RSS 1.0Transplantation
Recent Submissions
-
Design, analysis, and pitfalls of clinical trials using Ex Situ Liver Machine Perfusion: The International Liver Transplantation Society Consensus Guidelines.Background: Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs. Methods: The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine Perfusion" held in Venice, Italy, on January 31, 2020. Results: Twelve recommendations were proposed with the main conclusions that clinical trials investigating the effect of MP in liver transplantation should (1) make the protocol publicly available before the start of the trial, (2) be adequately powered, and (3) carefully consider timing of randomization in function of the primary outcome. Conclusions: There are issues with using accepted primary outcomes of liver transplantation trials in the context of MP trials, and no ideal endpoint could be defined by the working group. The setup of an international registry was considered vital by the working group.
-
Autoimmune cytopenias developing late post alemtuzumab-based allogeneic stem cell transplantation: presentation of short case series from a transplant center.Stem cell transplantation remains the curative option for many patients with hematological malignancies. The long-term effects of these treatments on the patients and their immune systems have been extensively investigated, but there remains a paucity of data regarding autoimmune manifestations post-transplant, although these effects are well recognized.Herein we present the clinical picture and therapeutic approach in three patients (cases 1-3), with varied presentations of autoimmune disease post-transplant. Case 1 exhibited autoimmune hemolytic anemia and other autoimmune manifestations (serositis, thyroiditis), that were probably linked to graft versus relapsed leukemia effect. Cases 2 and 3 had pure red white cell aplasia and pure red cell aplasia, respectively, which were associated with hyperglobulinemia and a clonal T cell expansion.
-
Metabolic characterization of deceased donor kidneys undergoing hypothermic machine perfusion before transplantation using c-enriched glucose.Background: The provision of a metabolic substrate is one mechanism by which hypothermic machine perfusion (HMP) of kidneys provides clinical benefit. This study aimed to describe de novo metabolism in ex vivo human kidneys undergoing HMP before transplantation using 13C-labeled glucose as a metabolic tracer. Methods: Cadaveric human kidneys were perfused with modified clinical-grade perfusion fluid (kidney perfusion solution [KPS-1], Organ Recovery Systems), in which glucose was uniformly enriched with the stable isotope 13C ([U-13C] glucose). The sampled perfusion fluid was analyzed using a blood gas analyzer, and metabolic profiling was performed using 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. Functional outcome measures included serum creatinine levels and the development of delayed graft function. Results: Fourteen kidneys were perfused with the modified KPS-1 and successfully transplanted. The mean duration of HMP was 8.7 h. There was a sustained increase in the conversion of glucose into de novo glycolytic end products, such as lactate, in donor kidneys during HMP. There was no significant association between functional outcomes and metabolism during the HMP. De novo anaerobic metabolism was indicated by continuing lactate production, as indicated by increasing concentrations of universally 13C-labeled lactate ([U-13C] lactate) in perfusion fluid from all kidneys. This was more evident in donation after circulatory death donor kidneys. Conclusions: Our study is the first to use [U-13C] glucose to describe the metabolism during HMP. The consequences of an initial warm ischemic insult on circulatory death in donor kidneys continue during the preservation period.
-
A reproducible extended ex-vivo normothermic machine liver perfusion protocol utilising improved nutrition and targeted vascular flows.Background: Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. Methods: Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. Results: Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120-184 h), with preserved viability throughout. Conclusions: Livers can be reproducibly perfused in excess of 120 (range 121-184) hours with evidence of preserved hepatocyte and cholangiocyte function.
-
Brief O2 uploading during continuous hypothermic machine perfusion is simple yet effective oxygenation method to improve initial kidney function in a porcine autotransplant modelWith oxygenation proposed as a resuscitative measure during hypothermic models of preservation, the aim of this study was to evaluate the optimal start time of oxygenation during continuous hypothermic machine perfusion (HMP). In this porcine ischemia-reperfusion autotransplant model, the left kidney of a ±40 kg pig was exposed to 30 minutes of warm ischemia prior to 22 hours of HMP and autotransplantation. Kidneys were randomized to receive 2 hours of oxygenation during HMP either at the start (n = 6), or end of the perfusion (n = 5) and outcomes were compared to standard, nonoxygenated HMP (n = 6) and continuous oxygenated HMP (n = 8). The brief initial and continuous oxygenated HMP groups were associated with superior graft recovery compared to either standard, nonoxygenated HMP or kidneys oxygenated at the end of HMP. This correlated with significant metabolic differences in perfusate (eg, lactate, succinate, flavin mononucleotide) and tissues (eg, succinate, adenosine triphosphate, hypoxia-inducible factor-1α, nuclear factor erythroid 2-related factor 2) suggesting superior mitochondrial preservation with initial oxygenation. Brief initial O2 uploading during HMP at procurement site might be an easy and effective preservation strategy to maintain aerobic metabolism, protect mitochondria, and achieve an improved early renal graft function compared with standard HMP or oxygen supply shortly at the end of HMP preservation.
-
Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damageBackground: Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population. Methods: Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed. Results: Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities. Conclusions: In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.
-
Biomarkers of liver injury during transplantation in an era of machine perfusionLiver ischaemia-reperfusion injury (IRI) is an intrinsic part of the transplantation process and damages the parenchymal cells of the liver including hepatocytes, endothelial cells and cholangiocytes. Many biomarkers of IRI have been described over the past two decades that have attempted to quantify the extent of IRI involving different hepatic cellular compartments, with the aim to allow clinicians to predict the suitability of donor livers for transplantation. The advent of machine perfusion has added an additional layer of complexity to this field and has forced researchers to re-evaluate the utility of IRI biomarkers in different machine preservation techniques. In this review, we summarise the current understanding of liver IRI biomarkers and discuss them in the context of machine perfusion.
-
Basiliximab with delayed tacrolimus improves short-term renal outcomes post-liver transplantation - a real-world experienceBackground: Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a "renal-sparing" strategy. The aim of this study was to assess this approach in a real-world setting in an LT center. Methods: A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset. Results: The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy. Conclusion: This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.
-
Role of hypertension in kidney transplant recipientsCardiovascular events are one of the leading causes of mortality in kidney transplant recipients. Hypertension is the most common comorbidity accompanying chronic kidney disease, with prevalence remaining as high as 90% even after kidney transplantation. It is often poorly controlled. Abnormal blood pressure profiles, such as masked or white-coat hypertension, are also extremely common in these patients. The pathophysiology of blood pressure elevation in kidney transplant recipients is complex and includes transplantation-specific risk factors, which are added to the traditional or chronic kidney disease-related factors. Despite these observations, hypertension management has been an under-researched area in kidney transplantation. Thus, relevant evidence derives either from studies in the general population or from small trials in kidney transplant recipients. Based on the relevant guidelines in the general population, lifestyle modifications should probably be applied as the first step of hypertension management in kidney transplant recipients. The optimal pharmacological management of hypertension in kidney transplant recipients is also not clear. Dihydropyridine calcium channel blockers are commonly used as first line agents because of their lack of adverse effects on the kidney, while other antihypertensive drug classes are under-utilised due to fear of the possible haemodynamic consequences on renal function. This review summarizes the existing data on the pathophysiology, diagnosis, prognostic significance and management of hypertension in kidney transplantation.
-
Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: a systematic reviewBackground: Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade. Previous surgeries, chemo-/radiotherapy, and ventriculo-peritoneal shunt placement can lead to a disruption of the blood-brain barrier, concurring to an increase in the transmission risk. Aim: To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas. Methods: We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligodendrogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade, the elapsed time from the diagnosis to the onset of metastases, sites and number of metastases, prior surgeries, prior radiotherapy and/or chemotherapy, ventriculo-atrial or ventriculo-peritoneal shunt placement, and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion. Statistical analysis was performed using R software. Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed using χ 2 and Fischer exact test. The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and: (1) Localization of metastases; (2) The occurrence of intracranial recurrences; and (3) The occurrence of multiple metastases. Results: Data on a total of 157 patients were retrieved. The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas. Respectively, 19% and 39% of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy. The most frequent metastatic sites were bone, bone marrow, and lymph nodes. The lungs and the liver were the most commonly involved visceral sites. There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy. Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra- central nervous system spread. Conclusion: A long follow-up time does not exclude the presence of extraneural metastases. Therefore, targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.
-
Risk aversion, organ utilization and changing behaviorImproving organ acceptance and utilization rates is critical to ensure we maximize usage of donated organs as a scarce resource. Many factors underlie unnecessary discard of viable organs. Declined transplantation opportunities for candidates is associated with increased wait-list mortality. Technological advancements in organ preservation may help bridge the gap between donation and utilization, but an overlooked obstacle is the practice of risk aversion by transplant professionals when decision-making under risk. Lessons from behavioral economics, where experimental work has outlined the impact of loss or risk aversion on decision-making, have not been translated to transplantation. Many external factors can influence decision-making when accepting or utilizing organs, which are potentially amendable if external conditions are improved. However, attitudes and perceptions to risk for transplant professionals can pervade decision-making and influence behaviour. If we wish to change this behavior, then the underlying nature of decision-making under risk when accepting or utilizing organs must be studied to facilitate the design of targeted behavior change interventions to convert risk aversion to risk tolerance. To ensure optimal use of donated organs, we need more research into decision-making under risk.
-
Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: a preclinical studyIntroduction: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post-operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by-products. We evaluated the impact of combined limb-kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods: Ten paired pig forelimbs were used for this study, grouped as either limb-only (LO, n = 5) perfusion, or limb-kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell-free DNA in the perfusate were recorded. Results: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro-inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. Conclusion: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis.
-
Recommendations for donor and recipient selection and risk prediction: working group report from the ILTS consensus conference in DCD liver transplantationAlthough the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors and prediction models in DCD-LT.
-
Adult liver transplantation: UK clinical guideline - part 2: surgery and post-operation.Survival rates for patients following liver transplantation exceed 90% at 12 months and approach 70% at 10 years. Part 1 of this guideline has dealt with all aspects of liver transplantation up to the point of placement on the waiting list. Part 2 explains the organ allocation process, organ donation and organ type and how this influences the choice of recipient. After organ allocation, the transplant surgery and the critical early post-operative period are, of necessity, confined to the liver transplant unit. However, patients will eventually return to their referring secondary care centre with a requirement for ongoing supervision. Part 2 of this guideline concerns three key areas of post liver transplantation care for the non-transplant specialist: (1) overseeing immunosuppression, including interactions and adherence; (2) the transplanted organ and how to initiate investigation of organ dysfunction; and (3) careful oversight of other organ systems, including optimising renal function, cardiovascular health and the psychosocial impact. The crucial significance of this holistic approach becomes more obvious as time passes from the transplant, when patients should expect the responsibility for managing the increasing number of non-liver consequences to lie with primary and secondary care.
-
Adult liver transplantation: a UK clinical guideline - part 1: pre-operation.Liver transplantation is a highly successful treatment for all types of liver failure, some non-liver failure indications and liver cancer. Most referrals come from secondary care. This first part of a two-part guideline outlines who to refer, and how that referral should be made, including patient details and additional issues such as those relevant to alcohol and drug misuse. The process of liver transplant assessment involves the confirmation of the diagnosis and non-reversibility, an evaluation of comorbidities and exclusion of contraindications. Finally, those making it onto the waiting list require monitoring and optimising. Underpinning this process is a need for good communication between patient, their carers, secondary care and the liver transplant service, synchronised by the transplant coordinator. Managing expectation and balancing the uncertainty of organ availability against the inevitable progression of underlying liver disease requires sensitivity and honesty from all healthcare providers and the assessment of palliative care needs is an integral part of this process.
-
Transarterial chemoembolization of hepatocellular carcinoma before liver transplantation and risk of post-transplant vascular complications: a multicentre observational cohort and propensity score-matched analysis.ackground: Transarterial chemoembolization (TACE) in patients with hepatocellular cancer (HCC) on the waiting list for liver transplantation may be associated with an increased risk for hepatic artery complications. The present study aims to assess the risk for, primarily, intraoperative technical hepatic artery problems and, secondarily, postoperative hepatic artery complications encountered in patients who received TACE before liver transplantation. Methods: Available data from HCC liver transplantation recipients across six European centres from January 2007 to December 2018 were analysed in a 1 : 1 propensity score-matched cohort (TACE versus no TACE). Incidences of intraoperative hepatic artery interventions and postoperative hepatic artery complications were compared. Results: Data on postoperative hepatic artery complications were available in all 876 patients (425 patients with TACE and 451 patients without TACE). Fifty-eight (6.6 per cent) patients experienced postoperative hepatic artery complications. In total 253 patients who had undergone TACE could be matched to controls. In the matched cohort TACE was not associated with a composite of hepatic artery complications (OR 1.73, 95 per cent c.i. 0.82 to 3.63, P = 0.149). Data on intraoperative hepatic artery interventions were available in 825 patients (422 patients with TACE and 403 without TACE). Intraoperative hepatic artery interventions were necessary in 69 (8.4 per cent) patients. In the matched cohort TACE was not associated with an increased incidence of intraoperative hepatic artery interventions (OR 0.94, 95 per cent c.i. 0.49 to 1.83, P = 0.870). Conclusion: In otherwise matched patients with HCC intended for liver transplantation, TACE treatment before transplantation was not associated with higher risk of technical vascular issues or hepatic artery complications.
-
Impact of donor obesity on graft and recipient survival outcomes after liver transplantation: A systematic review and meta-analysis.Background: The effect of donor body mass index (BMI) on liver transplantation (LT) outcomes remains unclear. Methods: A systematic search of the MEDLINE, CENTRAL, Web of Science, and bibliographic reference lists was conducted. All comparative studies evaluating the outcomes of LT in obese (BMI > 30 kg/m2) and nonobese donors (BMI < 30 kg/m2) were included, and their risk of bias was assessed using the ROBINS-I assessment tool. Patient and graft survival, acute rejection, and graft failure requiring retransplantation were evaluated as outcome parameters. A random-effects model was used for outcome synthesis. Results: We included 6 comparative studies reporting a total of 5071 liver transplant recipients from 708 obese and 4363 nonobese donors. There was no significant difference in 1-y (89.1% versus 84.0%, odds ratio [OR] 1.58; 95% CI 0.63-3.94, P = 0.33), 5-y (74.2%% versus 73.5%, OR 1.12; 95% CI 0.45-2.80, P = 0.81) graft survival, and 1-y (87.1% versus 90.3%, OR 0.71; 95% CI 0.43-1.15, P = 0.17) and 5-y (64.5% versus 71.6%, OR 0.71; 95% CI 0.49-1.05, P = 0.08) patient survival between 2 groups. Furthermore, recipients from obese and nonobese donors had a comparable risk of graft failure requiring retransplantation (OR 0.92; 95% CI 0.33-2.60, P = 0.88) or acute graft rejection (OR 0.70; 95% CI 0.45-1.11, P = 0.13). Conclusions: A meta-analysis of the best available evidence (level 2a) demonstrates that donor obesity does not seem to have a negative impact on graft or patient outcomes. The available studies might be subject to selection bias as the grafts from obese donors are usually subject to biopsy to exclude steatosis and the recipients usually belong to the low-risk group. Future research is needed to evaluate the impact of donors subgrouped by various higher BMI on graft and patient-related outcomes as well as to capture data of the discarded grafts from obese donors; hence, selection criteria for the grafts that could be used for transplantation from obese donors is identified.
-
Primary nonfunction of the liver allograftSevere allograft dysfunction, as opposed to the expected immediate function, following liver transplantation is a major complication, and the clinical manifestations of such that lead to either immediate retransplant or death are the catastrophic end of the spectrum. Primary nonfunction (PNF) has declined in incidence over the years, yet the impact on patient and healthcare teams, and the burden on the organ pool in case of the need for retransplant should not be underestimated. There is no universal test to define the diagnosis of PNF, and current criteria are based on various biochemical parameters surrogate of liver function; moreover, a disparity remains within different healthcare systems on selecting candidates eligible for urgent retransplantation. The impact on PNF from traditionally accepted risk factors has changed somewhat, mainly driven by the rising demand for organs, combined with the concerted approach by clinicians on the in-depth understanding of PNF, optimal graft recipient selection, mitigation of the clinical environment in which a marginal graft is reperfused, and postoperative management. Regardless of the mode, available data suggest machine perfusion strategies help reduce the incidence further but do not completely avert the risk of PNF. The mainstay of management relies on identifying severe allograft dysfunction at a very early stage and aggressive management, while excluding other identifiable causes that mimic severe organ dysfunction. This approach may help salvage some grafts by preventing total graft failure and also maintaining a patient in an optimal physiological state if retransplantation is considered the ultimate patient salvage strategy.