|
1
|
Goldberg D, Sandhu S. Expanding the Liver Donor Pool: Promise and Peril. Clin Liver Dis 2025; 29:235-252. [PMID: 40287269 DOI: 10.1016/j.cld.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Liver transplantation remains a life-saving therapy for a growing list of indications. Although 10,660 adult liver transplants were performed in the United States in 2023, a 50% increase over the preceding decade, the demand continues to far exceed the supply. Efforts to expand the liver donor pool by using donors that were previously considered unsuitable have remained an important strategy to help overcome shortages. We discuss the progress that has been made over the past decade, as well as potential future barriers that will need to be overcome to help successfully expand the liver donor pool.
Collapse
Affiliation(s)
- David Goldberg
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, Miami, FL, USA.
| | - Sunny Sandhu
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, Miami, FL, USA
| |
Collapse
|
|
2
|
Ross-Driscoll K, Kubal C, Ayuk-Arrey AT, Fridell J, Axelrod D. Association of a Liver Allocation Policy Change With Domestic Travel for Liver Transplantation. Transplant Direct 2025; 11:e1749. [PMID: 39866679 PMCID: PMC11759321 DOI: 10.1097/txd.0000000000001749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 01/28/2025] Open
Abstract
Background In 2020, liver allocation policy in the United States was changed to allow for broader organ sharing, which was hypothesized to reduce patient incentives to travel for transplant. Our objective was to describe patterns of travel for domestic liver transplant pre- and post-acuity circle (AC) implementation. Methods Incident adult liver transplant listings between August 16, 2016, and February 3, 2020 (pre-AC) or June 13, 2020, and December 3, 2023 (post-AC) were obtained from the Scientific Registry of Transplant Recipients. We used previously defined geographic catchment areas to classify patients as (1) no travel, (2) travel to a neighboring region, and (3) travel beyond a neighboring region. We used multinomial logistic regression to identify characteristics associated with travel and cause-specific hazards modeling to estimate the association between travel and time to deceased donor transplant, stratified by model for end-stage liver disease (MELD) score and AC era. Results Among 83 033 liver candidates, 76% were listed in their home region. Black race, lower educational attainment, increased neighborhood social deprivation, and Medicaid were significantly associated with decreased odds of traveling beyond a neighboring region. After AC, traveling beyond a neighboring region was associated with an increased hazard of transplant for patients with a MELD score <15 (cause-specific hazard ratio [csHR]: 1.25; 95% confidence interval [CI], 1.11-1.40), MELD score 15-24 (csHR: 1.19; 95% CI, 1.07-1.31), and MELD score 25-34 (csHR: 1.15; 95% CI, 1.01-1.32). Conclusions Travel frequency, geographic patterns of travel, and characteristics associated with travel were largely unchanged after AC. Changes to allocation policy alone may not equalize patient means or desire to travel for transplant care.
Collapse
Affiliation(s)
- Katie Ross-Driscoll
- Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
- Center for Health Services Research, Regenstrief Institute, Indianapolis, IN
| | - Chandrashekhar Kubal
- Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | | | - Jonathan Fridell
- Division of Transplantation, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - David Axelrod
- Division of Transplantation, Department of Surgery, University of Iowa School of Medicine, Iowa City, IA
| |
Collapse
|
|
3
|
Concors SJ, Hernandez PT, O'Brien C, DePaolo J, Murken DR, Aufhauser DD, Wang Z, Xiong Y, Krumeich L, Ge G, Beier UH, Bhatti TR, Kozikowski AP, Avelar LAA, Kurz T, Hancock WW, Levine MH. Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-Reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain. Transplantation 2024; 108:2084-2092. [PMID: 38685198 DOI: 10.1097/tp.0000000000005042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. METHODS Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. RESULTS Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage ( P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI ( P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia ( P < 0.01 for AST and P < 0.01 for ALT). CONCLUSIONS Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.
Collapse
Affiliation(s)
- Seth J Concors
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Paul T Hernandez
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Ciaran O'Brien
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - John DePaolo
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Douglas R Murken
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | | | - Zhonglin Wang
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Yan Xiong
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Lauren Krumeich
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Guanghui Ge
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Ulf H Beier
- Division of Nephrology and Department of Pediatrics, Children's Hospital of Pennsylvania and University of Pennsylvania, Philadelphia, PA
| | - Tricia R Bhatti
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
| | | | - Leandro A Alves Avelar
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Kurz
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Düsseldorf, Germany
| | - Wayne W Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
| | - Matthew H Levine
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
- Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA
| |
Collapse
|
|
4
|
Wang BK, Shubin AD, Harvey JA, MacConmara MM, Hwang CS, Patel MS, Vagefi PA. From Patients to Providers: Assessing Impact of Normothermic Machine Perfusion on Liver Transplant Practices in the US. J Am Coll Surg 2024; 238:844-852. [PMID: 38078619 DOI: 10.1097/xcs.0000000000000924] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2024]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) of livers allows for the expansion of the donor pool and minimization of posttransplant complications. Results to date have focused on both donor and recipient outcomes, but there remains potential for NMP to also impact transplant providers. STUDY DESIGN Using United Network for Organ Sharing Standard Transplant Analysis file data, adult deceased donors who underwent transplantation between January 1, 2016, and December 31, 2022, were identified. Transplanted livers were divided by preservation methods (static cold storage [SCS] and NMP) and case time (day-reperfusion 8 am to 6 pm ). Patient factors, transplant characteristics, and short-term outcomes were analyzed between Mahalanobis-metric-matched groups. RESULTS NMP livers represented 742 (1.4%) of 52,132 transplants. NMP donors were more marginal with higher Donor Risk Index scores (1.78 ± 0.50 NMP vs 1.49 ± 0.38 SCS, p < 0.001) and donation after cardiac death frequency (36.9% vs 8.4%, p < 0.001). NMP recipients more often had model for end-stage liver disease (MELD) exception status (29.9% vs 23.4%, p < 0.001), lower laboratory MELD scores (20.7 ± 9.7 vs 24.3 ± 10.9, p < 0.001), and had been waitlisted longer (111.5 [21.0 to 307.0] vs 60.0 [9.0 to 245.0] days, p < 0.001). One-year graft survival (90.2% vs 91.6%, p = 0.505) was similar between groups, whereas length of stay was lower for NMP recipients (8.0 [6.0 to 14.0] vs 10.0 [6.0 to 16.0], p = 0.017) after adjusting for confounders. Notably, peak case volume occurred at 11 am with NMP livers (vs 9 pm with SCS). Overall, a higher proportion of transplants was performed during daytime hours with NMP (51.5% vs 43.0%, p < 0.001). CONCLUSIONS NMP results in increased use of marginal allografts, which facilitated transplantation in lower laboratory MELD recipients who have been waitlisted longer and often have exception points. Importantly, NMP also appeared to shift peak caseloads from nighttime to daytime, which may have significant effects on the quality of life for the entire liver transplant team.
Collapse
Affiliation(s)
- Benjamin K Wang
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| | - Andrew D Shubin
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| | - Jalen A Harvey
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| | | | - Christine S Hwang
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| | - Madhukar S Patel
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| | - Parsia A Vagefi
- From the Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX (Wang, Shubin, Harvey, Hwang, Patel, Vagefi)
| |
Collapse
|
|
5
|
Cox DR, Lee E, Wong BK, McClure T, Zhang F, Goh SK, Vago A, Jackett L, Fink M, Jones R, Perini MV, Dobrovic A, Testro A, Starkey G, Muralidharan V. Graft-derived cfDNA Monitoring in Plasma and Bile During Normothermic Machine Perfusion in Liver Transplantation Is Feasible and a Potential Tool for Assessing Graft Viability. Transplantation 2024; 108:958-962. [PMID: 37902630 PMCID: PMC10962428 DOI: 10.1097/tp.0000000000004842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/12/2023] [Accepted: 08/09/2023] [Indexed: 10/31/2023]
Abstract
BACKGROUND Ex vivo normothermic machine perfusion (NMP) is an organ preservation technique that enables an extended assessment of graft suitability before liver transplantation (LT). Established monitoring protocols used during NMP vary significantly in their assessment of transplant suitability when applied to the same grafts. Graft-derived cell-free DNA (gdcfDNA) analysis is an emerging tool for monitoring graft health post-transplantation. We investigated the feasibility of monitoring gdcfDNA during NMP for LT in a proof-of-concept, observational study. METHODS Serial plasma and bile samples were collected during NMP for 10 consecutive grafts, at 15 min post-machine reperfusion and then 2-h intervals. Digital polymerase chain reaction was used to quantify gdcfDNA at each time point. RESULTS Five grafts were suitable for LT, there were no cases of primary nonfunction or death in the recipients. gdcfDNA was quantified in all bile and plasma samples (n > 100). In plasma, gdcfDNA concentrations climbed post-machine reperfusion until 4.25 h (median 2.25 h = 15.98 × 10 6 copies/mL, 4.25 h = 40.21 × 10 6 copies/mL). gdcfDNA levels then diverged significantly when comparing the viable and non-viable graft groups (6.25 h, median viable: 117.15 × 10 6 copies/mL versus non-viable: 16.72 × 10 6 copies/mL, P = 0.01). These opposing trends correlated in each graft and in all cases with the viable/non-viable outcome. There was a trend of gradual decline in bile gdcfDNA from viable grafts post-machine reperfusion; discarded grafts showed more variable patterns of release. CONCLUSIONS gdcfDNA analysis during NMP is a feasible and potential tool to inform viability assessment during NMP for LT. Bile gdcfDNA monitoring offers the prospect of an objective means to assess the degree of biliary injury associated with organ procurement.
Collapse
Affiliation(s)
- Daniel R.A. Cox
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
- Translational Genomics and Epigenomics Laboratory, Department of Surgery (Austin), University of Melbourne, Melbourne, VIC, Australia
| | - Eunice Lee
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
| | - Boris K.L. Wong
- Translational Genomics and Epigenomics Laboratory, Department of Surgery (Austin), University of Melbourne, Melbourne, VIC, Australia
| | - Tess McClure
- Translational Genomics and Epigenomics Laboratory, Department of Surgery (Austin), University of Melbourne, Melbourne, VIC, Australia
- Liver Transplant Unit, Austin Health, Melbourne, VIC, Australia
| | - Fan Zhang
- Translational Genomics and Epigenomics Laboratory, Department of Surgery (Austin), University of Melbourne, Melbourne, VIC, Australia
| | - Su Kah Goh
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
| | - Angela Vago
- Liver Transplant Unit, Austin Health, Melbourne, VIC, Australia
| | - Louise Jackett
- Department of Anatomical Pathology, Austin Health, Melbourne, VIC, Australia
| | - Michael Fink
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
| | - Robert Jones
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
- Liver Transplant Unit, Austin Health, Melbourne, VIC, Australia
| | - Marcos V. Perini
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
| | - Alexander Dobrovic
- Translational Genomics and Epigenomics Laboratory, Department of Surgery (Austin), University of Melbourne, Melbourne, VIC, Australia
| | - Adam Testro
- Liver Transplant Unit, Austin Health, Melbourne, VIC, Australia
| | - Graham Starkey
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
- Liver Transplant Unit, Austin Health, Melbourne, VIC, Australia
| | - Vijayaragavan Muralidharan
- Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia
- Hepatopancreatobiliary and Liver Transplant Surgery Unit, Austin Health, Melbourne, VIC, Australia
| |
Collapse
|
|
6
|
Abstract
PURPOSE OF REVIEW Kidney transplantation is vital for those with end-stage renal disease, enhancing quality of life and longevity. It is the preferred treatment but is hindered by a global disparity between donor kidney availability and demand. Therefore, optimizing organ storage techniques is crucial to mitigate the effects of ischemia reperfusion injury in available organs. Recent interest has centered on innovative methods like oxygenated normothermic perfusion and abdominal regional perfusion. RECENT FINDINGS Multiple recent metanalyses, including a Cochrane review, confirm the benefits of hypothermic machine perfusion (HMP) for deceased donor kidneys, demonstrating its utility and cost effectiveness. The benefits of oxygenated normothermic perfusion have been seen in retrospective data sets but not in prospective trials. Abdominal regional perfusion (aNRP) is gaining interest, especially for liver transplantation, but kidney specific data are scant. SUMMARY High-quality evidence backs the use of HMP for deceased donor kidneys. Despite interest in other techniques, clinical evidence for their benefits in kidney transplantation is lacking. The gap between innovation and verified success emphasizes the need for continued research and collaboration between medical professionals, researchers, and ethical committees. This review aims to further illuminate the complexities and advancements in the field, bridging the knowledge gap and aiding in the continual pursuit of excellence in transplantation.
Collapse
Affiliation(s)
- Yanbo Guo
- Division of Urology, Department of Surgery, McMaster University, Hamilton
| | - Patrick Luke
- Division of Urology, Department of Surgery, Western University, London, ON, Canada
| | - Alp Sener
- Division of Urology, Department of Surgery, Western University, London, ON, Canada
| |
Collapse
|
|
7
|
Snashall CM, Sutton CW, Faro LL, Ceresa C, Ploeg R, Shaheed SU. Comparison of in-gel and in-solution proteolysis in the proteome profiling of organ perfusion solutions. Clin Proteomics 2023; 20:51. [PMID: 37968584 PMCID: PMC10648346 DOI: 10.1186/s12014-023-09440-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/25/2023] [Indexed: 11/17/2023] Open
Abstract
PURPOSE The organ perfusion solution (perfusate), collected at clinically and temporally significant stages of the organ preservation and transplantation process, provides a valuable insight into the biological status of an organ over time and prior to reperfusion (transplantation) in the recipient. The objective of this study was to assess two bottom-up proteomics workflows for the extraction of tryptic peptides from the perfusate. EXPERIMENTAL DESIGN Two different kinds of perfusate samples from kidney and liver trials were profiled using liquid chromatography-mass spectrometry (LC-MS/MS). The preparation of clean peptide mixtures for downstream analysis was performed considering different aspects of sample preparation; protein estimation, enrichment, in-gel and urea-based in-solution digestion. RESULTS In-solution digestion of perfusate allowed identification of the highest number of peptides and proteins with greater sequence coverage and higher confidence data in kidney and liver perfusate. Key pathways identified by gene ontology analysis included complement, coagulation and antioxidant pathways, and a number of biomarkers previously linked to ischemia-reperfusion injury were also observed in perfusate. CONCLUSIONS This study showed that in-solution digestion is a more efficient method for LC-MS/MS analysis of kidney and liver organ perfusion solutions. This method is also quicker and easier than in-gel digestion, allowing for greater sample throughput, with fewer opportunities for experimental error or peptide loss.
Collapse
Affiliation(s)
- Corinna M Snashall
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- School of Biosciences, The University of Sheffield, Sheffield, UK
| | - Chris W Sutton
- Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
| | - Letizia Lo Faro
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Carlo Ceresa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Rutger Ploeg
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Leiden University Medical Centre, Leiden University, Leiden, Netherlands
- Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Sadr Ul Shaheed
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
- NHSBT Oxford Blood Donor Centre John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9BQ, UK.
| |
Collapse
|
|
8
|
Elderkin J, Al Hallak N, Azmi AS, Aoun H, Critchfield J, Tobon M, Beal EW. Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management. Cancers (Basel) 2023; 15:5118. [PMID: 37958294 PMCID: PMC10647678 DOI: 10.3390/cancers15215118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future.
Collapse
Affiliation(s)
- Jessica Elderkin
- Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Asfar S. Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Hussein Aoun
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Jeffrey Critchfield
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Miguel Tobon
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Eliza W. Beal
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
| |
Collapse
|
|
9
|
Blondeel J, Gilbo N, Heedfeld V, Wylin T, Libbrecht L, Jochmans I, Pirenne J, Korf H, Monbaliu D. The Distinct Innate Immune Response of Warm Ischemic Injured Livers during Continuous Normothermic Machine Perfusion. Int J Mol Sci 2023; 24:12831. [PMID: 37629012 PMCID: PMC10454045 DOI: 10.3390/ijms241612831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Although normothermic machine perfusion (NMP) provides superior preservation of liver grafts compared to static cold storage and allows for viability testing of high-risk grafts, its effect on the liver immune compartment remains unclear. We investigated the innate immune response during 6 h of continuous NMP (cNMP) of livers that were directly procured (DP, n = 5) or procured after 60 min warm ischemia (WI, n = 5), followed by 12 h of whole blood (WB) reperfusion. WI livers showed elevated transaminase levels during cNMP but not after WB reperfusion. Perfusate concentrations of TNF-α were lower in WI livers during cNMP and WB reperfusion, whereas IL-8 concentrations did not differ significantly. TGF-β concentrations were higher in WI livers during NMP but not after WB reperfusion, whereas IL-10 concentrations were similar. Endoplasmic stress and apoptotic signaling were increased in WI livers during cNMP but not after WB reperfusion. Additionally, neutrophil mobilization increased to a significantly lesser extent in WI livers at the end of NMP. In conclusion, WI livers exhibit a distinct innate immune response during cNMP compared to DP livers. The cytokine profile shifted towards an anti-inflammatory phenotype during cNMP and WB reperfusion, and pro-apoptotic signaling was stronger during cNMP. During WB reperfusion, livers exhibited a blunted cytokine release, regardless of ischemic damage, supporting the potential reconditioning effect of cNMP.
Collapse
Affiliation(s)
- Joris Blondeel
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Nicholas Gilbo
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Veerle Heedfeld
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Tine Wylin
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Louis Libbrecht
- Department of Pathology, AZ Groeninge, 8500 Kortrijk, Belgium;
- Laboratory of Hepatology, CHROMETA Department, KU Leuven, 3000 Leuven, Belgium;
| | - Ina Jochmans
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Jacques Pirenne
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Hannelie Korf
- Laboratory of Hepatology, CHROMETA Department, KU Leuven, 3000 Leuven, Belgium;
| | - Diethard Monbaliu
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, 3000 Leuven, Belgium; (J.B.); (N.G.); (V.H.); (T.W.); (I.J.); (J.P.)
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| |
Collapse
|
|
10
|
Durán M, Calleja R, Hann A, Clarke G, Ciria R, Nutu A, Sanabria-Mateos R, Ayllón MD, López-Cillero P, Mergental H, Briceño J, Perera MTPR. Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence? World J Gastroenterol 2023; 29:3066-3083. [PMID: 37346149 PMCID: PMC10280793 DOI: 10.3748/wjg.v29.i20.3066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/01/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.
Collapse
Affiliation(s)
- Manuel Durán
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Rafael Calleja
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - George Clarke
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Ruben Ciria
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Anisa Nutu
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | | | - María Dolores Ayllón
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Pedro López-Cillero
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Javier Briceño
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| |
Collapse
|
|
11
|
Staubli SM, Ceresa CDL, Pollok JM. The Current Role and Future Applications of Machine Perfusion in Liver Transplantation. Bioengineering (Basel) 2023; 10:bioengineering10050593. [PMID: 37237663 DOI: 10.3390/bioengineering10050593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/07/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and have allowed for the prediction of graft function through the analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and to provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts.
Collapse
Affiliation(s)
- Sebastian M Staubli
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
| | - Carlo D L Ceresa
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxfordshire OX3 9DU, UK
| | - Joerg M Pollok
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Division of Surgery & Interventional Science, University College London, London WC1E 6BT, UK
| |
Collapse
|
|
12
|
Hautz T, Salcher S, Fodor M, Sturm G, Ebner S, Mair A, Trebo M, Untergasser G, Sopper S, Cardini B, Martowicz A, Hofmann J, Daum S, Kalb M, Resch T, Krendl F, Weissenbacher A, Otarashvili G, Obrist P, Zelger B, Öfner D, Trajanoski Z, Troppmair J, Oberhuber R, Pircher A, Wolf D, Schneeberger S. Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver. Nat Commun 2023; 14:2285. [PMID: 37085477 PMCID: PMC10121614 DOI: 10.1038/s41467-023-37674-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/27/2023] [Indexed: 04/23/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- T Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - M Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - G Sturm
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - S Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - M Trebo
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - G Untergasser
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
- Tyrolpath Obrist Brunhuber GmbH, Zams, Austria
| | - S Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - B Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A Martowicz
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
- Tyrolpath Obrist Brunhuber GmbH, Zams, Austria
| | - J Hofmann
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S Daum
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - M Kalb
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - T Resch
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - F Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - G Otarashvili
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - P Obrist
- Tyrolpath Obrist Brunhuber GmbH, Zams, Austria
| | - B Zelger
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - D Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - Z Trajanoski
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - J Troppmair
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - R Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria
| | - D Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria.
| | - S Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory and D. Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria.
| |
Collapse
|
|
13
|
Olumba FC, Zhou F, Park Y, Chapman WC. Normothermic Machine Perfusion for Declined Livers: A Strategy to Rescue Marginal Livers for Transplantation. J Am Coll Surg 2023; 236:614-625. [PMID: 36728302 DOI: 10.1097/xcs.0000000000000555] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Organ waste is a major cause of the donor liver shortage. Roughly 67% of recovered organ donors have liver utilization annually. A new technology called normothermic machine perfusion (NMP) offers a way to recover marginal and declined livers for transplant. We report interim results of the RESTORE trial (FDA investigational drug exemption trial NCT04483102) that aims to transplant NMP-treated livers that would otherwise be discarded. STUDY DESIGN Declined livers were screened for NMP eligibility (eg donation after circulatory death [DCD] grafts with warm ischemic time <40 minutes, donation after brain death [DBD] grafts with cold ischemic time <8 hours). Livers meeting pre-NMP eligibility criteria received NMP using the OrganOx metra device for a minimum of 4 hours. All NMP-treated livers meeting the viability criteria were transplanted to consented recipients. RESULTS Over 22 months, 60 declined livers from three organ procurement organizations (OPOs; 40 DCD and 20 DBD donor livers) were offered, and 22 livers (10 DCD and 12 DBD livers) met the pre-NMP eligibility. After NMP, 16 of 22 livers passed viability testing and were transplanted into needy recipients (median Model for End-Stage Liver Disease [MELD] score of 8, range 6 to 24), resulting in a 72.7% rescue rate (50% DCD, 91.7% DBD). The rate of early allograft dysfunction was 31.3%, but there were no graft-related deaths, primary nonfunction, or instances of nonanastomotic biliary strictures. CONCLUSIONS Interim results of the RESTORE trial suggest that a sizable number of declined livers can be reclaimed. They are safe for transplantation and can enable lower MELD patients at high risk of morbidity and mortality to receive lifesaving grafts while offering OPOs a way to allocate more livers and reduce organ waste.
Collapse
Affiliation(s)
- Franklin C Olumba
- From the Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO (Olumba, Zhou, Chapman)
| | - Fangyu Zhou
- From the Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO (Olumba, Zhou, Chapman)
| | - Yikyung Park
- the Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO (Park)
| | - William C Chapman
- From the Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO (Olumba, Zhou, Chapman)
| |
Collapse
|
|
14
|
Patrono D, Colli F, Colangelo M, De Stefano N, Apostu AL, Mazza E, Catalano S, Rizza G, Mirabella S, Romagnoli R. How Can Machine Perfusion Change the Paradigm of Liver Transplantation for Patients with Perihilar Cholangiocarcinoma? J Clin Med 2023; 12:jcm12052026. [PMID: 36902813 PMCID: PMC10004136 DOI: 10.3390/jcm12052026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Perihilar cholangiocarcinomas (pCCA) are rare yet aggressive tumors originating from the bile ducts. While surgery remains the mainstay of treatment, only a minority of patients are amenable to curative resection, and the prognosis of unresectable patients is dismal. The introduction of liver transplantation (LT) after neoadjuvant chemoradiation for unresectable pCCA in 1993 represented a major breakthrough, and it has been associated with 5-year survival rates consistently >50%. Despite these encouraging results, pCCA has remained a niche indication for LT, which is most likely due to the need for stringent candidate selection and the challenges in preoperative and surgical management. Machine perfusion (MP) has recently been reintroduced as an alternative to static cold storage to improve liver preservation from extended criteria donors. Aside from being associated with superior graft preservation, MP technology allows for the safe extension of preservation time and the testing of liver viability prior to implantation, which are characteristics that may be especially useful in the setting of LT for pCCA. This review summarizes current surgical strategies for pCCA treatment, with a focus on unmet needs that have contributed to the limited spread of LT for pCCA and how MP could be used in this setting, with a particular emphasis on the possibility of expanding the donor pool and improving transplant logistics.
Collapse
|
|
15
|
Shen C, Cheng H, Zong T, Zhu H. The role of normothermic machine perfusion (NMP) in the preservation of ex-vivo liver before transplantation: A review. Front Bioeng Biotechnol 2023; 11:1072937. [PMID: 36845187 PMCID: PMC9947506 DOI: 10.3389/fbioe.2023.1072937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. There is a limited access to liver transplantation, as a result, it is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. However, there are still many unknown risks associated with the use of ECD, among which preservation before liver transplantation is important in determining whether patients would experience complications survive after liver transplantation. In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability, and potentially ex vivo assessment of graft viability before transplantation. Data seem to suggest that NMP can enhance the preservation of liver transplantation to some extent and improve the early outcome after transplantation. In this review, we provided an overview of NMP and its application in ex vivo liver preservation and pre-transplantation, and we summarized the data from current clinical trials of normothermic liver perfusion.
Collapse
Affiliation(s)
- Chuanyan Shen
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Hongwei Cheng
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Tingting Zong
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Hongli Zhu
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China,National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, China,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, China,*Correspondence: Hongli Zhu,
| |
Collapse
|
|
16
|
Kanani T, Isherwood J, Issa E, Chung WY, Ravaioli M, Oggioni MR, Garcea G, Dennison A. A Narrative Review of the Applications of Ex-vivo Human Liver Perfusion. Cureus 2023; 15:e34804. [PMID: 36915839 PMCID: PMC10008027 DOI: 10.7759/cureus.34804] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2023] [Indexed: 02/11/2023] Open
Abstract
Ex-vivo perfusion describes the extra-corporeal delivery of fluid to an organ or tissue. Although it has been widely studied in the context of organ preservation and transplantation, it has also proven to be an invaluable tool in the development of novel models for translational pre-clinical research. Here, we review the literature reporting ex-vivo human liver perfusion experiments to further understand current perfusion techniques and protocols together with their applications. A computerised search was made of Ovid, MEDLINE, and Embase using the search words "ex-vivo liver or hepatic perfusion". All relevant studies in English describing experiments using ex-vivo perfusion of human livers between 2016 and 2021, inclusive, were included. Of 21 reviewed studies, 19 used ex-vivo human liver perfusion in the context of allogeneic liver transplantation. The quality and size of the studies varied considerably. Human liver perfusion was almost exclusively limited to whole organs and "split" livers, although one study did describe the successful perfusion of tissue sections following a partial hepatectomy. This review of recent literature involving ex-vivo human liver perfusion demonstrates that the technique is not limited to whole liver perfusion. Split-liver perfusion is extremely valuable allowing one lobe to act as a control and increasing the number available for research. This review also highlights the present lack of any reports of segmental liver perfusion. The discarded donor liver is a scarce resource, and the successful use of segmental perfusion has the potential to expand the available experimental models to facilitate pre-clinical experimentation.
Collapse
Affiliation(s)
- Trisha Kanani
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| | - John Isherwood
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| | - Eyad Issa
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| | - Wen Y Chung
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| | - Matteo Ravaioli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, ITA
| | - Marco R Oggioni
- Department of Genetics and Genome Biology, University of Leicester, Leicester, GBR
| | - Giuseppe Garcea
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| | - Ashley Dennison
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester NHS Trust, Leicester, GBR
| |
Collapse
|
|
17
|
Łuczykowski K, Warmuzińska N, Kollmann D, Selzner M, Bojko B. Biliary Metabolome Profiling for Evaluation of Liver Metabolism and Biliary Tract Function Related to Organ Preservation Method and Degree of Ischemia in a Porcine Model. Int J Mol Sci 2023; 24:2127. [PMID: 36768452 PMCID: PMC9916698 DOI: 10.3390/ijms24032127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/25/2023] Open
Abstract
The development of surgical techniques, immunosuppressive strategies and new organ preservation methods have meant that transplant centers have to face the problem of an insufficient number of organs for transplantation concerning the constantly growing demand. Therefore, using organs from expanded criteria donors and developing new analytical solutions to find parameters or compounds that would allow a more efficient assessment of organ quality before transplantation are options for meeting this challenge. This study proposed bile metabolomic analysis to evaluate liver metabolism and biliary tract function depending on the organ preservation method and degree of warm ischemia time. The analyses were performed on solid-phase microextraction-prepared bile samples from porcine model donors with mild (heart beating donor [HBD]) and moderate warm ischemia (donation after circulatory death [DCD]) grafts subjected to static cold storage (SCS) or normothermic ex vivo liver perfusion (NEVLP) before transplantation. Bile produced in the SCS-preserved livers was characterized by increased levels of metabolites such as chenodeoxycholic acid, arachidonic acid and 5S-hydroxyeicosatetraeonic acid, as well as saturated and monounsaturated lysophosphatidylcholines (LPC). Such changes may be associated with differences in the bile acid synthesis pathways and organ inflammation. Moreover, it has been shown that NEVLP reduced the negative effect of ischemia on organ function. A linear relationship was observed between levels of lipids from the LPC group and the time of organ ischemia. This study identified metabolites worth considering as potential markers of changes occurring in preserved grafts.
Collapse
Affiliation(s)
- Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
| | - Dagmar Kollmann
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Markus Selzner
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
| |
Collapse
|
|
18
|
Azizieh Y, Westhaver LP, Badrudin D, Boudreau JE, Gala-Lopez BL. Changing liver utilization and discard rates in clinical transplantation in the ex-vivo machine preservation era. FRONTIERS IN MEDICAL TECHNOLOGY 2023; 5:1079003. [PMID: 36908294 PMCID: PMC9996101 DOI: 10.3389/fmedt.2023.1079003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/30/2023] [Indexed: 02/25/2023] Open
Abstract
Liver transplantation is a well-established treatment for many with end-stage liver disease. Unfortunately, the increasing organ demand has surpassed the donor supply, and approximately 30% of patients die while waiting for a suitable liver. Clinicians are often forced to consider livers of inferior quality to increase organ donation rates, but ultimately, many of those organs end up being discarded. Extensive testing in experimental animals and humans has shown that ex-vivo machine preservation allows for a more objective characterization of the graft outside the body, with particular benefit for suboptimal organs. This review focuses on the history of the implementation of ex-vivo liver machine preservation and how its enactment may modify our current concept of organ acceptability. We provide a brief overview of the major drivers of organ discard (age, ischemia time, steatosis, etc.) and how this technology may ultimately revert such a trend. We also discuss future directions for this technology, including the identification of new markers of injury and repair and the opportunity for other ex-vivo regenerative therapies. Finally, we discuss the value of this technology, considering current and future donor characteristics in the North American population that may result in a significant organ discard.
Collapse
Affiliation(s)
- Yara Azizieh
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | | | - David Badrudin
- Department of Surgery, Université de Montréal, Montréal, QC, Canada
| | - Jeanette E Boudreau
- Department of Pathology, Dalhousie University, Halifax, NS, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Boris L Gala-Lopez
- Department of Pathology, Dalhousie University, Halifax, NS, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada.,Department of Surgery, Dalhousie University, Halifax, NS, Canada
| |
Collapse
|
|
19
|
Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
Collapse
Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
| |
Collapse
|
|
20
|
Fodor M, Lanser L, Hofmann J, Otarashvili G, Pühringer M, Cardini B, Oberhuber R, Resch T, Weissenbacher A, Maglione M, Margreiter C, Zelger P, Pallua JD, Öfner D, Sucher R, Hautz T, Schneeberger S. Hyperspectral Imaging as a Tool for Viability Assessment During Normothermic Machine Perfusion of Human Livers: A Proof of Concept Pilot Study. Transpl Int 2022; 35:10355. [PMID: 35651880 PMCID: PMC9150258 DOI: 10.3389/ti.2022.10355] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/22/2022] [Indexed: 11/23/2022]
Abstract
Normothermic machine perfusion (NMP) allows for ex vivo viability and functional assessment prior to liver transplantation (LT). Hyperspectral imaging represents a suitable, non-invasive method to evaluate tissue morphology and organ perfusion during NMP. Liver allografts were subjected to NMP prior to LT. Serial image acquisition of oxygen saturation levels (StO2), organ hemoglobin (THI), near-infrared perfusion (NIR) and tissue water indices (TWI) through hyperspectral imaging was performed during static cold storage, at 1h, 6h, 12h and at the end of NMP. The readouts were correlated with perfusate parameters at equivalent time points. Twenty-one deceased donor livers were included in the study. Seven (33.0%) were discarded due to poor organ function during NMP. StO2 (p < 0.001), THI (p < 0.001) and NIR (p = 0.002) significantly augmented, from static cold storage (pre-NMP) to NMP end, while TWI dropped (p = 0.005) during the observational period. At 12-24h, a significantly higher hemoglobin concentration (THI) in the superficial tissue layers was seen in discarded, compared to transplanted livers (p = 0.036). Lactate values at 12h NMP correlated negatively with NIR perfusion index between 12 and 24h NMP and with the delta NIR perfusion index between 1 and 24h (rs = -0.883, p = 0.008 for both). Furthermore, NIR and TWI correlated with lactate clearance and pH. This study provides first evidence of feasibility of hyperspectral imaging as a potentially helpful contact-free organ viability assessment tool during liver NMP.
Collapse
Affiliation(s)
- Margot Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia Hofmann
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Giorgi Otarashvili
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Marlene Pühringer
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Philipp Zelger
- Department for Hearing, Speech, and Voice Disorders, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes D. Pallua
- University Hospital for Orthopedics and Traumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Sucher
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Clinic, Leipzig, Germany
| | - Theresa Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria,*Correspondence: Stefan Schneeberger,
| |
Collapse
|
|
21
|
Normothermic Machine Perfusion as a Tool for Safe Transplantation of High-Risk Recipients. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3020018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Normothermic machine perfusion (NMP) should no longer be considered a novel liver graft preservation strategy, but rather viewed as the standard of care for certain graft–recipient scenarios. The ability of NMP to improve the safe utilisation of liver grafts has been demonstrated in several publications, from numerous centres. This is partly mediated by its ability to limit the cold ischaemic time while also extending the total preservation period, facilitating the difficult logistics of a challenging transplant operation. Viability assessment of both the hepatocytes and cholangiocytes with NMP is much debated, with numerous different parameters and thresholds associated with a reduction in the incidence of primary non-function and biliary strictures. Maximising the utilisation of liver grafts is important as many patients require transplantation on an urgent basis, the waiting list is long, and significant morbidity and mortality is experienced by patients awaiting transplants. If applied in an appropriate manner, NMP has the ability to expand the pool of grafts available for even the sickest and most challenging of recipients. In addition, this is the group of patients that consume significant healthcare resources and, therefore, justify the additional expense of NMP. This review describes, with case examples, how NMP can be utilised to salvage suboptimal grafts, and our approach of transplanting them into high-risk recipients.
Collapse
|
|
22
|
Boteon YL, Hessheimer AJ, Brüggenwirth IMA, Boteon APCS, Padilla M, de Meijer VE, Domínguez-Gil B, Porte RJ, Perera MTPR, Martins PN. The economic impact of machine perfusion technology in liver transplantation. Artif Organs 2022; 46:191-200. [PMID: 34878658 DOI: 10.1111/aor.14131] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/03/2021] [Accepted: 11/14/2021] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Several clinical studies have demonstrated the safety, feasibility, and efficacy of machine perfusion in liver transplantation, although its economic outcomes are still underexplored. This review aimed to examine the costs related to machine perfusion and its associated outcomes. METHODS Expert opinion of several groups representing different machine perfusion modalities. Critical analysis of the published literature reporting the economic outcomes of the most used techniques of machine perfusion in liver transplantation (normothermic and hypothermic ex situ machine perfusion and in situ normothermic regional perfusion). RESULTS Machine perfusion costs include disposable components of the perfusion device, perfusate components, personnel and facility fees, and depreciation of the perfusion device or device lease fee. The limited current literature suggests that although this upfront cost varies between perfusion modalities, its use is highly likely to be cost-effective. Optimization of the donor liver utilization rate, local conditions of transplant programs (long waiting list times and higher MELD scores), a decreased rate of complications, changes in logistics, and length of hospital stay are potential cost savings points that must highlight the expected benefits of this intervention. An additional unaccounted factor is that machine perfusion optimizing donor organ utilization allows patients to be transplanted earlier, avoiding clinical deterioration while on the waiting list and the costs associated with hospital admissions and other required procedures. CONCLUSION So far, the clinical benefits have guided machine perfusion implementation in liver transplantation. Albeit there is data suggesting the economic benefit of the technique, further investigation of its costs to healthcare systems and society and associated outcomes is needed.
Collapse
Affiliation(s)
- Yuri L Boteon
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Amelia J Hessheimer
- Hepatopancreatobiliary Surgery & Transplantation, General & Digestive Surgery Service, Hospital Universitario La Paz, Madrid, Spain
| | - Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - María Padilla
- Organización Nacional de Trasplantes, Ministerio de Sanidad, Madrid, Spain
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Robert J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Paulo N Martins
- Department of Surgery, Transplant Division, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| |
Collapse
|
|
23
|
Riveros S, Marino C, Ochoa G, Morales E, Soto D, Alegría L, Zenteno MJ, Brañes A, Achurra P, Rebolledo RA. Implementation and design of customized ex vivo machine perfusion. Analysis of its first results. Artif Organs 2021; 46:210-218. [PMID: 34519358 DOI: 10.1111/aor.14060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022]
Abstract
The lack of organs available for transplantation is a global problem. The high mortality rates on the waiting list and the high number of discarded livers are reasons to develop new tools in the preservation and transplantation process. New tools should also be available for low-income countries. This article reports the development of customized normothermic machine perfusion (NMP). An ex vivo dual perfusion machine was designed, composed of a common reservoir organ box (CRO), a centrifugal pump (portal system, low pressure), and a roller pump (arterial system, high pressure). Porcine livers (n = 5) were perfused with an oxygenated normothermic (37℃) strategy for 3 hours. Hemodynamic variables, metabolic parameters, and bile production during preservation were analyzed. Arterial and portal flow remain stable during perfusion. Total bilirubin production was 11.25 mL (4-14.5) at 180 minutes. The median pH value reached 7.32 (7.25-7.4) at 180 minutes. Lactate values decreased progressively to normalization at 120 minutes. This perfusion setup was stable and able to maintain the metabolic activity of a liver graft in a porcine animal model. Design and initial results from this customized NMP are promising for a future clinical application in low-income countries.
Collapse
Affiliation(s)
- Sergio Riveros
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlo Marino
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriela Ochoa
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Emilio Morales
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Dagoberto Soto
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leyla Alegría
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Alejandro Brañes
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| | - Pablo Achurra
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando A Rebolledo
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| |
Collapse
|
|
24
|
|
|
25
|
van Beekum CJ, Vilz TO, Glowka TR, von Websky MW, Kalff JC, Manekeller S. Normothermic Machine Perfusion (NMP) of the Liver - Current Status and Future Perspectives. Ann Transplant 2021; 26:e931664. [PMID: 34426566 PMCID: PMC8400594 DOI: 10.12659/aot.931664] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022] Open
Abstract
A shortage of available organs for liver transplantation has led transplant surgeons and researchers to seek for innovative approaches in hepatoprotection and improvement of marginal allografts. The most exciting development in the past decade has been continuous mechanical perfusion of livers with blood or preservation solution to mitigate ischemia-reperfusion injury in contrast to the current standard of static cold storage. Two variations of machine perfusion have emerged in clinical practice. During hypothermic oxygenated perfusion the liver is perfused using a red blood cell-free perfusate at 2-10°C. In contrast, normothermic machine perfusion mimics physiologic liver perfusion using a red blood cell-based solution at 35.5-037.5°C, offering a multitude of potential advantages. Putative effects of normothermic perfusion include abrogation of hyperfibrinolysis after reperfusion and inflammation, glycogen repletion, and regeneration of adenosine triphosphate. Research in normothermic machine perfusion focuses on development of biomarkers predicting allograft quality and susceptibility to ischemia-reperfusion injury. Moreover, normothermic perfusion of marginal allografts allows for application of a variety of therapeutic interventions potentially enhancing organ quality. Both methods need to be subjected to translational investigation and evaluation in clinical trials. A clear advantage is transformation of an emergency procedure at night into a planned daytime surgery. Current clinical trials suggest that normothermic perfusion not only increases the use of hepatic allografts but is also associated with milder ischemia-reperfusion injury, resulting in a reduced risk of early allograft dysfunction and less biliary complications, including ischemic cholangiopathy, compared to static cold storage. The aim of this review is to give a concise overview of normothermic machine perfusion and its current applications, benefits, and possible advances in the future.
Collapse
|
|
26
|
Fodor M, Cardini B, Peter W, Weissenbacher A, Oberhuber R, Hautz T, Otarashvili G, Margreiter C, Maglione M, Resch T, Krendl F, Meszaros AT, Bogensperger C, Gasteiger S, Messner F, Henninger B, Zoller H, Tilg H, Öfner D, Schneeberger S. Static cold storage compared with normothermic machine perfusion of the liver and effect on ischaemic-type biliary lesions after transplantation: a propensity score-matched study. Br J Surg 2021; 108:1082-1089. [PMID: 34027968 DOI: 10.1093/bjs/znab118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/05/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Given the susceptibility of organs to ischaemic injury, alternative preservation methods to static cold storage (SCS), such as normothermic machine perfusion (NMP) are emerging. The aim of this study was to perform a comparison between NMP and SCS in liver transplantation with particular attention to bile duct lesions. METHODS The outcomes of 59 consecutive NMP-preserved donor livers were compared in a 1 : 1 propensity score-matched fashion to SCS control livers. Postoperative complications, patient survival, graft survival and bile duct lesions were analysed. RESULTS While patients were matched for cold ischaemia time, the total preservation time was significantly longer in the NMP group (21 h versus 7 h, P < 0.001). Patient and graft survival rates at 1 year were 81 versus 82 per cent (P = 0.347) and 81 versus 79 per cent (P = 0.784) in the NMP and SCS groups, respectively. The postoperative complication rate was comparable (P = 0.086); 37 per cent NMP versus 34 per cent SCS patients had a Clavien-Dindo grade IIIb or above complication. There was no difference in early (30 days or less) (NMP 22 versus SCS 19 per cent, P = 0.647) and late (more than 30 days) (NMP 27 versus SCS 36 per cent, P = 0.321) biliary complications. However, NMP-preserved livers developed significantly fewer ischaemic-type bile duct lesions (NMP 3 versus SCS 14 per cent, P = 0.047). CONCLUSION The use of NMP allowed for a significantly prolonged organ preservation with a lower rate of observed ischaemic-type bile duct lesions.
Collapse
Affiliation(s)
- M Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - B Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - W Peter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - A Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - R Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - T Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - G Otarashvili
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - C Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - M Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - T Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - F Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - A T Meszaros
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - C Bogensperger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - S Gasteiger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - F Messner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - B Henninger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - H Zoller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - H Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - D Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - S Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
27
|
Martins PN, Rizzari MD, Ghinolfi D, Jochmans I, Attia M, Jalan R, Friend PJ. Design, Analysis, and Pitfalls of Clinical Trials Using Ex Situ Liver Machine Perfusion: The International Liver Transplantation Society Consensus Guidelines. Transplantation 2021; 105:796-815. [PMID: 33760791 DOI: 10.1097/tp.0000000000003573] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs. METHODS The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine Perfusion" held in Venice, Italy, on January 31, 2020. RESULTS Twelve recommendations were proposed with the main conclusions that clinical trials investigating the effect of MP in liver transplantation should (1) make the protocol publicly available before the start of the trial, (2) be adequately powered, and (3) carefully consider timing of randomization in function of the primary outcome. CONCLUSIONS There are issues with using accepted primary outcomes of liver transplantation trials in the context of MP trials, and no ideal endpoint could be defined by the working group. The setup of an international registry was considered vital by the working group.
Collapse
Affiliation(s)
- Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, University of Massachusetts Memorial Hospital, University of Massachusetts, Worcester, MA
| | - Michael D Rizzari
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI
| | - Davide Ghinolfi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Ina Jochmans
- Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Magdy Attia
- Department of Hepatobiliary & Transplantation Surgery, Leeds Teaching Hospitals Trust, Leeds, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, London, United Kingdom
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
28
|
Current review of machine perfusion in liver transplantation from the Japanese perspective. Surg Today 2021; 52:359-368. [PMID: 33754175 DOI: 10.1007/s00595-021-02265-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 02/21/2021] [Indexed: 12/11/2022]
Abstract
In light of the present evidence, machine perfusion is opening up new horizons in the field of liver transplantation. Although many advances have been made in liver transplantation, organ preservation methods have so far changed very little. Static cold storage is universally used for graft preservation in liver transplantation; however, there is a need for better preservation methods, such as ex vivo machine perfusion, to improve the outcomes by decreasing warm ischemic damage. Based on the findings of basic and clinical trials, hypothermic and normothermic machine perfusion techniques are now commercially available and include the OrganOx metra, Liver Assist, Cleveland NMP device, Organ Care System, and LifePort Liver. Recent clinical trials have provided further evidence for the potential role of normothermic machine perfusion to resuscitate and subsequently improve utilization of marginal or currently discarded livers. Further studies are required to explore the longer-term outcomes, late biliary complications, outcomes in specific high-risk groups, viability biomarkers, optimum and maximum perfusion duration, perfusate composition, and liver-directed therapeutic interventions during normothermic machine perfusion. The use of organs from marginal donors after brain death, such as fatty livers and the livers from elderly donors with multiple comorbidities, may be accepted for machine perfusion in Japan in the near future.
Collapse
|
|
29
|
Tatum R, O'Malley TJ, Bodzin AS, Tchantchaleishvili V. Machine perfusion of donor organs for transplantation. Artif Organs 2021; 45:682-695. [PMID: 33349946 DOI: 10.1111/aor.13894] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022]
Abstract
The ever-widening gap between organ supply and demand has resulted in an organ shortage crisis that affects patients all over the world. For decades, static cold storage (SCS) was the gold standard preservation strategy because of its simplicity and cost-effectiveness, but the rising unmet demand for donor organ transplants has prompted investigation into preservation strategies that can expand the available donor pool. Through ex vivo functional assessment of the organ prior to transplant, newer methods to preserve organs such as perfusion-based therapy can potentially expand the available organ pool. This review will explain the physiologic rationale for SCS before exploring the advantages and disadvantages associated with the two broad classes of preservation strategies that have emerged to address the crisis: hypothermic and normothermic machine perfusion. A detailed analysis of how each preservation strategy works will be provided before investigating the current status of clinical data for each preservation strategy for the kidney, liver, pancreas, heart, and lung. For some organs there is robust data to support the use of machine perfusion technologies over SCS, and in others the data are less clear. Nonetheless, machine perfusion technologies represent an exciting frontier in organ preservation research and will remain a crucial component of closing the gap between organ supply and recipient demand.
Collapse
Affiliation(s)
- Robert Tatum
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Thomas J O'Malley
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam S Bodzin
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | | |
Collapse
|
|
30
|
Magro B, Tacelli M, Mazzola A, Conti F, Celsa C. Biliary complications after liver transplantation: current perspectives and future strategies. Hepatobiliary Surg Nutr 2021; 10:76-92. [PMID: 33575291 DOI: 10.21037/hbsn.2019.09.01] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 08/29/2019] [Indexed: 12/29/2022]
Abstract
Importance Liver transplantation (LT) is a life-saving therapy for patients with end-stage liver disease and with acute liver failure, and it is associated with excellent outcomes and survival rates at 1 and 5 years. The incidence of biliary complications (BCs) after LT is reported to range from 5% to 20%, most of them occurring in the first three months, although they can occur also several years after transplantation. Objective The aim of this review is to summarize the available evidences on pathophysiology, risk factors, diagnosis and therapeutic management of BCs after LT. Evidence Review a literature review was performed of papers on this topic focusing on risk factors, classifications, diagnosis and treatment. Findings Principal risk factors include surgical techniques and donor's characteristics for biliary leakage and anastomotic biliary strictures and vascular alterations for non- anastomotic biliary strictures. MRCP is the gold standard both for intra- and extrahepatic BCs, while invasive cholangiography should be restricted for therapeutic uses or when MRCP is equivocal. About treatment, endoscopic techniques are the first line of treatment with success rates of 70-100%. The combined success rate of ERCP and PTBD overcome 90% of cases. Biliary leaks often resolve spontaneously, or with the positioning of a stent in ERCP for major bile leaks. Conclusions and Relevance BCs influence morbidity and mortality after LT, therefore further evidences are needed to identify novel possible risk factors, to understand if an immunological status that could lead to their development exists and to compare the effectiveness of innovative surgical and machine perfusion techniques.
Collapse
Affiliation(s)
- Bianca Magro
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy.,Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Matteo Tacelli
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| | - Alessandra Mazzola
- Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Filomena Conti
- Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Ciro Celsa
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| |
Collapse
|
|
31
|
Parente A, Osei-Bordom DC, Ronca V, Perera MTPR, Mirza D. Organ Restoration With Normothermic Machine Perfusion and Immune Reaction. Front Immunol 2020; 11:565616. [PMID: 33193335 PMCID: PMC7641637 DOI: 10.3389/fimmu.2020.565616] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation is the only recognized effective treatment for end-stage liver disease. However, organ shortages have become the main challenge for patients and physicians within the transplant community. Waiting list mortality remains an issue with around 10% of patients dying whilst waiting for an available organ. The post-transplantation period is also associated with an adverse complication rate for these specific cohorts of high-risk patients, particularly regarding patient and graft survival. Ischaemia reperfusion injury (IRI) has been highlighted as the mechanism of injury that increases parenchymal damage, which eventually lead to significant graft dysfunction and other poor outcome indicators. The consequences of IRI in clinical practice such as reperfusion syndrome, primary non-function of graft, allograft dysfunction, ischaemic biliary damage and early biliary complications can be life-threatening. IRI dictates the development of a significant inflammatory response that drives the pathway to eventual cell death. The main mechanisms of IRI are mitochondrial damage due to low oxygen tension within the hepatic micro-environment and severe adenosine triphosphate (ATP) depletion during the ischaemic period. After the restoration of normal blood flow, this damage is further enhanced by reoxygenation as the mitochondria respond to reperfusion by releasing reactive oxygen species (ROS), which in turn activate Kupffer cells within the hepatic micro-environment, leading to a pro-inflammatory response and eventual parenchymal cell apoptosis and associated tissue degradation. Machine perfusion (MP) is one emergent strategy considered to be one of the most important advances in organ preservation, restoration and transplantation. Indeed, MP has the potential to rescue frequently discarded organs and has been shown to limit the extent of IRI, leading to suppression of the deleterious pro-inflammatory response. This immunomodulation reduces the prevalence of allograft rejection, the use of immunosuppression therapy and minimizes post-transplant complications. This review aims to update the current knowledge of MP with a focus on normothermic machine liver perfusion (NMLP) and its potential role in immune response pathways.
Collapse
Affiliation(s)
- Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Daniel-Clement Osei-Bordom
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Research Birmingham Liver Biomedical Research Centre, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - M. Thamara P. R. Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Darius Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
|
32
|
Karangwa SA, Lisman T, Porte RJ. Anticoagulant Management and Synthesis of Hemostatic Proteins during Machine Preservation of Livers for Transplantation. Semin Thromb Hemost 2020; 46:743-750. [DOI: 10.1055/s-0040-1715452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AbstractLiver transplantation remains the only curative treatment for patients with end-stage liver disease. Despite a steadily increasing demand for suitable donor livers, the current pool of donor organs fails to meet this demand. To resolve this discrepancy, livers traditionally considered to be of suboptimal quality and function are increasingly utilized. These marginal livers, however, are less tolerant to the current standard cold preservation of donor organs. Therefore, alternative preservation methods have been sought and are progressively applied into clinical practice. Ex situ machine perfusion is a promising alternative preservation modality particularly for suboptimal donor livers as it provides the ability to resuscitate, recondition, and test the viability of an organ prior to transplantation. This review addresses the modalities of machine perfusion currently being applied, and particularly focuses on the hemostatic management employed during machine perfusion. We discuss the anticoagulant agents used, the variation in dosage, and administration, as well as the implications of perfusion for extended periods of time in terms of coagulation activation associated with production of coagulation factors during perfusion. Furthermore, in regard to viability testing of an organ prior to transplantation, we discuss the possibilities and limitations of utilizing the synthesis of liver-derived coagulation factors as potential viability markers.
Collapse
Affiliation(s)
- Shanice A. Karangwa
- Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J. Porte
- Section of HPB Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
33
|
Owen A, Newsome PN. Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation? Front Immunol 2020; 11:1306. [PMID: 32636850 PMCID: PMC7318292 DOI: 10.3389/fimmu.2020.01306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
In response to the global burden of liver disease there has been a commensurate increase in the demand for liver transplantation. However, due to a paucity of donor organs many centers have moved toward the routine use of marginal allografts, which can be associated with a greater risk of complications and poorer clinical outcomes. Mesenchymal stromal cells (MSC) are a multi-potent progenitor cell population that have been utilized to modulate aberrant immune responses in acute and chronic inflammatory conditions. MSC exert an immunomodulatory effect on innate and adaptive immune systems through the release of both paracrine soluble factors and extracellular vesicles. Through these routes MSC can switch the regulatory function of the immune system through effects on macrophages and T regulatory cells enabling a switch of phenotype from injury to restoration. A key benefit seems to be their ability to tailor their response to the inflammatory environment without compromising the host ability to fight infection. With over 200 clinical trials registered to examine MSC therapy in liver disease and an increasing number of trials of MSC therapy in solid organ transplant recipients, there is increasing consideration for their use in liver transplantation. In this review we critically appraise the potential role of MSC therapy in the context of liver transplantation, including their ability to modulate reperfusion injury, their role in the reduction of medium term complications in the biliary tree and their potential to enhance tolerance in transplanted organs.
Collapse
Affiliation(s)
- Andrew Owen
- National Institute for Health Research Birmingham, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Department of Anesthesia and Critical Care, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research Birmingham, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| |
Collapse
|
|
34
|
Resch T, Cardini B, Oberhuber R, Weissenbacher A, Dumfarth J, Krapf C, Boesmueller C, Oefner D, Grimm M, Schneeberger S. Transplanting Marginal Organs in the Era of Modern Machine Perfusion and Advanced Organ Monitoring. Front Immunol 2020; 11:631. [PMID: 32477321 PMCID: PMC7235363 DOI: 10.3389/fimmu.2020.00631] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/19/2020] [Indexed: 12/11/2022] Open
Abstract
Organ transplantation is undergoing profound changes. Contraindications for donation have been revised in order to better meet the organ demand. The use of lower-quality organs and organs with greater preoperative damage, including those from donation after cardiac death (DCD), has become an established routine but increases the risk of graft malfunction. This risk is further aggravated by ischemia and reperfusion injury (IRI) in the process of transplantation. These circumstances demand a preservation technology that ameliorates IRI and allows for assessment of viability and function prior to transplantation. Oxygenated hypothermic and normothermic machine perfusion (MP) have emerged as valid novel modalities for advanced organ preservation and conditioning. Ex vivo prolonged lung preservation has resulted in successful transplantation of high-risk donor lungs. Normothermic MP of hearts and livers has displayed safe (heart) and superior (liver) preservation in randomized controlled trials (RCT). Normothermic kidney preservation for 24 h was recently established. Early clinical outcomes beyond the market entry trials indicate bioenergetics reconditioning, improved preservation of structures subject to IRI, and significant prolongation of the preservation time. The monitoring of perfusion parameters, the biochemical investigation of preservation fluids, and the assessment of tissue viability and bioenergetics function now offer a comprehensive assessment of organ quality and function ex situ. Gene and protein expression profiling, investigation of passenger leukocytes, and advanced imaging may further enhance the understanding of the condition of an organ during MP. In addition, MP offers a platform for organ reconditioning and regeneration and hence catalyzes the clinical realization of tissue engineering. Organ modification may include immunological modification and the generation of chimeric organs. While these ideas are not conceptually new, MP now offers a platform for clinical realization. Defatting of steatotic livers, modulation of inflammation during preservation in lungs, vasodilatation of livers, and hepatitis C elimination have been successfully demonstrated in experimental and clinical trials. Targeted treatment of lesions and surgical treatment or graft modification have been attempted. In this review, we address the current state of MP and advanced organ monitoring and speculate about logical future steps and how this evolution of a novel technology can result in a medial revolution.
Collapse
Affiliation(s)
- Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia Dumfarth
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Krapf
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Claudia Boesmueller
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Oefner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Grimm
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
35
|
Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts? Int J Mol Sci 2020; 21:ijms21093132. [PMID: 32365506 PMCID: PMC7246795 DOI: 10.3390/ijms21093132] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/18/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.
Collapse
|
|
36
|
Preclinical Models: Boosting Synergies for Improved Translation. J Clin Med 2020; 9:jcm9041011. [PMID: 32260102 PMCID: PMC7230432 DOI: 10.3390/jcm9041011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/01/2020] [Indexed: 11/17/2022] Open
|
|
37
|
Split Liver Transplantation and Pediatric Waitlist Mortality in the United States: Potential for Improvement. Transplantation 2019; 103:552-557. [PMID: 29684000 DOI: 10.1097/tp.0000000000002249] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND In the United States, 1 in 10 infants and 1 in 20 older children die on the liver transplant waiting list. Increasing split liver transplantation could increase organ availability for these children, without decreasing transplants in adults. METHODS Using United Network for Organ Sharing Standard Transplant Analysis and Research data, we identified livers transplanted 2010 to 2015 that could potentially have been used for split transplant, based on strict criteria. Livers not suitable for pediatric patients or allocated to high-risk recipients were excluded. Number and distribution of potentially "split-able" livers were compared to pediatric waitlist deaths in each region. RESULTS Of 37 333 deceased donor livers transplanted, 6.3% met our strict criteria for utilization in split liver transplant. Only 3.8% of these were actually utilized for split liver transplantation. 96% were used for a single adult recipient. Of the 2253 transplanted as whole livers, 82% of their recipients were listed as willing to accept a segmental liver, and only 3% were listed as requiring a cold ischemia time less than 6 hours. Over the same 5 years, 299 children died on the waitlist. In every United Network for Organ Sharing region, there were more potentially "split-able" livers than pediatric waitlist deaths. Thirty-seven percent of pediatric waitlist deaths occurred at transplant centers that averaged 1 or less pediatric split liver transplantation annually during the study period. CONCLUSIONS This comparison, although not conclusive, suggests that we might be missing opportunities to reduce pediatric waitlist mortality without decreasing access for adults-using split liver transplant. Barriers are significant, but further work on strategies to increase split liver transplant is warranted.
Collapse
|
|
38
|
Pezzati D, Pieroni E, Martinelli C, Rreka E, Balzano E, Catalano G, Tincani G, Ghinolfi D, De Simone P. Liver Machine Preservation: State of the Art. CURRENT TRANSPLANTATION REPORTS 2019. [DOI: 10.1007/s40472-019-00249-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
39
|
|
|
40
|
Dutkowski P, Guarrera JV, de Jonge J, Martins PN, Porte RJ, Clavien PA. Evolving Trends in Machine Perfusion for Liver Transplantation. Gastroenterology 2019; 156:1542-1547. [PMID: 30660724 DOI: 10.1053/j.gastro.2018.12.037] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/17/2018] [Accepted: 12/20/2018] [Indexed: 02/07/2023]
Affiliation(s)
| | | | - Jeroen de Jonge
- Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | | | | |
Collapse
|
|
41
|
Minor T, von Horn C. Rewarming Injury after Cold Preservation. Int J Mol Sci 2019; 20:ijms20092059. [PMID: 31027332 PMCID: PMC6539208 DOI: 10.3390/ijms20092059] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/05/2019] [Accepted: 04/24/2019] [Indexed: 01/14/2023] Open
Abstract
Organ dysfunction pertinent to tissue injury related to ischemic ex vivo preservation during transport from donor to recipient still represents a pivotal impediment in transplantation medicine. Cold storage under anoxic conditions minimizes metabolic activity, but eventually cannot prevent energetic depletion and impairment of cellular signal homeostasis. Reoxygenation of anoxically injured tissue may trigger additional damage to the graft, e.g., by abundant production of oxygen free radicals upon abrupt reactivation of a not yet equilibrated cellular metabolism. Paradoxically, this process is driven by the sudden restoration of normothermic conditions upon reperfusion and substantially less pronounced during re-oxygenation in the cold. The massive energy demand associated with normothermia is not met by the cellular systems that still suffer from hypothermic torpor and dys-equilibrated metabolites and eventually leads to mitochondrial damage, induction of apoptosis and inflammatory responses. This rewarming injury is partly alleviated by preceding supply of oxygen already in the cold but more effectively counteracted by an ensuing controlled and slow oxygenated warming up of the organ prior to implantation. A gentle restitution of metabolic turnover rates in line with the resumption of enzyme kinetics and molecular homeostasis improves post transplantation graft function and survival.
Collapse
Affiliation(s)
- Thomas Minor
- Department for Surgical Research, University Hospital Essen, Hufelandstr. 55, D-45147 Essen, Germany.
| | - Charlotte von Horn
- Department for Surgical Research, University Hospital Essen, Hufelandstr. 55, D-45147 Essen, Germany.
| |
Collapse
|
|
42
|
Report of the 24th Annual Congress of the International Liver Transplantation Society. Transplantation 2019; 103:465-469. [DOI: 10.1097/tp.0000000000002549] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
43
|
Hameed AM, Pang T, Yoon P, Balderson G, De Roo R, Yuen L, Lam V, Laurence J, Crawford M, D M Allen R, Hawthorne WJ, Pleass HC. Aortic Versus Dual Perfusion for Retrieval of the Liver After Brain Death: A National Registry Analysis. Liver Transpl 2018; 24:1536-1544. [PMID: 30192420 DOI: 10.1002/lt.25331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/21/2018] [Indexed: 02/07/2023]
Abstract
There is lack of consensus in the literature regarding the comparative efficacy of in situ aortic-only compared with dual (aortic and portal venous) perfusion for retrieval and transplantation of the liver. Recipient outcomes from the Australia/New Zealand Liver Transplant Registry (2007-2016), including patient and graft survival and causes of graft loss, were stratified by perfusion route. Subgroup analyses were conducted for higher-risk donors. A total of 1382 liver transplantation recipients were analyzed (957 aortic-only; 425 dual perfusion). There were no significant differences in 5-year graft and patient survivals between the aortic-only and dual cohorts (80.1% versus 84.6% and 82.6% versus 87.8%, respectively) or in the odds ratios of primary nonfunction, thrombotic graft loss, or graft loss secondary to biliary complications or acute rejection. When analyzing only higher-risk donors (n = 369), multivariate graft survival was significantly less in the aortic-only cohort (hazard ratio, 0.49; 95% confidence interval, 0.26-0.92). Overall, there was a trend toward improved outcomes when dual perfusion was used, which became significant when considering higher-risk donors alone. Inferences into the ideal perfusion technique in multiorgan procurement will require further investigation by way of a randomized controlled trial, and outcomes after the transplantation of other organs will also need to be considered.
Collapse
Affiliation(s)
- Ahmer M Hameed
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Tony Pang
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Peter Yoon
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | - Glenda Balderson
- Australia and New Zealand Liver Transplant Registry, Princess Alexandra Hospital, Brisbane, Australia
| | - Ronald De Roo
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | - Lawrence Yuen
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Jerome Laurence
- Department of Surgery, Royal Prince Alfred Hospital, Sydney, Australia.,Institute of Academic Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Michael Crawford
- Department of Surgery, Royal Prince Alfred Hospital, Sydney, Australia.,Institute of Academic Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Richard D M Allen
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Wayne J Hawthorne
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, Australia.,Sydney Medical School, University of Sydney
| | - Henry C Pleass
- Department of Surgery, Westmead Hospital, Sydney, Australia.,Sydney Medical School, University of Sydney.,Department of Surgery, Royal Prince Alfred Hospital, Sydney, Australia
| |
Collapse
|
|
44
|
Pavel MC, Reyner E, Fuster J, Garcia-Valdecasas JC. Trasplante hepático con injerto de donante en asistolia tipo 2 con perfusión regional normotérmica y máquina de perfusión normotérmica. Cir Esp 2018; 96:508-513. [DOI: 10.1016/j.ciresp.2018.06.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/06/2018] [Accepted: 06/21/2018] [Indexed: 01/14/2023]
|
|
45
|
Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9180757. [PMID: 30255101 PMCID: PMC6145150 DOI: 10.1155/2018/9180757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 12/25/2022]
Abstract
Background Liver allograft preservation frequently involves static cold storage (CS) and machine perfusion (MP). With its increasing popularity, we investigated whether MP was superior to CS in terms of beneficial outcomes. Methods Human studies and large animal studies that optimized livers for transplantation using MP versus CS were assessed (PubMed/Medline/EMBASE). Meta-analyses were conducted for comparisons. Study quality was assessed according to the Newcastle-Ottawa quality assessment scale and SYRCLE's risk of bias tool. Results Nineteen studies were included. Among the large animal studies, lower levels of lactate dehydrogenase (SMD -3.16, 95% CI -5.14 to -1.18), alanine transferase (SMD -2.46, 95% CI -4.03 to -0.90), and hyaluronic acid (SMD -2.48, 95% CI -4.21 to -0.74) were observed in SNMP-preserved compared to CS-preserved livers. NMP-preserved livers showing lower level of hyaluronic acid (SMD -3.97, 95% CI -5.46 to -2.47) compared to CS-preserved livers. Biliary complications (RR 0.45, 95% CI 0.28 to 0.73) and early graft dysfunction (RR 0.56, 95% CI 0.34 to 0.92) also significantly reduced with HMP preservation in human studies. No evidence of publication bias was found. Conclusions MP preservation could improve short-term outcomes after transplantation compared to CS preservation. Additional randomized controlled trials (RCTs) are needed to develop clinical applications of MP preservation.
Collapse
|
|
46
|
Green CJ, Parry SA, Gunn PJ, Ceresa CDL, Rosqvist F, Piché ME, Hodson L. Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models. Horm Mol Biol Clin Investig 2018; 41:/j/hmbci.ahead-of-print/hmbci-2018-0038/hmbci-2018-0038.xml. [PMID: 30098284 DOI: 10.1515/hmbci-2018-0038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.
Collapse
Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Siôn A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Pippa J Gunn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Carlo D L Ceresa
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fredrik Rosqvist
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden
| | - Marie-Eve Piché
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- Quebec Heart and Lung Institute, Laval University, Quebec, Canada
| | - Leanne Hodson
- University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital,Old Road Headington, Oxford OX3 7LE, United Kingdom of Great Britain and Northern Ireland
| |
Collapse
|
|
47
|
Jia JJ, Li JH, Xie HY, Zhou L, Zheng SS. Implementing an innovated liver ex-situ machine perfusion technology: The 2018 Joint International Congress of ILTS, ELITA and LICAGE. Hepatobiliary Pancreat Dis Int 2018; 17:283-285. [PMID: 30097405 DOI: 10.1016/j.hbpd.2018.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/20/2018] [Indexed: 02/05/2023]
Affiliation(s)
- Jun-Jun Jia
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian-Hui Li
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hai-Yang Xie
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| |
Collapse
|
|
48
|
Reduced Hypoxia-Related Genes in Porcine Limbs in Ex Vivo Hypothermic Perfusion Versus Cold Storage. J Surg Res 2018; 232:137-145. [PMID: 30463709 DOI: 10.1016/j.jss.2018.05.067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 04/15/2018] [Accepted: 05/30/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND Ischemia-reperfusion injury remains the major limiting factor for limb replantation and transplantation. Static cold storage (SCS) on ice currently represents the standard mode of preservation but is limited to 6 h of duration. Ex vivo machine perfusion has evolved as a potential alternative to safely extend the duration of ex vivo preservation by providing continuous supply of oxygen and nutrients. This study aims to evaluate underlying molecular mechanisms of both preservation modalities. METHODS We assessed molecular changes in amputated porcine forelimbs stored on ice at 4°C for 2 h (n = 2) and limbs perfused with Perfadex solution at 10°C for 2 h (n = 3) or 12 h (n = 3) before replantation. Muscle biopsies were examined for histological changes and gene expression levels using H&E staining and a hypoxia-related PCR gene array, respectively. RESULTS Histology revealed only minor differences between the ice (SCS) and perfusion groups after 2 h of preservation, with decreased muscle fiber disruption in the perfusion groups compared with the ice (SCS) group. Perfused limbs demonstrated downregulation of genes coding for glycolytic pathways and glucose transporters after 2 h and 12 h when compared with SCS after 2 h. Similarly, genes that induce angiogenesis and those that are activated on DNA damage were downregulated in both perfusion groups as compared with SCS. CONCLUSIONS Perfusion of porcine limbs resulted in less activation of hypoxia-related gene families when compared with SCS. This may indicate a state more closely resembling physiological conditions during perfusion and potentially limiting ischemic injury. Our study confirms ex vivo perfusion for up to 12 h as a viable alternative for preservation of vascularized composite tissues.
Collapse
|