Publications by authors named "Gabriel C Oniscu"

82 Publications

Management of obesity in kidney transplant candidates and recipients: A clinical practice guideline by the Descartes working group of ERA.

Nephrol Dial Transplant 2021 Nov 12. Epub 2021 Nov 12.

Department of Nephrology, Ghent University Hospital, Belgium.

The clinical practice guideline 'Management of obesity in kidney transplant candidates and recipients' was developed to guide decision making in caring for people with end-stage kidney disease living with obesity. The document considers the challenges in defining obesity, weighs interventions for treating obesity in kidney transplant candidates as well as recipients and reflects on the impact of obesity on the likelihood of waitlisting as well as its effect on transplant outcomes. It was designed to inform management decisions related to this topic and provide the backdrop for shared decision making. This guideline was developed by ERA's Descartes working group on Transplantation. The group was supplemented with selected methodologists to supervise the project and provide methodological expertise in guideline development throughout the process. The guideline targets any health care professional treating or caring for people with end-stage kidney disease being considered for kidney transplantation or having received a donor kidney. This includes nephrologists, transplant physicians, transplant surgeons, general practitioners, dialysis and transplant nurses. Development of this guideline followed an explicit process of evidence review. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Limitations of the evidence are discussed, and areas of future research are presented.
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http://dx.doi.org/10.1093/ndt/gfab310DOI Listing
November 2021

Tissue Proteomic Analysis Identifies Mechanisms and Stages of Immunopathology in Fatal COVID-19.

Am J Respir Cell Mol Biol 2021 Oct 28. Epub 2021 Oct 28.

University of Edinburgh, Centre for Inflammation Research, Edinburgh, United Kingdom of Great Britain and Northern Ireland;

Immunopathology occurs in the lung and spleen in fatal COVID-19, involving monocytes/macrophages and plasma cells. Anti-inflammatory therapy reduces mortality but additional therapeutic targets are required. We aimed to gain mechanistic insight into COVID-19 immunopathology by targeted proteomic analysis of pulmonary and splenic tissues. Lung parenchymal and splenic tissue was obtained from 13 post-mortem examinations of patients with fatal COVID-19. Control tissue was obtained from cancer resection samples (lung) and deceased organ donors (spleen). Protein was extracted from tissue by phenol extraction. Olink® multiplex immunoassay panels were used for protein detection and quantification. Proteins with increased abundance in the lung included MCP-3, antiviral TRIM21 and pro-thrombotic TYMP. OSM and EN-RAGE/S100A12 abundance was correlated, and associated with inflammation severity. Unsupervised clustering identified 'early viral' and 'late inflammatory' clusters with distinct protein abundance profiles, and differences in illness duration prior to death and presence of viral RNA. In the spleen, lymphocyte chemotactic factors and CD8A were decreased in abundance, and pro-apoptotic factors were increased. B-cell receptor signalling pathway components and macrophage colony stimulating factor (CSF-1) were also increased. Additional evidence for a sub-set of host factors (including DDX58, OSM, TYMP, IL-18, MCP-3 and CSF-1) was provided by overlap between (i) differential abundance in spleen and lung tissue, (ii) meta-analysis of existing datasets, and (iii) plasma proteomic data. This proteomic analysis of lung parenchymal and splenic tissue from fatal COVID-19 provides mechanistic insight into tissue anti-viral responses, inflammation and disease stages, macrophage involvement, pulmonary thrombosis, splenic B-cell activation and lymphocyte depletion. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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http://dx.doi.org/10.1165/rcmb.2021-0358OCDOI Listing
October 2021

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation.

J Hepatol 2021 Oct 13. Epub 2021 Oct 13.

Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy.

Background: To identify the best possible outcomes in liver transplantation from donation after circulatory death donors (DCD) and to propose outcome values, which serve as reference for individual liver recipients or patient groups.

Methods: Based on 2219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1012 low-risk, primary, adult liver transplantations with a laboratory MELD of ≤20points, receiving a DCD liver with a total donor warm ischemia time of ≤30minutes and asystolic donor warm ischemia time of ≤15minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the Comprehensive Complication Index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75-percentile was considered.

Results: Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centers. The one-year retransplant and mortality rate was 5.23% and 9.01%, respectively. Within the first year of follow-up, 51.1% of recipients developed at least one major complication (≥Clavien-Dindo-Grade-III). Benchmark cut-offs were ≤3days and ≤16days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade-III), ≤16.8% for ischemic cholangiopathy, and ≤38.9CCI points at one-year posttransplant. Comparisons with higher risk groups showed more complications and impaired graft survival, outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk.

Conclusions: Despite excellent 1-year survival, morbidity in benchmark cases remains high with more than half of recipients developing severe complications during 1-year follow-up. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups, and provide a valid comparator cohort for future clinical trials.

Lay Summary: The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2219 liver transplantations following controlled DCD donation in 17 centres worldwide. The following benchmark cut-offs for the most relevant outcome parameters were developed: ICU and hospital stay: ≤3 and ≤16 days; primary non function: ≤2.5%; renal replacement therapy: ≤9.6%; ischemic cholangiopathy: ≤16.8% and anastomotic strictures ≤28.4%. One-year graft loss and mortality were defined as ≤14.4% and 9.6%, respectively. Donor and recipient combinations with higher risk had significantly worse outcomes. The use of novel organ perfusion technology achieved similar, good results in this high-risk group with prolonged donor warm ischemia time, when compared to the benchmark cohort.
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http://dx.doi.org/10.1016/j.jhep.2021.10.004DOI Listing
October 2021

Assessment of Pre-Donation Glomerular Filtration Rate: Going Back To Basics A Position Paper from the DESCARTES Working Group of the ERA-EDTA.

Nephrol Dial Transplant 2021 Sep 14. Epub 2021 Sep 14.

Department of Medicine and Surgery, University of Parma, Italy.

The 2017 version of the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines is the most recent international framework for the evaluation and care of living kidneys donors. Along with the call for an integrative approach evaluating the long-term end-stage kidney disease risk for the future potential donor, several recommendations are formulated regarding the predonation glomerular filtration rate (GFR) adequacy with no or little consideration for the donor candidate's age and for the importance of using reference methods of GFR measurements. Herein, we question the position of the KDIGO guidelines and discuss the rationale and modalities for a more basic, but not less demanding GFR evaluation susceptible to enable a more efficient selection of the potential kidney donor.
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http://dx.doi.org/10.1093/ndt/gfab259DOI Listing
September 2021

Addressing ethical confusion in deceased donation and transplantation research: the need for dedicated guidance.

Transpl Int 2021 Sep 13. Epub 2021 Sep 13.

Division of Medical Ethics, New York University School of Medicine, New York, NY, USA.

Innovative research in deceased donation and transplantation often presents ethical challenges for researchers and those responsible for ethical governance of research. These challenges have been recognized as potential barriers to the conduct of research. We review the literature to identify and describe ethical considerations that may cause confusion or uncertainty in the context of research involving potential deceased donors or deceased donor transplantation. We normatively examine these considerations and discuss their implications for the ethical conduct of research. In addition to the complexities of research involving critically ill, dying or recently deceased individuals, uncertainty may arise regarding the ethical status of various individuals who may be involved in research aimed at improving availability and outcomes of organ transplantation. Consequently, routine ethical guidelines for clinical research may fail to provide clear guidance with regards to the design, conduct and governance of some deceased donation or transplantation studies. Ethical uncertainty may result in delays or barriers to research, or neglect of important ethical considerations. Specific ethical guidance is needed to support research in deceased donation and transplantation as the ethical considerations that arise in the design and conduct of such research may not be addressed in the existing guidelines for human research.
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http://dx.doi.org/10.1111/tri.14108DOI Listing
September 2021

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study.

Gut 2021 10 19;70(10):1914-1924. Epub 2021 Jul 19.

Department of Gastroenterology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Lombardia, Italy.

Objective: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course.

Design: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed.

Results: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170).

Conclusions: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).
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http://dx.doi.org/10.1136/gutjnl-2021-324879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300535PMC
October 2021

Equity of access to renal transplantation: a European perspective.

Curr Opin Organ Transplant 2021 08;26(4):347-352

Edinburgh Transplant Centre, Royal Infirmary of Edinburgh.

Purpose Of Review: Renal transplantation offers the chance for patients with end-stage renal disease (ESRD) to have a significantly longer, healthier and better quality life compared with remaining on dialysis. Inequities have been demonstrated at multiple points in the transplantation pathway. In this review, the factors contributing to inequity in access to renal transplantation will be explored from a European perspective.

Recent Findings: Despite improvements in patient assessment and revision of organ-offering schemes, there remain persistent inequities in access to the waiting list, allocation of a deceased donor transplant, receiving a living donor transplant and achieving preemptive transplantation. Older age, lower socioeconomic status and health literacy are key factors that continue to impact equity of access to transplantation.

Summary: A number of modifiable factors have been identified affecting access to transplantation, Increased patient education together with a better access to and promotion of living donation may help address some of these inequities.
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http://dx.doi.org/10.1097/MOT.0000000000000895DOI Listing
August 2021

Have we reached the limits in altruistic kidney donation?

Transpl Int 2021 07 19;34(7):1187-1197. Epub 2021 Jun 19.

Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, UK.

Altruistic donation (unspecified donation) is an important aspect of living donor kidney transplantation. Although donation to a stranger is lawful and supported in many countries, it remains uncommon and not actively promoted. Herein, we ask the question if we have reached the limit in altruistic donation. In doing so, we examine important ethical questions that define the limits of unspecified donation, such as the appropriate balance between autonomous decision-making and paternalistic protection of the donor, the extent of outcome uncertainty and risk-benefit analyses that donors should be allowed to accept. We also consider the scrutiny and acceptance of donor motives, the potential for commercialization, donation to particular categories of recipients (including those encountered through social media) and the ethical boundaries of active promotion of unspecified kidney donation. We conclude that there is scope to increase the number of living donation kidney transplants further by optimizing existing practices to support and promote unspecified donation. A number of strategies including optimization of the assessment process, innovative approaches to reach potential donors together with reimbursement of expenses and a more specific recognition of unspecified donation are likely to lead to a meaningful increase in this type of donation.
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http://dx.doi.org/10.1111/tri.13921DOI Listing
July 2021

Organ donation and transplantation: a multi-stakeholder call to action.

Nat Rev Nephrol 2021 08 5;17(8):554-568. Epub 2021 May 5.

Edinburgh Transplant Centre, Royal Infirmary of Edinburgh & University of Edinburgh, Edinburgh, UK.

Although overall donation and transplantation activity is higher in Europe than on other continents, differences between European countries in almost every aspect of transplantation activity (for example, in the number of transplantations, the number of people with a functioning graft, in rates of living versus deceased donation, and in the use of expanded criteria donors) suggest that there is ample room for improvement. Herein we review the policy and clinical measures that should be considered to increase access to transplantation and improve post-transplantation outcomes. This Roadmap, generated by a group of major European stakeholders collaborating within a Thematic Network, presents an outline of the challenges to increasing transplantation rates and proposes 12 key areas along with specific measures that should be considered to promote transplantation. This framework can be adopted by countries and institutions that are interested in advancing transplantation, both within and outside the European Union. Within this framework, a priority ranking of initiatives is suggested that could serve as the basis for a new European Union Action Plan on Organ Donation and Transplantation.
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http://dx.doi.org/10.1038/s41581-021-00425-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097678PMC
August 2021

REPLY.

Hepatology 2021 Oct 9;74(4):2310-2311. Epub 2021 Sep 9.

Department of Chemistry, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1002/hep.31880DOI Listing
October 2021

Changes in quality of life (QoL) and other patient-reported outcome measures (PROMs) in living-donor and deceased-donor kidney transplant recipients and those awaiting transplantation in the UK ATTOM programme: a longitudinal cohort questionnaire survey with additional qualitative interviews.

BMJ Open 2021 04 14;11(4):e047263. Epub 2021 Apr 14.

Health Psychology Research Unit, Royal Holloway University of London, Egham, UK

Objective: To examine quality of life (QoL) and other patient-reported outcome measures (PROMs) in kidney transplant recipients and those awaiting transplantation.

Design: Longitudinal cohort questionnaire surveys and qualitative semi-structured interviews using thematic analysis with a pragmatic approach.

Setting: Completion of generic and disease-specific PROMs at two time points, and telephone interviews with participants UK-wide.

Participants: 101 incident deceased-donor (DD) and 94 incident living-donor (LD) kidney transplant recipients, together with 165 patients on the waiting list (WL) from 18 UK centres recruited to the Access to Transplantation and Transplant Outcome Measures (ATTOM) programme completed PROMs at recruitment (November 2011 to March 2013) and 1 year follow-up. Forty-one of the 165 patients on the WL received a DD transplant and 26 received a LD transplant during the study period, completing PROMs initially as patients on the WL, and again 1 year post-transplant. A subsample of 10 LD and 10 DD recipients participated in qualitative semi-structured interviews.

Results: LD recipients were younger, had more educational qualifications and more often received a transplant before dialysis. Controlling for these and other factors, cross-sectional analyses at 12 months post-transplant suggested better QoL, renal-dependent QoL and treatment satisfaction for LD than DD recipients. Patients on the WL reported worse outcomes compared with both transplant groups. However, longitudinal analyses (controlling for pre-transplant differences) showed that LD and DD recipients reported similarly improved health status and renal-dependent QoL (p<0.01) pre-transplant to post-transplant. Patients on the WL had worsened health status but no change in QoL. Qualitative analyses revealed transplant recipients' expectations influenced their recovery and satisfaction with transplant.

Conclusions: While cross-sectional analyses suggested LD kidney transplantation leads to better QoL and treatment satisfaction, longitudinal assessment showed similar QoL improvements in PROMs for both transplant groups, with better outcomes than for those still wait-listed. Regardless of transplant type, clinicians need to be aware that managing expectations is important for facilitating patients' adjustment post-transplant.
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http://dx.doi.org/10.1136/bmjopen-2020-047263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098938PMC
April 2021

Pancreas utilization rates in the UK - an 11-year analysis.

Transpl Int 2021 07 11;34(7):1306-1318. Epub 2021 Jun 11.

Scottish Pancreas Transplant Unit, Edinburgh Transplant Centre, Edinburgh, UK.

Utilization of pancreases for transplantation remains inferior to that of other organs. Herein, we analysed UK pancreas discards to identify the reasons for the low utilization rates. Data on all pancreases offered first for solid organ transplantation between 1st January 2005 and 31st December 2015 were extracted from the UK Transplant Registry. The number of organs discarded, reasons and the time point of discard were analysed. A centre specific comparison was also undertaken. 7367 pancreases were offered first for solid organ transplantation. 35% were donors after circulatory death (DCD). 3668 (49.7%) organs were not retrieved. Of the 3699 pancreases retrieved, 38% were initially accepted but subsequently discarded. 2145 (29%) grafts offered were transplanted as simultaneous pancreas-kidney or solitary pancreas. 1177 (55%) were transplanted on the first offer whilst the remaining 968 were transplanted after a median of three offers. 52% DBD pancreases were accepted and transplanted on the first offer compared with 68% DCD grafts. There were significant differences in discard rates between centres (30-80% for DBD and 3-78% for DCD, P < 0.001). A significant number of solid pancreases are discarded. Better graft assessment at retrieval could minimize unnecessary organ travel and discards. Closer links with islet programmes may allow for better utilization of discarded grafts.
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http://dx.doi.org/10.1111/tri.13876DOI Listing
July 2021

Noninvasive Detection of Ischemic Vascular Damage in a Pig Model of Liver Donation After Circulatory Death.

Hepatology 2021 Jul 15;74(1):428-443. Epub 2021 Jun 15.

Department of Chemistry, University of Edinburgh, Edinburgh, United Kingdom.

Background And Aims: Liver graft quality is evaluated by visual inspection prior to transplantation, a process highly dependent on the surgeon's experience. We present an objective, noninvasive, quantitative way of assessing liver quality in real time using Raman spectroscopy, a laser-based tool for analyzing biomolecular composition.

Approach And Results: A porcine model of donation after circulatory death (DCD) with normothermic regional perfusion (NRP) allowed assessment of liver quality premortem, during warm ischemia (WI) and post-NRP. Ten percent of circulating blood volume was removed in half of experiments to simulate blood recovery for DCD heart removal. Left median lobe biopsies were obtained before circulatory arrest, after 45 minutes of WI, and after 2 hours of NRP and analyzed using spontaneous Raman spectroscopy, stimulated Raman spectroscopy (SRS), and staining. Measurements were also taken in situ from the porcine liver using a handheld Raman spectrometer at these time points from left median and right lateral lobes. Raman microspectroscopy detected congestion during WI by measurement of the intrinsic Raman signal of hemoglobin in red blood cells (RBCs), eliminating the need for exogenous labels. Critically, this microvascular damage was not observed during WI when 10% of circulating blood was removed before cardiac arrest. Two hours of NRP effectively cleared RBCs from congested livers. Intact RBCs were visualized rapidly at high resolution using SRS. Optical properties of ischemic livers were significantly different from preischemic and post-NRP livers as measured using a handheld Raman spectrometer.

Conclusions: Raman spectroscopy is an effective tool for detecting microvascular damage which could assist the decision to use marginal livers for transplantation. Reducing the volume of circulating blood before circulatory arrest in DCD may help reduce microvascular damage.
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http://dx.doi.org/10.1002/hep.31701DOI Listing
July 2021

A propensity score-matched analysis indicates screening for asymptomatic coronary artery disease does not predict cardiac events in kidney transplant recipients.

Kidney Int 2021 02 7;99(2):431-442. Epub 2020 Nov 7.

Richard Bright Renal Service, North Bristol National Health Service Trust, Bristol, UK.

Screening for asymptomatic coronary artery disease prior to kidney transplantation aims to reduce peri- and post-operative cardiac events. It is uncertain if this is achieved. Here, we investigated whether pre-transplant screening with a stress test or coronary angiogram associated with any difference in major adverse cardiac events (MACE) up to five years post-transplantation. We examined a national prospective cohort recruited to the Access to Transplant and Transplant Outcome Measures study who received a kidney transplant between 2011-2017, and linked patient demographics and details of cardiac screening investigations to outcome data extracted from the Hospital Episode Statistics dataset and United Kingdom Renal Registry. Propensity score matched groups were analyzed using Kaplan-Meier and Cox survival analyses. Overall, 2572 individuals were transplanted in 18 centers; 51% underwent screening and the proportion undergoing screening by center ranged from 5-100%. The incidence of MACE at 90 days, one and five years was 0.9%, 2.1% and 9.4% respectively. After propensity score matching based on the presence or absence of screening, 1760 individuals were examined (880 each in screened and unscreened groups). There was no statistically significant association between screening and MACE at 90 days (hazard ratio 0.80, 95% Confidence Interval 0.31-2.05), one year (1.12, 0.51-2.47) or five years (1.31, 0.86-1.99). Age, male sex and history of ischemic heart disease were associated with MACE. Thus, there is no association between screening for asymptomatic coronary artery disease and MACE up to five years post-transplant. Practices involving unselected screening of transplant recipients should be reviewed.
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http://dx.doi.org/10.1016/j.kint.2020.10.019DOI Listing
February 2021

SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Am J Transplant 2020 11 16;20(11):3008-3018. Epub 2020 Sep 16.

Medical Director, NHS Blood and Transplant, Bristol, UK.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.1111/ajt.16247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436919PMC
November 2020

The trials and tribulations of liver allocation.

Transpl Int 2020 11 28;33(11):1343-1352. Epub 2020 Aug 28.

Edinburgh Transplant Centre, Edinburgh, UK.

Allocation policies are necessary to ensure a fair distribution of a scarce resource. The goal of any liver transplant allocation policy is to achieve the best possible outcomes for the waiting list population, irrespective of the indication for transplant, whilst maximizing organ utilization. Organ allocation for liver transplantation has evolved from simple centre-based approaches driven by local issues, to complex, evidence-based algorithm prioritizing according to need. Despite the rapid evolution of allocation policies, there remain a number of challenges and new approaches are required to ensure transparency and equity on the decision-making process and the best possible outcomes for patients on the waiting list. New ways of modelling, together with novel outcome criteria, will be required to enable a dynamic adaptability of the allocation policies to the ever changing demographics of the donor population and the changing landscape of indications for transplantation.
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http://dx.doi.org/10.1111/tri.13710DOI Listing
November 2020

Changes in quality of life, health status and other patient-reported outcomes following simultaneous pancreas and kidney transplantation (SPKT): a quantitative and qualitative analysis within a UK-wide programme.

Transpl Int 2020 10 9;33(10):1230-1243. Epub 2020 Aug 9.

Health Psychology Research Unit, Royal Holloway University of London, London, UK.

We examined quality of life (QoL) and other patient-reported outcome measures (PROMs) in 95 simultaneous pancreas and kidney transplant (SPKT) recipients and 41 patients wait-listed for SPKT recruited to the UK Access to Transplantation and Transplant Outcome Measures (ATTOM) programme. Wait-listed patients transplanted within 12 months of recruitment (n = 22) were followed 12 months post-transplant and compared with those still wait-listed (n = 19) to examine pre- to post-transplant changes. Qualitative interviews with ten SPKT recipients 12 months post-transplant were analysed thematically. Cross-sectional analyses showed several better 12-month outcomes for SPKT recipients compared with those still wait-listed, a trend to better health utilities but no difference in diabetes-specific QoL or diabetes treatment satisfaction. Pre- to post-transplant, SPKT recipients showed improved treatment satisfaction, well-being, self-reported health, generic QoL and less negative impact on renal-specific QoL (ps < 0.05). Health utility values were better overall in transplant recipients and neither these nor diabetes-specific QoL changed significantly in either group. Pre-emptive transplant advantages seen in 12-month cross-sectional analyses disappeared when controlling for baseline values. Qualitative findings indicated diabetes complications, self-imposed blood glucose monitoring and dietary restrictions continued to impact QoL negatively post-transplant. Unrealistic expectations of SPKT caused some disappointment. Measuring condition-specific PROMs over time will help in demonstrating the benefits and limitations of SPKT.
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http://dx.doi.org/10.1111/tri.13677DOI Listing
October 2020

Abdominal Normothermic Regional Perfusion in Donation After Circulatory Death: A Systematic Review and Critical Appraisal.

Transplantation 2020 09;104(9):1776-1791

Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Background: Abdominal normothermic regional perfusion (aNRP) for donation after circulatory death is an emerging organ preservation technique that might lead to increased organ utilization per donor by facilitating viability testing, improving transplant outcome by early reversal of ischemia, and decreasing the risk of unintentional surgical damage. The aim of the current review is to evaluate the recent literature on the added value of aNRP when compared to local standard perfusion technique.

Methods: The Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline for systematic reviews was used, and relevant literature databases were searched. Primary outcomes were organ utilization rate and patient and graft survival after 1 year. Secondary outcomes included delayed graft function, primary nonfunction, serum creatinine, and biliary complications.

Results: A total of 24 articles were included in this review. The technique is unanimously reported to be feasible and safe, but the available studies are characterized by considerable heterogeneity and bias.

Conclusions: Uniform reported outcome measures are needed to draw more definitive conclusions on transplant outcomes and organ utilization. A randomized controlled trial comparing aNRP with standard procurement technique in donation after circulatory death donors would be needed to show the added value of the procedure and determine its place among modern preservation techniques.
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http://dx.doi.org/10.1097/TP.0000000000003345DOI Listing
September 2020

Inequity in Access to Transplantation in the United Kingdom.

Clin J Am Soc Nephrol 2020 06 28;15(6):830-842. Epub 2020 May 28.

Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Background And Objectives: Despite the presence of a universal health care system, it is unclear if there is intercenter variation in access to kidney transplantation in the United Kingdom. This study aims to assess whether equity exists in access to kidney transplantation in the United Kingdom after adjustment for patient-specific factors and center practice patterns.

Design, Setting, Participants, & Measurements: In this prospective, observational cohort study including all 71 United Kingdom kidney centers, incident RRT patients recruited between November 2011 and March 2013 as part of the Access to Transplantation and Transplant Outcome Measures study were analyzed to assess preemptive listing (=2676) and listing within 2 years of starting dialysis (=1970) by center.

Results: Seven hundred and six participants (26%) were listed preemptively, whereas 585 (30%) were listed within 2 years of commencing dialysis. The interquartile range across centers was 6%-33% for preemptive listing and 25%-40% for listing after starting dialysis. Patient factors, including increasing age, most comorbidities, body mass index >35 kg/m, and lower socioeconomic status, were associated with a lower likelihood of being listed and accounted for 89% and 97% of measured intercenter variation for preemptive listing and listing within 2 years of starting dialysis, respectively. Asian (odds ratio, 0.49; 95% confidence interval, 0.33 to 0.72) and Black (odds ratio, 0.43; 95% confidence interval, 0.26 to 0.71) participants were both associated with reduced access to preemptive listing; however Asian participants were associated with a higher likelihood of being listed after starting dialysis (odds ratio, 1.42; 95% confidence interval, 1.12 to 1.79). As for center factors, being registered at a transplanting center (odds ratio, 3.1; 95% confidence interval, 2.36 to 4.07) and a universal approach to discussing transplantation (odds ratio, 1.4; 95% confidence interval, 1.08 to 1.78) were associated with higher preemptive listing, whereas using a written protocol was associated negatively with listing within 2 years of starting dialysis (odds ratio, 0.7; 95% confidence interval, 0.58 to 0.9).

Conclusions: Patient case mix accounts for most of the intercenter variation seen in access to transplantation in the United Kingdom, with practice patterns also contributing some variation. Socioeconomic inequity exists despite having a universal health care system.
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http://dx.doi.org/10.2215/CJN.11460919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274279PMC
June 2020

Model for early allograft function is predictive of early graft loss in donation after circulatory death liver transplantation.

Clin Transplant 2020 08 10;34(8):e13982. Epub 2020 Jun 10.

University of Cambridge Department of Surgery, Addenbrooke's Hospital, Cambridge, UK.

Donation after circulatory death (DCD) liver transplantation is associated with higher rates of graft loss. In this paper, we explored whether the Model for Early Allograft Function (MEAF) predicted outcome in DCD liver transplantation. We performed a retrospective analysis of prospectively collected data from all adult DCD (Maastricht 3) livers transplanted in Cambridge and Edinburgh between 1 January 2011 and 30 June 2017, excluding those undergoing any form of machine perfusion. 187 DCD liver transplants were performed during the study period. DCD liver transplants with a lower MEAF score had a significantly better survival compared to those with a high MEAF score (Mantel-Cox P < .0001); this was largely due to early graft loss. Beyond 28 days post-transplant, there were no significant long-term graft or patient survival differences irrespective of the grade of MEAF (Mantel-Cox P = .64 and P = .43, respectively). The MEAF score correlated with the length of ICU (P = .0011) and hospital stay (P = .0007), but did not predict the requirement for retransplantation for ischemic cholangiopathy (P = .37) or readmission (P = .74). In this study, a high MEAF score predicted early graft loss, but not the subsequent need for re-transplantation or late graft failure as a result of intrahepatic ischemic bile duct pathology.
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http://dx.doi.org/10.1111/ctr.13982DOI Listing
August 2020

Regional Differences in Human Biliary Tissues and Corresponding In Vitro-Derived Organoids.

Hepatology 2021 01;73(1):247-267

Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.

Background And Aims: Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown.

Approach And Results: Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions.

Conclusions: Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.
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http://dx.doi.org/10.1002/hep.31252DOI Listing
January 2021

Novel Organ Perfusion and Preservation Strategies in Transplantation - Where Are We Going in the United Kingdom?

Transplantation 2020 09;104(9):1813-1824

Department of Transplant Surgery, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, United Kingdom.

This review article focuses on current clinical outcomes with novel perfusion strategies in organ transplantation. Broadly, these approaches can be divided into in situ regional perfusion in the donor and ex situ machine perfusion of individual organs. In both settings, hypothermic and normothermic techniques are in clinical use. Evidence from full text articles, abstracts, and data presented at scientific meetings has been considered. Animal studies have been excluded. The review focuses on kidney, liver, pancreas, heart, and lungs. The level of evidence ranges from quasi-experimental work in human pancreas to multiple meta-analyses of Randomized Controlled Trials for hypothermic machine perfusion of kidneys. The data in this review were presented to experts in organ perfusion and preservation at the National Health Service Blood and Transplant Preservation and Perfusion Future Strategy Summit in London in October 2018. The outcomes of the meeting are discussed in the review after due consideration of the available evidence base.
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http://dx.doi.org/10.1097/TP.0000000000003106DOI Listing
September 2020

Maintaining the permanence principle for death during in situ normothermic regional perfusion for donation after circulatory death organ recovery: A United Kingdom and Canadian proposal.

Am J Transplant 2020 08 27;20(8):2017-2025. Epub 2020 Jan 27.

Department of Surgery, University of Cambridge, Cambridge, UK.

There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post-mortem interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion because, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoracoabdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.
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http://dx.doi.org/10.1111/ajt.15775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540256PMC
August 2020

Donor pretreatment and machine perfusion: current views.

Curr Opin Organ Transplant 2020 02;25(1):59-65

Edinburgh Transplant Centre, Royal Infirmary of Edinburgh.

Purpose Of Review: To summarise recently published studies of donor pretreatment and machine perfusion strategies in kidney transplantation.

Recent Findings: The sparsity of donor pretreatment trials has resulted in the re-analysis of already existing data, and RCTs are urgently needed to reinvigorate this aspect of donor research. Uncontrolled donation after circulatory death kidney transplantation has the highest risk of delayed graft function and graft failure, and recent studies have reported that normothermic regional perfusion improves graft function and survival in this setting. Hypothermic machine perfusion reduces delayed graft function following deceased donor kidney transplantation across donor types but unanswered questions still remain regarding its use. The use of oxygenated hypothermic machine perfusion appears to improve graft function in controlled donation after circulatory death mediated by a reduction in acute rejection. Ex-situ normothermic perfusion is emerging and while technically challenging it may facilitate the delivery of pretreatments.

Summary: RCTs are urgently needed to reinvigorate research into donor pretreatment and to establish the place of specific preservation techniques in deceased donor kidney transplantation.
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http://dx.doi.org/10.1097/MOT.0000000000000725DOI Listing
February 2020

Lessons from a pilot for uncontrolled donation after circulatory death in the ED in the UK.

Emerg Med J 2020 Mar 22;37(3):155-161. Epub 2019 Nov 22.

College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.

Worldwide there is a shortage of available organs for patients requiring transplants. However, some countries such as France, Italy and Spain have had greater success by allowing donations from patients with unexpected and unrecoverable circulatory arrest who arrive in the ED. Significant advances in the surgical approach to organ recovery from donation after circulatory death (DCD) led to the establishment of a pilot programme for uncontrolled DCD in the ED of the Royal Infirmary of Edinburgh. This paper describes the programme and discusses the lessons learnt.
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http://dx.doi.org/10.1136/emermed-2019-208650DOI Listing
March 2020

Recipient Comorbidity and Survival Outcomes After Kidney Transplantation: A UK-wide Prospective Cohort Study.

Transplantation 2020 06;104(6):1246-1255

Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Background: Comorbidity is increasingly common in kidney transplant recipients, yet the implications for transplant outcomes are not fully understood. We analyzed the relationship between recipient comorbidity and survival outcomes in a UK-wide prospective cohort study-Access to Transplantation and Transplant Outcome Measures (ATTOM).

Methods: A total of 2100 adult kidney transplant recipients were recruited from all 23 UK transplant centers between 2011 and 2013. Data on 15 comorbidities were collected at the time of transplantation. Multivariable Cox regression models were used to analyze the relationship between comorbidity and 2-year graft survival, patient survival, and transplant survival (earliest of graft failure or patient death) for deceased-donor kidney transplant (DDKT) recipients (n = 1288) and living-donor kidney transplant (LDKT) recipients (n = 812).

Results: For DDKT recipients, peripheral vascular disease (hazard ratio [HR] 3.04, 95% confidence interval [CI]: 1.37-6.74; P = 0.006) and obesity (HR 2.27, 95% CI: 1.27-4.06; P = 0.006) were independent risk factors for graft loss, while heart failure (HR 3.77, 95% CI: 1.79-7.95; P = 0.0005), cerebrovascular disease (HR 3.45, 95% CI: 1.72-6.92; P = 0.0005), and chronic liver disease (HR 4.36, 95% CI: 1.29-14.71; P = 0.018) were associated with an increased risk of mortality. For LDKT recipients, heart failure (HR 3.83, 95% CI: 1.15-12.81; P = 0.029) and diabetes (HR 2.23, 95% CI: 1.03-4.81; P = 0.042) were associated with poorer transplant survival.

Conclusions: The key comorbidities that predict poorer 2-year survival outcomes after kidney transplantation have been identified in this large prospective cohort study. The findings will facilitate assessment of individual patient risks and evidence-based decision making.
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http://dx.doi.org/10.1097/TP.0000000000002931DOI Listing
June 2020
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