Xenotransplantation: past, present, and future Purpose of review
To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future.
Starting from early 2000, with the introduction of galactose-α1,3-galactose (Gal)-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to non-Gal antigens continue to be the hurdle to overcome. The production of genetically engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently clustered regularly interspaced short palindromic repeats (CRISPR) technology made the production of genetically engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached more than 900, more than 400, and more than 600 days, respectively. The availability of multiple-gene pigs (five or six genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus.
Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.
Tolerance in xenotransplantation Purpose of review
This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation.
Using advanced gene editing technologies, xenotransplantation from multitransgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and more than 2 years in a heterotopic nonlife-supporting cardiac xenograft model. Continuous administration of multiple immunosuppressive drugs has been required and attempts to taper immunosuppression have been unsuccessful. It appears likely that low levels of T cell dependent antibodies and activation of innate responses are responsible for xenograft loss. Mixed chimerism and thymic transplantation approaches have achieved xenogeneic tolerance in pig-to-mouse models and both have recently been extended to pig-to-baboon models. Encouraging results have been reported, including persistence of macrochimerism, prolonged pig skin graft survival, donor-specific unresponsiveness in vitro and detection of recent T cell emigrants in vivo.
Although tolerance induction in vivo has not yet been achieved in pig-to-baboon models, recent results are encouraging that this goal will be attainable through genetic engineering of porcine donors.
Xenoislets: porcine pancreatic islets for the treatment of type I diabetes Purpose of review
Porcine islets are being extensively investigated as alternative sources of insulin-secreting cells for transplantation in insulin-dependent diabetic patients. The present review focuses on recent advances in porcine islet transplantation with particular emphasis on new transgenic pig models, islet encapsulation, and biosafety considerations.
Genetic modifications aimed to reduce islet cell immunogenicity, to prolong their survival, and to improve their secretory function have been reported. Micro- and macroencapsulation of porcine islets should allow their use in the clinic with no or minimal immunosuppression. The risk of porcine endogenous retrovirus transmission is being re-evaluated since no evidence for infection was found in several clinical and preclinical studies.
Pig islet xenotransplantation is still a serious contestant in the race for novel treatments for type I diabetes. Adequate pathogen screening, animal selection, and the establishment of microbiological, genetic, and potency release quality controls should increase safety and efficacy of future porcine islets transplantation clinical trials.
Liver xenotransplantation Purpose of review
There continues to be an inadequate organ supply and lack of effective temporary support, for patients with liver failure. The purpose of this review is to discuss recent progress in the field of orthotopic pig-to-nonhuman primate (NHP) liver xenotransplantation (LXT).
From 1968 to 2012, survival in pig-to-NHP LXT was limited to 9 days, initially due to hyperacute rejection which has been ameliorated through use of genetically engineered donor organs, but ultimately because of profound thrombocytopenia, thrombotic microangiopathy, and bleeding. Most recently, however, demise secondary to lethal coagulopathy has been avoided with LXT of α(1,3)-galactosyltransferase knockouts and cytomegalovirus-negative porcine xenografts into baboons receiving exogenous administration of coagulation factors and co-stimulation blockade, establishing that a porcine liver is capable of supporting NHP life for nearly a month.
Continued consistent achievement of pig-to-NHP LXT survival beyond 2 weeks justifies consideration of a clinical application as a bridge to allotransplantation for patients with acute hepatic failure. Further genetic modifications to the donor, as well as additional studies, are required in order to apply LXT as destination therapy.
Lung xenotransplantation Purpose of review
This review describes the most recent progress in xeno lung transplantation (XLTx) to date. It describes the potential mechanisms of early xeno lung graft loss, as well as the latest therapeutic strategies to overcome them.
Using ex-vivo perfusion models of porcine lungs with human blood, the use of genetically modified pig lungs along with novel pharmaceutical approaches has recently been studied. Strategies that have demonstrated improved lung survival include the knockout of known xenoantigens (GalTKO and N-glycolylneuraminic acid-KO), genes that regulate complement activation (hCD46 and hCD55), as well as the inflammation/coagulation cascade (human leukocyte antigen-E, human thrombomodulin, human endothelial protein C receptor, hCD47, hCD39, hCD73 and heme oxygenase-1). Furthermore, pharmacologic interventions including the depletion of pulmonary intravascular macrophages or von Willebrand factor, inhibition of thromboxane synthase and blockade of histamine receptors have also demonstrated protective effects on xeno lung grafts. Using in-vivo pig to nonhuman primate lung transplant models, these approaches have been shown to extend pulmonary xenograft survival to 5 days.
The development of new multitransgenic GalTKO pigs has demonstrated prolongation of porcine xenograft survival; however, advancement in XLTx has remained frustratingly limited. Further intensive and innovative strategies including genetic manipulation of donors, as well as inflammation/coagulation dysregulation, are required to make XLTx a clinical possibility.
Heart xenotransplantation Purpose of review
Cardiac xenotransplantation has entered an exciting era, marked by numerous considerable advances in the field, and continues to be of great interest because of its potential ability in ameliorating the current constraints of limited allograft availability. This review aims to examine recent progress in this rapidly changing discipline.
Although several hurdles remain, the use of rapidly evolving transgenic technology, in combination with novel immunosuppression regimens, has the potential to address current allogenic donor pool constraints and mechanical circulatory system device limitations. Furthermore, innovative uses of biomarker tools, such as miRNA, serve as a method for improved monitoring of xenograft status. These tools may allow for more targeted immunosuppressive strategies as well as earlier interventions to mitigate xenograft rejection. Finally, coinciding with these remarkable advances, preliminary consideration of the clinical application for cardiac xenotransplantation has begun, particularly regarding specific patient criteria for these initial clinical trials.
The studies in this review highlight efforts in multiple disciplines to optimize perioperative and postxenotransplant outcomes. In examining these individual topics, this article reflects the exciting and ongoing progress in the field of cardiac xenotransplantation.
Recent advances in the field of warm ex-vivo liver perfusion Purpose of review
Organ shortage remains a major obstacle for liver transplantation, resulting in an increased mortality on the liver transplant waiting list. The usage of extended criteria donors (ECD) is a strategy to increase the number of available donor organs, however, with the risk of a higher rate of posttransplant graft dysfunction. Novel preservation strategies, such as warm ex-vivo liver perfusion, could improve the outcome of liver transplantation with ECD grafts. The present review summarizes the advances in the field of warm ex-vivo liver perfusion over the last 12 months.
The feasibility and safety of warm ex-vivo liver perfusion has been determined in several single center clinical trials. Furthermore, a large phase III multicenter trial demonstrated decreased liver injury and improved graft function in warm perfused versus cold stored grafts. New strategies for graft assessment and modification during machine perfusion have been evaluated with promising results.
Warm ex-vivo liver perfusion has been successfully translated into the clinical setting. Recent research is focusing on graft assessment and graft modification during machine perfusion.
Hypothermic liver perfusion Purpose of review
The review describes recent developments in hypothermic machine liver perfusion with a special focus on underlying protective mechanisms, and the role of this perfusion technique in high-risk donor–recipient combinations.
To maximize the number of transplantable donor livers, several centres are exploring new machine preservation techniques. In this context, hypothermic machine perfusion has been recently introduced into the clinical setting of human liver transplantation, and the effect of endischemic cold liver perfusion on posttransplant complications is currently under investigation in two multicentre, randomized controlled trials. In addition, current case series demonstrated promising results regarding the protection from intrahepatic biliary complications, particularly when livers from extended criteria donors including donation after circulatory death grafts were used. Hypothermic machine perfusion may, therefore, help to push the boundaries of acceptance criteria for high-risk donor livers.
In this review, we, first, describe the concept of hypothermic machine liver perfusion and present results from current clinical studies. Next, we provide details of our perfusion approach step-by-step and highlight novel pathways of reperfusion injury and protection. Third, we discuss the impact of this perfusion approach in different clinical scenarios. Finally, we report on recent clinical implementations and future aspects.
Normothermic machine perfusion of the kidney Purpose of review
Normothermic machine perfusion (NMP) is a preservation method that is generating increasing interest. The aim of this review is to summarise the current status of NMP in regards of kidney viability assessment, reducing organ damage and improving transplant logistics.
The results of recent large animal experiments and clinical trials show that continuous prolonged normothermic ex-vivo kidney perfusion appears better than a brief period of NMP after static cold storage in terms of renal injury and function. A recently developed clinical scoring system appears to correlate with renal and tubular function. A prospective clinical phase II trial to investigate the initial graft function after 1 h of NMP or static cold storage in kidneys from donors after circulatory death has been initiated in the United Kingdom.
Progress has been made in normothermic kidney perfusion, mainly in experimental settings. These results need to be translated into clinical trials to evaluate long-term NMP and its impact in human organs. Future investigations of optimal perfusion parameters are needed.
Alcoholic hepatitis: appropriate indication for liver transplantation? Purpose of review
The majority of liver transplantation centers have required patients with alcohol-induced liver disease to demonstrate a period of abstinence (generally 6 months’ duration) to qualify for transplant listing. This requirement has excluded patients with alcoholic hepatitis from transplant consideration. Since 2011, several studies have examined the outcomes of patients undergoing liver transplantation with brief abstinence as a lifesaving intervention for alcoholic hepatitis. This review includes each of the recent studies and discusses their implications for general transplant practice.
A Medical Literature Analysis and Retrieval System search revealed five published studies – three prospective and two retrospective – pertaining to liver transplantation for alcoholic hepatitis. Among patients with medication-nonresponsive alcoholic hepatitis, those who underwent transplantation had superior survival. Liver recipients with alcoholic hepatitis had comparable survival to those with 6 or more months of abstinence. Their relapse rates were not statistically different in the short term over those transplanted with longer abstinence, although some patients in each prospective cohort relapsed to drinking despite narrow inclusion criteria and extensive pretransplant staff reviews and posttransplant surveillance.
Liver transplantation is a reasonable treatment consideration for highly selective cases of alcoholic hepatitis. Further research is needed to refine inclusion criteria, address posttransplant relapse prevention interventions, and monitor long-term outcomes.
Altruistic nondirected kidney donation: attitudes, characteristics and ethical implications Purpose of review
Altruistic nondirected kidney donation involves a person donating one of their kidneys to an unknown recipient. The donor's mental health and motives are frequently questioned. We want to highlight this topic and also encourage discussions about ethical implications.
The main topics are the mental health of altruistic nondirected kidney donors and the general attitude towards the practice of this form of donation as well as the willingness of the public to donate this way. Soliciting organ donation via social networks or financial support is debated extensively in the media.
There is a lack of studies on altruistic nondirected kidney donation. Most studies focus on related donors. Studies with larger samples should be performed on altruistic nondirected kidney donors to learn more about their motives and assess their mental health.
Elderly recipients of liver transplantation: impact of age and psychosocial variables on outcome Purpose of review
With expanding experience and success of liver transplantation, increasing numbers of elderly candidates await and undergo liver transplantation. There is accumulating evidence that graft survival and mortality does not appear to differ significantly between the young and carefully selected elderly liver transplantation recipients. Although existing evidence suggests that psychosocial factors impact outcomes after liver transplantation in general, no such information is available specifically for elderly (age ≥65 years) liver transplantation recipients. We conducted a broad medical literature review of outcome studies of elderly liver transplantation recipients. In this review article, we summarize the findings and comment on psychosocial variables included in these studies.
Ten outcome studies have reported on the impact of age on the liver transplantation outcomes. There is increasing evidence of favorable outcomes in elderly liver transplantation recipients. Few of these studies include measures of quality of life, functional improvement and other psychosocial variables.
Very limited information is available about the impact of psychosocial factors on outcomes in elderly liver transplantation recipients. This dearth of information represents a critical gap in our knowledge and has implications for optimal candidate selection and outcomes after liver transplantation.
The ethical challenges of uterus transplantation Purpose of review
As the techniques of uterus transplantation have evolved, culminating in a birth in 2014, the ethical debate has been enriched by several considerations. Uterus transplantation raises issues because of its unique features of being temporary, nonlifesaving, experimental, and expensive, with established alternatives.
Uterus transplantation entails risks for the recipient related to multiple surgeries and immunosuppression, yet studies have shown that women see infertility as a distressing element in their lives, justifying the risks. The alternative of surrogacy has its own ethical issues, and adoption does not provide for genetic progeny. Although patient decisions are susceptible to inconsistent reasoning, misconception of risks or wishful thinking, a carefully drafted and clearly explained informed consent can represent a valid ethical response in balancing risks and benefits. There is no evidence of increased risks for children born from uterus transplant. For living donors, the risks of hysterectomy are known and can be explained to facilitate proper informed consent. Allocation of deceased donor organs needs to be determined, as guidelines for other organs cannot readily be applied. Cost is an issue, as the procedure is expensive and not covered by insurance.
In this rapidly advancing field, a strong ethical foundation is needed to guide regulations and legislation.
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