Optimal Policies for the Acceptance of Living- and Cadaveric-Donor Livers

Transplantation is the only viable therapy for end-stage liverdiseases (ESLD) such as hepatitis B. In the United States,patients with ESLD are placed on a waiting list. When organsbecome available, they are offered to the patients on this waitinglist. This dissertation focuses on the decision problem faced bythese patients: which offer to accept and which to refuse? Thisdecision depends on two major components: the patient's currentand future health, as well as the current and future prospect fororgan offers. A recent analysis of liver transplant data indicatesthat 60\% of all livers offered to patients for transplantationare refused.This problem is formulated as a discrete-time Markov decisionprocess (MDP). This dissertation analyzes three MDP models, eachrepresenting a different situation. The Living-Donor-Only Modelconsiders the problem of optimal timing of living-donor livertransplantation, which is accomplished by removing an entire lobeof a living donor's liver and implanting it into the recipient.The Cadaveric-Donor-Only Model considers the problem ofaccepting/refusing a cadaveric liver offer when the patient is onthe waiting list but has no available living donor. In this model,the effect of the waiting list is incorporated into the decisionmodel implicitly through the probability of being offered a liver.The Living-and-Cadaveric-Donor Model is the most general model.This model combines the first two models, in that the patient isboth listed on the waiting list and also has an available livingdonor. The patient can accept the cadaveric liver offer, declinethe cadaveric liver offer and use the living-donor liver, ordecline both and continue to wait.This dissertation derives structural properties of all threemodels, including several sets of conditions that ensure theexistence of intuitively structured policies such as control-limitpolicies. The computational experiments use clinical data, andshow that the optimal policy is typically of control-limit type

Specific issues concerning the management of patients on the waiting list and after liver transplantation

The present document is a second contribution collecting the recommendations of an expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF) concerning the management of certain aspects of liver transplantation, including: the issue of prompt referral; the management of difficult candidates; malnutrition; living related liver transplants; hepatocellular carcinoma; and the role of direct acting antiviral agents before and after transplantation. The statements on each topic were approved by participants at the AISF Transplant Hepatology Expert Meeting organized by the Permanent Liver Transplant Commission in Mondello on 12-13 May 2017. They are graded according to the GRADE grading system

Role of perfusion machines in the setting of clinical liver transplantation. A qualitative systematic review

Growing enthusiasm around machine perfusion (MP) in clinical liver transplantation (LT) may be the preamble for standardized practice to expand the donors' pool. The present systematic review investigated all the liver transplantations performed using grafts treated with MP. A systematic review of 309 papers was performed. Eventually, 27 articles were enrolled for the study. A total number of 173 cases was reported. Only 12 cohort studies were identified: the remaining ones were case reports or case series. Hypothermic machine perfusion was performed in 102 (59.0%), normothermic machine perfusion in 65 (37.6%), and controlled oxygenated rewarming in the remaining 6 (3.4%) cases. Donor characteristics, evaluation of graft quality and end-points were not homogeneous among the studies. Overall, post-LT results were excellent, with 1.2 and 4.0% of patients experienced primary non-function and ischemic-type biliary lesions, respectively

Competition and Post-Transplant Outcomes in Cadaveric Liver Transplantation under the MELD Scoring System

Previous researchers have modelled the decision to accept a donor organ for transplantation as a Markov decision problem, the solution to which is often a control-limit optimal policy: accept any organ whose match quality exceeds some health-dependent threshold; otherwise, wait for another. When competing transplant centers vie for the same organs, the decision rule changes relative to no competition; the relative size of competing centers affects the decision rules as well. Using center-specific graft and patient survival-rate data for cadaveric adult livers in the United States, we have found empirical evidence supporting these predictions.liver transplantation, competition, optimal stopping

Lymphoid/nonlymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct bone marrow

Background. The role of leukocyte migration and chimerism in organ allograft acceptance has been obscured by the lack of information about the late localization of the donor cells. Methods. Male Lewis rat→female Brown Norway abdominal heart transplantation was performed under tacrolimus immunosuppression (days 0-13, 20, and 27) with or without donor bone marrow and (in bone marrow subgroups) a 1-week postoperative course of a possibly chimerism-enhancing drug. Using rat sex-determining region-Y-specific oligonucleotide primers, we determined the donor DNA concentration by polymerase chain reaction in serial venous blood sampies for 100 days and in tissue specimens when animals were killed. Results. Chimerism was detected out to 56 days in 89% of the blood samples but in none of the samples at 100 days. However, donor DNA was detected when animals were killed in 95% of the native hearts, 80% of the skin biopsy specimens, and 23% of the spleens. The presence and quantity of early and late chimerism were strongly correlated the administration of adjunct bone marrow and with a reduction in the vasculopathy and inflammation index in the cardiac allografts. Marginally significant further increases in chimerism and/or reductions in chronic heart rejection beyond those achieved with adjunct bone marrow alone were associated with additional treatment with the growth factors Flt-3 ligand, granulocyte colonystimulating factor, and a recombinant molecular variant of interleukin-6 (interleukin-6 mutein) but not with hepatocyte growth factor or lisofylline. Conclusions. The previously suspected shift of early chimerism in the blood and lymphoid organs to dominance in host nonlymphoid tissues is consistent with the dual mechanisms of clonal exhaustion and immune indifference, governed by antigen migration and localization, that have been postulated elsewhere to account for organ allograft acceptance

Murine liver allograft transplantation: Tolerance and donor cell chimerism

Nonarterialized orthotopic liver transplantation with no immunosuppression was performed in 13 mouse‐strain combinations. Two strain combinations with major histocompatibility complex class I and class II and minor histocompatibility complex disparity had 20% and 33% survival of more than 100 days, but the other 11 combinations, including four that were fully allogeneic and all with only class I, class II or minor disparities, yielded 45% to 100% survival of more than 100 days. Long‐living recipients permanently accepted donor‐strain heterotopic hearts transplanted on the same day or donor‐strain skin 3 mo after liver transplantation, in spite of detectable antidonor in vitro activity with mixed lymphocyte reaction and cellmediated lymphocytotoxicity testing (split tolerance). In further donor‐specific experiments, liver grafts were not rejected by presensitized major histocompatibility complex class I‐disparate recipients and they protected donor‐strain skin grafts from second set (or any) rejection. Less frequently, liver transplantation rescued rejecting skin grafts placed 1 wk earlier in major histocompatibility complex class I, class II and minor histocompatibility complex, class II or minor histocompatibility complex‐disparate strain combinations. Donor‐derived leukocyte migration to the central lymphoid organs occurred within 1 to 2 hr after liver transplantation in all animals examined, persisted in the surviving animals until they were killed (>375 days), and was demonstrated with double‐immunolabeling to be multilineage. The relation of these findings to so‐called hepatic tolerogenicity and to tolerance in general is discussed. (HEPATOLOGY 1994;19:916–924.) Copyright © 1994 American Association for the Study of Liver Disease