ, Becker D, Graf R, et al. Long-term ex situ normothermic perfusion of human split livers for more than 1 week. Nat Commun. 2023;14(1):4755.
25. Krendl FJ, Oberhuber R, Singh J, Fodor M, Resch T, Maglione M, et al. Normothermic liver machine perfusion at a large European center—real life insights following 238 applications. HPB (Oxford). 2024;26(Suppl 1):S202.
26. Rezania V, Marsh RE, Coombe D, Tuszynski JA. A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model. arXiv preprint arXiv:1111.1228. 2011.
27. Lukeš V, Jiřík M, Jonášová A, Rohan E, Bublík O, Cimrman R. Numerical simulation of liver perfusion: from CT scans to FE model. arXiv preprint arXiv:1412.6412. 2014.
28. Kotsiliti E. Long-term normothermic liver perfusion. Nat Rev Gastroenterol Hepatol. 2023;20(11):694.
29. Watson CJ, Kosmoliaptsis V, Pley C, Randle LV, Fear C, Crick K, et al. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-20.
30. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-6.
31. van Leeuwen OB, de Vries Y, Fujiyoshi M, Nijsten MW, de Boer MT, Schurink IJ, 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. 2019;270(5):906-14.
32. Minor T, Efferz P, Fox M, Wohlschlaeger J, Luer B. Controlled oxygenated rewarming of cold stored livers prior to transplantation: first clinical application of a new concept. Transplantation. 2021;105(1):e4-e5.
33. Shroff S. Organ donation and transplantation in India: legal aspects and solutions to enhance organ donation. J Pract Cardiovasc Sci. 2021;7(1):14-9.
34. Dhanasekaran R, Nair S, Devarbhavi H. Management of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2018;8(3):281-6.
35. Jha PK, Pandey A, Kumar S. Challenges and opportunities of normothermic machine perfusion in liver transplantation in India. Indian J Transplant. 2020;14(2):95-9.
36. Singh M, Sharma S, Aggarwal S. Ethical issues in liver transplantation: use of marginal donors. J Clin Exp Hepatol. 2019;9(2):216-23.
37. Kumar V, Gupta S, Sharma S. Initial experience with normothermic machine perfusion in liver transplantation in India. Indian J Gastroenterol. 2022;41(1):55-60.
38. Sharma S, Kumar V, Gupta S. Development of cost-effective machine perfusion systems for liver transplantation in India. Transplant Proc. 2021;53(3):1031-5.
39. Selzner M, Goldaracena N, Echeverri J, Kaths JM, Linares I, Selzner N, et al. Normothermic ex vivo liver perfusion using an acellular solution for transplantation of a steatotic graft. Liver Transpl. 2016;22(3):333-343.
40. Watson CJ, Kosmoliaptsis V, Pley C, Randle LV, Fear C, Crick K, et al. Observations on the ex-situ perfusion of livers for transplantation. Am J Transplant. 2018;18(8):2005-2020.
41. Mergental H, Laing RW, Kirkham AJ, Perera MT, Boteon YL, Attard J, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. 2020;11(1):2939.
42. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-56.
43. Ghinolfi D, Pezzati D, Rreka E, De Simone P. Normothermic machine perfusion in liver transplantation: current status and perspectives. World J Gastroenterol. 2020;26(13):1557-1568.
How to Cite
1.
Gautam K, Deveshkumar K, Ovesh D, Jithendran A. Challenges and Opportunities in Normothermic Liver Perfusion: A Standard Research Review from an Indian Perspective. Int J Med Res Rev [Internet]. 2025Apr.21 [cited 2025May17];13(2):20-6. Available from: https://ijmrr.medresearch.in/index.php/ijmrr/article/view/1540
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Review Article
Copyright (c) 2025 Author (s). Published by Siddharth Health Research and Social Welfare Society
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