RESUMO
Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.
Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Aloenxertos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
Outcomes of retransplantation after initial living donor liver transplantation (LDLT) are poorly understood. The aim of this study is to better understand the indications, timing, and outcomes of retransplantation after initial LDLT when compared to after initial deceased donor transplantation (DDLT). From 2002 to 2013, 209 retransplant recipients after initial LDLT and 2893 after initial DDLT were identified in Organ Procurement and Transplantation Network/United Network for Organ Sharing. Multivariable logistic models evaluated the association between initial transplant type and 1-year mortality. The most frequent reason for early graft failure (≤14 days) in LDLT recipients was vascular thrombosis (63.6%) versus primary graft failure in initial DDLT recipients (59.1%). LDLT recipients were more often acutely and/or critically ill with a greater proportion of Status 1 (42.6% vs. 27.3%; p < 0.001) and intensive care unit (52.2% vs. 39.9%; p = 0.001) recipients at the time of retransplantation. There was no difference in adjusted 1-year mortality between retransplant recipients after initial LDLT versus DDLT (odds ratio 0.74; 95% confidence interval 0.51-1.08). The proportion of recipients who ultimately required retransplantation for a third time was not different between the two groups (4.8%). Retransplantation outcomes after LDLT are not different from other retransplant procedures, despite recipients having greater acuity of illness and different indications.
Assuntos
Transplante de Fígado/mortalidade , Doadores Vivos , Reoperação/mortalidade , Obtenção de Tecidos e Órgãos/métodos , Adulto , Aloenxertos , Cadáver , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.
Assuntos
Rejeição de Enxerto/etiologia , Transplante de Pulmão/efeitos adversos , Metagenômica , Disfunção Primária do Enxerto/etiologia , Sistema Respiratório/virologia , Doadores de Tecidos , Torque teno virus/genética , Adulto , Idoso , Estudos de Casos e Controles , DNA Viral/genética , Feminino , Seguimentos , Genoma Viral , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Disfunção Primária do Enxerto/patologia , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Over the last decade, advances in genetic technologies have accelerated our understanding of the genetic diversity across individuals and populations. Case-control and population-based studies have led to several thousand genetic associations across a range of phenotypes and traits being unveiled. Despite widespread and successful use of organ transplantation as a curative therapy for organ failure, genetic research has yet to make a major impact on transplantation practice aside from HLA matching. New studies indicate that non-HLA loci, termed minor histocompatibility antigens (mHAs), may play an important role in graft rejection. With several million common and rare polymorphisms observed between any two unrelated individuals, a number of these polymorphisms represent mHAs, and may underpin transplantation rejection. Genetic variation is also recognized as contributing to clinical outcomes including response to immunosuppressants, introducing the possibility of genotype-guided prescribing in the very near future. This review summarizes existing knowledge of the impact of genetics on transplantation outcomes and therapeutic responses, and highlights the translational potential that new genomic knowledge may bring to this field.
Assuntos
Rejeição de Enxerto/genética , Antígenos de Histocompatibilidade Menor/genética , Transplante de Órgãos , Polimorfismo Genético/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , PrognósticoRESUMO
Living donor liver transplantation (LDLT) demands a careful assessment of abnormal findings discovered during the evaluation process to determine if there will be any potential risks to the donor or recipient. Varying degrees of elevated hepatic iron levels are not uncommonly seen in otherwise healthy individuals. We questioned whether mild expression of hemosiderin deposition presents a safety concern when considering outcomes of living donation for both the donor and the recipient. We report on three LDLT patients who were found to have low- to moderate-grade hemosiderin deposition on liver biopsy. All other aspects of their evaluation proved satisfactory, and the decision was made to proceed with donation. There were no significant complications in the donors, and all demonstrated complete normalization of liver function postoperatively, with appropriate parenchymal regeneration. The recipients also had unremarkable postoperative recovery. We conclude that these individuals can be considered as potential donors after careful evaluation.