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.
Organ transplantation is undergoing profound changes. Contraindications for donation have been revised in order to better meet the organ demand. The use of lower-quality organs and organs with ...greater preoperative damage, including those from donation after cardiac death (DCD), has become an established routine but increases the risk of graft malfunction. This risk is further aggravated by ischemia and reperfusion injury (IRI) in the process of transplantation. These circumstances demand a preservation technology that ameliorates IRI and allows for assessment of viability and function prior to transplantation. Oxygenated hypothermic and normothermic machine perfusion (MP) have emerged as valid novel modalities for advanced organ preservation and conditioning.
prolonged lung preservation has resulted in successful transplantation of high-risk donor lungs. Normothermic MP of hearts and livers has displayed safe (heart) and superior (liver) preservation in randomized controlled trials (RCT). Normothermic kidney preservation for 24 h was recently established. Early clinical outcomes beyond the market entry trials indicate bioenergetics reconditioning, improved preservation of structures subject to IRI, and significant prolongation of the preservation time. The monitoring of perfusion parameters, the biochemical investigation of preservation fluids, and the assessment of tissue viability and bioenergetics function now offer a comprehensive assessment of organ quality and function
. Gene and protein expression profiling, investigation of passenger leukocytes, and advanced imaging may further enhance the understanding of the condition of an organ during MP. In addition, MP offers a platform for organ reconditioning and regeneration and hence catalyzes the clinical realization of tissue engineering. Organ modification may include immunological modification and the generation of chimeric organs. While these ideas are not conceptually new, MP now offers a platform for clinical realization. Defatting of steatotic livers, modulation of inflammation during preservation in lungs, vasodilatation of livers, and hepatitis C elimination have been successfully demonstrated in experimental and clinical trials. Targeted treatment of lesions and surgical treatment or graft modification have been attempted. In this review, we address the current state of MP and advanced organ monitoring and speculate about logical future steps and how this evolution of a novel technology can result in a medial revolution.
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.
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.
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.
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.
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.