Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal ...livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.
BACKGROUND.In an experimental murine liver clamping model, we aimed to investigate the efficacy of real-time confocal microscopy (RCM) in assessing viability of steatotic livers in comparison to ...standard assessment tools, including histopathological evaluation.
METHODS.C57Bl/6 mice were subjected to a methionine-choline-deficient diet causing nonalcoholic fatty liver disease or to Lieber DeCarli diet causing ethanol-induced liver injury. Untreated animals served as controls. Liver biopsies were analyzed following challenge with 45 min of warm ischemia time and either 4 h of reperfusion or 24 h of cold storage. Organ quality assessment was performed at defined time points by RCM, histological staining, measurement of serum alanine aminotransferase activity, and expression analyses of proinflammatory cytokines. Additionally, survival analysis was performed.
RESULTS.Cold as well as warm ischemia time resulted in a significant decrease in cell viability when compared with naive livers as well as nonischemic-challenged steatotic livers (P < 0.05) as assessed by RCM. Furthermore, RCM revealed the actual cellular damage at early time points, while established methods including H&E-staining and serum transaminase profile failed.
CONCLUSIONS.In a translational attempt, we demonstrate that RCM is a suitable diagnostic tool to obtain information about functional damage of the liver apart from standard approaches.
Summary
Background
The Doctor of Philosophy degree, PhD or DPhil, derives from the Latin Doctor Philosophiae (for DPhil) or Philosophiae Doctor (for PhD) and has been awarded by universities around ...the world.
Methods
Going through a DPhil at Oxford University.
Results
Doing a DPhil abroad exposes you to a new research environment and helps to enhance your personal development.
Conclusions
Studying for a DPhil in a foreign country will satisfy your intellectual curiosity, pep up your curriculum vitae, gain you language skills and enhance your career chances significantly.
Normothermic machine perfusion (NMP) has reshaped organ preservation in recent years. In this preclinical study, prolonged normothermic perfusions of discarded human kidney grafts were performed in ...order to investigate perfusion dynamics and identify potential quality and assessment indicators. Five human discarded kidney grafts were perfused normothermically (37°C) for 48 h using the Kidney Assist device with a red-blood-cell based perfusate with urine recirculation. Perfusion dynamics, perfusate and urine composition as well as injury markers were measured and analyzed. Donor age ranged from 41 to 68 years. All but one kidney were from brain dead donors. Perfusions were performed successfully for 48 h with all discarded kidneys. Median arterial flow ranged from 405 to 841 mL/min. All kidneys excreted urine until the end of perfusion (median 0.43 mL/min at the end of perfusion). While sodium levels were consistently lower in urine compared to perfusate samples, this was only seen for chloride and potassium in kidney KTX 2. Lactate, AST, LDH as well as pro-inflammatory cytokines increased over time, especially in kidneys KTX 3 and 4.
Ex vivo
normothermic perfusion is able to identify patterns of perfusion, biological function, and changes in inflammatory markers in heterogenous discarded kidney grafts.
Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time ...result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.
This letter reports the 20-year results in two men who underwent bilateral hand transplantation. Each of the patients can perform activities of daily living and, despite the effects of ...immunosuppressive therapy, are pleased with the functional outcome.
The prevalence of obesity and obesity-related morbidity in end-stage renal disease patients is rising. Although it is established that obesity does not abrogate the transplant benefit with respect to ...lower long-term mortality and cardiovascular risk, it is associated with increased graft failure, delayed graft function, surgical complications, prolonged hospital stay, and costs.
To examine the safety and efficacy of LSG (laparoscopic sleeve gastrectomy) in renal transplant candidates and evaluate transplant outcomes.
Single-center prospective nonrandomized trial METHODS: We here report on a prospective single-center trial establishing a 2-step approach for obese renal transplant candidates. Patients with end-stage renal disease and a BMI (body mass index) of 35 kg/m
or higher underwent laparoscopic sleeve gastrectomy. After reaching a BMI of<35 kg/m
, patients were waitlisted for kidney transplantation. Age, gender, body mass index (BMI), associated co-morbidities, cause of end-stage renal disease, surgical complications, and outcome after kidney transplantation (graft survival, incidence of delayed graft function, incidence of rejection, serum creatinine) were collected.
LSG was performed in 8 renal transplant candidates with a mean BMI of 38.8 kg/m
each. BMI dropped to below 35 kg/m
within a median of 3 months. Percent excess body mass index loss (%EBMIL) was 62.7% at 1 year after LSG. Within 17 months (mean) after metabolic surgery, 7 patients underwent kidney transplantation. All transplants were successful with a serum creatinine of 1.9±.8 mg/dL at discharge and stable allograft function thereafter. Mean follow-up was 3.2±1.4 years; no patient was lost to follow-up.
LSG is safe and efficacious for treatment of obesity in renal transplant candidates. Rapid and sustained weight loss and subsequent waitlisting for kidney transplantation may reduce overall and in particular posttransplant patient morbidity.
Obesity is increasingly impacting the overall health status and the global costs for health care. The increase in body mass index (BMI) is also observed in kidney allograft recipients and deceased ...organ donors.
In a retrospective single-center study, we analyzed 1132 deceased donor kidney grafts, transplanted at our institution between 2000 and 2009 for recipient and donor BMI and its correlation with delayed graft function (DGF). Recipients/donors were classified according to their BMI (<18.5, 18.5-24.9, 25-29.9, and >30 kg/m(2)). DGF was defined as requirement for one dialysis within the first week after transplantation.
Overall DGF rate was 32.4%, mean recipient BMI was 23.64 ± 3.75 kg/m(2), and mean donor BMI was 24.69 ± 3.44 kg/m(2). DGF rate was 25.2%, 29.8%, 40.9%, and 52.6% in recipients with BMI less than 18.5, 18.5 to 24.9, 25 to 29.9, and more than 30 kg/m, respectively (P<0.0001). Donor BMI less than 18.5, 18.5 to 24.9, 25 to 29.9, more than 30 kg/m(2) resulted in a DGF rate of 22.5%, 31.0%, 37.3%, and 51.2% (P < 0.0001). Multivariate analysis revealed recipient BMI and dialysis duration as independent risk factors for DGF. DGF results in inferior 1- and 5-year graft and patient survival.
Recipient and donor BMI correlate with the incidence of DGF. Awareness thereof should have an impact on peri- and posttransplant measures in renal transplant recipients.
The majority of organs used for liver transplantation come from brain-dead donors (DBD). In order to overcome the organ shortage, increasingly donation after circulatory death (DCD) organs are also ...considered. Since normothermic machine perfusion (NMP) restores metabolic activity and allows for in-depth assessment of organ quality and function prior to transplantation, such organs may benefit from NMP. We herein compare the bioenergetic performance through a comprehensive evaluation of mitochondria by high-resolution respirometry in tissue biopsies and the inflammatory response in DBD and DCD livers during NMP. While livers were indistinguishable by perfusate biomarker assessment and histology, our findings revealed a greater impairment of mitochondrial function in DCD livers after static cold storage compared to DBD livers. During subsequent NMPs, DCD organs recovered and eventually showed a similar performance as DBD livers. Cytokine expression analysis showed no differences in the early phase of NMP, while towards the end of NMP, significantly elevated levels of IL-1β, IL-5 and IL-6 were found in the perfusate of DCD livers. Based on our results, we find it worthwhile to reconsider more DCD organs for transplantation to further extend the donor pool. Therefore, donor organ quality criteria must be developed, which may include an assessment of bioenergetic function and cytokine quantification.
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