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Current Opinion in Organ Transplantation Apr 2022Ex-vivo machine perfusion has emerged as a promising alternative to static cold storage (SCS) for preservation of liver grafts over the last decade. This review... (Review)
Review
PURPOSE OF REVIEW
Ex-vivo machine perfusion has emerged as a promising alternative to static cold storage (SCS) for preservation of liver grafts over the last decade. This review describes the mechanistic benefits associated with hypothermic machine perfusion (HMP) for preservation of liver grafts and highlights clinical outcomes of liver transplantation using HMP technology.
RECENT FINDINGS
Over the last decade, several single-centre studies have shown decreased biliary complications, decreased early allograft dysfunction (EAD) rates and improved patient survival in liver transplant recipients after application of HMP for liver graft preservation. This has led to initiation of prospective, multicentre, randomized controlled trials (RCTs) in both Europe and North America focused on clinical outcomes in liver transplant recipients using HMP-preserved liver grafts. In addition, recent single-centre studies have shown the utility of perfusate biomarker analysis during HMP in predicting EAD after liver transplantation.
SUMMARY
HMP technology has potential to increase the available donor liver organ pool for liver transplant recipients and improve clinical outcomes after liver transplantation. Broader clinical application of HMP in resuscitation and preservation of liver grafts is anticipated over the next decade once regulatory, logistical and financial challenges are overcome.
Topics: Humans; Liver; Liver Transplantation; Organ Preservation; Perfusion; Tissue Donors
PubMed: 35184093
DOI: 10.1097/MOT.0000000000000973 -
Surgery Mar 2023The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential...
BACKGROUND
The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation.
METHODS
With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device.
RESULTS
Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference.
CONCLUSION
Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.
Topics: Humans; Liver Transplantation; Brain Death; Living Donors; Perfusion; Lactates; Organ Preservation
PubMed: 36302699
DOI: 10.1016/j.surg.2022.07.035 -
Artificial Organs Nov 2022Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We... (Review)
Review
BACKGROUND
Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We reviewed the evidence on the use of labeled metabolites (tracers) to understand "on-pump" kidney behavior.
METHODS
PubMed, Embase, Web of Science, and Cochrane databases were systematically searched for studies evaluating metabolism of (non)radioactively labeled endogenous compounds during kidney perfusion.
RESULTS
Of 5899 articles, 30 were included. All were animal studies [rat (70%), dog (13%), pig (10%), rabbit (7%)] perfusing but not transplanting kidneys. Perfusion took place at hypothermic (4-12°C) (20%), normothermic (35-40°C) (77%), or undefined temperatures (3%). Hypothermic perfusion used albumin or a clinical kidney preservation solution, mostly in the presence of oxygen. Normothermic perfusion was mostly performed with oxygenated crystalloids often containing glucose and amino acids with unclear partial oxygen tensions. Active metabolism of carbohydrate, amino acid, lipids, and large molecules was shown in hypothermic and normothermic perfusion. Production of macromolecules, such as prostaglandin, thromboxane, and vitamin D, takes place during normothermic perfusion. No experiments compared differences in metabolic activity between hypothermic and normothermic perfusion. One conference abstract showed increased anaerobic metabolism in kidneys donated after circulatory death by adding labeled glucose to hypothermically perfused human kidneys.
CONCLUSIONS
Tracer studies during kidney perfusion contribute to unraveling kidney metabolic behavior in pre-clinical models. Whether findings are truly translational needs further investigation in large animal models of human kidneys. Furthermore, it is essential to better understand how ischemia changes this metabolic behavior.
Topics: Swine; Humans; Rats; Animals; Rabbits; Dogs; Organ Preservation; Kidney Transplantation; Perfusion; Kidney; Oxygen; Glucose
PubMed: 35848397
DOI: 10.1111/aor.14355 -
Nature Communications Aug 2023Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion...
Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion of livers is an emerging field with tremendous potential for the assessment, recovery, and modification of organs. In this study, we aimed to develop a long-term model of ex situ perfusion including a surgical split and simultaneous perfusion of both partial organs. Human livers declined for transplantation were perfused using a red blood cell-based perfusate under normothermic conditions (36 °C) and then split and simultaneously perfused on separate machines. Ten human livers were split, resulting in 20 partial livers. The median ex situ viability was 125 h, and the median ex situ survival was 165 h. Long-term survival was demonstrated by lactate clearance, bile production, Factor-V production, and storage of adenosine triphosphate. Here, we report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
Topics: Humans; Liver Transplantation; Liver; Perfusion; Bile; Preservation, Biological
PubMed: 37553343
DOI: 10.1038/s41467-023-40154-8 -
Nature Medicine Jun 2023Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation... (Randomized Controlled Trial)
Randomized Controlled Trial
Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .
Topics: Humans; Kidney Transplantation; Organ Preservation; Kidney; Perfusion; Tissue Donors
PubMed: 37231075
DOI: 10.1038/s41591-023-02376-7 -
Transplantation Proceedings Apr 2022Liver normothermic machine perfusion (NMP) is being adopted as a method of optimizing livers before transplantation. However, there is further potential to use the NMP...
BACKGROUND
Liver normothermic machine perfusion (NMP) is being adopted as a method of optimizing livers before transplantation. However, there is further potential to use the NMP model as a platform for drug delivery. Pregnane X receptor (PXR) activation upregulates CYP3A expression and has been shown to be protective against ischemia-reperfusion in rodents. We introduced a PXR activator during NMP and assessed activation of its downstream targets.
METHODS AND MATERIALS
Organs were perfused on a NMP circuit using an oxygenated red cell-based perfusate. A series of livers were allocated to PXR treatment and compared with a control group. Biopsies were taken at the start and end of the perfusion process to quantify CYP3A expression. Perfusion samples were taken throughout the perfusion process and used to measure biochemical variables (lactate and alanine transaminase).
RESULTS
Quantification polymerase chain reaction using the delta computed tomography method on 5 livers which received Avasimibe demonstrated successful upregulation of CYP3A43 and CYP3A4 over the course of perfusion by 3.8-fold and 2.2-fold, respectively (P = .026 and P = .098, respectively; Student t test). The 4 control livers had no significant change in expression of CYP3A43 or CYP3A over the course of perfusion.
CONCLUSIONS
We have demonstrated that NMP can be successfully used as a platform for drug delivery with reliable transcription activation of downstream targets. Although it remains to be seen whether PXR therapy is beneficial in humans, the model suggests that perfusion could be used clinically in the future to further optimize grafts by acting as a drug delivery system.
Topics: Cold Ischemia; Cytochrome P-450 CYP3A; Humans; Liver; Liver Transplantation; Organ Preservation; Perfusion; Pregnane X Receptor; Reperfusion Injury
PubMed: 35272879
DOI: 10.1016/j.transproceed.2021.12.044 -
International Angiology : a Journal of... Jun 2023To perform a scoping review analyzing the current evidence reporting on acute kidney injury (AKI) after elective open surgery (OS) of complex abdominal aortic aneurysms... (Review)
Review
INTRODUCTION
To perform a scoping review analyzing the current evidence reporting on acute kidney injury (AKI) after elective open surgery (OS) of complex abdominal aortic aneurysms (c-AAAs) and evaluate the impact of renal perfusion, and the different types of solutions on renal morbidity.
EVIDENCE ACQUISITION
Research questions were defined, and a literature search was performed following the PRISMA guidelines for scoping reviews. Multicenter, single-center observational studies were considered eligible. No abstracts only and unpublished literature were included.
EVIDENCE SYNTHESIS
Two hundred and fifty studies were screened, 20 studies met screening criteria and were included, reporting 1552 patients treated for c-AAAs. The majority did not receive renal perfusion and the others received different types of renal perfusions. Acute kidney injury is a common complication after c-AAAs OS, with an incidence up to 32.5%. Heterogeneity in AKI classifications reduce the ability to compare outcomes after perfusion and nonperfusion strategies. Pre-existing CKD, ischemic injury due to suprarenal aortic clamping are major determinants of AKI after aortic surgery. Most papers reported chronic kidney disease (CKD) at admission. Another debated topic is the indication for renal perfusion during c-AAAs OS. Controversial results for cold renal perfusion have been found.
CONCLUSIONS
In the context of c-AAAs, this review identified the need to standardize the definition of AKI to reduce reporting bias. Besides this, it showed the need to assess the indication for renal perfusion and the type of perfusion solution to be used.
Topics: Humans; Acute Kidney Injury; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Multicenter Studies as Topic; Perfusion; Renal Insufficiency, Chronic
PubMed: 37222507
DOI: 10.23736/S0392-9590.23.05021-6 -
The Journal of Heart and Lung... Jan 2021Despite the advancements in medical treatment, mechanical support, and stem cell therapy, heart transplantation remains the most effective treatment for selected... (Review)
Review
Despite the advancements in medical treatment, mechanical support, and stem cell therapy, heart transplantation remains the most effective treatment for selected patients with advanced heart failure. However, with an increase in heart failure prevalence worldwide, the gap between donor hearts and patients on the transplant waiting list keeps widening. Ex situ machine perfusion has played a key role in augmenting heart transplant activities in recent years by enabling the usage of donation after circulatory death hearts, allowing longer interval between procurement and implantation, and permitting the safe use of some extended-criteria donation after brainstem death hearts. This exciting field is at a hinge point, with 1 commercially available heart perfusion machine, which has been used in hundreds of heart transplantations, and a number of devices being tested in the pre-clinical and Phase 1 clinical trial stage. However, no consensus has been reached over the optimal preservation temperature, perfusate composition, and perfusion parameters. In addition, there is a lack of objective measurement for allograft quality and viability. This review aims to comprehensively summarize the lessons about ex situ heart perfusion as a platform to preserve, assess, and repair donor hearts, which we have learned from the pre-clinical studies and clinical applications, and explore its exciting potential of revolutionizing heart transplantation.
Topics: Heart Transplantation; Humans; Organ Preservation; Perfusion; Tissue Donors
PubMed: 33162304
DOI: 10.1016/j.healun.2020.10.004 -
Current Opinion in Organ Transplantation Apr 2023This review is intended to provide an update on the logistics, technique, and outcomes associated with normothermic regional perfusion (NRP), as well as provide a... (Review)
Review
PURPOSE OF REVIEW
This review is intended to provide an update on the logistics, technique, and outcomes associated with normothermic regional perfusion (NRP), as well as provide a discussion of the associated ethical issues.
RECENT FINDINGS
There has been renewed interest in utilizing NRP to increase quality and availability of organs from donation after circulatory death (DCD) donors. Our institution has increasing experience with thoraco-abdominal NRP (TA-NRP) in controlled DCD donors (cDCD), whereas abdominal NRP (A-NRP) has been used with success in both cDCD and uncontrolled DCD (uDCD). There is increasing evidence that NRP can be conducted in a practical and cost-efficient manner, and that the organ yield may be of better quality than standard direct procurement and perfusion (DPP).
SUMMARY
NRP is increasingly successful and will likely prove to be a superior method for cDCD recovery. However, before TA-NRP can be widely accepted the ethical debate surrounding this technique must be settled.
VIDEO ABSTRACT
http://links.lww.com/COOT/A11.
Topics: Humans; Organ Preservation; Tissue Donors; Perfusion; Death; Tissue and Organ Procurement; Graft Survival
PubMed: 36409266
DOI: 10.1097/MOT.0000000000001038 -
Artificial Organs Feb 2022
Topics: Humans; Kidney Transplantation; Organ Preservation; Perfusion
PubMed: 34888895
DOI: 10.1111/aor.14134