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Kidney Machine Preservation: State of the Art

  • Laura Ioana Mazilescu
  • Markus SelznerEmail author
Machine Preservation of the Liver (C Miller and C. Quintini, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Machine Preservation of the Liver

Abstract

Purpose of the Review

Machine perfusion has become an important asset in solid organ transplantation to improve the constant organ shortage. This review summarizes advances in machine perfusion of kidney grafts over the last 3 years.

Recent Findings

Because of the severe organ shortage, more and more marginal grafts are being accepted for transplantation. In an attempt to decrease preservation injury and better assess grafts before transplantation, research studies have focused their attention on ex vivo machine perfusion. Hypothermic machine perfusion has been used in a clinical setting for years and has proven to be superior to cold storage. Recently, novel technologies, such as normothermic ex vivo machine perfusion, controlled oxygenated rewarming, and normothermic in situ perfusion, have triggered interest to decrease preservation injury and improve the outcome of marginal grafts. Keeping grafts metabolically active allows for a better assessment, reconditioning, and organ repair. Preclinical results suggest that normothermic perfusion is superior to hypothermic perfusion and static cold storage. Normothermic ex vivo perfusion has been translated into clinical trials, with encouraging first results. Currently, there is no consensus regarding a protocol for warm perfusion. Normothermic regional perfusion is used to recirculate blood in situ to restore the changes after warm ischemic injury. First results are promising, but further assessments are needed to explore the potential of this novel approach.

Summary

Ex vivo machine perfusion is a superior preservation method compared with cold storage. Optimal perfusion solution, temperature, and machine technology are still controversial. Graft assessment and repair are the central research focuses at the moment.

Keywords

(Ex vivo) machine perfusion Marginal grafts Kidney transplantation Graft assessment Graft repair Ischemia reperfusion injury 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Carrel A, Lindbergh CA. The culture of whole organs. Science. 1935;81(2112):621–3.CrossRefGoogle Scholar
  2. 2.
    Belzer FO, Ashby BS, Dunphy JE. 24-hour and 72-hour preservation of canine kidneys. Lancet. 1967;2(7515):536–8.CrossRefGoogle Scholar
  3. 3.
    Collins GM, Bravo-Shugarman M, Terasaki PI. Kidney preservation for transportation. Initial perfusion and 30 hours’ ice storage. Lancet. 1969;2(7632):1219–22.CrossRefGoogle Scholar
  4. 4.
    Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis. 2008;52(3):553–86.CrossRefGoogle Scholar
  5. 5.
    Weber M, Dindo D, Demartines N, Ambuhl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med. 2002;347(4):248–55.CrossRefGoogle Scholar
  6. 6.
    Hamed MO, Chen Y, Pasea L, Watson CJ, Torpey N, Bradley JA, et al. Early graft loss after kidney transplantation: risk factors and consequences. Am J Transplant. 2015;15(6):1632–43.CrossRefGoogle Scholar
  7. 7.
    Stubenitsky BM, Booster MH, Brasile L, Araneda D, Haisch CE, Kootstra G. Exsanguinous metabolic support perfusion--a new strategy to improve graft function after kidney transplantation. Transplantation. 2000;70(8):1254–8.CrossRefGoogle Scholar
  8. 8.
    Brasile L, Clarke J, Green E, Haisch C. The feasibility of organ preservation at warmer temperatures. Transplant Proc. 1996;28(1):349–51.Google Scholar
  9. 9.
    Maathuis MH, Manekeller S, van der Plaats A, Leuvenink HG, t Hart NA, Lier AB, et al. Improved kidney graft function after preservation using a novel hypothermic machine perfusion device. Ann Surg. 2007;246(6):982–8.CrossRefGoogle Scholar
  10. 10.
    Thuillier R, Allain G, Celhay O, Hebrard W, Barrou B, Badet L, et al. Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors. J Surg Res. 2013;184(2):1174–81.CrossRefGoogle Scholar
  11. 11.
    Metcalfe MS, Waller JR, Hosgood SA, Shaw M, Hassanein W, Nicholson ML. A paired study comparing the efficacy of renal preservation by normothermic autologous blood perfusion and hypothermic pulsatile perfusion. Transplant Proc. 2002;34(5):1473–4.CrossRefGoogle Scholar
  12. 12.
    Harper S, Hosgood S, Kay M, Nicholson M. Leucocyte depletion improves renal function during reperfusion using an experimental isolated haemoperfused organ preservation system. Br J Surg. 2006;93(5):623–9.CrossRefGoogle Scholar
  13. 13.
    Hosgood SA, Barlow AD, Yates PJ, Snoeijs MG, van Heurn EL, Nicholson ML. A pilot study assessing the feasibility of a short period of normothermic preservation in an experimental model of non heart beating donor kidneys. J Surg Res. 2011;171(1):283–90.CrossRefGoogle Scholar
  14. 14.
    Schopp I, Reissberg E, Luer B, Efferz P, Minor T. Controlled Rewarming after Hypothermia: Adding a New Principle to Renal Preservation. Clin Transl Sci. 2015;8(5):475–8.CrossRefGoogle Scholar
  15. 15.
    Kaths JM, Echeverri J, Goldaracena N, Louis KS, Chun YM, Linares I, et al. Eight-hour continuous normothermic ex vivo kidney perfusion is a safe preservation technique for kidney transplantation: a new opportunity for the storage, assessment, and repair of kidney grafts. Transplantation. 2016;100(9):1862–70.CrossRefGoogle Scholar
  16. 16.
    Kaths JM, Spetzler VN, Goldaracena N, Echeverri J, Louis KS, Foltys DB, et al. Normothermic ex vivo kidney perfusion for the preservation of kidney grafts prior to transplantation. J Vis Exp. 2015;15(101):52909.Google Scholar
  17. 17.
    Kron P, Schlegel A, de Rougemont O, Oberkofler CE, Clavien PA, Dutkowski P. Short, cool, and well oxygenated - HOPE for kidney transplantation in a rodent model. Ann Surg. 2016;264(5):815–22.CrossRefGoogle Scholar
  18. 18.
    Nath J, Smith TB, Patel K, Ebbs SR, Hollis A, Tennant DA, et al. Metabolic differences between cold stored and machine perfused porcine kidneys: A (1)H NMR based study. Cryobiology. 2017;74:115–20.CrossRefGoogle Scholar
  19. 19.
    Nath J, Smith T, Hollis A, Ebbs S, Canbilen SW, Tennant DA, et al. (13)C glucose labelling studies using 2D NMR are a useful tool for determining ex vivo whole organ metabolism during hypothermic machine perfusion of kidneys. Transp Res. 2016;5(7):016–0037.Google Scholar
  20. 20.
    He N, Li JH, Jia JJ, Xu KD, Zhou YF, Jiang L, et al. Hypothermic machine perfusion’s protection on porcine kidney graft uncovers greater Akt-Erk phosphorylation. Transplant Proc. 2017;49(8):1923–9.CrossRefGoogle Scholar
  21. 21.
    Yang Z, Zhong Z, Li M, Xiong Y, Wang Y, Peng G, et al. Hypothermic machine perfusion increases A20 expression which protects renal cells against ischemia/reperfusion injury by suppressing inflammation, apoptosis and necroptosis. Int J Mol Med. 2016;38(1):161–71.CrossRefGoogle Scholar
  22. 22.
    Gregorini M, Corradetti V, Pattonieri EF, Rocca C, Milanesi S, Peloso A, et al. Perfusion of isolated rat kidney with mesenchymal stromal cells/extracellular vesicles prevents ischaemic injury. J Cell Mol Med. 2017;21(12):3381–93.CrossRefGoogle Scholar
  23. 23.
    Bhattacharjee RN, Richard-Mohamed M, Sun Q, Haig A, Aboalsamh G, Barrett P, et al. CORM-401 Reduces ischemia reperfusion injury in an ex vivo renal porcine model of the donation after circulatory death. Transplantation. 2018;102(7):1066–74.CrossRefGoogle Scholar
  24. 24.
    Opatrny V, Molacek J, Treska V, Matejka R, Hes O. Perfusion of a kidney graft from a donor after cardiac death based on immediately started pulsatile machine perfusion-an experimental study on a small animal. Transplant Proc. 2018;50(5):1544–8.CrossRefGoogle Scholar
  25. 25.
    Hamaoui K, Gowers S, Boutelle M, Cook TH, Hanna G, Darzi A, et al. Organ Pretreatment with cytotopic endothelial localizing peptides to ameliorate microvascular thrombosis and perfusion deficits in ex vivo renal hemoreperfusion models. Transplantation. 2016;100(12):e128–e39.CrossRefGoogle Scholar
  26. 26.
    Sedigh A, Nordling S, Carlsson F, Larsson E, Norlin B, Lubenow N, et al. Perfusion of porcine kidneys with macromolecular heparin reduces early ischemia reperfusion injury. Transplantation. 2019;103(2):420–7.CrossRefGoogle Scholar
  27. 27.
    • Darius T, Gianello P, Vergauwen M, Mourad N, Buemi A, De Meyer M, et al. The effect on early renal function of various dynamic preservation strategies in a preclinical pig ischemia-reperfusion autotransplant model. Am J Transplant. 2018;1(10):15100 Using a porcine DCD autotransplantation model, this study compared end-ischemic cold and warm perfusion with SCS and cold machine perfusion with or without oxygen for the entire preservation period. Google Scholar
  28. 28.
    Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2009;360(1):7–19.CrossRefGoogle Scholar
  29. 29.
    Gallinat A, Moers C, Smits JM, Strelniece A, Pirenne J, Ploeg RJ, et al. Machine perfusion versus static cold storage in expanded criteria donor kidney transplantation: 3-year follow-up data. Transpl Int. 2013 Jun;26(6):E52–3.  https://doi.org/10.1111/tri.12094.CrossRefGoogle Scholar
  30. 30.
    Zhong Z, Lan J, Ye S, Liu Z, Fan L, Zhang Y, et al. Outcome improvement for hypothermic machine perfusion versus cold storage for kidneys from cardiac death donors. Artif Organs. 2017;41(7):647–53.CrossRefGoogle Scholar
  31. 31.
    Gallinat A, Amrillaeva V, Hoyer DP, Kocabayoglu P, Benko T, Treckmann JW, et al. Reconditioning by end-ischemic hypothermic in-house machine perfusion: A promising strategy to improve outcome in expanded criteria donors kidney transplantation. Clin Transpl. 2017;31(3):12904.CrossRefGoogle Scholar
  32. 32.
    • Sandal S, Luo X, Massie AB, Paraskevas S, Cantarovich M, Segev DL. Machine perfusion and long-term kidney transplant recipient outcomes across allograft risk strata. Nephrol Dial Transplant. 2018;33(7):1251–9 This study showed varying results to previous studies regarding the benefits of anoxic HMP compared with SCS. CrossRefGoogle Scholar
  33. 33.
    Diuwe P, Domagala P, Durlik M, Trzebicki J, Chmura A, Kwiatkowski A. The effect of the use of a TNF-alpha inhibitor in hypothermic machine perfusion on kidney function after transplantation. Contemp Clin Trials. 2017;59:44–50.CrossRefGoogle Scholar
  34. 34.
    Minor T, Sutschet K, Witzke O, Paul A, Gallinat A. Prediction of renal function upon reperfusion by ex situ controlled oxygenated rewarming. Eur J Clin Investig. 2016;46(12):1024–30.CrossRefGoogle Scholar
  35. 35.
    von Horn C, Minor T. Improved approach for normothermic machine perfusion of cold stored kidney grafts. Am J Transl Res. 2018;10(6):1921–9.Google Scholar
  36. 36.
    Minor T, von Horn C, Paul A. Role of erythrocytes in short-term rewarming kidney perfusion after cold storage. Artif Organs. 2018;4(10):13403.Google Scholar
  37. 37.
    • Gallinat A, Lu J, von Horn C, Kaths M, Ingenwerth M, Paul A, et al. Transplantation of cold stored porcine kidneys after controlled oxygenated rewarming. Artif Organs. 2018;42(6):647–54 This large animal study shows data on kidney graft function and survival after controlled rewarmed perfusion. CrossRefGoogle Scholar
  38. 38.
    Kaths JM, Echeverri J, Linares I, Cen JY, Ganesh S, Hamar M, et al. Normothermic ex vivo kidney perfusion following static cold storage-brief, intermediate, or prolonged perfusion for optimal renal graft reconditioning? Am J Transplant. 2017;17(10):2580–90.CrossRefGoogle Scholar
  39. 39.
    Kaths JM, Hamar M, Echeverri J, Linares I, Urbanellis P, Cen JY, et al. Normothermic ex vivo kidney perfusion for graft quality assessment prior to transplantation. Am J Transplant. 2018;18(3):580–9.CrossRefGoogle Scholar
  40. 40.
    • Kaths JM, Echeverri J, Chun YM, Cen JY, Goldaracena N, Linares I, et al. Continuous normothermic ex vivo kidney perfusion improves graft function in donation after circulatory death pig kidney transplantation. Transplantation. 2017;101(4):754–63 This study highlights the benefits of NEVKP compared with static cold storage in a DCD porcine autotransplantation model. CrossRefGoogle Scholar
  41. 41.
    Kaths JM, Cen JY, Chun YM, Echeverri J, Linares I, Ganesh S, et al. Continuous normothermic ex vivo kidney perfusion is superior to brief normothermic perfusion following static cold storage in donation after circulatory death pig kidney transplantation. Am J Transplant. 2017;17(4):957–69.CrossRefGoogle Scholar
  42. 42.
    • Hamar M, Urbanellis P, Kaths MJ, Kollmann D, Linares I, Ganesh S, et al. Normothermic ex vivo kidney perfusion reduces warm ischemic injury of porcine kidney grafts retrieved after circulatory death. Transplantation. 2018;102(8):1262–70 Using a large animal model, this study demonstrated that NEVKP reduces kidney injury in marginal renal grafts. CrossRefGoogle Scholar
  43. 43.
    Hosgood SA, Moore T, Qurashi M, Adams T, Nicholson ML. Hydrogen gas does not ameliorate renal ischemia reperfusion injury in a preclinical model. Artif Organs. 2018;7:723–7.CrossRefGoogle Scholar
  44. 44.
    Hosgood SA, Moore T, Kleverlaan T, Adams T, Nicholson ML. Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model. J Transl Med. 2017;15(1):017–1314.CrossRefGoogle Scholar
  45. 45.
    von Horn C, Minor T. Isolated kidney perfusion: the influence of pulsatile flow. Scand J Clin Lab Invest. 2018;78(1-2):131–5.CrossRefGoogle Scholar
  46. 46.
    Hosgood SA, Nicholson ML. First in man renal transplantation after ex vivo normothermic perfusion. Transplantation. 2011;92(7):735–8.CrossRefGoogle Scholar
  47. 47.
    Hosgood SA, Saeb-Parsy K, Wilson C, Callaghan C, Collett D, Nicholson ML. Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation. BMJ Open. 2017;7(1):2016–012237.CrossRefGoogle Scholar
  48. 48.
    Hosgood SA, Nicholson ML. An Assessment of urinary biomarkers in a series of declined human kidneys measured during ex vivo normothermic kidney perfusion. Transplantation. 2017;101(9):2120–5.CrossRefGoogle Scholar
  49. 49.
    • Hosgood SA, Thompson E, Moore T, Wilson CH, Nicholson ML. Normothermic machine perfusion for the assessment and transplantation of declined human kidneys from donation after circulatory death donors. Br J Surg. 2018;105(4):388–94 This clinical study presents data of kidney grafts that were transplanted after assessment using normothermic ex vivo perfusion, despite initial evaluation as unsuitable for transplantation. CrossRefGoogle Scholar
  50. 50.
    Tietjen GT, Hosgood SA, DiRito J, Cui J, Deep D, Song E et al. Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys. Sci Transl Med. 2017;9(418).  https://doi.org/10.1126/scitranslmed.aam6764.
  51. 51.
    Sierra-Parraga JM, Eijken M, Hunter J, Moers C, Leuvenink H, Moller B, et al. Mesenchymal stromal cells as anti-inflammatory and regenerative mediators for donor kidneys during normothermic machine perfusion. Stem Cells Dev. 2017;26(16):1162–70.CrossRefGoogle Scholar
  52. 52.
    Brasile L, Henry N, Orlando G, Stubenitsky B. Potentiating renal regeneration using mesenchymal stem cells. Transplantation. 2019;103(2):307–13.CrossRefGoogle Scholar
  53. 53.
    Sanchez-Fructuoso AI, Prats D, Torrente J, Perez-Contin MJ, Fernandez C, Alvarez J, et al. Renal transplantation from non-heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol. 2000;11(2):350–8.Google Scholar
  54. 54.
    • Hessheimer AJ, Garcia-Valdecasas JC, Fondevila C. Abdominal regional in-situ perfusion in donation after circulatory determination of death donors. Curr Opin Organ Transplant. 2016;21(3):322–8 This study reports first results of kidney transplantation of grafts subjected to normothermic regional perfusion. CrossRefGoogle Scholar
  55. 55.
    Reznik ON, Skvortsov AE, Reznik AO, Ananyev AN, Tutin AP, Kuzmin DO et al. Uncontrolled donors with controlled reperfusion after sixty minutes of asystole: a novel reliable resource for kidney transplantation. PLoS One. 2013;8(5).Google Scholar
  56. 56.
    Rojas-Pena A, Sall LE, Gravel MT, Cooley EG, Pelletier SJ, Bartlett RH, et al. Donation after circulatory determination of death: the university of michigan experience with extracorporeal support. Transplantation. 2014;98(3):328–34.CrossRefGoogle Scholar
  57. 57.
    Demiselle J, Augusto JF, Videcoq M, Legeard E, Dube L, Templier F, et al. Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion. Transpl Int. 2016;29(4):432–42.  https://doi.org/10.1111/tri.12722.
  58. 58.
    Hessheimer AJ, Billault C, Barrou B, Fondevila C. Hypothermic or normothermic abdominal regional perfusion in high-risk donors with extended warm ischemia times: impact on outcomes? Transpl Int. 2015;28(6):700–7.CrossRefGoogle Scholar
  59. 59.
    Oniscu GC, Randle LV, Muiesan P, Butler AJ, Currie IS, Perera MT, et al. In situ normothermic regional perfusion for controlled donation after circulatory death--the United Kingdom experience. Am J Transplant. 2014;14(12):2846–54.CrossRefGoogle Scholar
  60. 60.
    Minambres E, Suberviola B, Dominguez-Gil B, Rodrigo E, Ruiz-San Millan JC, Rodriguez-San Juan JC, et al. Improving the outcomes of organs obtained from controlled donation after circulatory death donors using abdominal normothermic regional perfusion. Am J Transplant. 2017;17(8):2165–72.CrossRefGoogle Scholar
  61. 61.
    Nicholson ML, Hosgood SA. Renal transplantation after ex vivo normothermic perfusion: the first clinical study. Am J Transplant. 2013;13(5):1246–52.CrossRefGoogle Scholar
  62. 62.
    Kerforne T, Allain G, Giraud S, Bon D, Ameteau V, Couturier P, et al. Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study. Am J Transplant. 2018;9(10):15063.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Multi Organ Transplant Program, Department of SurgeryToronto General Hospital, University Health NetworkTorontoCanada
  2. 2.Division of NephrologyThe Hospital for Sick ChildrenTorontoCanada

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