23 results on '"Mergental, Hynek"'
Search Results
2. How Machine Perfusion Ameliorates Hepatic Ischaemia Reperfusion Injury.
- Author
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Clarke G, Mergental H, Hann A, Perera MTPR, Afford SC, and Mirza DF
- Subjects
- Animals, Humans, Graft Survival, Liver blood supply, Liver Transplantation methods, Organ Preservation methods, Perfusion, Reperfusion Injury therapy
- Abstract
The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ-it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4-10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft's response to this.
- Published
- 2021
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3. Reply to 'Hypothermic machine perfusion before viability testing of previously discarded human livers'.
- Author
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Mergental H, Laing RW, Afford SC, and Mirza DF
- Subjects
- Humans, Perfusion, Liver, Liver Transplantation
- Published
- 2021
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- View/download PDF
4. Lactate measurements in an integrated perfusion machine for human livers.
- Author
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Stephenson BTF, Afford SC, Mergental H, and Mirza DF
- Subjects
- Humans, Perfusion, Lactates, Liver
- Published
- 2020
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5. Transplantation of discarded livers following viability testing with normothermic machine perfusion.
- Author
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Mergental H, Laing RW, Kirkham AJ, Perera MTPR, Boteon YL, Attard J, Barton D, Curbishley S, Wilkhu M, Neil DAH, Hübscher SG, Muiesan P, Isaac JR, Roberts KJ, Abradelo M, Schlegel A, Ferguson J, Cilliers H, Bion J, Adams DH, Morris C, Friend PJ, Yap C, Afford SC, and Mirza DF
- Subjects
- Aged, Female, Humans, Liver metabolism, Male, Middle Aged, Non-Randomized Controlled Trials as Topic, Organ Preservation statistics & numerical data, Perfusion methods, Prospective Studies, Survival Analysis, Temperature, Time Factors, Tissue and Organ Harvesting methods, Tissue and Organ Harvesting statistics & numerical data, Graft Survival physiology, Liver physiology, Liver Function Tests methods, Liver Transplantation methods, Organ Preservation methods, Tissue Donors statistics & numerical data
- Abstract
There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.
- Published
- 2020
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6. The impact on the bioenergetic status and oxidative-mediated tissue injury of a combined protocol of hypothermic and normothermic machine perfusion using an acellular haemoglobin-based oxygen carrier: The cold-to-warm machine perfusion of the liver.
- Author
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Boteon YL, Laing RW, Schlegel A, Wallace L, Smith A, Attard J, Bhogal RH, Reynolds G, Perera MTPR, Muiesan P, Mirza DF, Mergental H, and Afford SC
- Subjects
- Adult, Aged, Blood Substitutes, Cadaver, Female, Humans, Liver blood supply, Liver Transplantation, Male, Middle Aged, Oxidative Stress, Reperfusion Injury prevention & control, Tissue Donors, Cold Ischemia, Energy Metabolism, Hemoglobins metabolism, Liver metabolism, Organ Preservation methods, Oxygen metabolism, Perfusion methods, Warm Ischemia
- Abstract
Introduction: The combination of hypothermic and normothermic machine perfusion (HMP+NMP) of the liver provides individual benefits of both techniques, improving the rescue of marginal organs. The aim of this study was to investigate the effect on the bioenergetic status and the oxidative-mediated tissue injury of an uninterrupted combined protocol of HMP+NMP using a single haemoglobin-based oxygen carrier (HBOC)-based perfusate., Methods: Ten discarded human donor livers had either 2 hours of dual hypothermic oxygenated perfusion (D-HOPE) with sequential controlled rewarming (COR) and then NMP using the HBOC-based perfusate uninterruptedly (cold-to-warm group); or 2 hours of hypothermic oxygenated perfusion (HOPE) with an oxygen carrier-free perfusate, followed by perfusate exchange and then NMP with an HBOC-based perfusate. Markers of liver function, tissue adenosine triphosphate (ATP) levels and tissue injury were systematically assessed., Results: The hypothermic phase downregulated mitochondrial respiration and increased ATP levels in both groups. The cold-to-warm group presented higher arterial vascular resistance during rewarming/NMP (p = 0.03) with a trend of lower arterial flow (p = 0.09). At the end of NMP tissue expression of markers of reactive oxygen species production, oxidative injury and inflammation were comparable between the groups., Conclusion: The uninterrupted combined protocol of HMP+NMP using an HBOC-based perfusate-cold-to-warm MP-mitigated the oxidative-mediated tissue injury and enhanced hepatic energy stores, similarly to an interrupted combined protocol; however, it simplified the logistics of this combination and may favour its clinical applicability., Competing Interests: The machine perfusion research was funded by the Queen Elizabeth Hospital Birmingham Charity’s Liver Foundation UK. YLB is funded by the NIHR Wellcome Trust. Hemopure® was provided free of charge by Hemoglobin Oxygen Therapeutics LLC. The company has not had any role in the study design, data collection, analysis, interpretation or manuscript preparation. The authors are employees of the University Hospital Birmingham or the University of Birmingham and none of them received any payment or have any conflict of interest related to this manuscript. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2019
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7. Severe Unresolved Cholestasis Due to Unknown Etiology Leading to Early Allograft Failure Within the First 3 Months of Liver Transplantation.
- Author
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Angelico R, Gerlach UA, Gunson BK, Neil D, Mergental H, Isaac J, Muiesan P, Mirza D, and Perera MTP
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- Adolescent, Adult, Aged, Biopsy, Female, Follow-Up Studies, Graft Rejection immunology, Graft Survival, Humans, Male, Middle Aged, Postoperative Complications, Postoperative Period, Proportional Hazards Models, Prospective Studies, Retrospective Studies, Risk, Time Factors, Treatment Outcome, Ultrasonography, Doppler, United Kingdom, Young Adult, Cholestasis complications, Cholestasis etiology, Liver pathology, Liver Transplantation adverse effects
- Abstract
Background: Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge., Methods: This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 μmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed., Results: All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%)., Conclusions: Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.
- Published
- 2018
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8. The Emerging Importance of Liver Sinusoidal Endothelial Cells in Regulating Injury during Machine Perfusion of Deceased Liver Donors.
- Author
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Bhogal RH, Mergental H, Mirza DF, and Afford SC
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- Animals, Donor Selection, Endothelial Cells metabolism, Endothelial Cells pathology, Graft Survival, Humans, Liver metabolism, Liver pathology, Liver Transplantation adverse effects, Organ Preservation adverse effects, Organ Preservation instrumentation, Perfusion adverse effects, Perfusion instrumentation, Reperfusion Injury etiology, Reperfusion Injury metabolism, Reperfusion Injury pathology, Risk Factors, Signal Transduction, Treatment Outcome, Waiting Lists, Endothelial Cells transplantation, Liver surgery, Liver Transplantation methods, Organ Preservation methods, Perfusion methods, Reperfusion Injury prevention & control, Tissue Donors supply & distribution
- Abstract
While majority of liver transplants worldwide continue to be performed using deceased donor organs, the demands for donor livers continues to exceed the current supply. In an attempt to maximize the number of potentially usable donor livers and expand the current donor pool, there is intense global research by various groups exploring the role of machine perfusion in the liver transplantation, particularly with respect to the machine perfusion of extended-criteria liver donors. In this review, the authors summarize the current field of machine perfusion strategies as applied to deceased donor liver transplantation and how therapeutic targeting of the liver sinusoidal endothelial cell may improve the quality of donor livers., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2018
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9. An effective protocol for pharmacological defatting of primary human hepatocytes which is non-toxic to cholangiocytes or intrahepatic endothelial cells.
- Author
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Boteon YL, Wallace L, Boteon APCS, Mirza DF, Mergental H, Bhogal RH, and Afford S
- Subjects
- Bile Ducts cytology, Bile Ducts drug effects, Bile Ducts metabolism, Cell Survival drug effects, Cells, Cultured, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells metabolism, Epithelial Cells cytology, Epithelial Cells drug effects, Epithelial Cells metabolism, Fatty Acids metabolism, Fatty Liver metabolism, Hep G2 Cells, Hepatocytes cytology, Hepatocytes metabolism, Humans, Ketone Bodies metabolism, Liver cytology, Liver metabolism, Fats metabolism, Fatty Liver drug therapy, Hepatocytes drug effects, Liver drug effects, Triglycerides metabolism
- Abstract
Introduction: Pharmacological defatting of rat hepatocytes and hepatoma cell lines suggests that the same method could be used to ameliorate macrovesicular steatosis in moderate to severely fatty livers. However there is no data assessing the effects of those drugs on primary human liver cells. We aimed to determine the effectiveness of a pharmacological cocktail in reducing the in vitro lipid content of primary human hepatocytes (PHH). In addition we sought to determine the cytotoxicity of the cocktail towards non-parenchymal liver cells., Methods: Steatosis was induced in PHH by supplementation with a combination of saturated and unsaturated free fatty acids. This was followed by addition of a defatting drug cocktail for up to 48 hours. The same experimental method was used with human intra-hepatic endothelial cells (HIEC) and human cholangiocytes. MTT assay was used to assess cell viability, triglyceride quantification and oil red O staining were used to determine intracellular lipids content whilst ketone bodies were measured in the supernatants following experimentation., Results: Incubation of fat loaded PHH with the drugs over 48 hours reduced the intracellular lipid area by 54%, from 12.85% to 5.99% (p = 0.002) (percentage of total oil red O area), and intracellular triglyceride by 35%, from 28.24 to 18.30 nmol/million of cells (p<0.001). Total supernatant ketone bodies increased 1.4-fold over 48 hours in the defatted PHH compared with vehicle controls (p = 0.002). Moreover incubation with the drugs for 48 hours increased the viability of PHH by 11%, cholangiocytes by 25% whilst having no cytotoxic effects on HIEC., Conclusion: These data demonstrate that pharmacological intervention can significantly decrease intracellular lipid content of PHH, increase fatty acids β-oxidation whilst being non-toxic to PHH, HIEC or cholangiocytes., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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10. A randomized trial of normothermic preservation in liver transplantation.
- Author
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Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, Chiocchia V, Dutton SJ, García-Valdecasas JC, Heaton N, Imber C, Jassem W, Jochmans I, Karani J, Knight SR, Kocabayoglu P, Malagò M, Mirza D, Morris PJ, Pallan A, Paul A, Pavel M, Perera MTPR, Pirenne J, Ravikumar R, Russell L, Upponi S, Watson CJE, Weissenbacher A, Ploeg RJ, and Friend PJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Allografts pathology, Allografts physiopathology, Allografts standards, Bile Ducts pathology, Bile Ducts physiology, Bile Ducts physiopathology, Female, Graft Survival, Humans, Length of Stay, Liver enzymology, Liver Transplantation adverse effects, Male, Middle Aged, Organ Preservation adverse effects, Perfusion, Survival Analysis, Tissue Donors supply & distribution, Tissue and Organ Harvesting adverse effects, Treatment Outcome, Waiting Lists, Young Adult, Allografts physiology, Liver physiology, Liver Transplantation methods, Organ Preservation methods, Temperature, Tissue and Organ Harvesting methods
- Abstract
Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.
- Published
- 2018
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11. Mechanisms of autophagy activation in endothelial cell and their targeting during normothermic machine liver perfusion.
- Author
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Boteon YL, Laing R, Mergental H, Reynolds GM, Mirza DF, Afford SC, and Bhogal RH
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- Autophagy drug effects, Humans, Liver blood supply, Liver cytology, Liver drug effects, Organ Preservation adverse effects, Organ Preservation methods, Perfusion adverse effects, Perfusion methods, Protective Agents pharmacology, Protective Agents therapeutic use, Reperfusion Injury etiology, Reperfusion Injury prevention & control, Signal Transduction drug effects, Signal Transduction physiology, Temperature, Autophagy physiology, Endothelial Cells physiology, Liver physiopathology, Liver Transplantation adverse effects, Reperfusion Injury physiopathology
- Abstract
Ischaemia-reperfusion injury (IRI) is the leading cause of injury seen in the liver following transplantation. IRI also causes injury following liver surgery and haemodynamic shock. The first cells within the liver to be injured by IRI are the liver sinusoidal endothelial cells (LSEC). Recent evidence suggests that LSEC co-ordinate and regulates the livers response to a variety of injuries. It is becoming increasingly apparent that the cyto-protective cellular process of autophagy is a key regulator of IRI. In particular LSEC autophagy may be an essential gatekeeper to the development of IRI. The recent availability of liver perfusion devices has allowed for the therapeutic targeting of autophagy to reduce IRI. In particular normothermic machine liver perfusion (NMP-L) allow the delivery of pharmacological agents to donor livers whilst maintaining physiological temperature and hepatic flow rates. In this review we summarise the current understanding of endothelial autophagy and how this may be manipulated during NMP-L to reduce liver IRI., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
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- 2017
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12. Viability testing and transplantation of marginal livers (VITTAL) using normothermic machine perfusion: study protocol for an open-label, non-randomised, prospective, single-arm trial.
- Author
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Laing RW, Mergental H, Yap C, Kirkham A, Whilku M, Barton D, Curbishley S, Boteon YL, Neil DA, Hübscher SG, Perera MTPR, Muiesan P, Isaac J, Roberts KJ, Cilliers H, Afford SC, and Mirza DF
- Subjects
- Feasibility Studies, Humans, Non-Randomized Controlled Trials as Topic, Perfusion methods, Practice Guidelines as Topic, Prospective Studies, Time Factors, Tissue Survival, Tissue and Organ Procurement methods, Transplant Recipients, Liver metabolism, Liver Transplantation, Organ Preservation methods, Tissue and Organ Procurement standards
- Abstract
Introduction: The use of marginal or extended criteria donor livers is increasing. These organs carry a greater risk of initial dysfunction and early failure, as well as inferior long-term outcomes. As such, many are rejected due to a perceived risk of use and use varies widely between centres. Ex situ normothermic machine perfusion of the liver (NMP-L) may enable the safe transplantation of organs that meet defined objective criteria denoting their high-risk status and are currently being declined for use by all the UK transplant centres., Methods and Analysis: Viability testing and transplantation of marginal livers is an open-label, non-randomised, prospective, single-arm trial designed to determine whether currently unused donor livers can be salvaged and safely transplanted with equivalent outcomes in terms of patient survival. The procured rejected livers must meet predefined criteria that objectively denote their marginal condition. The liver is subjected to NMP-L following a period of static cold storage. Organs metabolising lactate to ≤2.5 mmol/L within 4 hours of the perfusion commencing in combination with two or more of the following parameters-bile production, metabolism of glucose, a hepatic arterial flow rate ≥150 mL/min and a portal venous flow rate ≥500 mL/min, a pH ≥7.30 and/or maintain a homogeneous perfusion-will be considered viable and transplanted into a suitable consented recipient. The coprimary outcome measures are the success rate of NMP-L to produce a transplantable organ and 90-day patient post-transplant survival., Ethics and Dissemination: The protocol was approved by the National Research Ethics Service (London-Dulwich Research Ethics Committee, 16/LO/1056), the Medicines and Healthcare Products Regulatory Agency and is endorsed by the National Health Service Blood and Transplant Research, Innovation and Novel Technologies Advisory Group. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: NCT02740608; Pre-results., Competing Interests: Competing interests: RWL and YB receive salary as Wellcome Trust research fellows., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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13. The Use of an Acellular Oxygen Carrier in a Human Liver Model of Normothermic Machine Perfusion.
- Author
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Laing RW, Bhogal RH, Wallace L, Boteon Y, Neil DAH, Smith A, Stephenson BTF, Schlegel A, Hübscher SG, Mirza DF, Afford SC, and Mergental H
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- Adult, Aged, Apoptosis, Blood Substitutes toxicity, Cells, Cultured, Energy Metabolism drug effects, Female, Hemoglobins toxicity, Hepatectomy, Humans, Liver metabolism, Liver pathology, Liver surgery, Male, Middle Aged, Necrosis, Organ Preservation adverse effects, Oxygen Consumption drug effects, Perfusion adverse effects, Reactive Oxygen Species metabolism, Reperfusion Injury etiology, Reperfusion Injury metabolism, Reperfusion Injury pathology, Time Factors, Tissue Survival drug effects, Blood Substitutes pharmacology, Hemoglobins pharmacology, Liver drug effects, Organ Preservation methods, Perfusion methods, Reperfusion Injury prevention & control
- Abstract
Background: Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L., Methods: Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury., Results: The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species, and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure., Conclusions: Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid.
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- 2017
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14. Long-term follow-up after endovascular treatment of hepatic venous outflow obstruction following liver transplantation.
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Pitchaimuthu M, Roll GR, Zia Z, Olliff S, Mehrzad H, Hodson J, Gunson BK, Perera MT, Isaac JR, Muiesan P, Mirza DF, and Mergental H
- Subjects
- Adult, Aged, Databases, Factual, End Stage Liver Disease complications, Follow-Up Studies, Graft Survival, Humans, Immunosuppression Therapy, Middle Aged, Pressure, Prospective Studies, Retrospective Studies, Treatment Outcome, End Stage Liver Disease surgery, Endovascular Procedures methods, Hepatic Veins surgery, Liver blood supply, Liver Transplantation adverse effects
- Abstract
Hepatic venous outflow obstruction (HVOO) is a rare complication after liver transplantation (LT) associated with significant morbidity and reduced graft survival. Endovascular intervention has become the first-line treatment for HVOO, but data on long-term outcomes are lacking. We have analysed outcomes after endovascular intervention for HVOO in 905 consecutive patients who received 965 full-size LT at our unit from January 2007 to June 2014. There were 27 (3%) patients who underwent hepatic venogram for suspected HVOO, with persistent ascites being the most common symptom triggering the investigation (n = 19, 70%). Of those, only 10 patients demonstrated either stricture or pressure gradient over 10 mmHg on venogram, which represents a 1% incidence of HVOO. The endovascular interventions were balloon dilatation (n = 3), hepatic vein stenting (n = 4) and stenting with dilatation (n = 3). Two patients required restenting due to stent migration. The symptoms of HVOO completely resolved in all but one patient, with a median follow-up period of 74 (interquartile range 39-89) months. There were no procedure-related complications or mortality. In conclusion, the incidence of HVOO in patients receiving full-size LT is currently very low. Endovascular intervention is an effective and safe procedure providing symptom relief with long-lasting primary patency., (© 2016 Steunstichting ESOT.)
- Published
- 2016
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15. N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion.
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Clarke, George, Mao, Jingwen, Fan, Yiyu, Hann, Angus, Gupta, Amita, Nutu, Anisa, Buckel, Erwin, Kayani, Kayani, Murphy, Nicholas, Bangash, Mansoor N., Casey, Anna L., Wootton, Isla, Lawson, Alexander J., Dasari, Bobby V. M., Perera, M. Thamara P. R., Mergental, Hynek, and Afford, Simon C.
- Subjects
IRON oxidation ,LIVER ,ACETYLCYSTEINE ,PERFUSION ,LIVER transplantation ,ANTIOXIDANTS ,ERYTHROCYTES - Abstract
Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87–102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90–184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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16. Machine perfusion of the liver and bioengineering.
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Schlegel, Andrea, Mergental, Hynek, Fondevila, Constantino, Porte, Robert J., Friend, Peter J., and Dutkowski, Philipp
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BIOENGINEERING , *PERFUSION , *LIVER , *LIVER cells , *INJURY complications , *KIDNEY transplantation - Abstract
With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic preservation approaches have demonstrated various benefits, including improving liver function and graft survival, and reducing liver injury and post-transplant complications. Consequently, organ perfusion techniques are being used in clinical practice in many countries. Despite this success, a proportion of livers do not meet current viability tests required for transplantation, even with the use of modern perfusion techniques. Therefore, devices are needed to further optimise machine liver perfusion – one promising option is to prolong machine liver perfusion for several days, with ex situ treatment of perfused livers. For example, stem cells, senolytics, or molecules targeting mitochondria or downstream signalling can be administered during long-term liver perfusion to modulate repair mechanisms and regeneration. Besides, today's perfusion equipment is also designed to enable the use of various liver bioengineering techniques, to develop scaffolds or for their re-cellularisation. Cells or entire livers can also undergo gene modulation to modify animal livers for xenotransplantation, to directly treat injured organs or to repopulate such scaffolds with "repaired" autologous cells. This review first discusses current strategies to improve the quality of donor livers, and secondly reports on bioengineering techniques to design optimised organs during machine perfusion. Current practice, as well as the benefits and challenges associated with these different perfusion strategies are discussed. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery
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Boteon, Yuri L., Attard, Joseph, Boteon, Amanda P. C. S., Wallace, Lorraine, Reynolds, Gary, Hubscher, Stefan, Mirza, Darius F., Mergental, Hynek, Bhogal, Ricky H., and Afford, Simon C.
- Subjects
Male ,Living Donors ,Humans ,Nicotinamide Phosphoribosyltransferase ,Perylene ,Pretreatment Assessment and Conditions ,Anthracenes ,Phenylurea Compounds ,Colforsin ,Original Articles ,Organ Preservation ,Middle Aged ,Allografts ,Lipid Metabolism ,Liver Transplantation ,Fatty Liver ,Perfusion ,Butyrates ,Pharmaceutical Solutions ,Thiazoles ,Liver ,Reperfusion Injury ,Tissue and Organ Harvesting ,Feasibility Studies ,Original Article ,Female - Abstract
Strategies to increase the use of steatotic donor livers are required to tackle the mortality on the transplant waiting list. We aimed to test the efficacy of pharmacological enhancement of the lipid metabolism of human livers during ex situ normothermic machine perfusion to promote defatting and improve the functional recovery of the organs. Because of steatosis, 10 livers were discarded and were allocated either to a defatting group that had the perfusate supplemented with a combination of drugs to enhance lipid metabolism or to a control group that received perfusion fluid with vehicle only. Steatosis was assessed using tissue homogenate and histological analyses. Markers for lipid oxidation and solubilization, oxidative injury, inflammation, and biliary function were evaluated by enzyme‐linked immunosorbent assay, immunohistochemistry, and in‐gel protein detection. Treatment reduced tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours. This effect was driven by increased solubility of the triglycerides (P = 0.04), and mitochondrial oxidation as assessed by increased ketogenesis (P = 0.008) and adenosine triphosphate synthesis (P = 0.01) were associated with increased levels of the enzymes acyl‐coenzyme A oxidase 1, carnitine palmitoyltransferase 1A, and acetyl‐coenzyme A synthetase. Concomitantly, defatted livers exhibited enhanced metabolic functional parameters such as urea production (P = 0.03), lower vascular resistance, lower release of alanine aminotransferase (P = 0.049), and higher bile production (P = 0.008) with a higher bile pH (P = 0.03). The treatment down‐regulated the expression of markers for oxidative injury as well as activation of immune cells (CD14; CD11b) and reduced the release of inflammatory cytokines in the perfusate (tumor necrosis factor α; interleukin 1β). In conclusion, pharmacological enhancement of intracellular lipid metabolism during normothermic machine perfusion decreased the lipid content of human livers within 6 hours. It also improved the intracellular metabolic support to the organs, leading to successful functional recovery and decreased expression of markers of reperfusion injury.
- Published
- 2018
18. The role of normothermic machine perfusion in liver transplantation.
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Martins, Paulo N., Buchwald, Julianna E., Mergental, Hynek, Vargas, Luciano, and Quintini, Cristiano
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LIVER surgery ,CLINICAL trials ,LIVER ,PRESERVATION of organs, tissues, etc. ,TREATMENT effectiveness ,LIVER transplantation ,PERFUSION ,TRANSPLANTATION of organs, tissues, etc. - Abstract
To expand the donor pool of suitable organs for transplantation, there is an increased interest in utilizing extended criteria donor grafts (ECD). Ex-situ machine perfusion has shown to be a promising new modality in the organ preservation field to reduce injury and recover ECD liver grafts. Machine perfusion (MP) is considered a significant improvement in the field of transplantation over the past 20 years. Normothermic machine perfusion has entered the clinical arena in the last decade and has shown promising results to improve the quality of marginal organs and to increase the pool of liver grafts. It allows assessment of viability and function of grafts prior to transplantation. In addition, it has the potential to serve as a platform for pharmacologic organ treatment and graft optimization. Machine perfusion moved from the experimental phase to a more mature phase after safety was confirmed by initial clinical trials. Now, it is time to confirm its superiority and cost-effectiveness before a broader clinical use. In this paper we review the history, current status including outcomes of all clinical trials, limitations, and future trends of normothermic machine preservation. [ABSTRACT FROM AUTHOR]
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- 2020
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19. Honoring the contract with our patients: outcome after repeated re-transplantation of the liver
- Author
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Eguchi, Susumu, Soyama, Akihiko, Mergental, Hynek, van den Berg, Aad P., Scheenstra, Rene, Porte, Robert J., Slooff, Maarten J. H., Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
multiple ,re-transplantation ,COMPLICATIONS ,surgical procedures, operative ,SURVIVAL ,EXPERIENCE ,FAILURE ,ADULTS ,repeated ,liver ,HEPATIC RETRANSPLANTATION ,SINGLE-CENTER - Abstract
The aim of this study was to describe the outcome after repeated orthotopic liver re-transplantations (re-OLT) in a population of adults and children, and to determine whether such repeated re-transplantations are an effective treatment or should be considered futile. In a consecutive series of 867 patients, 628 adults and 239 children, who underwent OLT at the University Medical Center Groningen, 23 patients (2.7%), 10 adults and 13 children, underwent more than two re-transplantations of the liver between March 1979 and October 2008. All 23 patients had a second re-transplantation, and seven of them received a third transplant. The overall actuarial patient survival at 1, 5, and 10 yr after primary OLT was 96%, 87%, and 71%, respectively. The overall actuarial patient survival after the second re-OLT was 78%, 73%, and 67%, respectively. Sixteen patients (70%) survived long term. However, for the 23 repeated re-transplantation patients, 76 grafts were used. In a simulation calculation, it was shown that honoring the initial commitment to the 23 patients ultimately led to more surviving patients and less death than if treatment of the original patients was stopped after the first re-transplantation and the remaining grafts were allocated to other primary graft recipients.
- Published
- 2011
20. Is Hepatocyte Necrosis a Good Marker of Donor Liver Viability During Machine Perfusion?
- Author
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Neil, Desley A.H., Mergental, Hynek, Hann, Angus, Laing, Richard W, Hartog, Hermien, Mirza, Darius F, and Perera, M. Thamara P.R.
- Subjects
LIVER ,PERFUSION ,NECROSIS ,MACHINERY - Abstract
They use histological assessment of hepatocyte necrosis as the basis of determining whether a liver is nonviable and conclude that lactate clearance during NMP is not able to differentiate between viable and nonviable livers. In conclusion, significant hepatocyte necrosis in DBD grafts can be successfully transplanted following NMP, indicating that hepatocyte necrosis I per se i is not a reliable surrogate for viability of a donor liver. [Extracted from the article]
- Published
- 2022
- Full Text
- View/download PDF
21. Comment on: Static cold storage compared with normothermic machine perfusion of the liver and effect on ischaemic-type biliary lesions after transplantation: a propensity-score matched study.
- Author
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Hann, Angus, Raza, Syed Soulat, Sneiders, Dimitri, Nutu, Anisa, Mergental, Hynek, Mirza, Darius F., Hartog, Hermien, and Perera, M. Thamara Pr
- Subjects
COLD storage ,PERFUSION ,LIVER ,REPERFUSION injury ,MACHINERY - Published
- 2022
- Full Text
- View/download PDF
22. Correction: The impact on the bioenergetic status and oxidative-mediated tissue injury of a combined protocol of hypothermic and normothermic machine perfusion using an acellular haemoglobin-based oxygen carrier: The cold-to-warm machine perfusion of the liver
- Author
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Boteon, Yuri L., Laing, Richard W., Schlegel, Andrea, Wallace, Lorraine, Smith, Amanda, Attard, Joseph, Bhogal, Ricky H., Reynolds, Gary, Thamara PR Perera, M., Muiesan, Paolo, Mirza, Darius F., Mergental, Hynek, and Afford, Simon C.
- Subjects
OXYGEN carriers ,PERFUSION ,LIVER ,TISSUES ,WOUNDS & injuries - Published
- 2020
- Full Text
- View/download PDF
23. A randomized trial of normothermic preservation in liver transplantation
- Author
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Nasralla, David, Coussios, Constantin C, Mergental, Hynek, Akhtar, M Zeeshan, Butler, Andrew J, Ceresa, Carlo DL, Chiocchia, Virginia, Dutton, Susan J, García-Valdecasas, Juan Carlos, Heaton, Nigel, Imber, Charles, Jassem, Wayel, Jochmans, Ina, Karani, John, Knight, Simon R, Kocabayoglu, Peri, Malagò, Massimo, Mirza, Darius, Morris, Peter J, Pallan, Arvind, Paul, Andreas, Pavel, Mihai, Perera, M Thamara PR, Pirenne, Jacques, Ravikumar, Reena, Russell, Leslie, Upponi, Sara, Watson, Chris JE, Weissenbacher, Annemarie, Ploeg, Rutger J, Friend, Peter J, and Consortium For Organ Preservation In Europe
- Subjects
Adult ,Aged, 80 and over ,Male ,Adolescent ,Waiting Lists ,Graft Survival ,Temperature ,Organ Preservation ,Length of Stay ,Middle Aged ,Allografts ,Survival Analysis ,Tissue Donors ,3. Good health ,Liver Transplantation ,Perfusion ,Young Adult ,Treatment Outcome ,Liver ,Tissue and Organ Harvesting ,Humans ,Female ,Bile Ducts ,Aged - Abstract
Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.
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