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Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion.

Sutton ME, op den Dries S, Karimian N, Weeder PD, de Boer MT, Wiersema-Buist J, Gouw AS, Leuvenink HG, Lisman T, Porte RJ - PLoS ONE (2014)

Bottom Line: Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group.Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group.It could potentially be used to identify extended criteria livers that are suitable for transplantation.

View Article: PubMed Central - PubMed

Affiliation: Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT
Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.

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Changes in hepatic energy content as reflected by hepatic ATP content.In contrast to livers with low bile output, livers in the high bile output group showed a significantly higher hepatic ATP content during the course of NMP. (AUC p = 0.04).
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pone-0110642-g003: Changes in hepatic energy content as reflected by hepatic ATP content.In contrast to livers with low bile output, livers in the high bile output group showed a significantly higher hepatic ATP content during the course of NMP. (AUC p = 0.04).

Mentions: At the start of NMP, median pO2 in the perfusate was 71 kPa (or 533 mmHg) with an interquartile range of 65–75 kPa (or 488–563 mmHg. After the start of NMP, the pO2 dropped in 4 out of the 6 livers with low bile output and median pO2 in this group after 6 hours of NMP was 35 kPa (or 263 mmHg). This was not significantly different from pO2 values in the high bile output group (Table 3) and this value is still far above the upper limit of normal arterial pO2in vivo (13.5 kPa or 101 mmHg). After 6 hr of NMP, there was a small, but significant difference in sO2 between the two groups (100% versus 98%), yet median values never fell below the normal range in vivo (normal values arterial sO2: 96–99%). In parallel with these changes, total hepatic ATP content was significantly higher during the course of NMP in the livers with high bile output, compared to those with low bile output. At baseline, all livers were ATP depleted with a median in the high bile output group 7 µmol/g protein compared to 8 µmol/g in the low bile output group. After 2 h of NMP the ATP had increased to 50 µmol/g in the high bile output group and to 15 µmol/g in the low bile output group. This difference in ATP content persisted during the course of NMP and the AUC analysis revealed statistical significant difference (p = 0.04; Figure 3). In addition, pO2 and sO2, oxygen consumption was higher in the group of livers with low bile output, compared to those with high bile output, but this did not reach statistical significance.


Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion.

Sutton ME, op den Dries S, Karimian N, Weeder PD, de Boer MT, Wiersema-Buist J, Gouw AS, Leuvenink HG, Lisman T, Porte RJ - PLoS ONE (2014)

Changes in hepatic energy content as reflected by hepatic ATP content.In contrast to livers with low bile output, livers in the high bile output group showed a significantly higher hepatic ATP content during the course of NMP. (AUC p = 0.04).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219693&req=5

pone-0110642-g003: Changes in hepatic energy content as reflected by hepatic ATP content.In contrast to livers with low bile output, livers in the high bile output group showed a significantly higher hepatic ATP content during the course of NMP. (AUC p = 0.04).
Mentions: At the start of NMP, median pO2 in the perfusate was 71 kPa (or 533 mmHg) with an interquartile range of 65–75 kPa (or 488–563 mmHg. After the start of NMP, the pO2 dropped in 4 out of the 6 livers with low bile output and median pO2 in this group after 6 hours of NMP was 35 kPa (or 263 mmHg). This was not significantly different from pO2 values in the high bile output group (Table 3) and this value is still far above the upper limit of normal arterial pO2in vivo (13.5 kPa or 101 mmHg). After 6 hr of NMP, there was a small, but significant difference in sO2 between the two groups (100% versus 98%), yet median values never fell below the normal range in vivo (normal values arterial sO2: 96–99%). In parallel with these changes, total hepatic ATP content was significantly higher during the course of NMP in the livers with high bile output, compared to those with low bile output. At baseline, all livers were ATP depleted with a median in the high bile output group 7 µmol/g protein compared to 8 µmol/g in the low bile output group. After 2 h of NMP the ATP had increased to 50 µmol/g in the high bile output group and to 15 µmol/g in the low bile output group. This difference in ATP content persisted during the course of NMP and the AUC analysis revealed statistical significant difference (p = 0.04; Figure 3). In addition, pO2 and sO2, oxygen consumption was higher in the group of livers with low bile output, compared to those with high bile output, but this did not reach statistical significance.

Bottom Line: Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group.Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group.It could potentially be used to identify extended criteria livers that are suitable for transplantation.

View Article: PubMed Central - PubMed

Affiliation: Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT
Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.

Show MeSH
Related in: MedlinePlus