Background: We evaluated the concept of whether liver failure patients with a superimposed kidney injury receiving a simultaneous liver and kidney transplant (SLKT) have similar outcomes compared to patients with liver failure without a kidney injury receiving a liver transplantation (LT) alone. Methods: Using data from the United Network of Organ Sharing (UNOS) database, patients were divided into five groups based on pre-transplant model for end-stage liver disease (MELD) scores and categorized as not having (serum creatinine (sCr) <= 1.5 mg/dL) or having (sCr > 1.5 mg/dL) renal dysfunction. Of 30,958 patients undergoing LT, 14,679 (47.5%) had renal dysfunction, and of those, 5,084 (16.4%) had dialysis. Results: Survival in those (liver failure with renal dysfunction) receiving SLKT was significantly worse (P < 0.001) as compared to those with sCr < 1.5 mg/dL (liver failure only). The highest mortality rate observed was 21% in the 36+ MELD group with renal dysfunction with or without SLKT. In high MELD recipients (MELD > 30) with renal dysfunction, presence of renal dysfunction affects the outcome and SLKT does not improve survival. In low MELD recipients (16 - 20), presence of renal dysfunction at the time of transplantation does affect post-transplant survival, but survival is improved with SLKT. Conclusions: SLKT improved 1-year survival only in low MELD (16 - 20) recipients but not in other groups. Performance of SLKT should be limited to patients where a benefit in survival and post-transplant outcomes can be demonstrated.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21623号 / 医博第4429号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 坂井 義治, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

An increasing prevalence of metabolic syndrome and obesity has been linked to the rise in transplant indication for cryptogenic cirrhosis and nonalcoholic fatty liver disease (NAFLD), creating a growing challenge to public health. NAFLD liver transplant (LT) candidates are listed with low priority, and their waiting mortality is high. The impact of community/geographic factors on donor risk models is unknown. The purpose of this study was to develop a parsimonious donor risk-adjusted model tailored to NAFLD recipients by assessing the impact of donor, recipient, transplant, and external factors on graft survival. The theoretical framework was the social ecological model. Secondary data were collected from 3,165 consecutive recipients from the Scientific Registry of Transplant Recipients and Community Health Scores, a proxy of community health disparities derived from the Robert Wood Johnson Foundation's community health rankings. Data were examined using univariate and multivariate analyses. The donor risk-adjusted model was developed using donor-only factors and supplemented with recipient and transplant factors, classifying donors as low, medium, and high risk. NAFLD residents in high-risk counties had increased likelihood of liver graft failure. Findings may be used to allocate high-risk donors to a subset of NAFLD with excellent outcomes, increasing the donor pool and decreasing mortality on the wait list.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22303号 / 医博第4544号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 川口 義弥, 教授 松村 由美 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Suite à une transplantation, les patients présentent un affaiblissement de leur système immunitaire laissant ainsi place libre aux infections opportunistes et principalement au CMV. L’implication de ce virus dans l’accélération de la mise en place du rejet chronique du greffon reste controversée et largement incomprise. Nos objectifs ont été d’une part de déterminer l’impact de l’infection à CMV du donneur sur la survie du greffon rénal et d’autre part d’identifier certains facteurs liés à la réponse immunitaire de l’hôte pouvant moduler ce risque. Selon nos résultats, l’infection à CMV du donneur est un facteur de risque indépendant de la perte des greffons rénaux, d’autant plus si le receveur est aussi infecté. Le SNP PD-1.3 est un facteur de risque génétique fort de la perte du greffon rénal associé au CMV du donneur et ce résultat est confirmé grâce à une cohorte de validation de patients transplantés pulmonaires. Ce travail suggère un lien fort entre ce SNP et l’épuisement de la réponse immunitaire anti-CMV et met en avant l’importance de la physiopathologie liée au CMV sur l’association clinique observée. / Following a solid organ transplant, and to prevent the risk of rejection, patients take immunosuppressive treatments that weaken their immune system and promote tumors and infections, including cytomegalovirus (CMV). This virus is the cause of clinical infectious syndromes but also many "indirect" effects which are not yet clearly understood. Our objectives were firstly to determine the impact of the CMV donor infection on the renal graft survival and secondly to identify factors related to the immune response of the host which can modulate the risk. We showed that the CMV donor is an independent risk factor for kidney graft loss, especially if the recipient is infected. The SNP PD-1.3 is a strong genetic risk factor for renal graft loss associated with CMV donor and this result is confirmed by a validation cohort of lung transplant patients. This work suggests a strong link between this SNP and the exhaustion of the immune response specific anti -CMV and highlights the importance of the pathophysiology associated with CMV on the observed clinical association.

INTRODUÇÃO: A reparação das lesões de nervos periféricos com perda extensa de substância, onde a sutura direta não é viável, ainda apresenta nos dias atuais resultados variáveis e dependentes de diversos fatores. O tratamento mais comumente utilizado nestes casos é a auto-enxertia de nervos, com sacrifício de um nervo de outra região do corpo, procedimento que, entretanto, pode trazer algumas dificuldades e consequências. Desta forma, a busca por novas técnicas, como a possibilidade de utilização de nervos preservados em baixas temperaturas, representa um avanço inestimável no campo da reparação de lesões nervosas. OBJETIVO: O objetivo deste estudo foi realizar avaliações funcionais, eletrofisiológicas e histomorfométricas que permitam comparar a regeneração nervosa autógena em enxerto convencional versus enxerto preservado a frio, em modelo experimental de ratos, após denervação a fresco ou conservação de um segmento do nervo em baixa temperatura por 14 dias e por 50 dias. MÉTODOS: Foram utilizados 20 ratos Wistar de peso e idades aproximadamente iguais, divididos em quatro grupos de cinco animais. Os grupos 1 e 3 serviram de controle respectivamente para os grupos 2 e 4, utilizando enxertia de nervo convencional por 14 dias (grupo 1) e por 50 dias (grupo 3). O grupo 2 utilizou enxertia de nervo preservado a 4 graus Celsius em solução Celsior® por 14 dias, enquanto o grupo 4 foi submetido à preservação a frio na mesma solução por 50 dias. Foram realizadas análises funcionais da marcha, análises de potenciais evocados e análises histomorfométricas dos animais em diversos momentos. As análises funcionais utilizaram uma aparelhagem própria para estudo da marcha em pequenos animais de experimentação, denominada catWalk®, que fornece medidas estáticas e dinâmicas da marcha, com parâmetros como a pressão em relação à pata contralateral e a área máxima da impressão plantar do animal, tendo sido captados os dados antes do procedimento de retirada do enxerto e após a realização da enxertia, neste último caso com avaliações quinzenais até que tenham sido completados 60 dias de pós- operatório. As análises de potenciais evocados motores analisaram a latência e a amplitude dos estímulos nervosos e foram realizadas 60 dias após os procedimentos de enxertia. As análises microscópicas observaram a contagem de axônios mielinizados e a área destas fibras nervosas nas regiões proximal e distal aos reparos, aos 60 dias após os procedimentos, comparando também as relações entre a região distal e proximal de cada um destes parâmetros através dos índices de regeneração e mudança de área. RESULTADOS: A enxertia com nervo preservado a frio por 14 dias apresentou resultado funcional semelhante ao seu grupo controle na análise da área máxima de contato e da pressão máxima de contato da pata operada em todas as avaliações. Já a conservação do enxerto a frio por 50 dias resultou em superioridade funcional em todos as avaliações em relação a seu grupo controle. Os estudos eletrofisiológicos mostraram cada grupo de enxertia preservada a frio com resultados similares a seu grupo controle, tanto em relação à latência, quanto à amplitude nos dois músculos avaliados. As análises histomorfométricas resultaram em índices de regeneração e de mudança de área semelhantes na comparação entre os grupos 60 dias após os procedimentos de enxertia. CONCLUSÕES: A conservação a frio do enxerto de nervo durante 14 dias e durante 50 dias apresentou resultados funcionais da regeneração iguais ou superiores aos enxertos convencionais e resultados eletrofisiológicos e histológicos semelhantes aos respectivos grupos controle de enxertos convencionais, demonstrando um futuro promissor para a utilização clínica de enxertos preservados a frio em um \"banco de nervos\" / INTRODUCTION: The repair of peripheral nerve injuries with extensive loss of substance, where direct suture is not feasible, at the present time still has variable results and dependence on many factors. The treatment most commonly used in these cases is the nerve autograft, with sacrifice of a nerve from another region of the body. This procedure, however, can sometimes lead to some difficulties and consequences. Therefore, the search for new techniques such as the possibility of using cold preserved nerves, is a great advancement in the field of repairing nerve damage. OBJECTIVE: The purpose of this study was to perform functional, electrophysiological and histomorphometric evaluations to compare conventional autografts versus cold-preserved autografts of the sciatic nerves of rats, after fresh denervation or conservation of a nerve segment at low temperature for 14 days and 50 days. METHODS: 20 Wistar rats of approximately equal ages and weight were divided into 4 groups of 5 animals. Groups 1 and 3 were treated with a conventional nerve graft after denervation for 14 days and 50 days, respectively; they served as controls for groups 2 and 4, which were treated with cold-preserved nerve grafts immersed in a Celsior® solution at 4 degrees Celsius for 14 and 50 days, respectively. Functional gait analysis, evoked potential analysis and histomorphometric analysis of the animals were performed at different times. Functional analysis used equipment for gait study in small animal experiments, called catWalk®, which provides static and dynamic measurements, with parameters such as pressure relative to contralateral paw and the maximum area of the footprint of the animal, and these data were captured before the graft withdrawal procedure and after grafting, in this latter case the functional analysis was made every 15 days until they had been completed 60 days after surgery. The motor evoked potential analysis examined the latency and amplitude of nerve stimuli and was made 60 days after the grafting procedures. The microscopic analysis measured myelinated axons and the area of these nerve fibers in the proximal and distal regions to the repair sites at the end of 60 days after the procedures, also comparing the relationship between the distal and proximal regions of each of these parameters through the regeneration and area change rates. RESULTS: Cold preservation of nerve graft for 14 days showed functional results similar to those of its control group for the maximum contact area and for the maximum pressure intensity of the operated paw in all evaluations. Cold preservation of nerve graft for 50 days resulted in functional superiority in all assessments compared with its control group. Cold preservation of nerve graft for 14 days and 50 days showed electrophysiological results similar to those of their respective control groups, both in terms of latency, as to the amplitude in the two muscles evaluated. Histomorphometric analysis showed similar regeneration and area change rates for all the groups 60 days after the grafting procedures. CONCLUSIONS: The cold preservation of nerve grafts for 14 days and 50 days showed similar or superior functional results and similar electrophysiological and histological results compared with their respective conventional graft control groups, indicating a promising future for the clinical utilization of cold preserved grafts in a \"nerve bank\"

Contexte : La réponse allo-immune induite par la transplantation à partir d'un donneur génétiquement différent est un obstacle majeur au succès de la greffe. Notre objectif est de caractériser les différents phénotypes de rejet d'allogreffe rénale et d'identifier la façon dont chacun est associé aux anticorps anti-HLA. Nous avons également évalué l’impact de certaines propriétés de ces anticorps, comme leur intensité ou leur capacité à fixer le complément, sur l'échec des allogreffes rénales. Pour finir, nous avons étudié l’impact pronostic des formes indolentes de rejets ainsi que l’apport des nouvelles technologies d’analyses transcriptomique des biopsies de patients transplantés. Méthodes : Nous avons utilisé une approche en population, basée sur l’étude de larges cohortes de receveurs de greffes rénales. L’étude concomitante des données immunologiques et histologiques, nous a permis de corréler les caractéristiques des anticorps anti-HLA circulants aux phénotypes lésionnels. Résultats : Nous avons identifié et caractérisé 4 types distincts de rejet : les rejets vasculaires médiés par les lymphocytes T (9%) et par les anticorps (21%), non reconnus par les classifications internationales, et les rejets cellulaires (46%) et humoraux sans vascularite (24%). Le risque de perte de greffons est le plus important dans les cas de rejet vasculaire médié par anticorps. Les anticorps dirigés contre le donneur (DSA) fixant le complément induisent un phénotype histologique plus sévère, dominé par des lésions inflammatoires et plus de dépôts de la fraction C4d du complément dans les greffons. En leur présence, le risque de perte de greffons est augmenté de 3,7 fois (IC95 1,9-7,2). Les formes indolentes de rejet médié par les anticorps sont également associées à un risque accru de perte du greffon. L’utilisation d’approches moléculaires permet d’améliorer la stratification du risque au sein du groupe des patients présentant des rejets humoraux. Conclusion : Ce travail répond à un besoin clinique pressant dans le domaine de la transplantation, celui de déterminer l’impact clinique des anticorps anti-HLA et d’améliorer la stratification du risque immunologique en se basant sur leurs propriétés et l’utilisation de nouvelles technologies pour mieux caractériser l’activité et le stade des rejets humoraux. / Background : The alloimmune response induced by transplantation from a donor who differs genetically from the kidney recipient has always been the major obstacle to graft success. The present work aimed to improve characterization of kidney-allograft rejection phenotypes and identify how each one is associated with anti-HLA antibodies. We also sought to determine whether characteristics of these antibodies i.e., their levels or complementbinding ability, might play a role in kidney allograft failure. Finally, we evaluated the clinical relevance of indolent forms of ABMR and the clinical relevance of new genes expression technologies to stratify the kidney recipients at risk for failure. Methods : We used a population-based approach in precisely phenotyped cohorts of kidney recipients. The design of our study, which is based on the concomitant evaluation of immunologic and histologic data, permits a precise connection of circulating anti-HLA antibodies with a phenotype of graft injury. Findings : We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (9%), antibody-mediated vascular rejection (21%), not included in international classifications, T cell- (46%) and antibody-mediated rejection without vasculitis (24%). Risk of graft loss was 9.07 times (95CI 3.6-19.7) higher in antibody-mediated vascular rejection than in T-cell mediated rejections (p<0.0001). Patients with post-transplant complement-binding DSA had more severe graft injury phenotype with higher inflammation and increased deposition of complement fraction C4d. They have the poorest graft survival with 3.7 fold increased risk of graft loss (95CI 1.9-7.2). Subclinical ABMR is a truncated for of rejection associated with risk of kidney allograft failure. Gene expression assessment in kidney allografts with early ABMR improves classification of individuals at risk for kidney allograft loss. Conclusion : This work addresses the unmet need of the deleterious impact of anti-HLA antibodies and the improvement of risk stratification in kidney transplantation. Recognition of distinct phenotypes could lead to the development of new treatment strategies. Gene expression assessment appears useful to evaluate disease activity, disease state and prediction of failure.

INTRODUÇÃO: A reparação das lesões de nervos periféricos com perda extensa de substância, onde a sutura direta não é viável, ainda apresenta nos dias atuais resultados variáveis e dependentes de diversos fatores. O tratamento mais comumente utilizado nestes casos é a auto-enxertia de nervos, com sacrifício de um nervo de outra região do corpo, procedimento que, entretanto, pode trazer algumas dificuldades e consequências. Desta forma, a busca por novas técnicas, como a possibilidade de utilização de nervos preservados em baixas temperaturas, representa um avanço inestimável no campo da reparação de lesões nervosas. OBJETIVO: O objetivo deste estudo foi realizar avaliações funcionais, eletrofisiológicas e histomorfométricas que permitam comparar a regeneração nervosa autógena em enxerto convencional versus enxerto preservado a frio, em modelo experimental de ratos, após denervação a fresco ou conservação de um segmento do nervo em baixa temperatura por 14 dias e por 50 dias. MÉTODOS: Foram utilizados 20 ratos Wistar de peso e idades aproximadamente iguais, divididos em quatro grupos de cinco animais. Os grupos 1 e 3 serviram de controle respectivamente para os grupos 2 e 4, utilizando enxertia de nervo convencional por 14 dias (grupo 1) e por 50 dias (grupo 3). O grupo 2 utilizou enxertia de nervo preservado a 4 graus Celsius em solução Celsior® por 14 dias, enquanto o grupo 4 foi submetido à preservação a frio na mesma solução por 50 dias. Foram realizadas análises funcionais da marcha, análises de potenciais evocados e análises histomorfométricas dos animais em diversos momentos. As análises funcionais utilizaram uma aparelhagem própria para estudo da marcha em pequenos animais de experimentação, denominada catWalk®, que fornece medidas estáticas e dinâmicas da marcha, com parâmetros como a pressão em relação à pata contralateral e a área máxima da impressão plantar do animal, tendo sido captados os dados antes do procedimento de retirada do enxerto e após a realização da enxertia, neste último caso com avaliações quinzenais até que tenham sido completados 60 dias de pós- operatório. As análises de potenciais evocados motores analisaram a latência e a amplitude dos estímulos nervosos e foram realizadas 60 dias após os procedimentos de enxertia. As análises microscópicas observaram a contagem de axônios mielinizados e a área destas fibras nervosas nas regiões proximal e distal aos reparos, aos 60 dias após os procedimentos, comparando também as relações entre a região distal e proximal de cada um destes parâmetros através dos índices de regeneração e mudança de área. RESULTADOS: A enxertia com nervo preservado a frio por 14 dias apresentou resultado funcional semelhante ao seu grupo controle na análise da área máxima de contato e da pressão máxima de contato da pata operada em todas as avaliações. Já a conservação do enxerto a frio por 50 dias resultou em superioridade funcional em todos as avaliações em relação a seu grupo controle. Os estudos eletrofisiológicos mostraram cada grupo de enxertia preservada a frio com resultados similares a seu grupo controle, tanto em relação à latência, quanto à amplitude nos dois músculos avaliados. As análises histomorfométricas resultaram em índices de regeneração e de mudança de área semelhantes na comparação entre os grupos 60 dias após os procedimentos de enxertia. CONCLUSÕES: A conservação a frio do enxerto de nervo durante 14 dias e durante 50 dias apresentou resultados funcionais da regeneração iguais ou superiores aos enxertos convencionais e resultados eletrofisiológicos e histológicos semelhantes aos respectivos grupos controle de enxertos convencionais, demonstrando um futuro promissor para a utilização clínica de enxertos preservados a frio em um \"banco de nervos\" / INTRODUCTION: The repair of peripheral nerve injuries with extensive loss of substance, where direct suture is not feasible, at the present time still has variable results and dependence on many factors. The treatment most commonly used in these cases is the nerve autograft, with sacrifice of a nerve from another region of the body. This procedure, however, can sometimes lead to some difficulties and consequences. Therefore, the search for new techniques such as the possibility of using cold preserved nerves, is a great advancement in the field of repairing nerve damage. OBJECTIVE: The purpose of this study was to perform functional, electrophysiological and histomorphometric evaluations to compare conventional autografts versus cold-preserved autografts of the sciatic nerves of rats, after fresh denervation or conservation of a nerve segment at low temperature for 14 days and 50 days. METHODS: 20 Wistar rats of approximately equal ages and weight were divided into 4 groups of 5 animals. Groups 1 and 3 were treated with a conventional nerve graft after denervation for 14 days and 50 days, respectively; they served as controls for groups 2 and 4, which were treated with cold-preserved nerve grafts immersed in a Celsior® solution at 4 degrees Celsius for 14 and 50 days, respectively. Functional gait analysis, evoked potential analysis and histomorphometric analysis of the animals were performed at different times. Functional analysis used equipment for gait study in small animal experiments, called catWalk®, which provides static and dynamic measurements, with parameters such as pressure relative to contralateral paw and the maximum area of the footprint of the animal, and these data were captured before the graft withdrawal procedure and after grafting, in this latter case the functional analysis was made every 15 days until they had been completed 60 days after surgery. The motor evoked potential analysis examined the latency and amplitude of nerve stimuli and was made 60 days after the grafting procedures. The microscopic analysis measured myelinated axons and the area of these nerve fibers in the proximal and distal regions to the repair sites at the end of 60 days after the procedures, also comparing the relationship between the distal and proximal regions of each of these parameters through the regeneration and area change rates. RESULTS: Cold preservation of nerve graft for 14 days showed functional results similar to those of its control group for the maximum contact area and for the maximum pressure intensity of the operated paw in all evaluations. Cold preservation of nerve graft for 50 days resulted in functional superiority in all assessments compared with its control group. Cold preservation of nerve graft for 14 days and 50 days showed electrophysiological results similar to those of their respective control groups, both in terms of latency, as to the amplitude in the two muscles evaluated. Histomorphometric analysis showed similar regeneration and area change rates for all the groups 60 days after the grafting procedures. CONCLUSIONS: The cold preservation of nerve grafts for 14 days and 50 days showed similar or superior functional results and similar electrophysiological and histological results compared with their respective conventional graft control groups, indicating a promising future for the clinical utilization of cold preserved grafts in a \"nerve bank\"

No description available.