On Some Paradoxes in Liver Transplantation

The Skeptik, 2017, Vol. 3. No. 1. Pgs. (11-13).

Kukan M. Slovak Medical University, emeritus, Bratislava, Slovakia

Abstract: This article describes some paradoxes in liver transplantation in both animals and human models.

1. Paradox: Cold rinse with Ringer lactate solution (RLS) vs. warm rinse RLS solution:  

Post and co-authors showed for the first time (in 1995) in the rat model that warm rinnse with Ringer lactated solution at 37 degrees of Celsius through portal vein compared to cold RLS (just to liver reperfusion with blood) protected hepatic graft function (1). This results indicated that the first minute of reperfsion could have strong impact on the overall results of transplantation in the rat (1, 2). 

Therefore, we always used 30 mL of warm RLS for washing rat livers just prior to reperfusion with oxygenated Krebs-Henseleit solution in my Laboratory of Perfused Organs. (Here is some some joke situation from my Lab.: During writting MS I came to check reperfusion experiment.  I saw how liver function was deterriorating. One PhD student made a mistake and instead of warm RLS used 4 0 C degrees RLS).

It should be noted that warm rinse with Ringer lactate at 37 C  degree markedly reduced  Kupffer cells activation (2). The use of this warm solution is enable to improve membrane fluidity (3).

2. "Oxygen paradox":
Minor and co-authors showed that nonparenchymal cell injury and ATP stores can overcome "oxygen paradox" upon reperfusion by persufllation of the rat liver during cold sorage (4). Nonparenchymal cell injury can also be overcamed by glycine, acidotitic pH, and by Carolina rinse in the rat model (5).
Bneficiall effects of oxygen persufllation was also found in the pig model of liver transplantation (6).   

3. Rewarming ischemia vs. Cold ischemia paradox:
It is well known that during liver cold preservation stores of ATP are decreasing with the preservation time. This makes liver succssebility to rewarming ischemia (7). Baron and co-authors found that rewarming ischemia had negative effect on severe reccurent hepatitis C (SRHC) after liver transplantation in humans. Cold ischemia did not corellated with (SRHC), but rewarming ischemia correlared with it (8) .

4. pH Paradox:
Currin and co-authors showed for the first time that perfusion of ischemic livers with acidotic pH had beneficiall effects on rat livers (9). Thus, a rapid increase of pH rather than reoxygenation accounted for tissue injury after reperfusion of ischemic liver (4,5, 9).

The above findings were confirmed in human liver transplanatatiuon model. Actually, serum acidification facilitated hemodynamic recovery following liver transplantation (11).     

5. Ischemic preconditioning paradox:
Ischemic preconditiong of human livers have several beneficial effects (see for Review 11). However, these protective effects were compromited by recent findings of Koneru and co-authors (12).

Other paradoxes in liver transplantation are beyond of this paper.

REFERENCES
1. Post S, Rentsch M, Gonzalez AP, Palma P, Otto G, Menger MD. Importance of the first minutes of reperfusion in hepatic preservation injury. Transplant Proc. 1995 Feb;27(1):727-8.

2. Rentsch M, Post S, Palma P, Gonzalez AP, Menger MD, Messmer K.  Intravital studies on beneficial effects of warm Ringer's lactate rinse in liver transplantation. Transpl Int. 1996;9(5):461-7. 

3. Kukan M, Haddad PS. Why and how to innovate liver transplantation: a multiple treatment strategy. Hepatology. 2001 Aug;34(2):440-1.

4. Minor T, Isselhard W, Klauke H. Reduction in nonparenchymal cell injury and vascular endothelial dysfunction after cold preservation of the liver by gaseous oxygen. Transpl Int. 1996;9 Suppl 1:S425-8.

5. Currin RT, Caldwell-Kenkel JC, Lichtman SN, Bachmann S, Takei Y, Kawano S, Thurman RG, Lemasters JJ. Protection by Carolina rinse solution, acidotic pH, and glycine against lethal reperfusion injury to sinusoidal endothelial cells of rat livers stored for transplantation.   Transplantation. 1996 Dec 15;62(11):1549-58
  
6. Minor T, Saad S, Nagelschmidt M, Kötting M, Fu Z, Paul A, Isselhard W. Successful transplantation of porcine livers after warm ischemic insult in situ and cold preservation including postconditioning with gaseous oxygen.   Transplantation. 1998 May 15;65(9):1262-4.

7. Vajdová K, Smreková R, Mislanová C, Kukan M, Lutterová M. Cold-preservation-induced sensitivity of rat hepatocyte function to rewarming injury and its prevention by short-term reperfusion. Hepatology. 2000;32:289-296.

8. Baron PW, Sindram D, Higdon D, Howell DN, Gottfried MR, Tuttle-Newhall JE, Clavien PA. Prolonged rewarming time during allograft implantation predisposes to recurrent hepatitis C infection after liver transplantation.  Liver Transpl. 2000 Jul;6(4):407-12. 

9. Currin RT, Gores GJ, Thurman RG, Lemasters JJ. Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox. FASEB J. 1991 Feb;5(2):207-10.

10. Fukazawa K, Vitin AA, Pretto EA Jr. Serum acidosis prior to reperfusion facilitates hemodynamic recovery following liver transplantation. J Anesth. 2016 Feb;30(1):80-8. doi: 10.1007/s00540-015-2080-2. Epub 2015 Oct 8.

11. de Rougemont O, Lehmann K, Clavien PA. Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver. Liver Transpl. 2009 Oct;15(10):1172-82. doi: 10.1002/lt.21876. Review. 

12. Koneru B, Shareef A, Dikdan G, Desai K, Klein KM, Peng B, Wachsberg RH, de la Torre AN, Debroy M, Fisher A, Wilson DJ, Samanta AK. The ischemic preconditioning paradox in deceased donor liver transplantation-evidence from a prospective randomized single blind clinical trial. Am J Transplant. 2007 Dec;7(12):2788-96. Epub 2007 Oct 19.