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da Silva GMA, Wagner MJ, Hatami S, Hassanzadeh P, Wang X, Adam BA, Nagendran J, Freed DH. Evaluation of target temperature on effectiveness of myocardial preservation during hypothermic machine perfusion. JHLT OPEN 2025; 8:100234. [PMID: 40144719 PMCID: PMC11935436 DOI: 10.1016/j.jhlto.2025.100234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background Ex-situ heart perfusion (ESHP) has been proposed as an optimal method for preserving donated hearts prior to transplantation. Hypothermic oxygenated perfusion (HOP) is a simple method from a device design perspective, with enhanced safety compared to normothermic perfusion in the event of device failure. However, the optimal temperature for cardiac HOP has yet to be determined. We evaluated the effectiveness of 12-hour HOP using University of Wisconsin Machine Perfusion Solution (UWMPS) in different temperatures compared to static cold storage (SCS) for 6 hours followed by simulated transplantation. Additionally, we sought to determine the impact of oxygen supplementation in hypothermic ESHP in the heart function preservation. Methods Hearts were procured from Yorkshire pigs (n = 35) randomized into 3 preservation therapies: 6 hours-SCS; 12 hours-HOP and 12 hours hypothermic non-oxygenated perfusion (HNOP-without oxygen supplementation). For either HOP or HNOP groups, 3 temperatures were tested (5°C; 10°C; 15°C). After the preservation period, hearts had their function assessed in a normothermic perfusion machine capable of working mode, simulating transplantation. Results All perfusion parameters were stable throughout (mean ± SD): aortic flow 65 ± 5.57 ml/min, aortic pressure: 11.51 ± 3.17 mm Hg. All HOP hearts presented a better cardiac index than SCS (p < 0.05). The HNOP hearts presented similar cardiac function results compared to SCS. Conclusions HOP for 12 hours had better heart function preservation than SCS for 6 hours. Even HNOP had similar results compared to SCS. Greater edema formation in ESHP hearts did not affect heart function. Hypothermic ESHP safely enhances function preservation compared to SCS.
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Affiliation(s)
| | - Mitchell J. Wagner
- Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Sanaz Hatami
- Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Parham Hassanzadeh
- Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Xiuhua Wang
- Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Benjamin A. Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Jayan Nagendran
- Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada
- Alberta Transplant Institute, Edmonton, Alberta, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada
| | - Darren H. Freed
- Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada
- Alberta Transplant Institute, Edmonton, Alberta, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada
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Prabhahar A, Batta A, Hatwal J, Kumar V, Ramachandran R, Batta A. Endothelial dysfunction in the kidney transplant population: Current evidence and management strategies. World J Transplant 2025; 15:97458. [PMID: 40104196 PMCID: PMC11612885 DOI: 10.5500/wjt.v15.i1.97458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/04/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators. Endothelial dysfunction (ED), characterized by impaired vasodilation, inflammation, and thrombosis, triggers future cardiovascular (CV) diseases. Chronic kidney disease, a state of chronic inflammation caused by oxidative stress, metabolic abnormalities, infection, and uremic toxins damages the endothelium. ED is also associated with a decline in estimated glomerular filtration rate. After kidney transplantation, endothelial functions undergo immediate but partial restoration, promising graft longevity and enhanced CV health. However, the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED, culminating in poor CV health and graft survival. ED in kidney transplant recipients is an under-recognized and poorly studied entity. CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts. ED contributes to the pathogenesis of many of the CV diseases. Various biomarkers and vasoreactivity tests are available to study endothelial functions. With an increasing number of transplants happening every year, and improved graft rejection rates due to the availability of effective immunosuppressants, the focus has now shifted to endothelial protection for the prevention, early recognition, and treatment of CV diseases.
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Affiliation(s)
- Arun Prabhahar
- Department of Telemedicine (Internal Medicine and Nephrology), Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Akshey Batta
- Department of Urology and Renal Transplant, Neelam Hospital, Rajpura 140401, Punjab, India
| | - Juniali Hatwal
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vivek Kumar
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Raja Ramachandran
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Akash Batta
- Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
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Kenny LA, Armstrong L, Berman M, Brierley J, Crossland D, Dark J, Gardiner D, Large SR, Manas D, Nassar M, Shaw D, Simpson E. Heart Transplantation and Donation After Circulatory Death in Children. A Review of the Technological, Logistical and Ethical Framework. Transpl Int 2025; 38:13801. [PMID: 40026599 PMCID: PMC11867792 DOI: 10.3389/ti.2025.13801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/23/2025] [Indexed: 03/05/2025]
Abstract
Heart transplant for adults following Donation after Circulatory Death (DCD) is well established in many parts of the world, including the United Kingdom (UK). Small child DCD hearts have now been recovered in the UK and internationally utilising novel technologies. Despite these recent advances, extension of this practice to pediatric cardiac transplantation has been slow and difficult despite the severe shortage of donors for children leading to a high number of deaths annually of children waiting for heart transplant. This is in direct contrast with the thriving UK programme of adult DCD heart transplant and pediatric DCD donation for non-cardiac organs. There has been insufficient action in addressing this inequality thus far. Barriers to development of a pediatric cardiac DCD programme are multifaceted: ethical concerns, technological paucity, financial and logistical hurdles. We describe the background, live issues, current developments and how we are driving resources toward a sustainable DCD programme for small children in the UK to provide valuable insights to other countries of the elements and principles at play. This is a call to responsible bodies to take urgent and achievable actions to establish an equitable paediatric DCD cardiac programme for donors, recipients and their families.
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Affiliation(s)
- Louise Amelia Kenny
- Paediatric Heart Unit, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Congenital Heart Disease Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Liz Armstrong
- National Health Service Blood and Transplant, Bristol, United Kingdom
| | - Marius Berman
- National Health Service Blood and Transplant, Bristol, United Kingdom
- Department of Cardiothoracic Surgery, Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Joe Brierley
- Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - David Crossland
- Paediatric Heart Unit, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - John Dark
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, England, United Kingdom
| | - Dale Gardiner
- National Health Service Blood and Transplant, Bristol, United Kingdom
- Intensive Care Unit, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Stephen Ralph Large
- Department of Cardiothoracic Surgery, Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Derek Manas
- Paediatric Heart Unit, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- National Health Service Blood and Transplant, Bristol, United Kingdom
| | - Mohamed Nassar
- Paediatric Heart Unit, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Congenital Heart Disease Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Faculty of Medicine, Alexandria, Egypt
| | - David Shaw
- Institute of Biomedical Ethics, University of Basel, Basel, Switzerland
- Institute of Care and Public Health Research, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
| | - Emma Simpson
- Paediatric Heart Unit, Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom
- Congenital Heart Disease Research Group, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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Vidgren M, Delorme C, Oniscu GC. Challenges and opportunities in organ donation after circulatory death. J Intern Med 2025; 297:124-140. [PMID: 39829342 PMCID: PMC11771584 DOI: 10.1111/joim.20051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
In recent years, there has been resurgence in donation after circulatory death (DCD). Despite that, the number of organs transplanted from these donors remains low due to concerns about their function and a lack of an objective assessment at the time of donation. This overview examines the current DCD practices and the classification modifications to accommodate regional perspectives. Several risk factors underscore the reluctance to accept DCD organs, and we discuss the modern strategies to mitigate them. The advent of machine perfusion technology has revolutionized the field of DCD transplantation, leading to improved outcomes and better organ usage. With many strategies at our disposal, there is an urgent need for comparative trials to determine the optimal use of perfusion technologies for each donated organ type. Additional progress in defining therapeutic strategies to repair the damage sustained during the dying process should further improve DCD organ utilization and outcomes. However, there remains wide variability in access to DCD donation and transplantation, and organizational efforts should be doubled up with consensus on key ethical issues that still surround DCD donation in the era of machine perfusion.
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Affiliation(s)
- Mathias Vidgren
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
| | - Capucine Delorme
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
| | - Gabriel C. Oniscu
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
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Calva Lopez A, Robles Garcia JE, Yanez Ruiz CA, Tapia Tapia MD, Talavera Cobo V, Muñoz Bastidas CA, Sanchez Zalabardo D, Miñana Lopez B. The Evolution of Kidney Graft Preservation Through the Years. Life (Basel) 2024; 14:1647. [PMID: 39768354 PMCID: PMC11676764 DOI: 10.3390/life14121647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/03/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic kidney disease (CKD) is a prevalent disease affecting almost 10% of the world's population, with many cases progressing to end-stage kidney disease (ESKD). Kidney transplantation (KT) is the gold-standard treatment for ESKD. Due to growing KT waitlists, the deceased kidney donor (DKDs) criteria have expanded to increase the number of available kidney grafts. Kidney graft preservation ensures optimal graft function after KT. Static cold storage (SCS) as a preservation method is still widely used. Hypothermic machine perfusion (HMP) has proven to decrease delayed graft function (DGF) and increase graft survival. Most recent studies advocate for the use of HMP regardless of donor type. However, emerging technologies, such as hypothermic oxygenated machine perfusion (HOPE) and normothermic machine perfusion (NMP), have shown promising results in specific scenarios. This review aims to provide a summary of the well-established kidney graft preservation methods and their outcomes, as well as novel technological advances that allow for newer preservation strategies.
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Affiliation(s)
- Andres Calva Lopez
- Department of Urology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
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Baryła M, Skrzycki M, Danielewicz R, Kosieradzki M, Struga M. Protein biomarkers in assessing kidney quality before transplantation‑current status and future perspectives (Review). Int J Mol Med 2024; 54:107. [PMID: 39370783 PMCID: PMC11448562 DOI: 10.3892/ijmm.2024.5431] [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] [Received: 04/05/2024] [Accepted: 07/31/2024] [Indexed: 10/08/2024] Open
Abstract
To meet the demand for kidney transplants (KTx), organs are frequently retrieved not only from standard criteria donors (SCD; a donor who is aged <50 years and suffered brain death from any number of causes, such as traumatic injuries or a stroke) but also from expanded criteria donors (any donor aged >60 years or donors aged >50 years with two of the following: A history of high blood pressure, a creatinine serum level ≥1.5 mg/dl or death resulting from a stroke). This comes at the cost of a higher risk of primary non‑function (the permanent hyperkalemia, hyperuremia and fluid overload that result in the need for continuous dialysis after KTx), delayed graft function (the need for dialysis session at least once during the first week after KTx), earlier graft loss and urinary complications (vesico‑ureteral reflux, obstruction of the vesico‑ureteral anastomosis, urine leakage). At present, there are no commercially available diagnostic tools for assessing kidney quality prior to KTx. Currently available predictive models based on clinical data, such as the Kidney Donor Profile Index, are insufficient. One promising option is the application of perfusion solutions for protein biomarkers of kidney quality and predictors of short‑ and long‑term outcomes. However, to date, protein markers that can be detected with ELISA, western blotting and cytotoxic assays have not been identified to be a beneficial predictors of kidney quality. These include lactate dehydrogenases, glutathione S‑transferases, fatty acid binding proteins, extracellular histones, IL‑18, neutrophil gelatinase‑associated lipocalin, MMPs and kidney injury molecule‑1. However, novel methods, including liquid chromatography‑mass spectrometry (LC‑MS) and microarrays, allow the analysis of all renal proteins suspended/dissolved in the acellular preservation solution used for kidney storage before KTx (including hypothermic machine perfusion as one of kidney storage methods) e.g. Belzer University of Wisconsin. Recent proteomic studies utilizing LC‑MS have identified complement pathway elements (C3, C1QB, C4BPA, C1S, C1R and C1RL), desmoplakin, blood coagulation pathway elements and immunoglobulin heavy variable 2‑26 to be novel predictors of kidney quality before transplantation. This was because they were found to correlate with estimated glomerular filtration rate at 3 and 12 months after kidney transplantation. However, further proteomic studies focusing on distinct markers obtained from hypothermic and normothermic machine perfusion are needed to confirm their predictive value and to improve kidney storage methods. Therefore, the present literature review from PubMed, Scopus, Embase and Web of Science was performed with the aims of summarizing the current knowledge on the most frequently studied single protein biomarkers. In addition, novel analytical methods and insights into organ injury during preservation were documented, where future directions in assessing organ quality before kidney transplantation were also discussed.
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Affiliation(s)
- Maksymilian Baryła
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Michał Skrzycki
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Roman Danielewicz
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Maciej Kosieradzki
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Marta Struga
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
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Keith DS, Lessmann E. Mechanical Preservation and Delayed Graft Function and Hospital Length of Stay as Deployed in the United States: Analysis of the Last Decade. Ann Transplant 2024; 29:e944338. [PMID: 39223780 PMCID: PMC11378686 DOI: 10.12659/aot.944338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Mechanical preservation (MP) of deceased donor kidney transplants showed a 30% to 50% reduction in delayed graft function (DGF) as defined by dialysis in the first week, when compared with cold storage. DGF is associated with longer hospital stays and increased costs. In this study, we sought to understand the impact of MP on rates of DGF and length of hospital stays in a contemporary cohort of deceased donor kidney transplants in the United States. MATERIAL AND METHODS All single deceased donor kidney transplants performed between January 1, 2010, and September 2, 2020, were identified in the Scientific Registry of Transplant Recipients database. Donor kidneys were considered pumped if the transplant center received the kidney on the pump. RESULTS Multivariate logistic regression showed that MP had similar odds of reduction of DGF for all subsets of donors. The unadjusted rate of DGF for pumped brain-dead standard criteria donor (BDSCD) recipients was similar to that of donors stored on ice. The rate of DGF for expanded criteria donors (ECD) and donors after cardiac death (DCD) was lower in the recipients who received MP. The similar DGF rates in BDSCD donor recipients were due to longer cold ischemia times in MP kidneys. The lower DGF rates seen in ECD and DCD recipients of pumped kidneys did not translate into a shortened length of hospitalization after transplant. CONCLUSIONS As currently deployed, only DCD and ECD donor recipients of MP kidneys experienced a lower DGF rate. In all subsets of patients, MP did not appreciably shorten the hospital length of stay.
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Affiliation(s)
- Douglas S Keith
- Ascension Sacred Heart Kidney Transplant Program, Ascension Sacred Heart Hospital, Pensacola, FL, USA
| | - Elizabeth Lessmann
- Ascension Sacred Heart Kidney Transplant Program, Ascension Sacred Heart Hospital, Pensacola, FL, USA
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Steinhauser C, Yakac AE, Markgraf W, Kromnik S, Döcke A, Talhofer P, Thiele C, Malberg H, Füssel S, Thomas C, Putz J. Assessment of hemodynamic and blood parameters that may reflect macroscopic quality of porcine kidneys during normothermic machine perfusion using whole blood. World J Urol 2024; 42:471. [PMID: 39110171 PMCID: PMC11306647 DOI: 10.1007/s00345-024-05139-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 06/21/2024] [Indexed: 08/10/2024] Open
Abstract
PURPOSE Using ex vivo normothermic machine perfusion (NMP) with whole blood we assessed marginal porcine kidneys under reperfusion. The aim was to link measureable machine and clinical blood parameters with the currently used visual assessment. This could serve as a baseline for a standardized evaluation score to identify potentially transplantable kidneys in the future. METHODS Kidneys and autologous whole blood were procured from slaughterhouse pigs (n = 33) and were perfused for 4 h using NMP. The hemodynamic parameters arterial pressure (AP), renal blood flow (RBF) and intrarenal resistance (IRR) were measured. Activity of aspartate transaminase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and lactate were assessed in blood at 0/1/2/4 h. Kidneys were grouped into "potentially transplantable" (PT) or "not transplantable" (NT) based on their overall macroscopic appearance after NMP by an experienced physician. RESULTS PT-kidneys (n = 20) had a significantly lower IRR and higher RBF than NT-kidneys (n = 13). GGT, ALP and LDH did not differ significantly, but at 4 h, AST was significantly higher in PT-kidneys compared to NT-kidneys. Lactate levels kept increasing during NMP in NT-kidneys and were significantly higher at 1/2/4 h than in PT-kidneys. CONCLUSION The immediately assessed macroscopic aspects of examined kidneys correlated with hemodynamic parameters, increased lactate and lower AST in this study. In the future, NMP with whole blood could be a useful tool to extend the donor pool by allowing the assessment of otherwise unknown characteristics of marginal kidneys before transplantation.
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Affiliation(s)
- Carla Steinhauser
- Department of Urology, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
| | - Abdulbaki Emre Yakac
- Department of Urology, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Wenke Markgraf
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Susanne Kromnik
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Andreas Döcke
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Philipp Talhofer
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Christine Thiele
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Hagen Malberg
- Institute of Biomedical Engineering, Technische Universität Dresden, Fetscherstraße 29, 01307, Dresden, Germany
| | - Susanne Füssel
- Department of Urology, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Christian Thomas
- Department of Urology, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Juliane Putz
- Department of Urology, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
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Kneifel F, Vondran F, Vogel T. [Machine perfusion in transplantation surgery]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:610-617. [PMID: 39052038 DOI: 10.1007/s00104-024-02122-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/27/2024]
Abstract
The use of machine perfusion in solid organ transplantation has developed tremendously worldwide in recent years. Although the number of randomized controlled trials in the field of organ preservation is still limited, machine perfusion has been shown to be superior to static cold storage of donor organs. Various devices for clinical use with hypothermia or normothermia are already available for most organs. Whether and which perfusion strategy is superior to the others is the subject of current clinical research. This also applies to the further evaluation of possible synergistic effects in the sequential use of the various protocols. The common goal of all dynamic perfusion technologies is to optimize organ preservation between removal and transplantation. By testing the quality of marginal donor organs prior to transplantation, it should also be possible to use these organs without exposing the patient to increased risk. This can lead to a significant expansion of the donor pool. This is particularly important in Germany, where there is an ongoing shortage of organs and restrictive legislation regarding the expansion of the donor pool. Furthermore, the perfusion technology offers the possibility to serve as a platform for other ex situ and in situ therapies on isolated organs. In addition to the conditioning of pre-damaged organs for transplantation, this could lead to further applications in the context of targeted organ therapies and also to improved transplant logistics in the future.
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Affiliation(s)
- Felicia Kneifel
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Florian Vondran
- Klinik für Allgemein‑, Viszeral‑, Kinder- und Transplantationschirurgie, RWTH Universitätsklinikum Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland
| | - Thomas Vogel
- Klinik für Allgemein‑, Viszeral‑, Kinder- und Transplantationschirurgie, RWTH Universitätsklinikum Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland.
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Tingle SJ, Thompson ER, Figueiredo RS, Moir JA, Goodfellow M, Talbot D, Wilson CH. Normothermic and hypothermic machine perfusion preservation versus static cold storage for deceased donor kidney transplantation. Cochrane Database Syst Rev 2024; 7:CD011671. [PMID: 38979743 PMCID: PMC11232102 DOI: 10.1002/14651858.cd011671.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
BACKGROUND Kidney transplantation is the optimal treatment for kidney failure. Donation, transport and transplant of kidney grafts leads to significant ischaemia reperfusion injury. Static cold storage (SCS), whereby the kidney is stored on ice after removal from the donor until the time of implantation, represents the simplest preservation method. However, technology is now available to perfuse or "pump" the kidney during the transport phase ("continuous") or at the recipient centre ("end-ischaemic"). This can be done at a variety of temperatures and using different perfusates. The effectiveness of these treatments manifests as improved kidney function post-transplant. OBJECTIVES To compare machine perfusion (MP) technologies (hypothermic machine perfusion (HMP) and (sub) normothermic machine perfusion (NMP)) with each other and with standard SCS. SEARCH METHODS We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies until 15 June 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA All randomised controlled trials (RCTs) and quasi-RCTs comparing machine perfusion techniques with each other or versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory death (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion. DATA COLLECTION AND ANALYSIS The results of the literature search were screened, and a standard data extraction form was used to collect data. Both of these steps were performed by two independent authors. Dichotomous outcome results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Survival analyses (time-to-event) were performed with the generic inverse variance meta-analysis of hazard ratios (HR). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was the incidence of delayed graft function (DGF). Secondary outcomes included graft survival, incidence of primary non-function (PNF), DGF duration, economic implications, graft function, patient survival and incidence of acute rejection. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Twenty-two studies (4007 participants) were included. The risk of bias was generally low across all studies and bias domains. The majority of the evidence compared non-oxygenated HMP with standard SCS (19 studies). The use of non-oxygenated HMP reduces the rate of DGF compared to SCS (16 studies, 3078 participants: RR 0.78, 95% CI 0.69 to 0.88; P < 0.0001; I2 = 31%; high certainty evidence). Subgroup analysis revealed that continuous (from donor hospital to implanting centre) HMP reduces DGF (high certainty evidence). In contrast, this benefit over SCS was not seen when non-oxygenated HMP was not performed continuously (low certainty evidence). Non-oxygenated HMP reduces DGF in both DCD and DBD settings in studies performed in the 'modern era' and when cold ischaemia times (CIT) were short. The number of perfusions required to prevent one episode of DGF was 7.69 and 12.5 in DCD and DBD grafts, respectively. Continuous non-oxygenated HMP versus SCS also improves one-year graft survival (3 studies, 1056 participants: HR 0.46, 0.29 to 0.75; P = 0.002; I2 = 0%; high certainty evidence). Assessing graft survival at maximal follow-up confirmed a benefit of continuous non-oxygenated HMP over SCS (4 studies, 1124 participants (follow-up 1 to 10 years): HR 0.55, 95% CI 0.40 to 0.77; P = 0.0005; I2 = 0%; high certainty evidence). This effect was not seen in studies where HMP was not continuous. The effect of non-oxygenated HMP on our other outcomes (PNF, incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain. Studies performing economic analyses suggest that HMP is either cost-saving (USA and European settings) or cost-effective (Brazil). One study investigated continuous oxygenated HMP versus non-oxygenated HMP (low risk of bias in all domains); the simple addition of oxygen during continuous HMP leads to additional benefits over non-oxygenated HMP in DCD donors (> 50 years), including further improvements in graft survival, improved one-year kidney function, and reduced acute rejection. One large, high-quality study investigated end-ischaemic oxygenated HMP versus SCS and found end-ischaemic oxygenated HMP (median machine perfusion time 4.6 hours) demonstrated no benefit compared to SCS. The impact of longer periods of end-ischaemic HMP is unknown. One study investigated NMP versus SCS (low risk of bias in all domains). One hour of end ischaemic NMP did not improve DGF compared with SCS alone. An indirect comparison revealed that continuous non-oxygenated HMP (the most studied intervention) was associated with improved graft survival compared with end-ischaemic NMP (indirect HR 0.31, 95% CI 0.11 to 0.92; P = 0.03). No studies investigated normothermic regional perfusion (NRP) or included any donors undergoing NRP. AUTHORS' CONCLUSIONS Continuous non-oxygenated HMP is superior to SCS in deceased donor kidney transplantation, reducing DGF, improving graft survival and proving cost-effective. This is true for both DBD and DCD kidneys, both short and long CITs, and remains true in the modern era (studies performed after 2008). In DCD donors (> 50 years), the simple addition of oxygen to continuous HMP further improves graft survival, kidney function and acute rejection rate compared to non-oxygenated HMP. Timing of HMP is important, and benefits have not been demonstrated with short periods (median 4.6 hours) of end-ischaemic HMP. End-ischaemic NMP (one hour) does not confer meaningful benefits over SCS alone and is inferior to continuous HMP in an indirect comparison of graft survival. Further studies assessing NMP for viability assessment and therapeutic delivery are warranted and in progress.
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Affiliation(s)
- Samuel J Tingle
- NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle upon Tyne, UK
| | - Emily R Thompson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
| | | | | | | | - David Talbot
- The Liver/Renal Unit, The Freeman Hospital, Newcastle upon Tyne, UK
| | - Colin H Wilson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
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11
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Mella A, Calvetti R, Barreca A, Congiu G, Biancone L. Kidney transplants from elderly donors: what we have learned 20 years after the Crystal City consensus criteria meeting. J Nephrol 2024; 37:1449-1461. [PMID: 38446386 PMCID: PMC11473582 DOI: 10.1007/s40620-024-01888-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 01/03/2024] [Indexed: 03/07/2024]
Abstract
Based on the current projection of the general population and the combined increase in end-stage kidney disease with age, the number of elderly donors and recipients is increasing, raising crucial questions about how to minimize the discard rate of organs from elderly donors and improve graft and patient outcomes. In 2002, extended criteria donors were the focus of a meeting in Crystal City (VA, USA), with a goal of maximizing the use of organs from deceased donors. Since then, extended criteria donors have progressively contributed to a large number of transplanted grafts worldwide, posing specific issues for allocation systems, recipient management, and therapeutic approaches. This review analyzes what we have learned in the last 20 years about extended criteria donor utilization, the promising innovations in immunosuppressive management, and the molecular pathways involved in the aging process, which constitute potential targets for novel therapies.
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Affiliation(s)
- Alberto Mella
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Ruggero Calvetti
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Antonella Barreca
- Division of Pathology, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Congiu
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy
| | - Luigi Biancone
- Renal Transplant Center" A. Vercellone," Nephrology, Dialysis, and Renal Transplant Division, "Città Della Salute e Della Scienza" Hospital, Department of Medical Sciences, University of Turin, Corso Bramante, 88, 10126, Turin, Italy.
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12
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Hippen BE, Hart GM, Maddux FW. A Transplant-Inclusive Value-Based Kidney Care Payment Model. Kidney Int Rep 2024; 9:1590-1600. [PMID: 38899170 PMCID: PMC11184397 DOI: 10.1016/j.ekir.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/06/2024] [Accepted: 02/05/2024] [Indexed: 06/21/2024] Open
Abstract
In the United States, kidney care payment models are migrating toward value-based care (VBC) models incentivizing quality of care at lower cost. Current kidney VBC models will continue through 2026. We propose a future transplant-inclusive VBC (TIVBC) model designed to supplement current models focusing on patients with advanced chronic kidney disease (CKD) and end-stage kidney disease (ESKD). The proposed TIVBC is structured as an episode-of-care model with risk-based reimbursement for "referral/evaluation/waitlisting" (REW, referencing kidney transplantation), "primary hospitalization to 180 days posttransplant," and "long-term graft survival." Challenges around organ acquisition costs, adjustments to quality metrics, and potential criticisms of the proposed model are discussed. We propose next steps in risk-adjustment and cost-prediction to develop as an end-to-end, TIVBC model.
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Affiliation(s)
- Benjamin E. Hippen
- Global Medical Office, Fresenius Medical Care, Waltham, Massachusetts, USA
| | | | - Franklin W. Maddux
- Global Medical Office, Fresenius Medical Care, Waltham, Massachusetts, USA
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13
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Berkane Y, Filz von Reiterdank I, Tawa P, Charlès L, Goutard M, Dinicu AT, Toner M, Bertheuil N, Mink van der Molen AB, Coert JH, Lellouch AG, Randolph MA, Cetrulo CL, Uygun K. VCA supercooling in a swine partial hindlimb model. Sci Rep 2024; 14:12618. [PMID: 38824189 PMCID: PMC11144209 DOI: 10.1038/s41598-024-63041-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 05/23/2024] [Indexed: 06/03/2024] Open
Abstract
Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance in advancing this field. It would result in improved donor-recipient matching as well as the potential for ex vivo manipulation with gene and cell therapies. Moreover, it would make logistically feasible immune tolerance induction protocols through mixed chimerism. Supercooling techniques have shown promising results in multi-day liver preservation. It consists of reaching sub-zero temperatures while preventing ice formation within the graft by using various cryoprotective agents. By drastically decreasing the cell metabolism and need for oxygen and nutrients, supercooling allows extended preservation and recovery with lower ischemia-reperfusion injuries. This study is the first to demonstrate the supercooling of a large animal model of VCA. Porcine hindlimbs underwent 48 h of preservation at - 5 °C followed by recovery and normothermic machine perfusion assessment, with no issues in ice formation and favorable levels of injury markers. Our findings provide valuable preliminary results, suggesting a promising future for extended VCA preservation.
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Affiliation(s)
- Yanis Berkane
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hôpital Sud, CHU Rennes, University of Rennes, Rennes, France
- SITI Laboratory, UMR INSERM 1236, Rennes University Hospital, Rennes, France
| | - Irina Filz von Reiterdank
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA, 02114, USA
| | - Pierre Tawa
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Laura Charlès
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Marion Goutard
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- SITI Laboratory, UMR INSERM 1236, Rennes University Hospital, Rennes, France
| | - Antonia T Dinicu
- Shriners Children's Boston, Boston, MA, USA
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA, 02114, USA
| | - Mehmet Toner
- Shriners Children's Boston, Boston, MA, USA
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA, 02114, USA
| | - Nicolas Bertheuil
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hôpital Sud, CHU Rennes, University of Rennes, Rennes, France
- SITI Laboratory, UMR INSERM 1236, Rennes University Hospital, Rennes, France
| | - Aebele B Mink van der Molen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J Henk Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Alexandre G Lellouch
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Innovative Therapies in Haemostasis, INSERM UMR-S 1140, University of Paris, 75006, Paris, France
| | - Mark A Randolph
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Curtis L Cetrulo
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Korkut Uygun
- Shriners Children's Boston, Boston, MA, USA.
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA, 02114, USA.
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14
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Hasjim BJ, Sanders JM, Alexander M, Redfield RR, Ichii H. Perfusion Techniques in Kidney Allograft Preservation to Reduce Ischemic Reperfusion Injury: A Systematic Review and Meta-Analysis. Antioxidants (Basel) 2024; 13:642. [PMID: 38929081 PMCID: PMC11200710 DOI: 10.3390/antiox13060642] [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: 03/27/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included (n = 41 MP; n = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.
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Affiliation(s)
- Bima J. Hasjim
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, University of California–Irvine, Orange, CA 92868, USA; (B.J.H.); (M.A.)
| | - Jes M. Sanders
- Department of Surgery, Division of Transplantation, Northwestern Memorial Hospital, Chicago, IL 60611, USA;
| | - Michael Alexander
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, University of California–Irvine, Orange, CA 92868, USA; (B.J.H.); (M.A.)
| | - Robert R. Redfield
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, University of California–Irvine, Orange, CA 92868, USA; (B.J.H.); (M.A.)
| | - Hirohito Ichii
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, University of California–Irvine, Orange, CA 92868, USA; (B.J.H.); (M.A.)
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15
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Longchamp A, Fontan FM, Aburawi MM, Eymard C, Karimian N, Detelich D, Pendexter C, Cronin S, Agius T, Nagpal S, Banik PD, Tessier SN, Ozer S, Delmonico FL, Uygun K, Yeh H, Markmann JF. Acellular Perfusate is an Adequate Alternative to Packed Red Blood Cells During Normothermic Human Kidney Perfusion. Transplant Direct 2024; 10:e1609. [PMID: 38481967 PMCID: PMC10936975 DOI: 10.1097/txd.0000000000001609] [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: 11/22/2023] [Revised: 12/26/2023] [Accepted: 01/06/2024] [Indexed: 03/17/2024] Open
Abstract
Background Brief normothermic machine perfusion is increasingly used to assess and recondition grafts before transplant. During normothermic machine perfusion, metabolic activity is typically maintained using red blood cell (RBC)-based solutions. However, the utilization of RBCs creates important logistical constraints. This study explored the feasibility of human kidney normothermic perfusion using William's E-based perfusate with no additional oxygen carrier. Methods Sixteen human kidneys declined for transplant were perfused with a perfusion solution containing packed RBCs or William's E medium only for 6 h using a pressure-controlled system. The temperature was set at 37 °C. Renal artery resistance, oxygen extraction, metabolic activity, energy metabolism, and histological features were evaluated. Results Baseline donor demographics were similar in both groups. Throughout perfusion, kidneys perfused with William's E exhibited improved renal flow (P = 0.041) but similar arterial resistance. Lactic acid levels remained higher in kidneys perfused with RBCs during the first 3 h of perfusion but were similar thereafter (P = 0.95 at 6 h). Throughout perfusion, kidneys from both groups exhibited comparable behavior regarding oxygen consumption (P = 0.41) and reconstitution of ATP tissue concentration (P = 0.55). Similarly, nicotinamide adenine dinucleotide levels were preserved during perfusion. There was no evidence of histological damage caused by either perfusate. Conclusions In human kidneys, William's E medium provides a logistically convenient, off-the-shelf alternative to packed RBCs for up to 6 h of normothermic machine perfusion.
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Affiliation(s)
- Alban Longchamp
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Fermin M. Fontan
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Mohamed M. Aburawi
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Corey Eymard
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Negin Karimian
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Danielle Detelich
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Casie Pendexter
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Stephanie Cronin
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Thomas Agius
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Sonal Nagpal
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Peony Dutta Banik
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Shannon N. Tessier
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Sinan Ozer
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Francis L. Delmonico
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- New England Donor Services, Waltham, MA
| | - Korkut Uygun
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - James F. Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Surgery, Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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16
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Zhang Y, Liu S, Miao Q, Zhang X, Wei H, Feng S, Li X. The Heterogeneity of Symptom Burden and Fear of Progression Among Kidney Transplant Recipients: A Latent Class Analysis. Psychol Res Behav Manag 2024; 17:1205-1219. [PMID: 38524288 PMCID: PMC10959014 DOI: 10.2147/prbm.s454787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/29/2024] [Indexed: 03/26/2024] Open
Abstract
Purpose Kidney transplant recipients (KTRs) may experience symptoms that increase their fear of progression (FoP), but a dearth of research examines the issue from a patient-centered perspective. Our study aimed to first determine the category of symptom burden, then to explore the differences in characteristics of patients in different subgroups, and finally to analyze the impact of symptom subgroup on FoP. Patients and Methods Sociodemographic and Clinical Characteristics, Symptom Experience Scale, and Fear of Progression Questionnaire-Short Form were used. Latent class analysis was used to group KTRs according to the occurrence of symptoms. We used multivariate logistic regression to analyze the predictors of different subgroups. The differences in FoP among symptom burden subgroups were analyzed by hierarchical multiple regression. Results Three subgroups were identified, designated all-high (20.5%), moderate (39.9%), and all-low (39.6%) according to their symptom occurrence. Multivariate logistic regression showed that gender, post-transplant time, per capita monthly income, and hyperuricemia were the factors that distinguished and predicted the all-high subgroup (P < 0.05). Hierarchical multiple regression showed that symptom burden had a significant effect on FoP (class1 vs class3: β = 0.327, P < 0.001; class2 vs class3: β = 0.104, P = 0.046), explaining the 8.0% variance of FoP (ΔR2 = 0.080). Conclusion KTRs generally experience moderate or low symptom burden, and symptom burden is an influencing factor in FoP. Identifying the traits of KTRs with high symptom burden can help clinicians develop targeted management strategies and ease FoP of KTRs.
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Affiliation(s)
- Ying Zhang
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Sainan Liu
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Qi Miao
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Xu Zhang
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - He Wei
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Shuang Feng
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Xiaofei Li
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
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17
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Pruett TL, Martin P, Gupta D. Outcomes of kidneys used for transplantation: an analysis of survival and function. FRONTIERS IN TRANSPLANTATION 2024; 3:1335999. [PMID: 38993770 PMCID: PMC11235350 DOI: 10.3389/frtra.2024.1335999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/19/2024] [Indexed: 07/13/2024]
Abstract
Introduction Kidney transplant recipients expect to survive the procedure with sufficient renal function for reliable dialysis freedom. Methods Transplant outcomes (survival and estimated renal function) were assessed after live and deceased donor transplantation from the US national database. Outcomes were stratified by age (donor and recipient) and donor type. Results Aggregate recipient outcomes were better transplanting living vs deceased donated kidneys. However, when stratified by the one-year renal function (within KDIGO CKD stage stratifications), surviving recipients had clinically similar dialysis-freedom, irrespective of donor type or age. The major outcome differences for recipients of age-stratified live and deceased kidneys was 1) the increasing frequency of one-year graft failures and 2) the increasing likelihood of severely limited renal function (CKD 4/5) with advancing donor age. Over 30% of recipients of deceased kidneys >65 years had either one-year graft failure or severely limited renal function contrasted to less than 15% of recipients of live kidneys aged >65 years. Conclusions Evolving techniques to reduce adverse events after urgent vs elective procedures, plus improved transplant outcome predictability with increased-age deceased donor kidneys using advanced predictive analytics (using age-stratified live kidney transplantation outcomes as a relevant reference point) should facilitate similar kidney transplant outcomes, irrespective of donor type.
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Affiliation(s)
- Timothy L. Pruett
- Division of Transplantation, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Paola Martin
- ODT, Kelley School of Business, Indiana University, Bloomington, IN, United States
| | - Diwakar Gupta
- IROM, The McCombs School of Business at University of Texas (Austin), Austin, TX, United States
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18
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Montagud-Marrahi E, Luque Y, Ros RR, Ajami T, Cuadrado-Payan E, Estrella H, Arancibia A, Sánchez-Etayo G, Bohils M, Marrero R, Fundora Y, Ramírez-Bajo MJ, Banon-Maneus E, Rovira J, Larque AB, Campistol JM, Diekmann F, Musquera M. Ex vivo normothermic preservation of a kidney graft from uncontrolled donation after circulatory death over 73 hours. Front Bioeng Biotechnol 2024; 11:1330043. [PMID: 38283171 PMCID: PMC10811075 DOI: 10.3389/fbioe.2023.1330043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/22/2023] [Indexed: 01/30/2024] Open
Abstract
The transplant community is focused on prolonging the ex vivo preservation time of kidney grafts to allow for long-distance kidney graft transportation, assess the viability of marginal grafts, and optimize a platform for the translation of innovative therapeutics to clinical practice, especially those focused on cell and vector delivery to organ conditioning and reprogramming. We describe the first case of feasible preservation of a kidney from a donor after uncontrolled circulatory death over a 73-h period using normothermic perfusion and analyze hemodynamic, biochemical, histological, and transcriptomic parameters for inflammation and kidney injury. The mean pressure and flow values were 71.24 ± 9.62 mmHg and 99.65 ± 18.54 mL/min, respectively. The temperature range was 36.7°C-37.2°C. The renal resistance index was 0.75 ± 0.15 mmHg/mL/min. The mean pH was 7.29 ± 0.15. The lactate concentration peak increased until 213 mg/dL at 6 h, reaching normal values after 34 h of perfusion (8.92 mg/dL). The total urine output at the end of perfusion was 1.185 mL. Histological analysis revealed no significant increase in acute tubular necrosis (ATN) severity as perfusion progressed. The expression of KIM-1, VEGF, and TGFβ decreased after 6-18 h of perfusion until 60 h in which the expression of these genes increased again together with the expression of β-catenin, Ki67, and TIMP1. We show that normothermic perfusion can maintain a kidney graft viable ex vivo for 3 days, thus allowing a rapid translation of pre-clinical therapeutics to clinical practice.
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Affiliation(s)
- Enrique Montagud-Marrahi
- Kidney Transplant Unit. Nephrology and Kidney Transplantation Department. Hospital Clinic of Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Yosu Luque
- Sorbonne Université - Inserm UMRS_1155, Paris, France
- Assistance Publique Hopitaux de Paris. Soins Intensifs Nephrologiques et Rein Aigu. Departement de Nephrologie. Hopital Tenon. Paris, France
| | - Ruben Rabadan Ros
- Group of Metabolism and Genetic Regulation of Disease, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, Guadalupe, Spain
| | - Tarek Ajami
- Kidney Transplant Unit. Urology Department, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Elena Cuadrado-Payan
- Kidney Transplant Unit. Nephrology and Kidney Transplantation Department. Hospital Clinic of Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Hector Estrella
- Kidney Transplant Unit. Urology Department, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Andres Arancibia
- Kidney Transplant Unit. Urology Department, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Gerard Sánchez-Etayo
- Donation and Transplant Coordination Section, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Marc Bohils
- Donation and Transplant Coordination Section, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Ramsés Marrero
- Donation and Transplant Coordination Section, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Yilliam Fundora
- Liver Transplant Unit, Institut Clínic de Malalties Digestives I Metabòliques, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Maria José Ramírez-Bajo
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Elisenda Banon-Maneus
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Ana-Belén Larque
- Department of Pathology. Hospital Clinic of Barcelona. Corresponding Author: Mireia Musquera, Barcelona, Spain
| | - Josep Maria Campistol
- Kidney Transplant Unit. Nephrology and Kidney Transplantation Department. Hospital Clinic of Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Fritz Diekmann
- Kidney Transplant Unit. Nephrology and Kidney Transplantation Department. Hospital Clinic of Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT). Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Mireia Musquera
- Kidney Transplant Unit. Urology Department, Hospital Clinic of Barcelona, Barcelona, Spain
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Longchamp A, Markmann JF. Kidney Preservation Strategies to Improve Transplant Outcomes. Clin J Am Soc Nephrol 2023; 18:1628-1630. [PMID: 37219010 PMCID: PMC10723915 DOI: 10.2215/cjn.0000000000000212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/16/2023] [Indexed: 05/24/2023]
Affiliation(s)
- Alban Longchamp
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, and
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - James F. Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, and
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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20
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Strandberg G, Öberg CM, Blom AM, Slivca O, Berglund D, Segelmark M, Nilsson B, Biglarnia AR. Prompt Thrombo-Inflammatory Response to Ischemia-Reperfusion Injury and Kidney Transplant Outcomes. Kidney Int Rep 2023; 8:2592-2602. [PMID: 38106604 PMCID: PMC10719603 DOI: 10.1016/j.ekir.2023.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/27/2023] [Accepted: 09/18/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction In kidney transplantation (KT), the role of the intravascular innate immune system (IIIS) in response to ischemia-reperfusion injury (IRI) is not well-understood. Here, we studied parallel changes in the generation of key activation products of the proteolytic cascade systems of the IIIS following living donor (LD) and deceased donor (DD) transplantation and evaluated potential associations with clinical outcomes. Methods In a cohort study, 63 patients undergoing LD (n = 26) and DD (n = 37) transplantation were prospectively included. Fifteen DD kidneys were preserved with hypothermic machine perfusion (HMP), and the remaining were cold stored. Activation products of the kallikrein-kinin, coagulation, and complement systems were measured in blood samples obtained systemically at baseline and locally from the transplant renal vein at 1, 10, and 30 minutes after reperfusion. Results DD kidneys exhibited a prompt and interlinked activation of all 3 cascade systems of IIIS postreperfusion, indicating a robust and local thrombo-inflammatory response to IRI. In this initial response, the complement activation product sC5b-9 exhibited a robust correlation with other IIIS activation markers and displayed a strong association with short-term and mid-term (24-month) graft dysfunction. In contrast, LD kidneys did not exhibit this thrombo-inflammatory response. The use of HMP was associated with reduced thromboinflammation and preserved mid-term kidney function. Conclusion Kidneys from DD are vulnerable to a prompt thrombo-inflammatory response to IRI, which adversely affects both short-term and long-term allograft function. Strategies aimed at minimizing graft immunogenicity prior to reperfusion are crucial to mitigate the intricate inflammatory response to IRI.
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Affiliation(s)
- Gabriel Strandberg
- Department of Surgery, Department of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Carl M. Öberg
- Department of Nephrology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - Anna M. Blom
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Oleg Slivca
- Department of Surgery, Department of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Malmö, Sweden
| | - David Berglund
- Department of Immunology, Genetics, and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Mårten Segelmark
- Department of Nephrology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - Bo Nilsson
- Department of Immunology, Genetics, and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Ali-Reza Biglarnia
- Department of Surgery, Department of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Malmö, Sweden
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21
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Fan H, Liu J, Sun J, Feng G, Li J. Advances in the study of B cells in renal ischemia-reperfusion injury. Front Immunol 2023; 14:1216094. [PMID: 38022595 PMCID: PMC10646530 DOI: 10.3389/fimmu.2023.1216094] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is a non-negligible clinical challenge for clinicians in surgeries such as renal transplantation. Functional loss of renal tubular epithelial cell (TEC) in IRI leads to the development of acute kidney injury, delayed graft function (DGF), and allograft rejection. The available evidence indicates that cellular oxidative stress, cell death, microvascular dysfunction, and immune response play an important role in the pathogenesis of IRI. A variety of immune cells, including macrophages and T cells, are actively involved in the progression of IRI in the immune response. The role of B cells in IRI has been relatively less studied, but there is a growing body of evidence for the involvement of B cells, which involve in the development of IRI through innate immune responses, adaptive immune responses, and negative immune regulation. Therefore, therapies targeting B cells may be a potential direction to mitigate IRI. In this review, we summarize the current state of research on the role of B cells in IRI, explore the potential effects of different B cell subsets in the pathogenesis of IRI, and discuss possible targets of B cells for therapeutic aim in renal IRI.
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Affiliation(s)
- Hongzhao Fan
- Kidney Transplantation Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Liu
- Dietetics Teaching and Research Section, Henan Medical College, Xinzheng, China
| | - Jiajia Sun
- Kidney Transplantation Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guiwen Feng
- Kidney Transplantation Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinfeng Li
- Kidney Transplantation Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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22
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Berkane Y, Hayau J, Filz von Reiterdank I, Kharga A, Charlès L, Mink van der Molen AB, Coert JH, Bertheuil N, Randolph MA, Cetrulo CL, Longchamp A, Lellouch AG, Uygun K. Supercooling: A Promising Technique for Prolonged Organ Preservation in Solid Organ Transplantation, and Early Perspectives in Vascularized Composite Allografts. FRONTIERS IN TRANSPLANTATION 2023; 2:1269706. [PMID: 38682043 PMCID: PMC11052586 DOI: 10.3389/frtra.2023.1269706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 09/29/2023] [Indexed: 05/01/2024]
Abstract
Ex-vivo preservation of transplanted organs is undergoing spectacular advances. Machine perfusion is now used in common practice for abdominal and thoracic organ transportation and preservation, and early results are in favor of substantially improved outcomes. It is based on decreasing ischemia-reperfusion phenomena by providing physiological or sub-physiological conditions until transplantation. Alternatively, supercooling techniques involving static preservation at negative temperatures while avoiding ice formation have shown encouraging results in solid organs. Here, the rationale is to decrease the organ's metabolism and need for oxygen and nutrients, allowing for extended preservation durations. The aim of this work is to review all advances of supercooling in transplantation, browsing the literature for each organ. A specific objective was also to study the initial evidence, the prospects, and potential applications of supercooling preservation in Vascularized Composite Allotransplantation (VCA). This complex entity needs a substantial effort to improve long-term outcomes, marked by chronic rejection. Improving preservation techniques is critical to ensure the favorable evolution of VCAs, and supercooling techniques could greatly participate in these advances.
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Affiliation(s)
- Yanis Berkane
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hôpital Sud, CHU Rennes, University of Rennes, Rennes, France
- MOBIDIC, UMR INSERM 1236, Rennes University Hospital, Rennes, France
| | - Justine Hayau
- Division of Plastic Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Irina Filz von Reiterdank
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, Netherlands
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Anil Kharga
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Laura Charlès
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
| | - Abele B. Mink van der Molen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, Netherlands
| | - J. Henk Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, Netherlands
| | - Nicolas Bertheuil
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hôpital Sud, CHU Rennes, University of Rennes, Rennes, France
- MOBIDIC, UMR INSERM 1236, Rennes University Hospital, Rennes, France
| | - Mark A. Randolph
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
| | - Curtis L. Cetrulo
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
| | - Alban Longchamp
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Center for Transplant Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Alexandre G. Lellouch
- Vascularized Composite Allotransplantation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
| | - Korkut Uygun
- Shriners Children’s Boston, Harvard Medical School, Boston, MA, United States
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Center for Transplant Sciences, Massachusetts General Hospital, Boston, MA, United States
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Zhu C, Yin H, Zhao S, Ma Y, Sun Z, Zhu M, Du Z, Yang T. Clinical study of renal artery cold perfusion combined with laparoscopic nephron retention in the treatment of complex renal angiomyolipoma. Front Oncol 2023; 13:1220380. [PMID: 37920170 PMCID: PMC10619158 DOI: 10.3389/fonc.2023.1220380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/27/2023] [Indexed: 11/04/2023] Open
Abstract
Objective The aim of this study is to summarize the surgical experience of renal artery cold perfusion combined with laparoscopic nephron preserving surgery for the treatment of complex renal angiomyolipoma and to evaluate the safety and feasibility of this surgical protocol. Materials and methods Clinical data of nine patients who received renal artery cold perfusion combined with laparoscopic nephron preserving surgery for complex renal angiomyolipoma in our hospital from February 2017 to August 2020 were retrospectively analyzed. The study parameters included imaging findings, total renal function before and after surgery, glomerular filtration rate (GFR) of affected kidney before and after surgery, and related complications. Results Eight of the nine patients successfully completed the operation, one patient was intolerant to renal artery balloon implantation, and the success rate of the operation was 88.89%. The mean maximum tumor diameter was 6.8 cm, and RENAL score was 7 points. Postoperative total renal function and GFR of the affected kidney had no significant changes compared with that before surgery, and imaging examination showed no tumor residue or recurrence. Conclusion This surgical procedure is safe and feasible for complex renal angiomyolipoma and can be used as a surgical option for renal hamartoma. The long-term effect needs to be confirmed by further studies.
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Affiliation(s)
| | | | | | | | | | | | | | - Tiejun Yang
- Department of Urology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Belarif L, Girerd S, Jaisser F, Lepage X, Merckle L, Duarte K, Girerd N, Guerci P. Potassium canrenoate in brain-dead organ donors: a randomised controlled clinical trial protocol (CANREO-PMO). BMJ Open 2023; 13:e073831. [PMID: 37821131 PMCID: PMC10582869 DOI: 10.1136/bmjopen-2023-073831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023] Open
Abstract
INTRODUCTION Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population. METHODS AND ANALYSIS CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR <20 mL/min/1.73 m2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in μmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m2), at 1 year, 3 years and 10 years after transplantation. ETHICS AND DISSEMINATION This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels. TRIAL REGISTRATION NUMBER NCT04714710.
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Affiliation(s)
- Lilia Belarif
- Department of Anesthesiology and Critical Care Medicine, CHRU de Nancy, Nancy, France
| | - Sophie Girerd
- Department of Nephrology, CHRU de Nancy, Nancy, France
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
| | - Frédéric Jaisser
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
- INSERM UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Universite, Paris, France
| | - Xavier Lepage
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
| | - Ludovic Merckle
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
| | - Kevin Duarte
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
| | - Nicolas Girerd
- Centre d'Investigations Cliniques-Plurithématique 1433 (CIC-P), INI-CRCT-Cardiovascular and Renal Clinical Trialists, CHRU de Nancy, Nancy, France
| | - Philippe Guerci
- Department of Anesthesiology and Critical Care Medicine, CHRU de Nancy, Nancy, France
- INSERM U1116, DCAC, University of Lorraine, Nancy, France
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Bocchi F, Beldi G, Kuhn C, Storni F, Müller N, Sidler D. Impact of suboptimal donor to suboptimal recipient kidney transplant on delayed graft function and outcome. FRONTIERS IN TRANSPLANTATION 2023; 2:1240155. [PMID: 38993921 PMCID: PMC11235345 DOI: 10.3389/frtra.2023.1240155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/17/2023] [Indexed: 07/13/2024]
Abstract
Introduction The demographics of donor and recipient candidates for kidney transplantation (KT) have substantially changed. Recipients tend to be older and polymorbid and KT to suboptimal recipients is associated with delayed graft function (DGF), prolonged hospitalization, inferior long-term allograft function, and poorer patient survival. In parallel, donors are also older, suffer from several comorbidities, and donations coming from circulatory death (DCD) predominate, which in turn leads to early and late complications. However, it is unclear how donor and recipient risk factors interact. Methods In this retrospective cohort study, we assess the impact of a KT from suboptimal donors to suboptimal recipients. We focused on: 1) DGF; 2) hospital stay and number of dialysis days after KT and 3) allograft function at 12 months. Results and discussion Among the 369 KT included, the overall DGF rate was 25% (n = 92) and median time from reperfusion to DGF resolution was 7.8 days (IQR: 3.0-13.8 days). Overall, patients received four dialysis sessions (IQR: 2-8). The combination of pre-KT anuria (<200 ml/24 h, 32%) and DCD procurement (14%) was significantly associated with DGF, length of hospital stay, and severe perioperative complications, predominantly in recipients 50 years and older.
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Affiliation(s)
- Federica Bocchi
- Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland
| | - Guido Beldi
- Departement of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Christian Kuhn
- Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland
| | - Federico Storni
- Departement of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Natalie Müller
- Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland
| | - Daniel Sidler
- Department of Nephrology and Hypertension, Inselspital, Bern, Switzerland
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Tingle SJ, Dobbins JJ, Thompson ER, Figueiredo RS, Mahendran B, Pandanaboyana S, Wilson C. Machine perfusion in liver transplantation. Cochrane Database Syst Rev 2023; 9:CD014685. [PMID: 37698189 PMCID: PMC10496129 DOI: 10.1002/14651858.cd014685.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
BACKGROUND Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box). OBJECTIVES To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023. SELECTION CRITERIA We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence. MAIN RESULTS We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies. AUTHORS' CONCLUSIONS In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.
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Affiliation(s)
- Samuel J Tingle
- NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle upon Tyne, UK
| | | | - Emily R Thompson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
| | | | | | - Sanjay Pandanaboyana
- HPB and Liver Transplant Surgery, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Colin Wilson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
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Chen Q, Niu YL, Zhang T. Diagnosis and treatment of Whipple disease after kidney transplantation: A case report. World J Clin Cases 2023; 11:6019-6024. [PMID: 37727483 PMCID: PMC10506035 DOI: 10.12998/wjcc.v11.i25.6019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/20/2023] [Accepted: 08/01/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Kidney transplantation is the standard treatment for end-stage renal disease. Particularly, rare and specific pathogenic infections which are asymptomatic are often difficult to diagnose, causing delayed and ineffective treatment and thus seriously affecting prognosis. Tropheryma whipplei (T. whipplei) is a Gram-positive actinomycete widely found in soil, sewage, and other external environments and is present in the population as an asymptomatic pathogen. There is relatively little documented research on T. whipplei in renal transplant patients, and there are no uniform criteria for treating this group of post-transplant patients. This article describes the treatment of a 42-year-old individual with post-transplant T. whipplei infection following kidney transplantation. CASE SUMMARY To analyze clinical features of Whipple's disease and summarize its diagnosis and treatment effects after renal transplantation. Clinical data of a Whipple's disease patient treated in the affiliated hospital of Guizhou Medical University were collected and assessed retrospectively. The treatment outcomes and clinical experience were then summarized via literature review. The patient was admitted to the hospital due to recurrent diarrhea for 1 mo, shortness of breath, and 1 wk of fever, after 3 years of renal transplantation. The symptoms of the digestive and respiratory systems were not significantly improved after adjusting immunosuppressive regimen and anti-diarrheal, empirical antibiotic treatments. Bronchoscopic alveolar fluid was collected for meta-genomic next-generation sequencing (mNGS). The deoxyribonucleic acid sequence of Tropheryma whipplei was detected, and Whipple's disease was diagnosed. Meropenem, ceftriaxone, and other symptomatic treatments were given, and water-electrolyte balance was maintained. Symptoms resolved quickly, and the patient was discharged after 20 d of hospitalization. The compound sulfamethoxazole tablet was continued for 3 mo after discharge. No diarrhea, fever, and other symptoms occurred during the 6-month follow-up. CONCLUSION Whipple's disease is rare, with no specific symptoms, which makes diagnosis difficult. Polymerase chain reaction or mNGS should be immediately performed when the disease is suspected to confirm the diagnosis.
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Affiliation(s)
- Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Yu-Lin Niu
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Tao Zhang
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
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Lin Y, Teixeira-Pinto A, Craig JC, Opdam H, Chapman JC, Pleass H, Carter A, Rogers NM, Davies CE, McDonald S, Yang J, Lim WH, Wong G. Trajectories of systolic blood pressure decline in kidney transplant donors prior to circulatory death and delayed graft function. Clin Kidney J 2023; 16:1170-1179. [PMID: 37398694 PMCID: PMC10310517 DOI: 10.1093/ckj/sfad047] [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: 12/21/2022] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Kidneys donated after circulatory death suffer a period of functional warm ischaemia before death, which may lead to early ischaemic injury. Effects of haemodynamic trajectories during the agonal phase on delayed graft function (DGF) is unknown. We aimed to predict the risk of DGF using patterns of trajectories of systolic blood pressure (SBP) declines in Maastricht category 3 kidney donors. METHODS We conducted a cohort study of all kidney transplant recipients in Australia who received kidneys from donation after circulatory death donors, divided into a derivation cohort (transplants between 9 April 2014 and 2 January 2018 [462 donors]) and a validation cohort (transplants between 6 January 2018 and 24 December 2019 [324 donors]). Patterns of SBP decline using latent class models were evaluated against the odds of DGF using a two-stage linear mixed effects model. RESULTS In the derivation cohort, 462 donors were included in the latent class analyses and 379 donors in the mixed effects model. Of the 696 eligible transplant recipients, 380 (54.6%) experienced DGF. Ten different trajectories, with distinct patterns of SBP decline were identified. Compared with recipients from donors with the slowest decline in SBP after withdrawal of cardiorespiratory support, the adjusted odds ratio (aOR) for DGF was 5.5 [95% confidence interval (CI) 1.38-28.0] for recipients from donors with a steeper decline and lowest SBP [mean 49.5 mmHg (standard deviation 12.5)] at the time of withdrawal. For every 1 mmHg/min reduction in the rate of decline of SBP, the respective aORs for DGF were 0.95 (95% CI 0.91-0.99) and 0.98 (95% CI 0.93-1.0) in the random forest and least absolute shrinkage and selection operator models. In the validation cohort, the respective aORs were 0.95 (95% CI 0.91-1.0) and 0.99 (95% CI 0.94-1.0). CONCLUSION Trajectories of SBP decline and their determinants are predictive of DGF. These results support a trajectory-based assessment of haemodynamic changes in donors after circulatory death during the agonal phase for donor suitability and post-transplant outcomes.
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Affiliation(s)
- Yingxin Lin
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Faculty of Science, School of Mathematics and Science, University of Sydney, Sydney, NSW, Australia
| | - Armando Teixeira-Pinto
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Jonathan C Craig
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Helen Opdam
- Department of Surgery, DonateLife, Organ and Tissue Authority, Canberra, ACT, Australia
| | - Jeremy C Chapman
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Henry Pleass
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
- Specialty of Surgery, University of Sydney, Sydney, NSW, Australia
| | - Angus Carter
- Intensive Care Unit, Cairns Hospital, Cairns, QLD, Australia
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Christopher E Davies
- Department of Renal Medicine, Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Stephen McDonald
- Department of Renal Medicine, Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Jean Yang
- Faculty of Science, School of Mathematics and Science, University of Sydney, Sydney, NSW, Australia
| | - Wai H Lim
- Faculty of Health and Medical Science, University of Western Australia, Perth, WA, Australia
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
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Hosgood SA, Callaghan CJ, Wilson CH, Smith L, Mullings J, Mehew J, Oniscu GC, Phillips BL, Bates L, Nicholson ML. Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial. Nat Med 2023; 29:1511-1519. [PMID: 37231075 PMCID: PMC10287561 DOI: 10.1038/s41591-023-02376-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 04/28/2023] [Indexed: 05/27/2023]
Abstract
Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .
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Affiliation(s)
- Sarah A Hosgood
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
| | - Christopher J Callaghan
- Department of Nephrology and Transplantation, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Colin H Wilson
- Freeman Hospital, Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Laura Smith
- NHS Blood and Transplant (NHSBT) Clinical Trials Unit, NHSBT Stoke Gifford, Bristol, UK
| | - Joanne Mullings
- NHS Blood and Transplant (NHSBT) Clinical Trials Unit, NHSBT Stoke Gifford, Bristol, UK
| | - Jennifer Mehew
- NHS Blood and Transplant (NHSBT) Clinical Trials Unit, NHSBT Stoke Gifford, Bristol, UK
| | - Gabriel C Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Benedict L Phillips
- Department of Nephrology and Transplantation, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Lucy Bates
- Freeman Hospital, Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Michael L Nicholson
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
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Chen J, Liu X, Hu Y, Chen X, Tan S. Cryopreservation of tissues and organs: present, bottlenecks, and future. Front Vet Sci 2023; 10:1201794. [PMID: 37303729 PMCID: PMC10248239 DOI: 10.3389/fvets.2023.1201794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/09/2023] [Indexed: 06/13/2023] Open
Abstract
Tissue and organ transplantation continues to be an effective measure for saving the lives of certain critically ill patients. The organ preservation methods that are commonly utilized in clinical practice are presently only capable of achieving short-term storage, which is insufficient for meeting the demand for organ transplantation. Ultra-low temperature storage techniques have garnered significant attention due to their capacity for achieving long-term, high-quality preservation of tissues and organs. However, the experience of cryopreserving cells cannot be readily extrapolated to the cryopreservation of complex tissues and organs, and the latter still confronts numerous challenges in its clinical application. This article summarizes the current research progress in the cryogenic preservation of tissues and organs, discusses the limitations of existing studies and the main obstacles facing the cryopreservation of complex tissues and organs, and finally introduces potential directions for future research efforts.
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Sousa Da Silva RX, Darius T, Mancina L, Eden J, Wernlé K, Ghoneima AS, Barlow AD, Clavien PA, Dutkowski P, Kron P. Real-time assessment of kidney allografts during HOPE using flavin mononucleotide (FMN) - a preclinical study. FRONTIERS IN TRANSPLANTATION 2023; 2:1132673. [PMID: 38993877 PMCID: PMC11235286 DOI: 10.3389/frtra.2023.1132673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/06/2023] [Indexed: 07/13/2024]
Abstract
INTRODUCTION The gap between available donor grafts and patients on the waiting lists is constantly growing. This leads to an increased utilization of high-risk and therefore more vulnerable kidney grafts. The use of high-risk organs requires further optimization of machine preservation and assessment strategies before transplantation. Hypothermic machine perfusion (HMP) is the standard of care for kidneys originating from donation after circulatory death (DCD), whereas the evidence of HMP with additional oxygen (HOPE) is still very limited. Furthermore, an objective quality assessment of HMP-perfused kidneys is lacking. Recently, the release of mitochondria derived fragments, i.e., flavin mononucleotide (FMN) of complex I during machine liver perfusion was shown to be predictive for liver graft function before implantation. Therefore, the aim of this study was to evaluate, if FMN is useful also for assessment of kidney injury before use. METHODS A porcine perfusion model was used to investigate the feasibility of assessment of kidney grafts during hypothermic oxygenated perfusion (HOPE) with either 0, 30 or 60 minutes of warm ischemia. The model with warm ischemia times (WIT) of 30 min and 60 min, was used to mimic a clinically relevant scenario. A group with no warm ischemia time (0' WIT) served as control group. The groups underwent minimal static cold storage (SCS) of 2 h followed by 2 h of end-ischemic HOPE with repeated real-time FMN measurements. In a further step, these values were related to the release of damage-associated molecular patterns (DAMPs) and to the functionality of the respiratory chain, represented by the capacity of ATP production. RESULTS We demonstrate, first, feasibility of perfusate FMN measurements in perfused kidneys, and secondly its correlation with donor warm ischemia time. Accordingly, FMN measurement showed significantly higher release in the 60-minute WIT group (n = 4) compared to the 30-minute WIT (n = 4) and the control group (n = 4). FMN release correlated also with DAMP signaling, such as the release of 8-OHdG and HMGB1. Finally, ATP replenishment proved to be best in control kidneys, followed by kidneys with 30 min and then by kidneys with 60 min of WIT. DISCUSSION This study demonstrates the feasibility of FMN measurement in kidneys during HOPE. In addition, we show a correlation between FMN quantification and pre-existing kidney graft injury. Based on this, real-time FMN measurement during HOPE may be an objective assessment tool to accept high-risk kidneys for transplantation while minimizing post-transplant dysfunction, moving away from former "gut feeling" towards objective criteria in accepting marginal kidney grafts for transplantation. Graft evaluation based on these results may close the gap between available grafts and patients on the waiting lists by increasing utilization rates without significant impact for the recipients.
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Affiliation(s)
- Richard X. Sousa Da Silva
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Tom Darius
- Department of Surgery, Surgery and Abdominal Transplant Unit, University Clinics Saint Luc, Université catholique de Louvain, Brussels, Belgium
- Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Chirurgie Expérimentale et Transplantation, Université catholique de Louvain, Brussels, Belgium
| | - Leandro Mancina
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Janina Eden
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Kendra Wernlé
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Ahmed S. Ghoneima
- Department of HPB and Transplant Surgery, St. James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Adam D. Barlow
- Department of HPB and Transplant Surgery, St. James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Pierre-Alain Clavien
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Kron
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
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Aldehyde Dehydrogenase 2 Protects the Kidney from Ischemia-Reperfusion Injury by Suppressing the I κB α/NF- κB/IL-17C Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:2264030. [PMID: 36865346 PMCID: PMC9974261 DOI: 10.1155/2023/2264030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 01/21/2023] [Accepted: 01/27/2023] [Indexed: 02/25/2023]
Abstract
Objective Ischemia-reperfusion injury (IRI) is an important cause of delayed functional recovery after transplantation. This study is aimed at investigating the molecular mechanism of ALDH2 in a kidney ischemia-reperfusion model based on RNA-seq. Methods We performed kidney ischemia-reperfusion in ALDH2-/- and WT mice and evaluated kidney function and morphology using SCr, HE staining, TUNEL staining, and TEM. We used RNA-seq to compare mRNA expression in ALDH2-/- and WT mice after IR, and then, we verified the related molecular pathways by PCR and western blotting. In addition, activators and inhibitors of ALDH2 were used to alter the activity of ALDH2. Finally, we established a model of hypoxia and reoxygenation in HK-2 cells and clarified the role of ALDH2 in IR by interfering with ALDH2 and using an NF-κB inhibitor. Results After kidney ischemia-reperfusion, the SCr value increased significantly, kidney tubular epithelial cells were damaged, and the apoptosis rate increased. In the microstructure, mitochondria were swollen and deformed, and ALDH2 deficiency aggravated these changes. The NF-κB pathway and IL-17 pathway were significantly enriched in ALDH2-/- mice compared with WT mice according to KEGG enrichment analysis of the RNA-seq data. The PCR results showed that the mRNA expression levels of IκBα and IL-17B, C, D, E, and F were significantly higher than those in the WT-IR group. Western blot verification results showed that ALHD2 knockdown resulted in increased phosphorylation of IκBα, increased phosphorylation of NF-κB, and increased expression of IL-17C. When we used ALDH2 agonists, the number of lesions and the expression levels of the corresponding proteins were reduced. Knockdown of ALDH2 in HK-2 cells resulted in a higher proportion of apoptotic cells after hypoxia and reoxygenation, but inhibiting the phosphorylation of NF-κB prevented the increase in apoptosis and reduced the protein expression level of IL-17C. Conclusion ALDH2 deficiency can lead to the aggravation of kidney ischemia-reperfusion injury. RNA-seq analysis and validation by PCR and western blotting revealed that this effect may be due to the promotion of IκBα/NF-κB p65 phosphorylation during ischemia-reperfusion caused by ALDH2 deficiency, which then leads to an increase in inflammatory factors, including IL-17C. Thus, cell death is promoted, and kidney IRI is eventually aggravated. We link ALDH2 deficiency with inflammation, revealing a new idea for ALDH2-related research.
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Mawad H, Pinard L, Medani S, Chagnon M, Boucquemont J, Turgeon J, Dieudé M, Hamelin K, Rimbaud AK, Belayachi A, Yang B, Collette S, Sénécal L, Foster BJ, Hébert MJ, Cardinal H. Hypothermic Perfusion Modifies the Association Between Anti-LG3 Antibodies and Delayed Graft Function in Kidney Recipients. Transpl Int 2023; 36:10749. [PMID: 36891519 PMCID: PMC9986256 DOI: 10.3389/ti.2023.10749] [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: 07/06/2022] [Accepted: 01/26/2023] [Indexed: 02/22/2023]
Abstract
We previously reported associations between autoantibodies to the LG3 fragment of perlecan, anti-LG3, and a higher risk of delayed graft function (DGF) in kidney transplant recipients. Here, we aimed to determine whether some factors that modulate ischemia-reperfusion injury (IRI) can modify this association. We performed a retrospective cohort study in kidney transplant recipients in 2 university-affiliated centers. In 687 patients, we show that high pre-transplant anti-LG3 are associated with DGF when the kidney is transported on ice (odds ratio (OR): 1.75, 95% confidence interval 1.02-3.00), but not when placed on hypothermic perfusion pump (OR: 0.78, 95% CI 0.43-1.37). In patients with DGF, high pre-transplant anti-LG3 are associated with a higher risk of graft failure (subdistribution hazard ratio (SHR): 4.07, 95% CI: 1.80, 9.22), while this was not the case in patients with immediate graft function (SHR: 0.50, 95% CI 0.19, 1.29). High anti-LG3 levels are associated with a higher risk of DGF in kidneys exposed to cold storage, but not when hypothermic pump perfusion is used. High anti-LG3 are also associated with a higher risk of graft failure in patients who experience DGF, a clinical manifestation of severe IRI.
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Affiliation(s)
- Habib Mawad
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Louis Pinard
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Samar Medani
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Miguel Chagnon
- Department of Mathematics and Statistics, Université de Montréal, Montreal, QC, Canada
| | - Julie Boucquemont
- Montreal Children's Hospital, McGill University, Montreal, QC, Canada
| | - Julie Turgeon
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada
| | - Mélanie Dieudé
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.,Héma-Québec, Québec, QC, Canada
| | - Katia Hamelin
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | | | - Ali Belayachi
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Bing Yang
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Suzon Collette
- Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.,Department of Medicine, Université de Montréal, Montréal, QC, Canada.,Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada
| | - Lynne Sénécal
- Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.,Department of Medicine, Université de Montréal, Montréal, QC, Canada.,Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada
| | - Bethany J Foster
- Montreal Children's Hospital, McGill University, Montreal, QC, Canada.,Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada
| | - Marie-Josée Hébert
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.,Héma-Québec, Québec, QC, Canada.,Department of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Héloïse Cardinal
- Research centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.,Héma-Québec, Québec, QC, Canada.,Department of Medicine, Université de Montréal, Montréal, QC, Canada
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Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation. Transplant Direct 2022; 8:e1399. [PMID: 36479278 PMCID: PMC9722559 DOI: 10.1097/txd.0000000000001399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/07/2022] [Indexed: 01/24/2023] Open
Abstract
UNLABELLED Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. METHODS We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. RESULTS During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. CONCLUSIONS BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.
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Abstract
BACKGROUND Quality in kidney transplantation is measured using 1-year patient and graft survival. Because 1-year patient and graft survival exceed 95%, this metric fails to measure a spectrum of quality. Textbook outcomes (TO) are a composite quality metric offering greater depth and resolution. We studied TO after living donor (LD) and deceased donor (DD) kidney transplantation. STUDY DESIGN United Network for Organ Sharing data for 69,165 transplant recipients between 2013 and 2017 were analyzed. TO was defined as patient and graft survival of 1 year or greater, 1-year glomerular filtration rate of greater than 40 mL/min, absence of delayed graft function, length of stay of 5 days or less, no readmissions during the first 6 months, and no episodes of rejection during the first year after transplantation. Bivariate analysis identified characteristics associated with TO, and covariates were incorporated into multivariable models. Five-year conditional survival was measured, and center TO rates were corrected for case complexity to allow center-level comparisons. RESULTS The national average TO rates were 54.1% and 31.7% for LD and DD transplant recipients. The hazard ratio for death at 5 years for recipients who did not experience TO was 1.92 (95% CI 1.68 to 2.18, p ≤ 0.0001) for LD transplant recipients and 2.08 (95% CI 1.93 to 2.24, p ≤ 0.0001) for DD transplant recipients. Center-level comparisons identify 18% and 24% of centers under-performing in LD and DD transplantation. High rates of TO do not correlate with transplantation center volume. CONCLUSION Kidney transplant recipients who experience TO have superior long-term survival. Textbook outcomes add value to the current standards of 1-year patient and graft survival.
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Dynamic Parameters of Hypothermic Machine Perfusion-An Image of Initial Graft Function in Adult Kidney Transplantation? J Clin Med 2022; 11:jcm11195698. [PMID: 36233566 PMCID: PMC9571023 DOI: 10.3390/jcm11195698] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 11/16/2022] Open
Abstract
Kidney allografts are subjected to ischemia reperfusion injury during the process of transplantation. Hypothermic machine perfusion (HMP) of deceased donor kidneys from organ procurement until transplantation is associated with a superior outcome when compared to static cold storage (SCS). Nevertheless, cold ischemia time (CIT) remains an independent risk factor for delayed graft function (DGF) in HMP-preserved kidney allografts as well. We performed a retrospective single-center study including all adult recipients who underwent deceased donor kidney-only transplantation at our center between January 2019 and December 2020. Beside the clinicopathological donor and recipient data, flow and resistance data during HMP were assessed. Short- and long-term kidney allograft outcome after end-ischemic HMP and SCS were analyzed and compared. Organ preservation consisted of either SCS (n = 88) or HMP (n = 45). There were no differences in recipient demographics and donor details between groups. CIT was significantly longer in the HMP group (16.5 [8.5−28.5] vs. 11.3 [5.4−24.1], p < 0.0001). The incidence of DGF as well as serum creatinine at discharge and at 1 year post transplant were comparable between groups. Duration of SCS prior to HMP was comparable among grafts with and without DGF. Flow rate and organ resistance at the start of HMP were significantly worse in DGF-kidney grafts (arterial flow 22.50 [18.00−48.00] vs. 51.83 [25.50−92.67] ml/min, p = 0.0256; organ resistance 123.33 [57.67−165.50] vs. 51.33 [28.17−111.50] mmHg/mL/min, p = 0.0050). Recipients with DGF had significantly worse creatinine levels at discharge (2.54 [1.08−7.64] vs. 1.67 [0.90−6.56], p < 0.0001) and at 1 year post transplant (1.80 [1.09−7.95] vs. 1.59 [0.87−7.40], p = 0.0105). In conclusion, baseline HMP parameters could be applied as a predictive tool for initial graft function, which in turn determines long-term outcome.
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Ponticelli C, Reggiani F, Moroni G. Delayed Graft Function in Kidney Transplant: Risk Factors, Consequences and Prevention Strategies. J Pers Med 2022; 12:jpm12101557. [PMID: 36294695 PMCID: PMC9605016 DOI: 10.3390/jpm12101557] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background. Delayed graft function is a frequent complication of kidney transplantation that requires dialysis in the first week posttransplant. Materials and Methods. We searched for the most relevant articles in the National Institutes of Health library of medicine, as well as in transplantation, pharmacologic, and nephrological journals. Results. The main factors that may influence the development of delayed graft function (DGF) are ischemia–reperfusion injury, the source and the quality of the donated kidney, and the clinical management of the recipient. The pathophysiology of ischemia–reperfusion injury is complex and involves kidney hypoxia related to the duration of warm and cold ischemia, as well as the harmful effects of blood reperfusion on tubular epithelial cells and endothelial cells. Ischemia–reperfusion injury is more frequent and severe in kidneys from deceased donors than in those from living donors. Of great importance is the quality and function of the donated kidney. Kidneys from living donors and those with normal function can provide better results. In the peri-operative management of the recipient, great attention should be paid to hemodynamic stability and blood pressure; nephrotoxic medicaments should be avoided. Over time, patients with DGF may present lower graft function and survival compared to transplant recipients without DGF. Maladaptation repair, mitochondrial dysfunction, and acute rejection may explain the worse long-term outcome in patients with DGF. Many different strategies meant to prevent DGF have been evaluated, but only prolonged perfusion of dopamine and hypothermic machine perfusion have proven to be of some benefit. Whenever possible, a preemptive transplant from living donor should be preferred.
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Affiliation(s)
| | - Francesco Reggiani
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy
- Correspondence:
| | - Gabriella Moroni
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy
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He J, Khan UZ, Qing L, Wu P, Tang J. Improving the ischemia-reperfusion injury in vascularized composite allotransplantation: Clinical experience and experimental implications. Front Immunol 2022; 13:998952. [PMID: 36189311 PMCID: PMC9523406 DOI: 10.3389/fimmu.2022.998952] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022] Open
Abstract
Long-time ischemia worsening transplant outcomes in vascularized composite allotransplantation (VCA) is often neglected. Ischemia-reperfusion injury (IRI) is an inevitable event that follows reperfusion after a period of cold static storage. The pathophysiological mechanism activates local inflammation, which is a barrier to allograft long-term immune tolerance. The previous publications have not clearly described the relationship between the tissue damage and ischemia time, nor the rejection grade. In this review, we found that the rejection episodes and rejection grade are usually related to the ischemia time, both in clinical and experimental aspects. Moreover, we summarized the potential therapeutic measures to mitigate the ischemia-reperfusion injury. Compare to static preservation, machine perfusion is a promising method that can keep VCA tissue viability and extend preservation time, which is especially beneficial for the expansion of the donor pool and better MHC-matching.
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Affiliation(s)
- Jiqiang He
- Department of Hand and Microsurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Umar Zeb Khan
- Department of Hand and Microsurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Liming Qing
- Department of Hand and Microsurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Panfeng Wu
- Department of Hand and Microsurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Juyu Tang
- Department of Hand and Microsurgery, Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, China
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Micó-Carnero M, Zaouali MA, Rojano-Alfonso C, Maroto-Serrat C, Ben Abdennebi H, Peralta C. A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation. Cells 2022; 11:2763. [PMID: 36078175 PMCID: PMC9455584 DOI: 10.3390/cells11172763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.
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Affiliation(s)
- Marc Micó-Carnero
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carlos Rojano-Alfonso
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | | | - Hassen Ben Abdennebi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carmen Peralta
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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Normothermic Machine Perfusion in Renal Transplantation. CURRENT TRANSPLANTATION REPORTS 2022. [DOI: 10.1007/s40472-022-00378-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Abstract
Purpose of Review
Normothermic machine perfusion (NMP) is a promising new tool in kidney transplantation to improve the outcome of marginal donor kidney transplantation. This review examines the current evidence for NMP in clinical practice and considers how the technology may be used in the future.
Recent Findings and Summary
There is emerging evidence to suggest that NMP has the potential to expand the donor pool of transplantable organs. The safety and feasibility of NMP have been established in a number of clinical studies but more research is needed to optimise the perfusion conditions. NMP shows promise as a viability assessment tool with particular focus on biomarkers and imaging techniques which provide real-time information to facilitate transplantation decision-making. Moreover, the exciting development of new potential therapeutics such as cell and gene-based therapies which are deliverable during NMP may also improve and recondition grafts prior to implantation.
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Bai Y, Yang Y, Wei H, Quan J, Wei F, Zhang Q, Liu F. Clinical outcomes of robotic-assisted laparoscopic partial nephrectomy with renal hypothermia perfusion by renal artery balloon catheter in treating patients with complex renal tumors. Front Oncol 2022; 12:918143. [PMID: 36091113 PMCID: PMC9459104 DOI: 10.3389/fonc.2022.918143] [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: 04/12/2022] [Accepted: 07/18/2022] [Indexed: 12/09/2022] Open
Abstract
Objective This study aimed to investigate the safety and efficacy of renal hypothermic perfusion by renal artery balloon catheter during robot-assisted laparoscopic partial nephrectomy (P-RALPN) for patients with complex renal tumors. Materials and methods We retrospectively identified 45 patients with complex renal tumors who received standard robot-assisted laparoscopic partial nephrectomy (S-RALPN) and 11 patients treated with P-RALPN from September 2017 to October 2021. Preoperative patients’ characteristics and intraoperative surgical parameters including operating time, blood loss, hospitalization, pre- and post-surgical glomerular filtration rate (GFR), and postoperative survival time were collected and compared between the two groups. The patients’ body temperature, real-time kidney temperature, and short-term renal function were analyzed in the P-RALPN group. Results There was no statistically significant difference on median intraoperative estimated blood loss and postoperative hospitalization between the two groups. Patients who received P-RALPN had a slightly longer operative time than those who received S-RALPN (103.1 versus 125.9; p = 0.09). In the P-RALPN group, the volume of perfusion solution was 533.2 ml (range, 255.0–750.0 ml), the median temperature of kidney was 22.6°C (range, 21.7–24.1°C) after the kidney cools down, and the median minimum intraoperative temperature of patients was 36.1°C (range 35.2–36.7°C). The ischemia time in the S-RALPN group was markedly lower than that in the P-RALPN group (21.5 versus 34.8; p < 0.01). However, the loss of GFR was much higher for the S-RALPN group after the surgery. (28.9 versus 18.4; p < 0.01). Importantly, patients had similar postoperative survival time between the two groups (p = 0.42; HR = 0.27). Conclusion P-RALPN is a safe and feasible surgery in the treatment of patients with complex renal tumors, which provides a new operative approach for clinicians to treat these patients.
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Affiliation(s)
- YuChen Bai
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - YunKai Yang
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - HaiBin Wei
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jing Quan
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Fei Wei
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qi Zhang
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Feng Liu, ; Qi Zhang,
| | - Feng Liu
- Urology and Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Feng Liu, ; Qi Zhang,
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Alomari M, Garg P, Yazji JH, Wadiwala IJ, Alamouti-fard E, Hussain MWA, Elawady MS, Jacob S. Is the Organ Care System (OCS) Still the First Choice With Emerging New Strategies for Donation After Circulatory Death (DCD) in Heart Transplant? Cureus 2022; 14:e26281. [PMID: 35754437 PMCID: PMC9229932 DOI: 10.7759/cureus.26281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2022] [Indexed: 12/14/2022] Open
Abstract
The scarcity of donor hearts continues to be a challenge in transplants for advanced heart failure patients. With an increasing number of patients on the waiting list for a heart transplant, the discrepancy in the number between donors and recipients is gradually increasing and poses a new challenge that plagues the healthcare systems when it comes to the heart. Several technologies have been developed to expand the donor pool in recent years. One such method is the organ care system (OCS). The standard method of organ preservation is the static cold storage (SCS) method which allows up to four hours of safe preservation of the heart. However, beyond four hours of cold ischemia, the incidence of primary graft dysfunction increases significantly. OCS keeps the heart perfused close to the physiological state beyond the four hours with superior results, which allows us to travel further and longer distances, leading to expansion in the donor pool. In this review, we discuss the OCS system, its advantages, and shortcomings.
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Hunter JP, Faro LL, Rozenberg K, Dengu F, Ogbemudia A, Weissenbacher A, Mulvey JF, Knijff L, Gopalakrishnan K, Ploeg RJ. Assessment of Mitochondrial Function and Oxygen Consumption Measured During Ex Vivo Normothermic Machine Perfusion of Injured Pig Kidneys Helps to Monitor Organ Viability. Transpl Int 2022; 35:10420. [PMID: 35711321 PMCID: PMC9194576 DOI: 10.3389/ti.2022.10420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/10/2022] [Indexed: 12/01/2022]
Abstract
Donor kidney assessment may improve organ utilisation. Normothermic Machine Perfusion (NMP) has the potential to facilitate this advance. The mechanism of action is not yet determined and we aimed to assess mitochondrial function during NMP. Anaesthetised pigs (n = 6) had one kidney clamped for 60 min. The healthy contralateral kidney was removed and underwent NMP for 8 h (healthy control (HC), n = 6). Following 60 min warm ischaemia the injured kidney underwent HMP for 24 h, followed by NMP for 8 h (n = 6). Mitochondria were extracted from fresh tissue for analysis. Injured kidneys were analysed as two separate groups (IMa, n = 3 and IMb, n = 3). Renal resistance was higher (0.39ï, ± 0.29 vs. 1.65ï, ± 0.85; p = 0.01) and flow was lower (55ï, ± 28 vs. 7ï, ± 4; p = 0.03) during HMP in IMb than IMa. NMP blood flow was higher in IMa versus IMb (2-way ANOVA; p < 0.001) After 60 min NMP, O2 consumption was significantly lower in IMb versus IMa (p ≤ 0.002). State-3 respiration was significantly different between the groups (37ï, ± 19 vs. 24ï, ± 14 vs. 10ï, ± 8; nmolO2/min/mg; p = 0.049). Lactate levels were significantly lower in IMa versus IMb (p = 0.028). Mitochondrial respiration levels during NMP may be suggestive of kidney viability. Oxygen consumption, renal blood flow and lactate can differentiate severity of kidney injury during NMP.
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Affiliation(s)
- James P. Hunter
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- *Correspondence: James P. Hunter,
| | - Letizia Lo Faro
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Kaithlyn Rozenberg
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Fungai Dengu
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Anne Ogbemudia
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Annemarie Weissenbacher
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - John F. Mulvey
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Laura Knijff
- Leiden University Medical Center, Leiden, Netherlands
| | | | - Rutger J. Ploeg
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
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Predictors of Kidney Delayed Graft Function and Its Prognostic Impact following Combined Liver-Kidney Transplantation: A Recent Single-Center Experience. J Clin Med 2022; 11:jcm11102724. [PMID: 35628851 PMCID: PMC9146237 DOI: 10.3390/jcm11102724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 12/04/2022] Open
Abstract
Combined liver−kidney transplantation (CLKT) improves patient survival among liver transplant recipients with renal dysfunction. However, kidney delayed graft function (kDGF) still represents a common and challenging complication that can negatively impact clinical outcomes. This retrospective study analyzed the incidence, potential risk factors, and prognostic impact of kDGF development following CLKT in a recently transplanted cohort. Specifically, 115 consecutive CLKT recipients who were transplanted at our center between January 2015 and February 2021 were studied. All transplanted kidneys received hypothermic pulsatile machine perfusion (HPMP) prior to transplant. The primary outcome was kDGF development. Secondary outcomes included the combined incidence and severity of developing postoperative complications; development of postoperative infections; biopsy-proven acute rejection (BPAR); renal function at 1, 3, 6, and 12 months post-transplant; and death-censored graft and patient survival. kDGF was observed in 37.4% (43/115) of patients. Multivariable analysis of kDGF revealed the following independent predictors: preoperative dialysis (p = 0.0003), lower recipient BMI (p = 0.006), older donor age (p = 0.003), utilization of DCD donors (p = 0.007), and longer delay of kidney transplantation after liver transplantation (p = 0.0003). With a median follow-up of 36.7 months post-transplant, kDGF was associated with a significantly increased risk of developing more severe postoperative complication(s) (p < 0.000001), poorer renal function (particularly at 1 month post-transplant, p < 0.000001), and worse death-censored graft (p = 0.00004) and patient survival (p = 0.0002). kDGF may be responsible for remarkable negative effects on immediate and potentially longer-term clinical outcomes after CLKT. Understanding the important risk factors for kDGF development in CLKT may better guide recipient and donor selection(s) and improve clinical decisions in this increasing group of transplant recipients.
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Chang A, Schaubel DE, Chen M, Abt PL, Bittermann T. Trends and Outcomes of Hypothermic Machine Perfusion Preservation of Kidney Allografts in Simultaneous Liver and Kidney Transplantation in the United States. Transpl Int 2022; 35:10345. [PMID: 35356400 PMCID: PMC8958417 DOI: 10.3389/ti.2022.10345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 01/18/2022] [Indexed: 11/18/2022]
Abstract
Optimal kidney graft outcomes after simultaneous liver-kidney (SLK) transplant may be threatened by the increased cold ischemia time and hemodynamic perturbations of dual organ transplantation. Hypothermic machine perfusion (MP) of kidney allografts may mitigate these effects. We analyzed U.S. trends and renal outcomes of hypothermic non-oxygenated MP vs. static cold storage (CS) of kidney grafts from 6,689 SLK transplants performed between 2005 and 2020 using the United Network for Organ Sharing database. Outcomes included delayed graft function (DGF), primary non-function (PNF), and kidney graft survival (GS). Overall, 17.2% of kidney allografts were placed on MP. Kidney cold ischemia time was longer in the MP group (median 12.8 vs. 10.0 h; p < 0.001). Nationally, MP utilization in SLK increased from <3% in 2005 to >25% by 2019. Center preference was the primary determinant of whether a graft underwent MP vs. CS (intraclass correlation coefficient 65.0%). MP reduced DGF (adjusted OR 0.74; p = 0.008), but not PNF (p = 0.637). Improved GS with MP was only observed with Kidney Donor Profile Index <20% (HR 0.71; p = 0.030). Kidney MP has increased significantly in SLK in the U.S. in a heterogeneous manner and with variable short-term benefits. Additional studies are needed to determine the ideal utilization for MP in SLK.
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Affiliation(s)
- Alex Chang
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Douglas E Schaubel
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Melissa Chen
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Peter L Abt
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Therese Bittermann
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Verstraeten L, Jochmans I. Sense and Sensibilities of Organ Perfusion as a Kidney and Liver Viability Assessment Platform. Transpl Int 2022; 35:10312. [PMID: 35356401 PMCID: PMC8958413 DOI: 10.3389/ti.2022.10312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/26/2022] [Indexed: 12/13/2022]
Abstract
Predicting organ viability before transplantation remains one of the most challenging and ambitious objectives in transplant surgery. Waitlist mortality is high while transplantable organs are discarded. Currently, around 20% of deceased donor kidneys and livers are discarded because of “poor organ quality”, Decisions to discard are still mainly a subjective judgement since there are only limited reliable tools predictive of outcome available. Organ perfusion technology has been posed as a platform for pre-transplant organ viability assessment. Markers of graft injury and function as well as perfusion parameters have been investigated as possible viability markers during ex-situ hypothermic and normothermic perfusion. We provide an overview of the available evidence for the use of kidney and liver perfusion as a tool to predict posttransplant outcomes. Although evidence shows post-transplant outcomes can be predicted by both injury markers and perfusion parameters during hypothermic kidney perfusion, the predictive accuracy is too low to warrant clinical decision making based upon these parameters alone. In liver, further evidence on the usefulness of hypothermic perfusion as a predictive tool is needed. Normothermic perfusion, during which the organ remains fully metabolically active, seems a more promising platform for true viability assessment. Although we do not yet fully understand “on-pump” organ behaviour at normothermia, initial data in kidney and liver are promising. Besides the need for well-designed (registry) studies to advance the field, the catch-22 of selection bias in clinical studies needs addressing.
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Affiliation(s)
- Laurence Verstraeten
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Ina Jochmans
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
- *Correspondence: Ina Jochmans,
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Juriasingani S, Vo V, Akbari M, Grewal J, Zhang M, Jiang J, Haig A, Sener A. Supplemental hydrogen sulfide in models of renal transplantation after cardiac death. Can J Surg 2022; 65:E193-E202. [PMID: 35292525 PMCID: PMC8929428 DOI: 10.1503/cjs.013920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2021] [Indexed: 12/26/2022] Open
Abstract
Background: The increasing use of kidneys from donations after cardiac death (DCD) for renal transplantation is hindered by negative outcomes owing to organ injury after prolonged warm and cold ischemia–reperfusion. Recently, hydrogen sulfide (H2S) has shown cytoprotective effects against ischemia–reperfusion injury; however, its effectiveness in the context of DCD renal transplantation is unknown. Methods: We tested a novel 30-day in vivo syngeneic murine model of DCD renal transplantation, in which the donor kidney was clamped for 30 minutes and stored for 18 hours in cold University of Wisconsin (UW) solution or UW with 150 μM sodium hydrogen sulfide (UW + NaHS) before transplantation. We also tested a 7-day in vivo porcine model of DCD renal autotransplantation, in which the left kidney was clamped for 60 minutes and preserved for 24 hours using hypothermic perfusion with UW or UW + 150 μM NaHS before autotransplantation. We collected blood and urine samples periodically, and collected kidney samples at the end point for histopathology and quantitative reverse transcription polymerase chain reaction. Results: Rats that received H2S-treated kidneys showed significantly higher survival, faster recovery of graft function and significantly lower acute tubular necrosis than controls. Pig kidneys perfused with UW + NaHS showed significantly higher renal blood flow and lower renal resistance than control kidneys after 24 hours of perfusion. After autotransplantation, pigs that received H2S-treated kidneys showed significantly lower serum creatinine on days 1 and 7 after transplantation. Rat and pig kidneys treated with H2S also showed more protective gene expression profiles than controls. Conclusion: Our findings support the potential use of H2S-supplemented UW solution during cold storage as a novel and practical means to improve DCD graft survival and function.
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Affiliation(s)
- Smriti Juriasingani
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Vicky Vo
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Masoud Akbari
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Jaskiran Grewal
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Max Zhang
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Jifu Jiang
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Aaron Haig
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
| | - Alp Sener
- From the Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Sener); the Matthew Mailing Centre for Translational Transplant Studies, University Hospital, London Health Sciences Centre, London, Ont. (Juriasingani, Vo, Akbari, Grewal, Zhang, Jiang, Sener); the Undergraduate Medical Education-MD program, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ont. (Vo); the Department of Pathology, Schulich School of Medicine & Dentistry, University of Western, London, Ont. (Haig); the Department of Surgery, Schulich School of Medicine & Dentistry, St. Joseph's Health Care, London, Ont. (Sener); and the Multi Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ont. (Sener)
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48
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Perico N, Casiraghi F, Remuzzi G. Clinical Kidney Xenotransplantation: Major Progress but More Work Needs to Be Done. Nephron Clin Pract 2022; 146:610-615. [PMID: 35340011 DOI: 10.1159/000524095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/12/2022] [Indexed: 01/01/2023] Open
Affiliation(s)
- Norberto Perico
- Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Bergamo, Italy
| | | | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Bergamo, Italy
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49
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Zulpaite R, Miknevicius P, Leber B, Strupas K, Stiegler P, Schemmer P. Ex-vivo Kidney Machine Perfusion: Therapeutic Potential. Front Med (Lausanne) 2021; 8:808719. [PMID: 35004787 PMCID: PMC8741203 DOI: 10.3389/fmed.2021.808719] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/06/2021] [Indexed: 01/11/2023] Open
Abstract
Kidney transplantation remains the gold standard treatment for patients suffering from end-stage kidney disease. To meet the constantly growing organ demands grafts donated after circulatory death (DCD) or retrieved from extended criteria donors (ECD) are increasingly utilized. Not surprisingly, usage of those organs is challenging due to their susceptibility to ischemia-reperfusion injury, high immunogenicity, and demanding immune regulation after implantation. Lately, a lot of effort has been put into improvement of kidney preservation strategies. After demonstrating a definite advantage over static cold storage in reduction of delayed graft function rates in randomized-controlled clinical trials, hypothermic machine perfusion has already found its place in clinical practice of kidney transplantation. Nevertheless, an active investigation of perfusion variables, such as temperature (normothermic or subnormothermic), oxygen supply and perfusate composition, is already bringing evidence that ex-vivo machine perfusion has a potential not only to maintain kidney viability, but also serve as a platform for organ conditioning, targeted treatment and even improve its quality. Many different therapies, including pharmacological agents, gene therapy, mesenchymal stromal cells, or nanoparticles (NPs), have been successfully delivered directly to the kidney during ex-vivo machine perfusion in experimental models, making a big step toward achievement of two main goals in transplant surgery: minimization of graft ischemia-reperfusion injury and reduction of immunogenicity (or even reaching tolerance). In this comprehensive review current state of evidence regarding ex-vivo kidney machine perfusion and its capacity in kidney graft treatment is presented. Moreover, challenges in application of these novel techniques in clinical practice are discussed.
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Affiliation(s)
- Ruta Zulpaite
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Povilas Miknevicius
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Bettina Leber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | | | - Philipp Stiegler
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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50
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Luo Y, Dong Z, Hu X, Tang Z, Zhang J, Deng W, Wei X, Miao B, Qin F, Na N. Donor Death Category Is an Effect Modifier Between Cold Ischemia Time and Post-transplant Graft Function in Deceased-Donor Kidney Transplant Recipients. Front Med (Lausanne) 2021; 8:743085. [PMID: 34888321 PMCID: PMC8649960 DOI: 10.3389/fmed.2021.743085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives: We aimed to analyze the effect of cold ischemia time (CIT) on post-transplant graft function through mixed-effect model analysis to reduce the bias caused by paired mate kidneys. Methods: We reviewed all kidney transplantation records from 2015 to 2019 at our center. After applying the exclusion criteria, 561 cases were included for analysis. All donor characteristics, preservation and matching information, and recipient characteristics were collected. Transplant outcomes included delayed graft function (DGF) and estimated glomerular filtration rate (eGFR). Generalized linear mixed models were applied for analysis. We also explored potential effect modifiers, namely, donor death category, expanded criteria donors, and donor death causes. Results: Among the 561 cases, 79 DGF recipients developed DGF, and 15 recipients who died after surgery were excluded from the eGFR estimation. The median stable eGFR of the 546 recipients was 60.39 (47.63, 76.97) ml/min/1.73 m2. After adjusting for confounding covariates, CIT had a negative impact on DGF incidence [odds ratio = 1.149 (1.006, 1.313), P = 0.041]. In the evaluation of the impact on eGFR, the regression showed that CIT had no significant correlation with eGFR [β = −0.287 (−0.625, 0.051), P = 0.096]. When exploring potential effect modifiers, only the death category showed a significant interaction with CIT in the effect on eGFR (Pinteraction = 0.027). In the donation after brain death (DBD) group, CIT had no significant effect on eGFR [β = 0.135 (−0.433, 0.702), P = 0.642]. In the donation after circulatory death/donation after brain death followed by circulatory death (DCD/DBCD) group, CIT had a significantly negative effect on eGFR [β= −0.700 (−1.196, −0.204), P = 0.006]. Compared to a CIT of 0–6 h, a CIT of 6–8 or 8–12 h did not decrease the post-transplant eGFR. CIT over 12 h (12–16 h or over 16 h) significantly decreased eGFR. With the increase in CIT, the regenerated eGFR worsened (Ptrend = 0.011). Conclusion: Considering the effect of paired mate kidneys, the risk of DGF increased with prolonged CIT. The donor death category was an effect modifier between CIT and eGFR. Prolonged CIT did not reduce the eGFR level in recipients from DBDs but significantly decreased the eGFR in recipients from DCDs/DBCDs. This result indicates the potential biological interaction between CIT and donor death category.
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Affiliation(s)
- You Luo
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhanwen Dong
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiao Hu
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zuofu Tang
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinhua Zhang
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Weiming Deng
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangling Wei
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Miao
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Feng Qin
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ning Na
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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