Antibody-mediated rejection: what is the clinical relevance? Purpose of review: The review outlines the diagnosis, clinical implications, and treatment strategies for acute and chronic antibody-mediated rejection (AMR) after orthotopic liver transplantation (OLT).
Recent findings: A combination of clinical work-up, histopathology, C4d staining, and donor-specific antibody (DSA) should be used to diagnose AMR. The differential diagnosis for idiopathic fibrosis now includes chronic AMR. Characterization of pathogenic DSA continues to progress. De-novo and persistent DSA, particularly of the IgG3 subtype, are associated with inferior long-term outcomes.
The liver allograft may confer long-term immunologic benefits to the kidney allograft after simultaneous liver-kidney transplant.
The more widespread use of rituximab has improved outcomes in ABO-incompatible OLT.
Although larger long-term studies of treatment options are needed, compliance with tacrolimus-based immunosuppression and transfusion minimization are agreed upon preventive strategies.
Summary: AMR has evolved into an established pathology in OLT recipients. Acute AMR may lead to early graft loss whereas chronic AMR results in progressive fibrosis if unrecognized. DSAs, likely in the setting of predisposing environmental factors, appear to play a role in T cell–mediated rejection and long-term graft outcomes.
Liver perfusion devices: how close are we to widespread application? Purpose of review: Ex-situ liver machine perfusion has been the focus of increasing interest over the past decade as a means to improve the quality of livers for transplantation and the applicability of liver transplantation in general. The present review aims to evaluate the experimental basis for liver machine perfusion and the significance of recent reports on its clinical application.
Recent findings: Although liver machine perfusion has been studied experimentally over a range of temperatures, clinical liver transplant work that has been performed to date has been done using either hypothermic machine perfusion (0–12 °C), HMP or normothermic machine perfusion (35–38 °C, NMP). Both HMP and NMP have been studied clinically in the context of phase I trials demonstrating the feasibility of their application. It has also been shown through a small number of cases that NMP may serve as a useful means to evaluate initially discarded livers to determine viability for subsequent transplantation.
Summary: Although initial clinical results are promising, higher level evidence is still needed to justify more widespread application of machine perfusion in human liver transplantation.
Liver redistricting: what are the upcoming changes in liver allocation in the United States? Purpose of review: Geographic disparity in liver transplantation is substantial in the United States, and primarily a byproduct of artificially created zones of organ distribution. In 2016, the United Network for Organ Sharing (UNOS) put forward a formal redistricting proposal with the goal of reducing this variability by regrouping the country's 58 donation service areas into eight new districts. This review provides a summary of the redistricting proposal's methodologies, expected results, criticisms and next steps.
Recent findings: Previous authors have extensively evaluated the limitations of the current organ allocation and distribution system and how inequities in access to liver transplantation occur. However, few have suggested or simulated new ways to solve or improve this process. The 2016 UNOS redistricting proposal constitutes the first formal evaluation of a novel distribution model. This proposal and its shortcomings have led to multiple discussions throughout the transplant community and encouraged further research in this field.
Summary: This review provides an updated perspective on the key organ distribution issues facing the US transplant community at large, and how UNOS and other experts suggest the problem of geographic disparity in liver transplantation should be solved.
Once-daily tacrolimus in liver transplantation: a ‘me-too drug’, or a therapeutic advantage Purpose of review: To provide latest information on differences between standard tacrolimus (TAC BID) and slow-released formulation of tacrolimus (Advagraf) in liver transplantation (LTx), and to discuss the latter's therapeutic value as a distinct entity.
Recent findings: Two articles on de-novo studies, several on conversion and one on survival analysis from the European Liver Transplant Registry published recently showed that low-dose Advagraf immediately after transplantation provided same protection to the kidney as standard dose delayed until day 5, and was associated with lower rejection rate; to maintain the same trough level after late conversion to Advagraf, an approximately 1.25-fold higher dose was needed on average; if studied by questionnaire, conversion improved medication adherence; and registry data provided evidence of long-term survival benefit of Advagraf over TAC BID (7 and 8% graft and patient survival rates over a 3-year period; P < 0.002 and P < 0.003, respectively).
Summary: Pharmacokinetic differences between TAC BID and Advagraf translate into less interpatient and intrapatient variability and improve adherence. If survival benefit of Advagraf administration de novo after LTx as demonstrated by the European Liver Transplant Registry analysis is confirmed in an independent cohort, Advagraf will leave the area of the ‘me-too’ drugs to become the immunosuppressant of choice.
Liver transplantation around the world Purpose of review: In the past few years, there have been important changes in the development of liver transplantation around the world. In particular, several emerging countries have rapidly developed transplant programs. There have also been important changes in liver allocation, utilization of donors by cardiac death, and living donors. A review of the practices in different countries around the world will help provide the reader with a better appreciation of their own program as well as the recognition of potential areas of improvement based on the experience of their colleagues.
Recent findings: A recent series of articles has been published in the journal Liver Transplantation summarizing the practice of liver transplantation from representative countries around the world.
Summary: The volume of liver transplant varies widely by country and there has been an important growth in volume in emerging countries. Most liver transplant candidates are prioritized for surgery by the Model for Endstage Liver Disease score and with the exception of Germany and the USA most patients are transplanted at Model for Endstage Liver Disease score from 18 to 20. Hepatitis C is the most common indication for liver transplant with the notable exception of several European countries. Innovative strategies to incentivize donation have been developed in several countries.
Liver transplantation for hepatocellular carcinoma: current update on treatment and allocation Purpose of review: This review discusses the current imaging modalities and criteria used to diagnose, and the role of liver transplantation as well as nonsurgical hepatic-directed therapies to treat hepatocellular carcinoma in the setting of chronic liver disease.
Recent findings: There has been continual evolution of guidelines, policies, and algorithms for the imaging diagnosis of hepatocellular carcinoma, particularly the Liver Imaging Reporting and Data System. The use of liver-directed therapy as a bridge to transplant is now common practice. Recently, patients have waited 6 months from listing before being granted a Model for End-Stage Liver Disease exception score of 28, with an increase every 3 months to a maximum score of 34. This policy change was developed to reduce disparities in outcomes for patients undergoing liver transplantation.
Summary: The use of liver transplantation to treat hepatocellular carcinoma within the Milan criteria has good outcomes with a 5-year disease-free survival rate comparable to patients transplanted without malignancy. The development of guidelines both for the radiologic diagnosis and staging of the primary tumor and guidelines for assessing response to treatment allows for a more unified approach to the management of patients. With the partnership of oncologists, hepatologists, radiologists, pathologists, and surgeons, the outcomes of liver transplantation as treatment for hepatocellular continue to improve.
Techniques for abdominal wall reconstruction in intestinal transplantation Purpose of review: One of the most important challenges in the intestinal (ITx) and multivisceral transplant (MVTx) is to achieve a successful abdominal wall closure.
Recent findings: A tension-free primary closure should be our aim. In most of the cases, we need to perform a component separation technique, alone or combined, to the use of a synthetic mesh. If those options are not feasible, the abdominal wall composite vascularized allograft transplant (AW-CVA) utilizing direct orthotopic vascularization can be considered. The nonvascularized abdominal rectus fascia has also become an alternative method used worldwide, proving to be simple and well tolerated procedure. Furthermore, the use of the AW has been recently proposed as a new tool for a sentinel monitoring of the intestinal or pancreas allograft.
Summary: There are different validated options for abdominal wall closure following intestinal transplantation. The long-term benefits of transplanting the abdominal wall, full or partial thickness and vascularized or nonvascularised, were shown. New developments might help to expand their applications in different areas such as reconstructive surgery and immunology.
Intravenous lipid emulsions in pediatric patients with intestinal failure The incidence of cholestatic liver disease (CLD) in pediatric patients suffering intestinal failure (IF) is not well established. Due to persistent portal inflammation, about 20% of these patients will progress to end-stage intestinal failure associated liver disease (IFALD) leading to liver transplant or death.
Purpose of review: Premature babies as well as infants with short bowel syndrome (SBS) and repeated sepsis (catheter or small intestinal bacterial overgrowth related) are at risk of developing CLD. Clinical data in SBS infants focused on intravenous lipid emulsion (ILE) as an important factor of CLD.
Recent findings: Compared to the last generation of composite ILE containing fish oil (FO), soybean oil (SO) based ILE, have marked differences in term of oil source, omega-3 fatty acids (FAs) composition, vitamin E (α-tocopherols) and plant sterols contents, that may explain CLD and CLD reversal. Randomized controlled trials and meta-analysis allow the following recommendations.
Summary: In pediatric patients with developing or established CLD or IFALD, potential causes should be explored and pure SO ILE should be avoided. A reduction of the ILE dosage and/or the use of the new composite FO based ILE, may be recommended along with the treatment and management of other risk factors. The 10% pure FO ILE should not be used as a sole provision of IV lipids in paediatric patients on total PN but can only serve as a short-term rescue treatment.
The impact of antibodies and virtual crossmatching on intestinal transplant outcomes Purpose of review: Sensitization to human leukocyte antigens (HLAs) limits access to potential donors and contributes to inferior graft survival after transplantation. In this article, we will review the effects of HLA-specific antibodies on intestinal transplant outcomes, and discuss considerations in the monitoring and treatment of anti-HLA antibodies.
Recent findings: Only a handful of studies has investigated the effects of donor-specific anti-HLA antibodies (DSAs) on intestinal allograft outcomes. Most have reported associations between DSA presence and rejection-related graft failure. The evolution of antibody detection methods and improvements in crossmatch testing have allowed for a systematic approach to the broadly sensitized transplant candidate, and facilitated the identification of compatible organ donors. The virtual crossmatch can be used to aid in organ allocation and avoid transplantation across preformed DSA. However, much remains unknown about the mechanisms of antibody-mediated injury in the intestinal graft, and the effectiveness of current therapies against DSA has yet to be established.
Summary: On the basis of available data, we will provide recommendations for the testing and management of DSA among intestinal transplant recipients. The precise management protocol should be tailored to each individual based on immunologic risk as well as clinical status.
An integrated understanding of the immunology of allograft inflammation Purpose of review: The purpose of this review is to summarize recent advances in our understanding of the complex immunology of intestinal transplantation and allograft rejection.
Recent findings: Recent findings highlight the importance of the intestinal microbiome for intestinal homeostasis and the role of newly discovered innate lymphoid cells in intestinal transplantation. In addition, the role of host antimicrobial Th17 responses in the pathogenesis of inflammatory bowel diseases and intestinal allograft rejection has been further elucidated.
Summary: Research on the complex immune system of the intestine has continued to reveal more intricacies and connections with each study performed, making treatment of intestinal transplant patients more multifaceted. The interaction, communication, and relationships between areas such as the microbiome, innate lymphoid cells, and Th17 cells reveal possible targets for therapy and further areas requiring ongoing research.
Liver allocation and distribution: time for a change Purpose of review: Liver allograft allocation has been a topic of hot debate for over a decade. New redistricting changes have been proposed by the Liver and Intestinal Transplant Committee to the existing United Network for Organ Sharing (UNOS) liver allocation policy. The basis of this new proposal is similar to the old one with an aim to distribute organs in a fair, efficient and equitable fashion. In this review, we plan to look in depth at the redistribution proposals thus far, their merits and how they may help patients who do not have adequate access to livers.
Recent findings: Many authors have criticized the proposed changes to organ distribution to reduce geographic disparity in access to liver transplantation. Our focus in this article is to bring forth the most recent literature and proposed changes in the current distribution system. We will also mention two other possible methods that have been proposed to redesign distribution using concentric circles and neighborhoods. In this article, we also look at the economics of the redistricting proposal and its effects on transplant centers.
Summary: The UNOS Liver and Intestinal Transplant Committee has recommended a proposal using the eight-district model with proximity circles and three additional Model for End-Stage Liver Disease (MELD) points with initial sharing MELD threshold of 25 as a starting point to reduce disparity in patient access to deceased donor livers for transplantation. This proposal has met with significant resistance because of concerns of cost, logistics and impact on existing transplant centers. Other methodologies have also been proposed that have the potential to significantly improve our current disparity of access to life-saving organs. Variation in the supply of donor organs vs. the demand or need for liver transplant by geography and the current defined areas of distribution drive this disparity. Cost benefits to the healthcare system in caring for patients with advanced stages of liver disease may outweigh increased costs of transportation and transplantation. The current allocation boundaries are not optimal for liver distribution, as modeled by all suggested solutions thus far. The need to identify a more optimal and equitable allocation/distribution system is paramount.
Outcomes and disparities in liver transplantation will be improved by redistricting-cons Purpose of review: Over the last 2 years, the liver transplant community has been debating a proposal to redraw the maps of organ distribution. The basis for these proposed changes is reported disparities in severity of illness at transplantation across the USA – however, this is based on the allocation model for end-stage liver disease score. In this review, we provide a critical overview of the redistribution proposal, its flaws and how it may worsen outcomes and exacerbate disparities in liver transplantation.
Recent findings: The main findings we highlight are data questioning the disparity metric used to justify the redistribution. We also review data published in recent articles and presented at public forums questioning whether there truly are disparities in access to transplant care among the broader population with liver disease, and whether disparities even getting to the waitlist are important and not to be ignored.
Summary: This review article highlights major methodological and policy flaws with the current redistribution proposal. We demonstrate how the waitlist disparities that the proposal is intended to fix are not as they seem. Furthermore, if this proposal is passed, outcomes of liver transplantation nationally may worsen, and disparities for those with limited access to healthcare will worsen.
Are geographic differences in transplantation inherently wrong? Purpose of review: Geographic variation in liver transplantation has been the subject of extensive scrutiny, reflecting concerns that location is unfairly determinative for people needing organ transplantation. Drawing upon a number of established ethical approaches, we examine whether geographic differences in access to livers are inherently unethical.
Recent findings: We posit that the ethical imperative for redistribution largely hinges upon the belief that access to organs systematically disadvantages certain identifiable groups of patients over others. Yet, our data suggest that regions likely to be net-contributors may suffer from less access to transplantation and other health services, fewer social protections and greater burden of liver disease. Drawing upon a number of ethical approaches, including strict egalitarianism, utilitarianism, Maximin, Reciprocity, Sen's Impartial Spectator and a health equity framework, we demonstrate that the current proposal has significant weaknesses, and may not achieve its goals of improving equity and efficiency.
Summary: Formulating effective policies and programs to ameliorate health inequalities requires an understanding of the interrelated causes of mortality disparities and specific interventions to mitigate these causes. Although our analysis does not indicate how ethically distribute livers, but it suggests that this be done with consideration for population-based health measures.
Organ donation and imminent death: pro position Purpose of review: Donation after cardiac death is associated with many problems including ischemic injury, high rates of delayed allograft function, prolonged time to asystole, and frequent organ discard. Imminent death donation (IDD) has been proposed as a separate category of organ donation: distinct from living donation and donation after cardiac death.
Recent findings: A protocol for IDD was developed at Rhode Island Hospital and published in the ethics literature. The United Network for Organ Sharing (UNOS) Ethics Committee reviewed the protocol and stated that IDD was ethically appropriate in some cases. A wider review by a working group within UNOS concluded similarly, but felt that a myriad of policy revisions would be required and were concerned about a possible negative impact on public trust in organ donation. Nonetheless, IDD and other nontraditional strategies continue to be proposed, implemented in other countries and discussed by patients and donor families.
Summary: This review, on the ‘Pro’ side of IDD, proposes that the medical community continue to work toward implementing IDD. Donor family's wishes are best met by organ donation, successful outcomes for the recipients, and a dignified death for their loved one. In some cases, IDD is the best strategy to meet these goals.
The case against imminent death donation Purpose of review: Imminent death donation (IDD) is a proposal to procure organs from patients prior to the withdrawal of life support, which is anticipated to lead to death. In this review, we outline substantial concerns that the transplant community should consider when deliberating the possibility of practicing IDD.
Recent findings: Although there are several compelling theoretical and intuitive reasons to support IDD, its application has been hindered because of inadequate definitions or protocols. A lack of published reports limits empirical data about the practice. Discussion on the topic has not adequately addressed potential harms to the donor, involvement of stakeholders, or the threat to public trust.
Summary: Although IDD has been proposed as a method to increase the number of organs or improve end-of-life care, the proposal currently poses more risk than benefit for patients and the transplant community. Until the major barriers to implementation of IDD are addressed, the transplant community should invest its efforts to increase the organ supply elsewhere.
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