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Journal of Hepatology Jun 2023With 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... (Review)
Review
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.
Topics: Animals; Liver Transplantation; Organ Preservation; Liver; Perfusion; Bioengineering
PubMed: 37208105
DOI: 10.1016/j.jhep.2023.02.009 -
World Journal of Gastroenterology May 2016Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First,... (Review)
Review
Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First, organ shortage remains a major limitation, and accounts for a large proportion of wait list mortality. While living donation has successfully increased the total number of liver transplants done in Asian countries, the total number of such transplants has been stagnant in the western hemisphere. As such, there has been a significant effort over the past decade to increase the existing deceased donor pool. This effort has resulted in a greater use of liver allografts following donation after cardiac death (DCD) along with marginal and extended criteria donors. Improved understanding of the pathophysiology of liver allografts procured after circulatory arrest has not only resulted in better selection and management of DCD donors, but has also helped in the development of mechanical perfusion strategies. Early outcomes demonstrating the clinical applicability of both hypothermic and normothermic perfusion and its potential to impact patient survival and allograft function have generated much interest. Second, long-term outcomes of liver transplant recipients have not improved significantly, as recipients continue to succumb to complications of long-term immunosuppression, such as infection, malignancy and renal failure. Furthermore, recent evidence suggests that chronic immune-mediated injury to the liver may also impact graft function.
Topics: Allografts; Animals; Donor Selection; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Perfusion; Risk Factors; Time Factors; Tissue Donors; Treatment Outcome
PubMed: 27182155
DOI: 10.3748/wjg.v22.i18.4438 -
Nature Aug 2022After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with...
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.
Topics: Animals; Cell Death; Cell Survival; Cytoprotection; Gene Expression Profiling; Ischemia; Organ Specificity; Perfusion; Swine; Warm Ischemia
PubMed: 35922506
DOI: 10.1038/s41586-022-05016-1 -
American Journal of Transplantation :... Feb 2023The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting... (Review)
Review
The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols.
Topics: Humans; United States; Tissue and Organ Procurement; Organ Transplantation; Tissue Donors; Cardiovascular System; Perfusion; Death; Organ Preservation
PubMed: 36695685
DOI: 10.1016/j.ajt.2022.10.009 -
Current Opinion in Organ Transplantation Dec 2017The review describes recent developments in hypothermic machine liver perfusion with a special focus on underlying protective mechanisms, and the role of this perfusion... (Review)
Review
PURPOSE OF REVIEW
The review describes recent developments in hypothermic machine liver perfusion with a special focus on underlying protective mechanisms, and the role of this perfusion technique in high-risk donor-recipient combinations.
RECENT FINDINGS
To maximize the number of transplantable donor livers, several centres are exploring new machine preservation techniques. In this context, hypothermic machine perfusion has been recently introduced into the clinical setting of human liver transplantation, and the effect of endischemic cold liver perfusion on posttransplant complications is currently under investigation in two multicentre, randomized controlled trials. In addition, current case series demonstrated promising results regarding the protection from intrahepatic biliary complications, particularly when livers from extended criteria donors including donation after circulatory death grafts were used. Hypothermic machine perfusion may, therefore, help to push the boundaries of acceptance criteria for high-risk donor livers.
SUMMARY
In this review, we, first, describe the concept of hypothermic machine liver perfusion and present results from current clinical studies. Next, we provide details of our perfusion approach step-by-step and highlight novel pathways of reperfusion injury and protection. Third, we discuss the impact of this perfusion approach in different clinical scenarios. Finally, we report on recent clinical implementations and future aspects.
Topics: Animals; Humans; Liver; Liver Transplantation; Organ Preservation; Perfusion
PubMed: 28922301
DOI: 10.1097/MOT.0000000000000472 -
Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation.The Cochrane Database of Systematic... Mar 2019Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes ischaemia reperfusion injury.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes ischaemia reperfusion injury. The current accepted standard is static cold storage (SCS) whereby the kidney is stored on ice after removal from the donor and then removed from the ice box at the time of implantation. However, technology is now available to perfuse or "pump" the kidney during the transport phase or at the recipient centre. This can be done at a variety of temperatures and using different perfusates. The effectiveness of treatment is manifest clinically as delayed graft function (DGF), whereby the kidney fails to produce urine immediately after transplant.
OBJECTIVES
To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies to 18 October 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All randomised controlled trials (RCTs) and quasi-RCTs comparing HMP/NMP versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
The results of the literature search were screened and a standard data extraction form was used to collect data. Both of these steps were performed by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was incidence of DGF. Secondary outcomes included: one-year graft survival, incidence of primary non-function (PNF), DGF duration, long term graft survival, economic implications, graft function, patient survival and incidence of acute rejection.
MAIN RESULTS
No studies reported on NMP, however one ongoing study was identified.Sixteen studies (2266 participants) comparing HMP with SCS were included; 15 studies could be meta-analysed. Fourteen studies reported on requirement for dialysis in the first week post-transplant (DGF incidence); there is high-certainty evidence that HMP reduces the risk of DGF when compared to SCS (RR 0.77; 95% CI 0.67 to 0.90; P = 0.0006). HMP reduces the risk of DGF in kidneys from DCD donors (7 studies, 772 participants: RR 0.75; 95% CI 0.64 to 0.87; P = 0.0002; high certainty evidence), as well as kidneys from DBD donors (4 studies, 971 participants: RR 0.78, 95% CI 0.65 to 0.93; P = 0.006; high certainty evidence). The number of perfusions required to prevent one episode of DGF (number needed to treat, NNT) was 7.26 and 13.60 in DCD and DBD kidneys respectively. Studies performed in the last decade all used the LifePort machine and confirmed that HMP reduces the incidence of DGF in the modern era (5 studies, 1355 participants: RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence). Reports of economic analysis suggest that HMP can lead to cost savings in both the North American and European settings.Two studies reported HMP also improves graft survival however we were not able to meta-analyse these results. A reduction in incidence of PNF could not be demonstrated. The effect of HMP on our other outcomes (incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain.
AUTHORS' CONCLUSIONS
HMP is superior to SCS in deceased donor kidney transplantation. This is true for both DBD and DCD kidneys, and remains true in the modern era (studies performed in the last decade). As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions are needed to prevent one episode of DGF (7.26 versus 13.60 in DBD kidneys).Further studies looking solely at the impact of HMP on DGF incidence are not required. Follow-up reports detailing long-term graft survival from participants of the studies already included in this review would be an efficient way to generate further long-term graft survival data.Economic analysis, based on the results of this review, would help cement HMP as the standard preservation method in deceased donor kidney transplantation.RCTs investigating (sub)NMP are required.
Topics: Delayed Graft Function; Graft Rejection; Graft Survival; Humans; Incidence; Kidney; Kidney Transplantation; Organ Preservation; Perfusion; Randomized Controlled Trials as Topic; Refrigeration; Time Factors; Tissue Donors
PubMed: 30875082
DOI: 10.1002/14651858.CD011671.pub2 -
Nature Communications Apr 2023Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition...
Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition and its dynamic changes during NMP is essential. We aimed for a comprehensive characterization of immune cell (sub)populations, cell trafficking and cytokine release during liver NMP. Single-cell transcriptome profiling of human donor livers prior to, during NMP and after transplantation shows an abundance of CXC chemokine receptor 1/2 (CXCR1/CXCR2) neutrophils, which significantly decreased during NMP. This is paralleled by a large efflux of passenger leukocytes with neutrophil predominance in the perfusate. During NMP, neutrophils shift from a pro-inflammatory state towards an aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. We herein describe the dynamics of the immune cell repertoire, phenotypic immune cell shifts and a dominance of neutrophils during liver NMP, which potentially contribute to the inflammatory response. Our findings may serve as resource to initiate future immune-interventional studies.
Topics: Humans; Aged; Liver Transplantation; Liver; Perfusion; Organ Preservation; Sequence Analysis, RNA
PubMed: 37085477
DOI: 10.1038/s41467-023-37674-8 -
Critical Care (London, England) Jun 2019Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this... (Review)
Review
Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this approach nevertheless implies to be effective that regional organ perfusion would increase in parallel to cardiac output or perfusion pressure and that the catecholamine does not have negative effects on the microcirculation. Inotropic agents may be considered in some conditions, but it requires prior optimization of cardiac preload. Alternative approaches would be either to minimize exposure to vasopressors, tolerating hypotension and trying to prioritize perfusion but this may be valid as long as perfusion of the organ is preserved, or to combine moderate doses of vasopressors to vasodilatory agents, especially if these are predominantly acting on the microcirculation. In this review, we will discuss the pros and cons of the use of catecholamines and alternative agents for improving tissue perfusion in septic shock.
Topics: Arterial Pressure; Cardiac Output; Catecholamines; Humans; Microcirculation; Perfusion; Resuscitation
PubMed: 31200777
DOI: 10.1186/s13054-019-2433-6 -
Transplant International : Official... Jan 2021There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the... (Review)
Review
There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the past decade, there has been considerable progress in technologies to preserve organs prior to transplantation to improve the function of these marginal organs. This has led to the development of normothermic machine perfusion, whereby an organ is perfused with warmed, oxygenated blood and nutrients to resume normal physiological function in an isolated ex-vivo platform. With this advance in preservation comes significant opportunities to recondition, repair and regenerate organs prior to transplantation using cellular therapies. This review aims to discuss the possibilities of machine perfusion technology; highlighting the potential for organ-directed reconditioning and the future avenues for investigation in this field.
Topics: Cell- and Tissue-Based Therapy; Humans; Liver Transplantation; Organ Preservation; Perfusion; Tissue Donors
PubMed: 33131097
DOI: 10.1111/tri.13780 -
The Journal of Extra-corporeal... Mar 2022Standards and guidelines for cardiopulmonary bypass have been established by various professional societies. They serve as an instrument to guide safe and effective...
Standards and guidelines for cardiopulmonary bypass have been established by various professional societies. They serve as an instrument to guide safe and effective patient care. We conducted a survey of practicing perfusionists in Kenya to learn about their background, education, current clinical practice and about their knowledge, and attitude regarding standards and guidelines. Two multiple-choice surveys were distributed to all known practicing perfusionist in Kenya using SurveyMonkey (San Mateo, CA). Multiple-choice questions related to professional background, training, annual procedure volume, staffing models, clinical practices, the use of safety devices, and the use of checklists were included in the questionnaires. The survey also inquired about familiarity with American and European perfusion practice standards and guidelines and opinions on establishing standards in Kenya. Responses were received from 12 perfusionists practicing at 10 centers. Professional backgrounds included anesthesia nursing, clinical officers, and critical care nursing. Sixty-seven percent (8/12) received formal training and 33% (4/12) trained primarily through clinical instruction. Of those that received formal training, 63% (5/8) received 1-2 years of training, 25% (2/8) <1 year but more than 6 months, and 12.5% (1/8) received 6 months of formal training. The median clinical experience was 5 years (range 1-22). The median annual case load was 54 (range 0-100). Use of safety devices was reported as follows: level sensor 75% (9/12), air bubble detector 17% (2/12), one-way vent valves 67% (8/12), continuous venous oxygen saturation monitoring 25% (3/12), and gas supply analyzers 33% (4/12). More than one-third of the respondents had no knowledge of the American and European perfusion practice standards, and nearly two-thirds were aware of or had read them. This survey provides contextual information about perfusion practice in Kenya in 2021. There was consensus among perfusionists to develop standards and practice guidelines for Kenya.
Topics: Humans; Kenya; Perfusion; Cardiopulmonary Bypass; Surveys and Questionnaires
PubMed: 36380824
DOI: 10.1182/ject-5-18