Skip to main content
Springer Nature Link
Log in

Moderne Konzepte zur dynamischen Konservierung von Leber und Nieren im Rahmen einer Transplantation

Modern concepts for the dynamic preservation of the liver and kidneys in the context of transplantation

  • Schwerpunkt: Transplantationspathologie
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Der steigende Organmangel führte zu einem Wandel in der experimentellen Erforschung von Organkonservierungsstrategien in der Transplantationsmedizin. Die einfache kalte Lagerung der Transplantate als Standardkonservierungsverfahren bietet für Spenderorgane mit erweiterten Kriterien nicht immer optimale Bedingungen. Als klassische dynamische Konservierungsmethode gilt die hypotherme oxygenierte Maschinenperfusion (HMP). Durch die HMP wird das Gewebe mit Sauerstoff und Nährstoffen versorgt und eine metabolische Erholung des Transplantats vor Implantation ermöglicht. Ein moderneres Konzept ist die normotherme Maschinenperfusion (NMP), die durch Simulation physiologischer Konditionen eine Evaluation und Behandlung des Organs vor Transplantation ermöglicht. Studien zur NMP zeigten allerdings, dass eine vorgeschaltete Periode kalter Lagerung den funktionellen Vorteil der NMP abschwächt. Das kontrolliert oxygenierte Wiedererwärmen (COR) ist eine Strategie, diesen Nachteil ausgleichen, indem das kalt gelagerte Transplantat langsam und schrittweise auf subnormotherme oder normotherme Temperaturen erwärmt wird. So kann eine schonende Adaptation des Energiestoffwechsels stattfinden und dem Wiedererwärmungsschaden vorgebeugt werden.

Abstract

The increasing demand on donor grafts has forced experimental research on transplantation medicine to develop more efficient organ preservation strategies. Simple cold storage of grafts rarely offers optimal conditions for extended criteria donor organs. Hypothermic, oxygenated machine perfusion (HMP) is a classical method of dynamic organ preservation, which enables the provision of oxygen and nutrients to the tissue and provides a metabolic recovery of the graft prior to implantation. A more modern approach is normothermic machine perfusion (NMP), which instead simulates physiological conditions and enables an ex vivo evaluation and treatment of organ grafts. However, studies have found that a preceding period of cold storage significantly mitigates the functional advantage of NMP. A strategy to circumvent this phenomenon is controlled oxygenated rewarming (COR). The cold-stored graft is slowly and gradually rewarmed to subnormothermic or normothermic temperatures, providing a gentle adaption of energy metabolism and counteracting events of rewarming injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Abbreviations

ATP:

Adenosintriphosphat

BES:

N,N-Bis-(2-hydroxyethyl)-2-aminoethansulfonsäure

COR:

„Controlled oxygenated rewarming“ (kontrollierte oxygenierte Wiedererwärmung)

CS:

„Cold storage“ (kalte Lagerung)

DCD:

„Donation after cardiac death“ (Spende nach Herztod)

ECD:

„Expanded criteria donor“ (Spender mit erweiterten Kriterien)

HMP:

Hypotherme Maschinenperfusion

HTK:

Histidin-Tryptophan-Ketoglutarat

KLF2:

Krüppel-like factor 2

mtHSP:

Mitochondriales Hitzeschockprotein

NAD:

Nicotinamidadenindinukleotid

NMP:

Normotherme Maschinenperfusion

RI:

„Rewarming injury“ (Wiedererwärmungsschaden)

UW:

University of Wisconsin

Literatur

  1. Bagul A, Hosgood SA, Kaushik M, Kay MD, Waller HL, Nicholson ML (2008) Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. Br J Surg 95:111–118

    Article  CAS  Google Scholar 

  2. Banan B, Xiao Z, Watson R, Xu M, Jia J, Upadhya GA, Mohanakumar T, Lin Y, Chapman W (2016) Novel strategy to decrease reperfusion injuries and improve function of cold-preserved livers using normothermic ex vivo liver perfusion machine. Liver Transpl 22:333–343

    Article  Google Scholar 

  3. Bessems M, Doorschodt BM, van Vliet AK, van Gulik TM (2005) Improved rat liver preservation by hypothermic continuous machine perfusion using polysol, a new, enriched preservation solution. Liver Transpl 11:539–546

    Article  Google Scholar 

  4. Bral M, Gala-Lopez B, Bigam D, Kneteman N, Malcolm A, Livingstone S, Andres A, Emamaullee J, Russell L, Coussios C, West LJ, Friend PJ, Shapiro AM (2017) Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: results of a clinical trial. Am J Transplant 17:1071–1080

    Article  CAS  Google Scholar 

  5. Brockmann JM, Reddy SF, Coussios CP, Pigott DF, Guirriero DM, Hughes DP, Morovat AP, Roy DF, Winter LM, Friend PJM (2009) Normothermic perfusion: a new paradigm for organ preservation. Ann Surg 250:1–6

    Article  Google Scholar 

  6. Collins GM, Bravo-Shugarman M, Terasaki PI (1969) Kidney preservation for transportation. Initial perfusion and 30 hours’ ice storage. Lancet 2:1219–1222

    Article  CAS  Google Scholar 

  7. D’Alessandro AM, Kalayoglu M, Sollinger HW, Pirsch JD, Southard JH, Belzer FO (1991) Current status of organ preservation with University of Wisconsin solution. Arch Pathol Lab Med 115:306–310

    PubMed  Google Scholar 

  8. Daemen JH, de Vries B, Oomen AP, DeMeester J, Kootstra G (1997) Effect of machine perfusion preservation on delayed graft function in non-heart-beating donor kidneys—early results. Transpl Int 10:317–322

    CAS  PubMed  Google Scholar 

  9. De Rougemont O, Breitenstein S, Leskosek B, Weber A, Graf R, Clavien PA, Dutkowski P (2009) One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death. Ann Surg 250:674–683

    Article  Google Scholar 

  10. Dutkowski P, Graf R, Clavien PA (2006) Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion. Am J Transplant 6:903–912

    Article  CAS  Google Scholar 

  11. Gallinat A, Paul A, Efferz P, Luer B, Kaiser G, Wohlschlaeger J, Treckmann J, Minor T (2012) Hypothermic reconditioning of porcine kidney grafts by short-term preimplantation machine perfusion. Transplantation 93:787–793

    Article  CAS  Google Scholar 

  12. Gracia-Sancho J, Villarreal G Jr., Zhang Y, Yu JX, Liu Y, Tullius SG, Garcia-Cardena G (2010) Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation 90:142–149

    Article  Google Scholar 

  13. Grune T, Muller K, Zollner S, Haseloff R, Blasig IE, David H, Siems W (1997) Evaluation of purine nucleotide loss, lipid peroxidation and ultrastructural alterations in post-hypoxic hepatocytes. Am J Physiol 498:511–522

    Article  CAS  Google Scholar 

  14. Guibert EE, Petrenko AY, Balaban CL, Somov AY, Rodriguez JV, Fuller BJ (2011) Organ preservation: current concepts and new strategies for the next decade. Transfus Med Hemother 38:125–142

    Article  Google Scholar 

  15. Hoffmann T, Minor T (2015) New strategies and concepts in organ preservation. Eur Surg Res 54:114–126

    Article  CAS  Google Scholar 

  16. Hosgood SA, Nicholson HFL, Nicholson ML (2012) Oxygenated kidney preservation techniques. Transplantation 93:455–459

    Article  CAS  Google Scholar 

  17. Hosgood SA, van Heurn E, Nicholson ML (2015) Normothermic machine perfusion of the kidney: better conditioning and repair? Transpl Int 28:657–664

    Article  Google Scholar 

  18. Hoyer DP, Mathe Z, Gallinat A, Canbay AC, Treckmann JW, Rauen U, Paul A, Minor T (2016) Controlled oxygenated rewarming of cold stored livers prior to transplantation: first clinical application of a new concept. Transplantation 100:147–152

    Article  CAS  Google Scholar 

  19. Hoyer DP, Paul A, Luer S, Reis H, Efferz P, Minor T (2016) End-ischemic reconditioning of liver allografts: controlling the rewarming. Liver Transplant 22:1223–1230

    Article  Google Scholar 

  20. Imber CJ, Peter StSD, Lopez de Cenarruzabeitia I, Pigott D, James T, Taylor R, McGuire J, Hughes D, Butler A, Rees M, Friend PJ (2002) Advantages of normothermic perfusion over cold storage in liver preservation. Transplantation 73:701–709

    Article  Google Scholar 

  21. Jamieson RW, Zilvetti M, Roy D, Hughes D, Morovat A, Coussios CC, Friend PJ (2011) Hepatic steatosis and normothermic perfusion-preliminary experiments in a porcine model. Transplantation 92:289–295

    Article  Google Scholar 

  22. Kaths JM, Cen JY, Chun YM, Echeverri J, Linares I, Ganesh S, Yip P, John R, Bagli D, Mucsi I, Ghanekar A, Grant DR, Robinson LA, Selzner M (2017) 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 17:957–969

    Article  CAS  Google Scholar 

  23. Kaths JM, Echeverri J, Goldaracena N, Louis KS, Chun Y‑M, Linares I, Wiebe A, Foltys DB, Yip PM, John R, Mucsi I, Ghanekar A, Bagli DJ, Grant DR, Robinson LA, Selzner M (2016) 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 100:1862–1870

    Article  CAS  Google Scholar 

  24. Kay MD, Hosgood SA, Harper SJ, Bagul A, Waller HL, Rees D, Nicholson ML (2007) Static normothermic preservation of renal allografts using a novel nonphosphate buffered preservation solution. Transpl Int 20:88–92

    Article  CAS  Google Scholar 

  25. Kelly DM, Shiba H, Nakagawa S, Irefin S, Eghtesad B, Quintini C, Aucejo F, Hashimoto K, Fung JJ, Miller C (2011) Hepatic blood flow plays an important role in ischemia-reperfusion injury. Liver Transpl 17:1448–1456

    Article  Google Scholar 

  26. Kim JS, NItta T, Mohuczy D, O’Malley KA, Moldawer LL, Dunn WA Jr, Behrns KE (2008) Impaired autophagy: a mechanism of mitochondrial dysfunction in anoxic rat hepatocytes. Hepatology 47:1725–1736

    Article  CAS  Google Scholar 

  27. Kron P, Schlegel A, de Rougemont O, Oberkofler CE, Clavien PA, Dutkowski P (2016) Short, cool, and well oxygenated—HOPE for kidney transplantation in a rodent model. Ann Surg 264:815–822

    Article  Google Scholar 

  28. Leducq N, Delmas-Beauvieux MC, Bourdel-Marchasson I, Dufour S, Gallis JL, Canioni P, Diolez P (1998) Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A. Biochem J 336(Pt 2):501–506

    Article  CAS  Google Scholar 

  29. Luer B, Fox M, Efferz P, Minor T (2014) Adding pulsatile vascular stimulation to venous systemic oxygen persufflation of liver grafts. Artif Organs 38:404–410

    Article  Google Scholar 

  30. Mahboub P, Ottens P, Seelen M, t Hart N, Van Goor H, Ploeg R, Martins PN, Leuvenink H (2015) Gradual Rewarming with Gradual Increase im Druckure during Machine Perfusion after Cold Static Preservation Reduces Kidney Ischemia Reperfusion Injury. PLoS ONE 10:e143859

    Article  Google Scholar 

  31. Mangus RS, Schroering JR, Hathaway TJ, Kubal CA, Fridell JA (2018) Comparison of Histidine-Tryptophan-Ketoglutarate and University of Wisconsin preservation solutions in pediatric liver transplantation. Pediatr Transplant e13252. https://doi.org/10.1111/petr.13252

    Article  PubMed  Google Scholar 

  32. Matsuno N, Obara H, Watanabe R, Iwata S, Kono S, Fujiyama M, Hirano T, Kanazawa H, Enosawa S (2014) Rewarming preservation by organ perfusion system for donation after cardiac death liver grafts in pigs. Transplant Proc 46:1095–1098

    Article  CAS  Google Scholar 

  33. Matsuno N, Sakurai E, Tamaki I, Uchiyama M, Kozaki K, Kozaki M (1994) The effect of machine perfusion preservation versus cold storage on the function of kidneys from non-heart-beating donors. Transplantation 57:293–294

    Article  CAS  Google Scholar 

  34. Mergental H, Perera MTPR, Laing RW, Muiesan P, Isaac JR, Smith A, Stephenson BTF, Cilliers H, Neil DAH, Hübscher SG, Afford SC, Mirza DF (2016) Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am J Transplant 16(11):3235–3245

    Article  CAS  Google Scholar 

  35. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM (2003) Expanded criteria donors for kidney transplantation. Am J Transplant 3(Suppl 4):114–125

    Article  Google Scholar 

  36. Minor T, Efferz P, Fox M, Wohlschlaeger J, Luer B (2013) Controlled oxygenated rewarming of cold stored liver grafts by thermally graduated machine perfusion prior to reperfusion. Am J Transplant 13:1450–1460

    Article  CAS  Google Scholar 

  37. Minor T, Isselhard W (1996) Synthesis of high energy phosphates during cold ischemic rat liver preservation with gaseous oxygen insufflation. Transplantation 61:20–22

    Article  CAS  Google Scholar 

  38. Minor T, Koetting M, Koetting M, Kaiser G, Efferz P, Lüer B, Paul A (2011) Hypothermic reconditioning by gaseous oxygen improves survival after liver transplantation in the pig. Am J Transplant 11:2627–2634

    Article  CAS  Google Scholar 

  39. Minor T, Saad S, Koetting M, Nagelschmidt M, Paul A (1998) Endischemic oxygen persufflation to improve viability of marginally preserved donor livers. Transpl Int 11:S400–S403

    Article  Google Scholar 

  40. Minor T, Sutschet K, Witzke O, Paul A, Gallinat A (2016) Prediction of renal function upon reperfusion by ex situ controlled oxygenated rewarming. Eur J Clin Invest 46:1024–1030

    Article  CAS  Google Scholar 

  41. Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, van Kasterop-Kutz M, van der Heide JJ, Squifflet JP, van Heurn E, Kirste GR, Rahmel A, Leuvenink HG, Paul A, Pirenne J, Ploeg RJ (2009) Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 360:7–19

    Article  CAS  Google Scholar 

  42. Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, Chiocchia V, Dutton SJ, Garcia-Valdecasas JC, Heaton N, Imber C, Jassem W, Jochmans I, Karani J, Knight SR, Kocabayoglu P, Malago M, Mirza D, Morris PJ, Pallan A, Paul A, Pavel M, Perera M, Pirenne J, Ravikumar R, Russell L, Upponi S, Watson CJE, Weissenbacher A, Ploeg RJ, Friend PJ, Consortium for Organ Preservation in E (2018) A randomized trial of normothermic preservation in liver transplantation. Nature 557:50–56

    Article  CAS  Google Scholar 

  43. Nassar A, Liu Q, Farias K, D’Amico G, Buccini L, Urcuyo D, Kelly D, Hashimoto K, Eghtesad B, Uso TD, Miller C, Quintini C (2014) Role of vasodilation during normothermic machine perfusion of DCD porcine livers. Int J Artif Organs 37:165–172

    Article  Google Scholar 

  44. Nayak L, Lin Z, Jain MK (2011) “Go with the flow”: how Kruppel-like factor 2 regulates the vasoprotective effects of shear stress. Antioxid Redox Signal 15:1449–1461

    Article  CAS  Google Scholar 

  45. Nicholson ML, Hosgood SA (2013) Renal transplantation after ex vivo normothermic perfusion: the first clinical study. Am J Transplant 13:1246–1252

    Article  CAS  Google Scholar 

  46. Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD (2010) Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 16:943–949

    Article  Google Scholar 

  47. Rauen U, Kerkweg U, de Groot H (2007) Iron-dependent vs. iron-independent cold-induced injury to cultured rat hepatocytes: a comparative study in physiological media and organ preservation solutions. Cryobiology 54:77–86

    Article  CAS  Google Scholar 

  48. Ravikumar R, Leuvenink H, Friend PJ (2015) Normothermic liver preservation: a new paradigm? Transpl Int 28:690–699

    Article  CAS  Google Scholar 

  49. Schlegel A, Graf Rougemont Od R, Clavien PA, Dutkowski P (2013) Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J Hepatol 58:278–286

    Article  Google Scholar 

  50. Schopp I, Reissberg E, Luer B, Efferz P, Minor T (2015) Controlled rewarming after hypothermia: adding a new principle to renal preservation. Clin Transl Sci 8:475–478

    Article  CAS  Google Scholar 

  51. Sen-Banerjee S, Mir S, Lin Z, Hamik A, Atkins GB, Das H, Banerjee P, Kumar A, Jain MK (2005) Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 112:720–726

    Article  CAS  Google Scholar 

  52. Stegemann J, Minor T (2009) Energy charge restoration, mitochondrial protection and reversal of preservation induced liver injury by hypothermic oxygenation prior to reperfusion. Cryobiology 58:331–336

    Article  CAS  Google Scholar 

  53. Taylor MJ, Baicu SC (2010) Current state of hypothermic machine perfusion preservation of organs: the clinical perspective. Cryobiology 60:S20–35

    Article  Google Scholar 

  54. Vajdova K, Graf R, Clavien PA (2002) ATP-supplies in the cold-preserved liver: a long-neglected factor of organ viability. Hepatology 36:1543–1552

    Article  CAS  Google Scholar 

  55. Vekemans K, Liu Q, Pirenne J, Monbaliu D (2008) Artificial circulation of the liver: machine perfusion as a preservation method in liver transplantation. Anat Rec (Hoboken) 291:735–740

    Article  Google Scholar 

  56. von Horn C, Baba HA, Hannaert P, Hauet T, Leuvenink H, Paul A, Minor T, partners Cc (2017) Controlled oxygenated rewarming up to normothermia for pretransplant reconditioning of liver grafts. Clin Transplant 31(11). https://doi.org/10.1111/ctr.13101

    Article  Google Scholar 

  57. Watson CJ, Kosmoliaptsis V, Randle LV, Russell NK, Griffiths WJ, Davies S, Mergental H, Butler AJ (2015) Preimplant normothermic liver perfusion of a suboptimal liver donated after circulatory death. Am J Transplant 16(1):353–357

    Article  Google Scholar 

  58. Williamson C, Dabkowski ER, Dillmann WH, Hollander JM (2008) Mitochondria protection from hypoxia/reoxygenation injury with mitochondria heat shock protein 70 overexpression. Am J Physiol Heart Circ Physiol 294:H249–H256

    Article  CAS  Google Scholar 

Download references

Danksagung

Die Autoren bedanken sich für die wertvolle Hilfe von B. Lüer für das Korrekturlesen des Manuskripts.

Author information

Authors and Affiliations

  1. Abteilung für chirurgische Forschung, Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland

    C. von Horn & T. Minor

Authors
  1. C. von Horn
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. T. Minor
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to C. von Horn.

Ethics declarations

Interessenkonflikt

C. von Horn und T. Minor geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Schwerpunktherausgeber

K. W. Schmid, Essen

H. A. Baba, Essen

H.-U. Schildhaus, Essen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

von Horn, C., Minor, T. Moderne Konzepte zur dynamischen Konservierung von Leber und Nieren im Rahmen einer Transplantation. Pathologe 40, 292–298 (2019). https://doi.org/10.1007/s00292-019-0595-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-019-0595-2

Schlüsselwörter

Keywords