scholarly journals Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial)

BMJ Open ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. e028596 ◽  
Author(s):  
Yvonne de Vries ◽  
Tim A Berendsen ◽  
Masato Fujiyoshi ◽  
Aad P van den Berg ◽  
Hans Blokzijl ◽  
...  
Keyword(s):  
Oxygen Carrier ◽  
Trial Registration ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Viability Assessment ◽  
Post Transplant ◽  
Number Of Patients ◽  
Increased Risk ◽  
Normothermic Machine Perfusion ◽  
Registration Number

IntroductionExtended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C–12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy.Methods and analysisThis prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation.Ethics and disseminationThis protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration numberTrial registration numberNTR5972, NCT02584283.

scholarly journals Reply to “Ex situ normothermic machine perfusion of donor livers using a haemoglobin-based oxygen carrier: a viable alternative to red blood cells”

2018 ◽  
Vol 31 (11) ◽  
pp. 1283-1284 ◽  
Author(s):  
Dilmurodjon Eshmuminov ◽  
Filippo Leoni ◽  
Marcel André Schneider ◽  
Dustin Becker ◽  
Xavier Muller ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Oxygen Carrier ◽  
Viable Alternative ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion

scholarly journals Maximizing organs for donation: the potential for ex situ normothermic machine perfusion

QJM ◽  
2020 ◽  
Author(s):  
C Griffiths ◽  
W E Scott ◽  
S Ali ◽  
A J Fisher
Keyword(s):  
Ex Situ ◽  
The Novel ◽  
Machine Perfusion ◽  
Donor Organ ◽  
Organ Function ◽  
Novel Therapeutics ◽  
Number Of Patients ◽  
Normothermic Machine Perfusion ◽  
Target Side ◽  
Donor Organs

Abstract Currently, there is a shortfall in the number of suitable organs available for transplant resulting in a high number of patients on the active transplant waiting lists worldwide. To address this shortfall and increase the utilization of donor organs, the acceptance criteria for donor organs is gradually expanding including increased use of organs from donation after circulatory death. Use of such extended criteria donors and exposure of organs to more prolonged periods of warm or cold ischaemia also increases the risk of primary graft dysfunction occurring. Normothermic machine perfusion (NMP) offers a unique opportunity to objectively assess donor organ function outside the donor body and potentially recondition those deemed unsuitable on initial evaluation prior to implantation in the recipient. Furthermore, NMP provides a platform to support the use of established and novel therapeutics delivered directly to the organ, without the need to worry about potential deleterious ‘off-target’ side effects typically considered when treating the whole patient. This review will explore some of the novel therapeutics currently being added to perfusion platforms during NMP experimentally in an attempt to improve organ function and post-transplant outcomes.

scholarly journals Ex situ normothermic machine perfusion of donor livers using a haemoglobin-based oxygen carrier: a viable alternative to red blood cells

2018 ◽  
Vol 31 (11) ◽  
pp. 1281-1282 ◽  
Author(s):  
Yvonne de Vries ◽  
Otto B. van Leeuwen ◽  
Alix P. M. Matton ◽  
Masato Fujiyoshi ◽  
Vincent E. de Meijer ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Oxygen Carrier ◽  
Viable Alternative ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion

scholarly journals Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers

2019 ◽  
Vol 103 (7) ◽  
pp. 1405-1413 ◽  
Author(s):  
Alix P.M. Matton ◽  
Yvonne de Vries ◽  
Laura C. Burlage ◽  
Rianne van Rijn ◽  
Masato Fujiyoshi ◽  
...  
Keyword(s):  
Ex Situ ◽  
Machine Perfusion ◽  
Human Donor ◽  
Normothermic Machine Perfusion

Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion

2019 ◽  
Vol 270 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Otto B. van Leeuwen ◽  
Yvonne de Vries ◽  
Masato Fujiyoshi ◽  
Maarten W. N. Nijsten ◽  
Rinse Ubbink ◽  
...  
Keyword(s):  
High Risk ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Normothermic Machine Perfusion

scholarly journals Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

2020 ◽  
Vol 40 (03) ◽  
pp. 264-281 ◽  
Author(s):  
E. Bonaccorsi-Riani ◽  
I.M.A. Brüggenwirth ◽  
J.E. Buchwald ◽  
S. Iesari ◽  
P.N. Martins
Keyword(s):  
Liver Transplantation ◽  
Clinical Trials ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Correct Trial ◽  
Gold Standard Method ◽  
Liver Preservation ◽  
Mature Phase ◽  
Normothermic Machine Perfusion ◽  
Human Livers

AbstractMachine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.

P1769POST TRANSPLANT MALIGNANCY - OUR EXPERIENCE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
George Kurian ◽  
Gauri Shankar Jagadesh ◽  
Sandeep Sreedharan ◽  
Zachariah Paul ◽  
Anil Mathew ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Solid Organ ◽  
Oncogenic Viruses ◽  
Factors Affecting ◽  
Post Transplant ◽  
Transplant Patients ◽  
Cell Immunity ◽  
Number Of Patients ◽  
Increased Risk ◽  
Histological Variant

Abstract Background and Aims Cancer is now increasingly recognized as a major cause of death among patients especially after kidney transplantation. Malignancy represent a major burden in transplantation medicine. The Incidence is about 12 fold higher for PTLD and 3.5 fold higher for non-cutaneous malignancy compare to age-matched population. The increased risk is multifactorial and attributed to oncogenic viruses, immunosuppression and altered T cell immunity. In the era of longer graft survival and with the introduction of more potent immunosuppressive medication, malignancy represents a major burden. The incidence of malignancy after renal transplantation is 3 to 5 times higher. Incidence is higher in transplant patients even when compared to patients on hemodialysis. Aim: We attempted to assess the incidence of post-transplant malignancies in patients who underwent renal transplantation at our centre, along with studying the presentation, type and other factors affecting their development. Method We analysed data retrospectively from 626patients who underwent renal transplantation atour centre from January 2003 to September 2018.Pre transplant history, post transplant course including duration on hemodialysis, immunosuppression details and duration till diagnosis of malignancies were collected. Details regarding type of malignancy, histopathology, staging and treatment given and outcome were collected. Results Number of transplant recipient-626. The total number of patients with malignancy is 12. Incidence of malignancy posttransplant is 1.9%.Male-7 and female-6.One patient was detected with 2 malignanciesduring her post transplant period. The types of malignancies encountered were Conclusion The incidence of malignancy – 1.9%.Probable reason for decreased incidence of malignancy is the decreased immunosuppression needed by South Asian people. The most common malignancy was solid organ tumour; tongue being the most common organ. Most common histological variant is squamous cell carcinoma.Non-Hodgkin is more common than Hodgkin. Incidence of malignancy is low. Decision regarding cancer screening should be made on individual basis.

The Risk of Day 100 Mortality Following Umbilical Cord Blood Transplantation Is Significantly Higher in Patients Who Do Not Achieve An ANC of 100 by Day +16 Post Transplant

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3033-3033 ◽  
Author(s):  
Ann Dahlberg ◽  
Filippo Milano ◽  
Ted A. Gooley ◽  
Colleen Delaney
Keyword(s):  
Cord Blood ◽  
Severe Neutropenia ◽  
Research Protocol ◽  
Post Transplant ◽  
Risk Of Death ◽  
Cord Blood Transplant ◽  
Number Of Patients ◽  
Increased Risk ◽  
Conditioning Regimens ◽  
The Relationship

Abstract Abstract 3033 Background: Cord blood transplant (CBT) recipients have higher infection-related morbidity and mortality than recipients of other stem cells sources following allogeneic transplant due to delayed hematopoietic recovery and immune reconstitution. Even in recipients of myeloablative (MA) double cord blood transplant (dCBT), time to engraftment (defined as the first of two consecutive days with an absolute neutrophil count (ANC) ≥ 500/μl) is delayed more than three weeks resulting in higher rates of infection in the first 100 days post-transplant. However, a better understanding of the relationship between duration of neutropenia and risk of early transplant related mortality is needed to assess the clinical impact of methodologies aimed at reducing neutropenia post transplant. Previously, the relationship between severe neutropenia (ANC ≤ 100/μl) and risk of death was evaluated for allogeneic bone marrow transplant recipients using proportional hazards models and demonstrated a significantly increased risk for those with severe neutropenia at day 15 or beyond following transplantation (Offner et al, Blood, 1996; 88(10): 4058–62). Here we use a similar model to determine how duration of severe neutropenia relates to risk of death following CBT. Methods: All patients (n=137) who received a CBT on a research protocol at a single institution from 2006–2010 were eligible. On each day from day 0 to day +100, surviving patients were divided into those with ANC ≤ 100/μl and those with ANC >100/μl and the number of patients who died by day +100 determined for each group. Hazard ratios (HR) with 95% confidence intervals for day +100 mortality were then calculated for day post-CBT with the HR representing the risk of day +100 death among those with ANC ≤ 100/μl relative to those with ANC >100/μl for each day. Results: Of the 137 patients who received a CBT on a research protocol, 99 patients (72%) received MA conditioning regimens and 38 patients (28%) received reduced-intensity conditioning regimens (RIC). Twenty-two patients (16%) received a single cord blood unit while the remainder received dCBT. As the overall results and trends observed for patients receiving MA or RIC regimens were similar, only the combined results are presented. Thirty-one patients (23%) died before day +100. Causes of death were primary graft failure (17), infection (7), disease relapse (5), multi-organ failure (1), and leukoencephalopathy (1). The median time to engraftment was the same (20 days) for those with death before day+100 (9–39 days) as those alive at day+100 (6–69 days). The hazard ratio for day 100 mortality by day post-CBT was significantly higher for patients with ANC ≤ 100/μl beginning on day +16 and remained so through day +50, at which point the number of patients with ANC ≤ 100/μl was small and thus the calculations were no longer significant. The HRs for each day post-CBT from day 0 to day +50 are plotted in Figure 1 along with their 95% upper and lower confidence intervals. From the graphical plot of these HRs, one can identify date ranges (days 0–12, days 13–23, days 24–40, days 41–100) where the HRs are roughly equivalent with a clear increase in HR in the next date range. Modeling ANC ≤ 100/μl as a time-dependent covariate, we calculated HRs for each of these date ranges and found a significantly increased risk of day 100 mortality for days 12–23 (HR=2.96, p=0.01), days 24–40 (HR=5.53, p=0.0004), and days 41–100 (HR=14.59, p<0.0001) for patients with ANC ≤ 100/μl. The HR was 1.16 (0.49–2.76, p=0.73) for days 0–12; however, some of these patients had initial autologous recovery following RIC regimens and poor outcomes. Conclusions: Our study demonstrates that severe neutropenia, defined as ANC ≤ 100, poses a significant increased risk of day 100 mortality for recipients of CBT as early as 12–23 days post-CBT. Importantly, this patient cohort was transplanted in the modern era of aggressive supportive care, including use of newer antimicrobials. However, despite this, severe neutropenia remains a significant risk factor for day 100 mortality in recipients of CBT. Interestingly, median time to engraftment (ANC ≥ 500/μl) was the same for those with death before day+100 as those alive at day+100 suggesting that time to ANC of 100 may be a better predictor of early death following CBT. Thus, strategies that result in more rapid myeloid recovery (to an ANC of 100) remain essential for recipients of CBT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mesenchymal Stromal Cell Treatment of Kidneys During Normothermic Machine Perfusion is Safe and Feasible with Effective Traceability after Transplantation

2020 ◽  
Vol 1 (2) ◽  
Author(s):  
Kaithlyn Rozenberg ◽  
Et al.
Keyword(s):  
The Netherlands ◽  
Clinical Medicine ◽  
Medical Center ◽  
Graft Function ◽  
University Hospital ◽  
Control Group ◽  
Machine Perfusion ◽  
Contralateral Kidney ◽  
Post Transplant ◽  
Normothermic Machine Perfusion

Lohmann 1/M. Pool 2, K. Rozenberg 3, M. Eijken 4, U. Møldrup 5, B.K. Møller 6, J.M. Sierra Parraga 7, M. Hoogduijn 7, L. Lo Faro 3, C. Moers 2, J. Hunter 3, A.K. Keller 1, H. Leuvenink 2, C.C. Baan 7, R.J. Ploeg 3, B. Jespersen 1 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Urology, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands Introduction Marginal kidneys are increasingly being accepted to decrease waiting time for a transplant. Normothermic machine perfusion (NMP) is a technique that allows delivery of therapies that may help condition or repair the organ prior to transplantation. Mesenchymal stromal cells (MSC) may be able to ameliorate ischaemia reperfusion injury as they possess potent anti-inflammatory and regenerative properties. We investigated the safety and effect of MSCs administered during ex vivo NMP prior to transplantation in a pig auto-transplant model of donation after circulatory death. Methods  Porcine kidneys subjected to 75 min warm ischaemia were retrieved and preserved for 14h by oxygenated HMP (oxHMP) and 4h NMP and then auto-transplantation. Kidneys were randomised to three different intervention strategies (n=7 per group): following 1h NMP, either a vehicle (NMP), 10 million pig MSC (NMP+pMSC) or 10 million human MSC (NMP+hMSC) were intra-arterially infused. The NMP groups were all compared to a control group, where kidneys were only preserved with oxHMP. The pig was re-anaesthetised, the contralateral kidney was removed and the treated kidney was auto-transplanted and the animals were recovered for 14 days. Results Renal blood flow during NMP was no different between the groups (p=0.0685). Post-transplant plasma creatinine increased in all groups but there were no significant differences between the groups (p=0.517). Plasma kidney injury biomarker NGAL was significantly higher in the NMP+pMSC group compared to the NMP (p=0.003) and NMP+hMSC (p=0.017) groups at day 14. On day 14, mGFR significantly improved in the NMP group compared to the control (55 ± 3 vs 42 ± 12 ml/min, p=0.025). No differences in GFR were observed on day 14 in the other groups (NMP+pMSC, p=0.090 and NMP+hMSC, p=0.387). MSC were detectable in biopsies of MSC treated kidney after NMP and post-transplantation. Conclusion NMP alone improved renal graft function compared to oxHMP of DCD kidneys post-transplant. The method of MSC administration during NMP proved to be safe, however in this model MSC treatment did not improve renal function. Nevertheless viable MSC remained detectable in the transplanted kidney at postoperative day 14 which may have an effect on longer term outcomes.

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