Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers

Rijn, Rianne van; Leeuwen, Otto B. van; Matton, A.; Burlage, Laura C.; Wiersema-Buist, Janneke; Heuvel, Marius C. van den; Kleine, Ruben H J de; Boer, Marieke T. de; Gouw, Annette S.H.; Porte, Robert J.

doi:10.1002/lt.25023

Cited by 99 publications

(62 citation statements)

References 37 publications

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“…(11) Future strategies such as the use of machine perfusion can be considered to increase the use of DCD liver allografts by mitigating ischemia/reperfusion injuries, including the effects of prolonged cold ischemia. (30,31) In a previous report, machine perfusion was effective in improving outcomes of marginal liver allografts. (32) A limitation related to the SRTR database is the lack of detailed granular data on some donor and recipient characteristics, for example, donor liver biopsy or administration of tissue plasminogen activator.…”

Section: Discussionmentioning

confidence: 96%

“…Recipient selection is also an important step in liver transplantation, especially in the allocation of marginal organs. (25)(26)(27) The recipients of DCD liver allografts presented a relatively low laboratory MELD score with a median equal to 18 (IQR, [12][13][14][15][16][17][18][19][20][21][22][23][24], whereas in the same period, the median MELD score for braindead donor allograft recipients was 21 (IQR, [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Similar findings with lower MELD score in DCD allografts were reported in previous studies.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation

et al. 2019

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The use of donation after circulatory death (DCD) liver allografts has been constrained by limitations in the duration of donor warm ischemia time (DWIT), donor agonal time (DAT), and cold ischemia time (CIT). The purpose of this study is to assess the impact of longer DWIT, DAT, and CIT on graft survival and other outcomes in DCD liver transplants. The Scientific Registry of Transplant Recipients was queried for adult liver transplants from DCD donors between 2009 and 2015. Donor, recipient, and center variables were included in the analysis. During the study period, 2107 patients underwent liver transplant with DCD allografts. In most patients, DWIT and DAT were <30 minutes. DWIT was <30 minutes in 1804 donors, between 30 and 40 minutes in 248, and >40 minutes in 37. There was no difference in graft survival, duration of posttransplant hospital length of stay, and readmission rate between DCD liver transplants from donors with DWIT <30 minutes and DWIT between 30 and 40 minutes. Similar outcomes were noted for DAT. In the multivariate analysis, DAT and DWIT were not associated with graft loss. The predictors associated with graft loss were donor age, donor sharing, CIT, recipient admission to the intensive care unit, recipient ventilator dependence, Model for End‐Stage Liver Disease score, and low‐volume transplant centers. Any CIT cutoff >4 hours was associated with increased risk for graft loss. Longer CIT was also associated with a longer posttransplant hospital stay, higher rate of primary nonfunction, and hyperbilirubinemia. In conclusion, slightly longer DAT and DWIT (up to 40 minutes) were not associated with graft loss, longer posttransplant hospitalization, or hospital readmissions, whereas longer CIT was associated with worse outcomes after DCD liver transplants.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation

et al. 2019

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“…HMP ameliorates ischemia-reperfusion injury in DCD liver grafts by restoring mitochondrial function before implantation, and it offers better preservation of the bile ducts and their vasculature. 6,7 This is an important step forward in reducing biliary complications after DCD liver transplantation.…”

Section: Introductionmentioning

confidence: 99%

First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion

Werner

Leeuwen

Jong

et al. 2019

Pediatric Transplantation

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One of the main limiting factors in pediatric liver transplantation is donor availability. For adults, DCD liver grafts are increasingly used to expand the donor pool. To improve outcome after DCD liver transplantation, ex situ machine perfusion is used as an alternative organ preservation strategy, with the supplemental value of providing oxygen to the graft during preservation. We here report the first successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion. The full‐size liver graft was derived from a 13‐year‐old, female DCD donor and was end‐ischemic pretreated with dual hypothermic oxygenated machine perfusion. Arterial and portal pressures were set at 18 and 4 mm Hg, slightly lower than protocolized settings for adult livers. During 2 hours of machine perfusion, portal and arterial flows increased from 100 to 210 mL/min and 30 to 63 mL/min, respectively. The pretreated liver graft was implanted in a 16‐year‐old girl with progressive familial intrahepatic cholestasis type 2. Postoperative AST, ALT, and prothrombin time normalized within a week. The recipient quickly recovered and was discharged from the hospital after 18 days. One year after transplantation, she is in excellent condition with a completely normal liver function and histology. This case is the first report of successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion and illustrates the potential role of ex situ machine perfusion in expanding the donor pool and improving outcome after pediatric liver transplantation.

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“…Machine preservation of ECD livers has been shown to improve outcomes after liver transplantation. Specifically, hypothermic machine perfusion (HMP) reduces peribiliary gland damage in treated donation after circulatory death livers versus controls . However, at this time, perfusion at cold temperatures lacks a reliable method to assess the energy (adenosine triphosphate) status of the liver, and a consensus regarding a biomarker profile of useable HMP livers has not been reached .…”

Section: Machine Preservation: a New Ex Vivo Delivery System Of Rnaimentioning

confidence: 99%

“…Specifically, hypothermic machine perfusion (HMP) reduces peribiliary gland damage in treated donation after circulatory death livers versus controls. (50) However, at this time, perfusion at cold temperatures lacks a reliable method to assess the energy (adenosine triphosphate) status of the liver, (51) and a consensus regarding a biomarker profile of useable HMP livers has not been reached. (52) At normothermic perfusion temperatures, even with extended preservation times, a marked decrease (~50%) in peak ALT was observed in treated livers compared with static cold storage grafts.…”

Section: Machine Preservation: a New Ex Vivo Delivery System Of Rnaimentioning

confidence: 99%

Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation

et al. 2019

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RNA interference (RNAi) is a natural process of posttranscriptional gene regulation that has raised a lot of attention culminating with the Nobel Prize in Medicine in 2006. RNAi‐based therapeutics have been tested in experimental transplantation to reduce ischemia/reperfusion injury (IRI) with success. Modulation of genes of the innate immune system, as well as apoptotic genes, and those involved in the nuclear factor kappa B pathways can reduce liver injury in rodent liver pedicle clamping and transplantation models of IRI. However, in vivo use of RNAi faces limitations regarding the method of administration, uptake, selectivity, and stability. Machine perfusion preservation, a more recent alternative approach for liver preservation showing superior results to static cold preservation, could be used as a platform for gene interference therapeutics. Our group was the first to demonstrate uptake of small interfering RNA (siRNA) during liver machine preservation under both normothermic and hypothermic perfusion. Administering siRNA in the perfusion solution during ex vivo machine preservation has several advantages, including more efficient delivery, lower doses and cost‐saving, and none/fewer side effects to other organs. Recently, the first RNAi drug was approved by the US Food and Drug Administration for clinical use, opening a new avenue for new drugs with different clinical applications. RNAi has the potential to have transformational therapeutic applications in several areas of medicine including transplantation. We believe that machine preservation offers great potential to be the ideal delivery method of siRNA to the liver graft, and future studies should be initiated to improve the clinical applicability of RNAi in solid organ transplantation.

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Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers

Cited by 99 publications

References 37 publications

Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation

Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation

First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion

Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation

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