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UW Versus HTK for Static Preservation in Liver Transplantation: Is There a “Solution Effect” on Outcomes?

Rosado, Jesus, MD1; Guarrera, James V., MD

doi: 10.1097/TP.0000000000002407
Commentaries

CThe authors critically evaluate the contribution from the Eurotransplant registry regarding the relative effectiveness of HTH and UW on clinical outcomes.

1 Division of Liver Transplant and Hepatobiliary Surgery, Department of Surgery Rutgers New Jersey Medical School and University Hospital, Newark, NJ.

Received 18 July 2018. Revision received 30 July 2018.

Accepted 6 August 2018.

J.R. has no financial conflicts of interests to disclose. J.V.G. acts as a consultant for ex vivo liver machine perfusion, Organ Recovery Systems.

Drafting of the manuscript: James V. Guarrera (JG), Jesus Rosado (JR); Critical revision of the manuscript: JG, JR.

Correspondence: James V. Guarrera, MD, Division of Liver Transplant Hepatobiliary Surgery, Rutgers New Jersey Medical School/University Hospital, 140 Bergen St, ACC-E-1620, Newark, NJ 07101. (james.guarrera@njms.rutgers.edu).

The goal of effective organ preservation is to limit ischemic injuries associated with recovery and transportation of the allograft. In the mid 1980s, the development of University of Wisconsin (UW) solution and cyclosporine A revolutionized the field of liver transplantation and brought it from an experimental procedure to the standard of care for treating end-stage liver disease.

Today, UW remains the “gold standard” preservation solution for liver transplantation. The UW solution is a high-potassium, somewhat viscous, solution with hydroxyethyl starch, which facilitates effective flushing and long term storage. Raffinose and lactobionate are constituents of UW to reduce cellular swelling. Histidine-tryptophan-ketoglutarate (HTK) solution was developed as a cardioplegia solution in Germany and was adopted for organ preservation also in the late 1980s and gained use in Europe and more recently in North America.1 The first clinical results of HTK for liver transplantation were reported in 1990.2 Proponents of HTK cite that its lower potassium and lower viscosity may provide a better initial flush of the liver microcirculation, which might be important particularly in living donor liver transplant and donation after cardiac death transplantation. At times, HTK has also been preferable in some areas due to lower costs.1 The first randomized comparison between University of Wisconsin and HTK solution was 20 years ago, and since then, HTK has seemed to show clinical equivalence when cold ischemia times are under 15 hours.2,3

In this issue, de Boer et al present a large retrospective study comparing outcomes between UW solution and HTK solution based on a large subset of data from the Eurotransplant registry. The authors should be commended for a detailed and extensive review of this large data set. The study, as pointed out by the authors, is somewhat limited as it is a retrospective review of results from multiple different countries with varying practice patterns, which the authors attempt to correct for by way of additional regional analysis. The authors attempt to explain the differences in outcomes between the 2 groups citing “regional differences in donor, recipient and transplant characteristics.” The authors cite statistically significant differences in variables, such as median donor age (56 years in HTK vs 55 years in UW), recipient Model for End-Stage Liver Disease greater than 35 (13% in HTK vs 6 % in UW), and extraregional allocation (53% in HTK vs 23% in UW), which would imply higher risk in HTK cases for the variables which would also be considered clinically significant. In their initial analysis, UW solution was associated with higher 30 day and 1 year graft survival but the authors later show that this might not be the case after they perform their regional analyses.4

Most of the liver transplant community would likely believe there is equivalence between both solutions in terms of short and long term outcomes based on what is described in the literature.5-7 Mangus et al looked at 698 ECD liver grafts and found the use of the 2 solutions was not clinically distinguishable.6 Kaltenborn et al also found minimal differences between the 2 solutions.5

However, some authors have found concerns with HTK and suggested inferiority. Adams et al compared UW to HTK and Celsior solutions. This study found that HTK led to a 10% increased risk of graft loss.8 These results were even corrected after some criticism removing German centers and living donors yet still showed lower overall graft survival in the HTK group.9 In the United Network for Organ Sharing region, Stewart et al in 2009, preformed a statistical analysis of the United Network for Organ Sharing database of 18 586 livers comparing the use of the 2 solutions. In this database, HTK was associated with an overall 14% increased risk of graft loss when compared to UW. This increased risk was even more pronounced when the analysis was narrowed to just DCD grafts with an increased risk of 44%.10

From a mechanistic standpoint, there have also been recurrent suggestions that UW provides better preservation through various mechanisms. Janssen et al in 2004 looked at HTK, UW, and Celsior solutions and their effects on human liver endothelial cells and concluded that UW was superior in terms of viability and maintenance of membrane integrity during ischemia and after reperfusion. Adenosine triphosphate levels were also noted to be statistically higher intracellularly in the livers preserved in UW vs those preserved in Celsior or HTK solutions.11

Considering the ongoing debate regarding UW versus HTK has not “cooled down” over the last 15 years, we believe the debate will likely continue until a prospective randomized controlled trial with adequate power is undertaken to answer the question definitively. However, it is unlikely this will ever happen. Doing prospective research in organ preservation has many potential pitfalls and difficulties in obtaining informed consent as it is common that recipients of the organs being studied may not be identified at the time of randomization of the research intervention. There are currently groups looking to improve the regulatory hurdles associated with organ preservation research. Another factor that makes a randomized controlled trial unlikely is the excitement around implementation of ex vivo machine perfusion as a preservation technique for liver allografts with multiple clinical trials underway and in planning stages. Despite the excitement for novel ex vivo perfusion techniques, we suggest that continued work on the development of new superior solutions for static preservation, which provide simple and reliable preservation, should continue with the ultimate goal to reduce the effects of Ischemia/ Reperfusion injury associated with liver preservation.

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REFERENCES

1. Parsons RF, Guarrera JV. Preservation solutions for static cold storage of abdominal allografts: which is best? Curr Opin Organ Transplant. 2014;19:100–107.
2. Erhard J, Lange R, Scherer R, et al. Comparison of histidine-tryptophan-ketoglutarate (HTK) solution versus University of Wisconsin (UW) solution for organ preservation in human liver transplantation. A prospective, randomized study. Transpl Int. 1994;7:177–181.
3. Gubernatis G, Pichlmayr R, Lamesch P, et al. HTK-solution (Bretschneider) for human liver transplantation. First clinical experiences. Langenbecks Arch Chir. 1990;375:66–70.
4. de Boer J, Strelniece A, van Rosmalen M, et al. The effect of histidine-tryptophan-ketoglutarate solution (HTK) and University of Wisconsin solution (UW): an analysis of the Eurotransplant registry. Transplantation. 2018;102:1870–1877.
5. Kaltenborn A, Gwiasda J, Amelung V, et al. Comparable outcome of liver transplantation with histidine-tryptophan-ketoglutarate vs. University of Wisconsin preservation solution: a retrospective observational double-center trial. BMC Gastroenterol. 2014;14:169.
6. Mangus RS, Tector AJ, Agarwal A, et al. Comparison of histidine-tryptophan-ketoglutarate solution (HTK) and University of Wisconsin solution (UW) in adult liver transplantation. Liver Transpl. 2006;12:226–230.
7. Feng L, Zhao N, Yao X, et al. Histidine-tryptophan-ketoglutarate solution vs. University of Wisconsin solution for liver transplantation: a systematic review. Liver Transpl. 2007;13:1125–1136.
8. Adam R, Delvart V, Karam V, et al. Compared efficacy of preservation solutions in liver transplantation: a long-term graft outcome study from the European liver transplant registry. Am J Transplant. 2015;15:395–406.
9. Adam R, Delvart V, Karam V. Reply to letter regarding “compared efficacy of preservation solutions in liver transplantation: a long-term graft outcome study from the European Liver Transplant Registry”. Am J Transplant. 2015;15:3274–3275.
10. Stewart ZA, Cameron AM, Singer AL, et al. Histidine-tryptophan-ketoglutarate (HTK) is associated with reduced graft survival in deceased donor livers, especially those donated after cardiac death. Am J Transplant. 2009;9:286–293.
11. Janssen H, Janssen PH, Broelsch CE. UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury. Liver Transpl. 2004;10:1514–1523.
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