Donor diabetes mellitus is a risk factor for diminished outcome after liver transplantation: a nationwide retrospective cohort study

With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. From a national cohort of adult liver transplant recipients (1996–2016), all recipients transplanted with a liver from a DM donor (n = 69) were matched 1:2 with recipients of livers from non-DM donors (n = 138). The primary end-point included early post-transplant outcome, such as the incidence of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analy

[Response to:] The first 100 hand-assisted laparoscopic donor nephrectomies at the Academic Medical Center in Amsterdam

Met grote interesse lazen wij het artikel van Polle et al. Enkele jaren na de introductie van de laparoscopische donornefrectomie is de met de hand begeleide methode door een aantal klinieken omarmd. De auteurs concluderen dat door het gebruik van een handpoort de operatieduur en de warme-ischemieduur bekort kunnen worden en de kans op conversie naar een open procedure verkleind kan worden.Wij willen erop wijzen dat er geen wetenschappelijke argumenten zijn om de bewering te rechtvaardigen dat de met de hand begeleide methode de techniek van keuze is om een nier bij een levende donor te verwijderen en dat deze methode te verkiezen zou zijn boven de volledig laparoscopische techniek. [...]Tenslotte willen wij ingaan op de vermelde risicoreductie wat betreft conversie, dat wil zeggen aanpassing van de operatietechniek vanwege technische problemen. Met de huidige wisselsnedetechnieken die toegepast worden in de meeste Nederlandse transplantatiecentra bij open donornefrectomie heeft conversie nauwelijks gevolgen voor de donor. De chirurgische benadering is een middel en geen doel op zich. De veiligheid van de donor dient centraal te staan

[Response to:] The first 100 hand-assisted laparoscopic donor nephrectomies at the Academic Medical Center in Amsterdam

Met grote interesse lazen wij het artikel van Polle et al. Enkele jaren na de introductie van de laparoscopische donornefrectomie is de met de hand begeleide methode door een aantal klinieken omarmd. De auteurs concluderen dat door het gebruik van een handpoort de operatieduur en de warme-ischemieduur bekort kunnen worden en de kans op conversie naar een open procedure verkleind kan worden.Wij willen erop wijzen dat er geen wetenschappelijke argumenten zijn om de bewering te rechtvaardigen dat de met de hand begeleide methode de techniek van keuze is om een nier bij een levende donor te verwijderen en dat deze methode te verkiezen zou zijn boven de volledig laparoscopische techniek. [...]Tenslotte willen wij ingaan op de vermelde risicoreductie wat betreft conversie, dat wil zeggen aanpassing van de operatietechniek vanwege technische problemen. Met de huidige wisselsnedetechnieken die toegepast worden in de meeste Nederlandse transplantatiecentra bij open donornefrectomie heeft conversie nauwelijks gevolgen voor de donor. De chirurgische benadering is een middel en geen doel op zich. De veiligheid van de donor dient centraal te staan

The problem of anti-pig antibodies in pig-to-primate xenografting: current and novel methods of depletion and/or suppression of production of anti-pig antibodies

The role of antibodies directed against Galalpha1-3Gal (alpha-Gal) epitopes in porcine-to-primate xenotransplantation has been widely studied during the past few years. These antibodies (anti-alpha-Gal) have been associated with both hyperacute rejection and acute vascular rejection of vascularized organs. Depletion and (temporary or permanent) suppression of production of anti-alpha-Gal seem to be essential to the long-term survival of these organs, even when the ultimate aim is accommodation or tolerance. Although more than 95% depletion of anti-alpha-Gal can be achieved by the use of immunoaffinity column technology, to date no regimen has been successful in preventing the return of anti-alpha-Gal (from continuing production). In this review, we discuss current and novel methods for achieving depletion or inhibition (i.e. extracorporeal immunoadsorption, anti-idiotypic antibodies, the intravenous infusion of immunoglobulin or oligosaccharides) and suppression of production (i.e. irradiation, pharmacologic agents, specific monoclonal antibodies, immunotoxins) of anti-alpha-Gal antibodies

Assessment of methotrexate as a potential immunosuppressive agent in baboons

Methotrexate is an anti-proliferative agent that affects both T-cell and B-cell immunity, and therefore might be expected to suppress antibody (Ab) production. Although it has been used in xenotransplantation studies to suppress anti-pig Ab production, it has always been used in combination with other immunosuppressants. The purpose of this study was to measure its effect as a single immunosuppressant on anti-Gal Ab production in baboons (n=4). Pharmacokinetic studies showed that methotrexate was not detected in the blood when administered per os. Prolonged daily IV or IM administration (i) reduced T-cell and B-cell numbers by 50% to 70% and modestly reduced responsiveness on mixed lymphocyte reaction (but only at toxic doses) and (ii) did not result in lowered anti-Gal Ab levels, only marginally reducing the rate of return of Ab after extracorporeal immunoadsorption. Our observations would suggest that methotrexate will not contribute significantly to immunosuppressive regimens in the baboon at non-toxic doses

Pharmacotherapeutic agents in xenotransplantation

The ability to transplant pig organs into humans would resolve the current crisis in the supply of cadaveric human organs for the treatment of end stage disease. Several immunologic barriers need to be overcome if pig-to-primate transplantation is to be successful. The presence of preformed antibodies in humans, apes and Old World monkeys directed against galactose epitopes on pig vascular endothelium provides the major barrier, as binding of antibody to antigen leads to graft destruction by complement activation and other mechanisms. Hyperacute rejection can result from the action of complement. If this is prevented, delayed antibody-mediated rejection develops, which can be associated with a state of consumptive coagulopathy (disseminated intravascular coagulation, DIC). Efforts being made to overcome antibody-mediated rejection include depletion of antibody by extracorporeal immunoadsorption, prevention of an induced antibody response by co-stimulatory blockade, B-cell and/or plasma cell depletion, depletion or inhibition of complement, or the use of organs from pigs transgenic for a human complement regulatory protein, such as hDAF. The ultimate solution would be the induction of both B- and T-cell tolerance to the transplanted pig organ, which is being explored by attempting to induce haematopoietic cell chimerism. One complication of this is a thrombotic microangiopathy, similar to thrombotic thrombocytopenic purpura. The many and diverse roles in which pharmacotherapy is involved in attempts to overcome the barriers of xenotransplantation are reviewed and current progress, particularly in our own laboratory, is discussed

Inhibition of platelet aggregation in baboons: therapeutic implications for xenotransplantation

Activation of endothelial cells and platelet sequestration play major roles in rejection of xenografts. The histopathology of both hyperacute and acute vascular or delayed rejection of vascularized discordant xenografts is characterized by interstitial hemorrhage and intravascular thrombosis. Agents that prevent platelet activation and consequent microthrombus formation have proven beneficial in xenograft rejection but do not fully preclude vascular thrombosis. Recently, several new anti-platelet therapies have undergone extensive clinical testing for atherosclerotic thrombotic vascular disorders; other putative therapies are undergoing pre-clinical evaluation. We have investigated the effect of several of these novel agents on platelet aggregation in baboons in order to screen for future potential in xenograft rejection models

Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. I. The roles of individual components of a transplantation conditioning regimen and of pig peripheral blood progenitor cells

The induction of tolerance to pig antigens in primates may facilitate the development of successful clinical xenotransplantation protocols. The infusion of mobilized porcine peripheral blood leukocytes (PBPCs, comprised of approximately 2% peripheral blood progenitor cells) into splenectomized preconditioned baboons, intended to induce mixed hematopoietic cell chimerism, however, results in a severe thrombotic microangiopathy (TM) that includes pronounced thrombocytopenia. Because the mechanisms responsible for this phenomenon are unclear, we have explored the effects of individual components of the conditioning regimen, of therapeutic adjuncts, and of PBPCs on platelet aggregation