scholarly journals Hypothermic Oxygenated Machine Perfusion of Extended Criteria Kidney Allografts from Brain Dead Donors: Protocol for a Prospective Pilot Study (Preprint)

2019 ◽  
Author(s):  
Franziska Alexandra Meister ◽  
Zoltan Czigany ◽  
Jan Bednarsch ◽  
Jörg Böcker ◽  
Iakovos Amygdalos ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Pilot Study ◽  
Brain Death ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Extended Criteria Donor ◽  
Prospective Pilot Study ◽  
Clinical Series

BACKGROUND Kidney transplantation is the only curative treatment option for end-stage renal disease. The unavailability of adequate organs for transplantation has resulted in a substantial organ shortage. As such, kidney donor allografts that would have previously been deemed unsuitable for transplantation have become an essential organ pool of extended criteria donor allografts that are now routinely being transplanted on a global scale. However, these extended criteria donor allografts are associated with significant graft-related complications. As a result, hypothermic oxygenated machine perfusion (HOPE) has emerged as a powerful, novel technique in organ preservation, and it has recently been tested in preclinical trials in kidney transplantation. In addition, HOPE has already provided promising results in a few clinical series of liver transplantations where the liver was donated after cardiac death. OBJECTIVE The present trial is an investigator-initiated prospective pilot study on the effects of HOPE on extended criteria donor allografts donated after brain death and used in kidney transplantation. METHODS A total of 15 kidney allografts with defined inclusion/exclusion criteria will be submitted to two hours of HOPE via the renal artery before implantation, and are going to be compared to a case-matched group of 30 patients (1:2 matching) who had kidneys transplanted after conventional cold storage. Primary (posttransplant dialysis within 7 days) and secondary (postoperative complications, early graft function, duration of hospital and intensive care unit stay, and six-month graft survival) endpoints will be analyzed within a six-month follow-up period. The extent of ischemia-reperfusion injury will be assessed using kidney tissue, perfusate, and serum samples taken during the perioperative phase of kidney transplantation RESULTS The results of this trial are expected in the first quarter of 2020 and will be presented at national and international scientific meetings and published in international peer-reviewed medical journals. The trial was funded in the third quarter of 2017 and patient enrollment is currently ongoing. CONCLUSIONS This prospective study is designed to explore the effects of HOPE on extended criteria donor kidney allografts donated after brain death. The present report represents the preresults phase. CLINICALTRIAL Clinicaltrials.gov NCT03378817; https://clinicaltrials.gov/ct2/show/NCT03378817

scholarly journals Hypothermic Oxygenated Machine Perfusion of Extended Criteria Kidney Allografts from Brain Dead Donors: Protocol for a Prospective Pilot Study

10.2196/14622 ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. e14622 ◽  
Author(s):  
Franziska Alexandra Meister ◽  
Zoltan Czigany ◽  
Jan Bednarsch ◽  
Jörg Böcker ◽  
Iakovos Amygdalos ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Pilot Study ◽  
Brain Death ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Extended Criteria Donor ◽  
Prospective Pilot Study ◽  
Clinical Series

Background Kidney transplantation is the only curative treatment option for end-stage renal disease. The unavailability of adequate organs for transplantation has resulted in a substantial organ shortage. As such, kidney donor allografts that would have previously been deemed unsuitable for transplantation have become an essential organ pool of extended criteria donor allografts that are now routinely being transplanted on a global scale. However, these extended criteria donor allografts are associated with significant graft-related complications. As a result, hypothermic oxygenated machine perfusion (HOPE) has emerged as a powerful, novel technique in organ preservation, and it has recently been tested in preclinical trials in kidney transplantation. In addition, HOPE has already provided promising results in a few clinical series of liver transplantations where the liver was donated after cardiac death. Objective The present trial is an investigator-initiated prospective pilot study on the effects of HOPE on extended criteria donor allografts donated after brain death and used in kidney transplantation. Methods A total of 15 kidney allografts with defined inclusion/exclusion criteria will be submitted to two hours of HOPE via the renal artery before implantation, and are going to be compared to a case-matched group of 30 patients (1:2 matching) who had kidneys transplanted after conventional cold storage. Primary (posttransplant dialysis within 7 days) and secondary (postoperative complications, early graft function, duration of hospital and intensive care unit stay, and six-month graft survival) endpoints will be analyzed within a six-month follow-up period. The extent of ischemia-reperfusion injury will be assessed using kidney tissue, perfusate, and serum samples taken during the perioperative phase of kidney transplantation Results The results of this trial are expected in the first quarter of 2020 and will be presented at national and international scientific meetings and published in international peer-reviewed medical journals. The trial was funded in the third quarter of 2017 and patient enrollment is currently ongoing. Conclusions This prospective study is designed to explore the effects of HOPE on extended criteria donor kidney allografts donated after brain death. The present report represents the preresults phase. Trial Registration Clinicaltrials.gov NCT03378817; https://clinicaltrials.gov/ct2/show/NCT03378817

scholarly journals The Use of the Oxygenated AirdriveTM Machine Perfusion System in Kidney Graft Preservation: A Clinical Pilot Study

2020 ◽  
Vol 61 (6) ◽  
pp. 153-162
Author(s):  
Julia H.E. Houtzager ◽  
Sebastiaan David Hemelrijk ◽  
Ivo C.J.H. Post ◽  
Mirza M Idu ◽  
Frederike J. Bemelman ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Pilot Study ◽  
Adverse Events ◽  
Deceased Donor ◽  
Kidney Graft ◽  
Machine Perfusion ◽  
End Points ◽  
Viable Solution ◽  
Technical Failures

Background: The shortage of donor kidneys has led to the use of marginal donors, e.g., those whose kidneys are donated after circulatory death. Preservation of the graft by hypothermic machine perfusion (HMP) provides a viable solution to reduce warm ischemic damage. This pilot study was undertaken to assess the feasibility and patient safety of the AirdriveTM HMP system in clinical kidney transplantation. Methods: Five deceased-donor kidneys were preserved using the oxygenated Airdrive HMP system between arrival at the recipient center (Amsterdam UMC) and implantation in the patient. The main study end-points were adverse effects due to the use of Airdrive HMP. Secondary end-points were clinical outcomes and perfusion parameters. All events occurring during the transplantation procedure or within 1 month of follow-up were monitored. Results: Five patients were included in this pilot study. No technical failures were observed during the preservation period using the Airdrive HMP. Mean perfusion parameters were: duration 8.5 h (3–15 h), pressure 25 mm Hg (18–25 mm Hg), flow 49.77 mL/min (19–58 mL/min), resistance 0.57 mm Hg/min/mL (0.34–1.3 mm Hg/min/mL), and temperature 8.2 °C (2–13°C). Mean cold ischemia time (CIT) was 20.2 h (11–29.5 h). No adverse events or technical failures were observed during preservation and transplantation or during the 1-month follow-up. Conclusions: This pilot study showed the feasibility of the use of the Airdrive HMP system with no adverse events in clinical kidney transplantation.

Pharmacogenetic-based strategy using de novo tacrolimus once daily after kidney transplantation: prospective pilot study

2016 ◽  
Vol 17 (9) ◽  
pp. 1019-1027 ◽  
Author(s):  
Martine De Meyer ◽  
Vincent Haufroid ◽  
Nada Kanaan ◽  
Tom Darius ◽  
Antoine Buemi ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Pilot Study ◽  
De Novo ◽  
Once Daily ◽  
Prospective Pilot Study

scholarly journals Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

2020 ◽  
Vol 9 (3) ◽  
pp. 846 ◽  
Author(s):  
Zoltan Czigany ◽  
Isabella Lurje ◽  
Moritz Schmelzle ◽  
Wenzel Schöning ◽  
Robert Öllinger ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Hypothermic Machine Perfusion ◽  
Critical Organ

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

The effect of pulsatile pump perfusion on hepatitis C transmission in kidney transplantation: A prospective pilot study

2020 ◽  
Vol 34 (8) ◽  
Author(s):  
Rachel C. Forbes ◽  
Beatrice P. Concepcion ◽  
Deana Clapper ◽  
Bernard J. DuBray ◽  
Saed Shawar ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Hepatitis C ◽  
Pilot Study ◽  
Pulsatile Pump ◽  
Prospective Pilot Study

scholarly journals Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion

2020 ◽  
Vol 9 (6) ◽  
pp. 1864 ◽  
Author(s):  
Anna Zhang ◽  
Cailah Carroll ◽  
Siavash Raigani ◽  
Negin Karimian ◽  
Viola Huang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ischemia Reperfusion ◽  
Energy Charge ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Ex Situ ◽  
Glutathione Metabolism ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Tissue Concentrations

Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as a platform to rehabilitate discarded or extended-criteria livers prior to transplantation, though there is a lack of data guiding the utilization of different perfusion modalities and therapeutics. Since amino acid derivatives involved in inflammatory and antioxidant pathways are critical in IRI, we analyzed differences in amino acid metabolism in seven discarded non-steatotic human livers during normothermic- (NMP) and subnormothermic-machine perfusion (SNMP) using data from untargeted metabolomic profiling. We found notable differences in tryptophan, histamine, and glutathione metabolism. Greater tryptophan metabolism via the kynurenine pathway during NMP was indicated by significantly higher kynurenine and kynurenate tissue concentrations compared to pre-perfusion levels. Livers undergoing SNMP demonstrated impaired glutathione synthesis indicated by depletion of reduced and oxidized glutathione tissue concentrations. Notably, ATP and energy charge ratios were greater in livers during SNMP compared to NMP. Given these findings, several targeted therapeutic interventions are proposed to mitigate IRI during liver machine perfusion and optimize marginal liver grafts during SNMP and NMP.

Machine perfusion in transplantation (Sponsor: Novartis Pharma GmbH, Nürnberg)

2018 ◽  
Vol 06 (01) ◽  
pp. 4-13
Keyword(s):  
Kidney Transplantation ◽  
Lung Transplantation ◽  
Organ Donation ◽  
Organ Transplantation ◽  
Standard Care ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Therapeutic Outcomes ◽  
Hypothermic Machine Perfusion ◽  
Transplantation Society

AbstractThe preservation of donor organs through machine perfusion (MP) creates new opportunities in transplantation medicine for the benefit of patients. In view of the organ shortage and the increasing number of marginal organs, there is a need to establish MP in Germany in order to improve organ utilization and therapeutic outcomes. In kidney transplantation, the use of MP can significantly improve 1-year survival. MP also offers advantages in liver, heart, and lung transplantation. As recommended by the Organ Donation Committee (KfO, Kommission für Organspende) of the German Transplantation Society (DTG, Deutsche Transplantationsgesellschaft) as well as the Permanent Committee on Organ Transplantation (StäKO, Ständige Kommission Organtransplantation), its use should be initially adopted in standard care in the form of hypothermic machine perfusion in kidney transplantation and then be further extended.

scholarly journals Hyperthermia-induced changes in liver physiology and metabolism: a rationale for hyperthermic machine perfusion

2020 ◽  
Vol 319 (1) ◽  
pp. G43-G50 ◽  
Author(s):  
Adam M. Thorne ◽  
Rinse Ubbink ◽  
Isabel M. A. Brüggenwirth ◽  
Maarten W. Nijsten ◽  
Robert J. Porte ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Core Body Temperature ◽  
Ischemia Reperfusion ◽  
Supply And Demand ◽  
Metabolic Effects ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Extended Criteria Donor ◽  
Different Temperatures ◽  
Donor Organs

Liver transplantation is the standard treatment for end-stage liver disease. However, due to the ongoing disparity between supply and demand for optimal donor organs, there is increasing usage of extended criteria donor organs, including steatotic liver grafts. To mitigate the increased risks associated with extended criteria donor livers, ex situ oxygenated machine perfusion (MP) has received increasing attention in recent years as an emerging platform for dynamic preservation, reconditioning, and viability assessment to increase organ utilization. MP can be applied at different temperatures. During hypothermic MP (4–12°C), liver metabolism is reduced, while oxygenation restores the intracellular levels of adenosine triphosphate. The liver is quickly “recharged” to support metabolism when at normothermia (35–37°C) and to ameliorate the detrimental effects of ischemia/reperfusion injury during transplantation. During normothermia, MP can be applied to assess hepatocellular and cholangiocellular viability. MP at hyperthermic (>38°C) temperatures (HyMP), however, remains relatively understudied. The liver is an important component in the regulation of core body temperature and, as such, displays significant physiological and metabolic changes in response to different temperatures. Hyperthermia may promote vasodilation, increase aerobic metabolism and induce production of protective molecules such as heat shock proteins. Therefore, HyMP could provide an attractive reconditioning strategy for steatotic livers. In this review, we describe current literature on the physiological and metabolic effects of the liver at hyperthermia for human, rodents, and pigs and provide a rationale for using therapeutic HyMP during isolated liver machine perfusion to recondition extended criteria donor livers, including steatotic livers, before transplantation.

scholarly journals Evaluation of Liver Quality after Circulatory Death versus Brain Death: A Comparative Preclinical Pig Model Study

2020 ◽  
Vol 21 (23) ◽  
pp. 9040
Author(s):  
Jérôme Danion ◽  
Raphael Thuillier ◽  
Géraldine Allain ◽  
Patrick Bruneval ◽  
Jacques Tomasi ◽  
...  
Keyword(s):  
Brain Death ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pig Model ◽  
Organ Shortage ◽  
Hepatic Transplantation ◽  
Model Study ◽  
Survival Pathways ◽  
Interesting Possibility ◽  
Circulatory Death

The current organ shortage in hepatic transplantation leads to increased use of marginal livers. New organ sources are needed, and deceased after circulatory death (DCD) donors present an interesting possibility. However, many unknown remains on these donors and their pathophysiology regarding ischemia reperfusion injury (IRI). Our hypothesis was that DCD combined with abdominal normothermic regional recirculation (ANOR) is not inferior to deceased after brain death (DBD) donors. We performed a mechanistic comparison between livers from DBD and DCD donors in a highly reproducible pig model, closely mimicking donor conditions encountered in the clinic. DCD donors were conditioned by ANOR. We determined that from the start of storage, pro-lesion pathways such as oxidative stress and cell death were induced in both donor types, but to a higher extent in DBD organs. Furthermore, pro-survival pathways, such as resistance to hypoxia and regeneration showed activation levels closer to healthy livers in DCD-ANOR rather than in DBD organs. These data highlight critical differences between DBD and DCD-ANOR livers, with an apparent superiority of DCD in terms of quality. This confirms our hypothesis and further confirms previously demonstrated benefits of ANOR. This encourages the expended use of DCD organs, particularly with ANOR preconditioning.

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