-
Hepatology (Baltimore, Md.) Nov 2022Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved... (Review)
Review
Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved challenge to the transplant community. To address this, transplant donor criteria have been expanded and, for example, more liver grafts with significant steatosis or from donors with circulatory death are being used. These marginal grafts, however, carry an increased risk of graft-associated complications, such as primary nonfunction, delayed graft function, or late biliary injuries. Therefore, reliable assessment of graft viability before use is essential for further success. To achieve this, machine liver perfusion, a procedure developed more than 50 years ago but almost forgotten at the end of the last century, is again of great interest. We describe in this review the clinical most applied machine perfusion techniques, their mechanistic background, and a novel concept of combining immediate organ assessment during hypothermic oxygenated perfusion, followed by an extended phase of normothermic machine perfusion, with simultaneous ex situ treatment of the perfused liver. Such a new approach may allow the pool of usable livers to dramatically increase and improve outcomes for recipients.
Topics: Humans; Liver Transplantation; Perfusion; Postoperative Complications; Tissue Donors
PubMed: 35488496
DOI: 10.1002/hep.32546 -
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 -
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 -
Expert Review of Medical Devices Dec 2022Lung transplantation is the gold standard for the treatment of end stage lung disease but is limited by donor availability. Recently, the donor pool has seen significant... (Review)
Review
INTRODUCTION
Lung transplantation is the gold standard for the treatment of end stage lung disease but is limited by donor availability. Recently, the donor pool has seen significant expansion with liberalization of donor criteria. However, extended criteria donors can require additional time to prepare for implantation, necessitating additional preservation time of donor lungs.
AREAS COVERED
We present a review of current lung transplant storage strategies including new methodologies and technological advancements. The current standard, static cold storage, is a simple and cost-effective method of preserving grafts, but offers little flexibility with limited ability to mitigate ischemic-reperfusion injury, inflammation, and hypothermic tissue damage. Novel ex vivo lung perfusion (EVLP) devices, TransMedics OCS and XVIVO perfusion systems, extend preservation time by perfusing, and ventilating donor lungs while simultaneously allowing for evaluation of lung viability. Perfusate, preservation solutions, additives, temperature regulation, and assessment of organ damage are all critical components when evaluating the success and outcomes of these devices.
EXPERT OPINION
EVLP devices are more costly and often require additional resources and personnel support compared to static cold storage, but may provide the opportunity to extend preservation time, perform functional assessment, mitigate ischemic injury, and optimize extended criteria donors.
Topics: Humans; Organ Preservation; Lung; Lung Transplantation; Perfusion; Tissue Donors
PubMed: 36444725
DOI: 10.1080/17434440.2022.2151359 -
Methods in Molecular Biology (Clifton,... 2018The Langendorff Perfused Heart Model is an experimental procedure developed at the end of the nineteenth century by Oskar Langendorff. In this procedure, an excised...
The Langendorff Perfused Heart Model is an experimental procedure developed at the end of the nineteenth century by Oskar Langendorff. In this procedure, an excised heart has a cannula inserted into its aorta so that the heart can be retrogradely perfused via the coronary artery. The procedure has been improved in recent times, and these improvements are used to evaluate the direct effect of medication on the heart as well as the effect of ischemia-reperfusion injury on heart function. In this chapter, we describe protocols for evaluating heart function in Langendorff perfused rat heart.
Topics: Animals; Cardiac Catheterization; Disease Models, Animal; Dissection; Equipment Design; Heart; Heart Rate; Myocardial Reperfusion Injury; Perfusion; Rats
PubMed: 29987814
DOI: 10.1007/978-1-4939-8597-5_8 -
Acta Pharmacologica Sinica May 2018Organ transplantation is the most effective therapy for patients with end-stage disease. Preservation solutions and techniques are crucial for donor organ quality, which... (Review)
Review
Organ transplantation is the most effective therapy for patients with end-stage disease. Preservation solutions and techniques are crucial for donor organ quality, which is directly related to morbidity and survival after transplantation. Currently, static cold storage (SCS) is the standard method for organ preservation. However, preservation time with SCS is limited as prolonged cold storage increases the risk of early graft dysfunction that contributes to chronic complications. Furthermore, the growing demand for the use of marginal donor organs requires methods for organ assessment and repair. Machine perfusion has resurfaced and dominates current research on organ preservation. It is credited to its dynamic nature and physiological-like environment. The development of more sophisticated machine perfusion techniques and better perfusates may lead to organ repair/reconditioning. This review describes the history of organ preservation, summarizes the progresses that has been made to date, and discusses future directions for organ preservation.
Topics: Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Organ Preservation; Organ Preservation Solutions; Perfusion
PubMed: 29565040
DOI: 10.1038/aps.2017.182 -
Current Opinion in Organ Transplantation Oct 2022Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations... (Review)
Review
PURPOSE OF REVIEW
Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations of proposed viability criteria and suggests a framework for future studies.
RECENT FINDINGS
Liver viability is most frequently assessed during normothermic MP by combining parameters relative to perfusate and bile composition, vascular flows and macroscopic aspect. Assessment protocols are largely heterogeneous and have significantly evolved over time, also within the same group, reflecting the ongoing evolution of the subject. Several recent preclinical studies using discarded human livers or animal models have explored other approaches to viability assessment. During hypothermic MP, perfusate flavin mononucleotide has emerged as a promising biomarker of mitochondrial injury and function. Most studies on the subject suffer from limitations, including low numbers, lack of multicenter validation, and subjective interpretation of some viability parameters.
SUMMARY
MP adds a further element of complexity in the process of assessing the quality of a liver graft. Understanding the physiology of the parameters included in the different assessment protocols is necessary for their correct interpretation. Despite the possibility of assessing liver viability during MP, the importance of donor-recipient matching and operational variables should not be disregarded.
Topics: Animals; Humans; Liver; Liver Transplantation; Organ Preservation; Perfusion; Tissue Donors
PubMed: 35857341
DOI: 10.1097/MOT.0000000000001004 -
Current Opinion in Organ Transplantation Jun 2016The purpose of the review is to report recent human application of hypothermic machine liver perfusion, and to discuss potential protective mechanisms. (Review)
Review
PURPOSE OF THE REVIEW
The purpose of the review is to report recent human application of hypothermic machine liver perfusion, and to discuss potential protective mechanisms.
RECENT FINDINGS
Human application of hypothermic machine liver perfusion is still very limited. Currently, three transplant centers apply this novel treatment in donation after cardiac death (DCD) or donation after brain death (DBD) liver grafts. In all cases, endischemic perfusion was performed after initial cold storage for organ transport. Perfusion conditions differ slightly in terms of oxygenation (pO2 15-60 kPa), perfusion route (dual vs. portal), perfusion time (2-4 h), and perfusate.
SUMMARY
The current data support the hypothesis that applying endischemic hypothermic machine liver perfusion protects extended criteria DBD and DCD livers from initial reperfusion injury, with better graft function and less biliary complications. Hypothermic machine perfusion may therefore offer revitalization of liver grafts before implantation by a simple and practical perfusion technique with a high impact on enlarging the donor pool. Multicentric phase III randomized control trials in DBD and DCD liver transplantation have been initiated to further test this strategy, which may establish machine liver perfusion in the clinical setting.
Topics: Humans; Hypothermia, Induced; Liver Transplantation; Organ Preservation; Perfusion; Reactive Oxygen Species
PubMed: 26918882
DOI: 10.1097/MOT.0000000000000303 -
Mammalian Genome : Official Journal of... Sep 2022Tissue organoids or "mini organs" can be invaluable tools for understanding health and disease biology, modeling tissue dynamics, or screening potential drug candidates.... (Review)
Review
Tissue organoids or "mini organs" can be invaluable tools for understanding health and disease biology, modeling tissue dynamics, or screening potential drug candidates. Effective vascularization of these models is critical for truly representing the in vivo tissue environment. Not only is the formation of a vascular network, and ultimately a microcirculation, essential for proper distribution and exchange of oxygen and nutrients throughout larger organoids, but vascular cells dynamically communicate with other cells to modulate overall tissue behavior. Additionally, interstitial fluid flow, mediated by a perfused microvasculature, can have profound influences on tissue biology. Thus, a truly functionally and biologically relevant organoid requires a vasculature. Here, we review existing strategies for fabricating and incorporating vascular elements and perfusion within tissue organoids.
Topics: Organoids; Oxygen; Perfusion
PubMed: 35333952
DOI: 10.1007/s00335-022-09951-2