RESUMO
Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs.
Assuntos
Modelos Animais de Doenças , Animais , Camundongos , Humanos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologia , Transplante de Órgãos , Modelos Animais , Reprodutibilidade dos Testes , Transplante/métodosRESUMO
Tuberculosis remains a global health threat, with increasing infection rates and mortality despite existing anti-TB drugs. The present work focuses on the research findings regarding the development and evaluation of thiadiazole-linked thiazole derivatives as potential anti-tuberculosis agents. We present the synthesis data and confirm the compound structures using spectroscopic techniques. The current study reports twelve thiazole-thiadiazole compounds (5 a-5 l) for their anti-tuberculosis and related bioactivities. This paper emphasizes compounds 5 g, 5 i, and 5 l, which exhibited promising MIC values, leading to further in silico and interaction analysis. Pharmacophore mapping data included in the present analysis identified tubercular ThyX as potential drug targets. The compounds were evaluated for anti-tubercular activity using standard methods, revealing significant MIC values, particularly compound 5 l, with the best MIC value of 7.1285â µg/ml. Compounds 5 g and 5 i also demonstrated moderate to good MIC values against M.â tuberculosis (H37Ra). Structural inspection of the docked poses revealed interactions such as hydrogen bonds, halogen bonds, and interactions containing Pi electron cloud, shedding light on conserved interactions with residues like Argâ 95, Cysâ 43, Hisâ 69, and Argâ 87 from the tubercular ThyX enzyme.
Assuntos
Antituberculosos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Tiadiazóis , Tiazóis , Antituberculosos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , HumanosRESUMO
OBJECTIVES: Lung fibrosis is the leading cause of death in SSc, with no cure currently available. Antifibrotic Endostatin (ES) production does not reach therapeutic levels in SSc patients, suggesting a deficit in its release from Collagen XVIII by the main cleavage enzyme, Cathepsin L (CTSL). Thus, elucidating a potential deficit in CTSL expression and activity unravels an underlying molecular cause for SSc-driven lung fibrosis. METHODS: Fibrosis was induced experimentally using TGF-ß in vitro, in primary human lung fibroblasts (pLFs), and ex vivo, in human lung tissues. ES and CTSL expression was quantified using ELISA, RT-qPCR, immunoblotting or immunofluorescence. Recombinant NC1-FLAG peptide was used to assess CTSL cleavage activity. CTSL expression was also compared between SSc vs normal (NL)-derived pLFs and lung tissues. RESULTS: ES levels were significantly reduced in media conditioned by TGF-ß-induced pLFs. TGF-ß-stimulated pLFs significantly reduced expression and secretion of CTSL into the extracellular matrix (ECM). CTSL was also sequestered in its inactive form into extracellular vesicles, further reducing its availability in the ECM. Media conditioned by TGF-ß-induced pLFs showed reduced cleavage of NC1-Flag and reduced release of the antifibrotic ES fragment. SSc-derived pLFs and lung tissues expressed significantly lower levels of CTSL compared with NL. CONCLUSIONS: Our findings identify CTSL as a protein protective against lung fibrosis via its activation of antifibrotic ES, and whose expression in SSc pLFs and lung tissues is suppressed. Identifying strategies to boost CTSL endogenous levels in SSc patients could serve as a viable therapeutic strategy.
Assuntos
Fibrose Pulmonar , Escleroderma Sistêmico , Humanos , Catepsina L/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Fibrose , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/patologia , Pele/patologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Patients undergoing organ transplantation transition from one life-altering issue (organ dysfunction) to a lifelong commitment-immunosuppression. Regimens of immunosuppressive agents (ISAs) come with significant side effects and comorbidities. Recently, the use of nanoparticles (NPs) as a solution to the problems associated with the long-term and systemic use of ISAs in transplantation has emerged. This minireview describes the role of NPs in organ transplantation and discusses obstacles to clinical implementation and pathways to clinical translation.
Assuntos
Imunossupressores , Transplante de Órgãos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Imunossupressores/uso terapêuticoRESUMO
Connexins are a class of membrane proteins widely distributed throughout the body and have various functions based on their location and levels of expression. More specifically, connexin proteins expressed in endothelial cells (ECs) have unique roles in maintaining EC barrier integrity and function-a highly regulated process that is critical for pro-inflammatory and pro-coagulant reactions. In this minireview, we discuss the regulatory influence connexin proteins have in maintaining EC barrier integrity and their role in ischemia-reperfusion injury as it relates to organ transplantation. It is evident that certain isoforms of the connexin protein family are uniquely positioned to have far-reaching effects on preserving organ function; however, there is still much to be learned of their roles in transplant immunology and the application of this knowledge to the development of targeted therapeutics.
Assuntos
Transplante de Órgãos , Traumatismo por Reperfusão , Humanos , Células Endoteliais/metabolismo , Conexinas/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Preservação de ÓrgãosRESUMO
Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8+ T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.
Assuntos
Transplante de Coração , Dinâmica Mitocondrial , Animais , Linfócitos T CD8-Positivos , Células Endoteliais , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.
Assuntos
Transplante de Rim , Tacrolimo , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêuticoRESUMO
Opioid use after kidney transplant has been shown to be a risk factor for chronic opioid use, which leads to an increased risk of mortality. The purpose of this study was to evaluate the early impact of a multimodal pain regimen and education quality improvement program on opioid use after kidney transplant 2 months after implementation. This was a retrospective, single-center analysis of post-operative opioid use, comparing the average daily Morphine milligram equivalents (MME) of the patients who received education on opioids and a multimodal pain regimen (preoperative TAP/QL block, scheduled APAP and gabapentin) compared to a historical control group. Despite having no differences in pre-transplant opioid exposure, daily and overall inpatient opioid utilization was significantly reduced in the multimodal pain protocol cohort (38.6 vs 8.0 MME/day; P < .001); 5% of patients in the multimodal pain protocol cohort were discharged with an opioid prescription, compared to 96% of controls (P < .001). Our early results demonstrate that a multimodal pain protocol can effectively and dramatically reduce short-term opioid utilization in kidney transplant recipients.
Assuntos
Transplante de Rim , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/uso terapêutico , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos RetrospectivosRESUMO
BACKGROUND: Allo-antigen-specific T-cytotoxic memory cells (TcM) which express CD40 ligand (CD154) in overnight lymphocyte co-culture are strongly associated with acute cellular rejection (ACR) seen in "for cause" biopsies for renal allograft dysfunction. Specifically, when the likelihood of rejection is increased, donor-specific allospecific TcM exceed those induced by HLA-non-identical third-party cell by 1.15-fold or greater. METHODS: The performance of allospecific TcM was evaluated retrospectively in primary renal transplant recipients (RTR) at routine clinical visits, cross-sectionally at presentation for biopsies, and serially. Performance metrics were sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: Twenty-two primary RTR, median age 45 years (range 19-72) were tested with allospecific CD154 + TcM. Samples were obtained at the mean ± SD time interval of 806 ± 239 days after kidney transplantation. Six of 22 patients experienced biopsy proven T- Cell Mediated Rejection (TCMR). A seventh showed antibody mediated rejection (ABMR). Of these seven patients six demonstrated increased likelihood of rejection with allospecific TcM (sensitivity 83%). Ten of these 15 patients with no rejection had a negative test (specificity 67%). False positive tests were seen in five patients. Six out of 11 patients with positive tests had ACR/ABMR with a PPV of 54%, while 10 out of 11 patients with negative tests were non-rejecters with a NPV of 91%. CONCLUSION: Allospecific T-cytotoxic memory cells distinguished primary RTR with quiescent allografts from those with dysfunction. With serial surveillance measures, this test system may facilitate decisions to manage immunosuppression in RTR.
Assuntos
Ligante de CD40/metabolismo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Transplante de Rim/efeitos adversos , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Aloenxertos , Feminino , Rejeição de Enxerto/patologia , Humanos , Memória Imunológica , Terapia de Imunossupressão , Rim/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.
Assuntos
Anticorpos/efeitos adversos , Progressão da Doença , Transplante de Pulmão/efeitos adversos , Enfisema Pulmonar/imunologia , Traumatismo por Reperfusão/etiologia , Animais , Autoanticorpos/sangue , Proteínas do Sistema Complemento/metabolismo , Epitopos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Enfisema Pulmonar/sangue , Traumatismo por Reperfusão/sangue , FumarRESUMO
BACKGROUND: Diabetes mellitus (DM) is associated with increased post-operative complications in various surgeries. Little data exist regarding the impact of long-standing DM (>25 years) on outcomes in pancreas transplantation (PTX). The objectives of our study were to determine if long-standing pre-transplant DM (>25 years) was associated with inferior outcomes following PTX. METHODS: Using a 13-year (April, 2000-May, 2012) retrospective analysis, we examined demographic and transplant factors, complications, and outcomes in patients without (Group A) and with (Group B) long-standing (>25 years) pre-PTX DM. RESULTS: Mean follow-up was 4.2 years. Of 214 consecutive PTX performed, 137 (105 simultaneous PTX (SPK), 25 PTX after kidney (PAK), 7 PTX alone (PTA)) had pre-PTX duration of DM recorded, including 65 in Group A and 72 in Group B. There were no differences between cohorts with respect to demographics. There were no differences in post-PTX surgical/medical complications. There were no differences in outcomes between cohorts (ie, rejection, graft loss or death). CONCLUSIONS: This large-scale analysis demonstrated that PTX can be performed in patients with long-standing DM with excellent patient and graft outcomes. Long-standing DM did not lead to an increased post-PTX infections or complications. Our study suggests that duration of DM should not impact PTX candidacy.
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Transplante de Pâncreas/efeitos adversos , Transplante de Pâncreas/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Transplante de Pâncreas/métodos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
AIMS: Following an acute myocardial infarction (MI) the extracellular matrix (ECM) undergoes remodeling in order to prevent dilation of the infarct area and maintain cardiac output. Excessive and prolonged inflammation following an MI exacerbates adverse ventricular remodeling. Macrophages are an integral part of the inflammatory response that contribute to this remodeling. Treatment with histone deacetylase (HDAC) inhibitors preserves LV function and myocardial remodeling in the post-MI heart. This study tested whether inhibition of HDAC activity resulted in preserving post-MI LV function through the regulation of macrophage phenotype and early resolution of inflammation. METHODS AND RESULTS: HDAC inhibition does not affect the recruitment of CD45+ leukocytes, CD45+/CD11b+ inflammatory monocytes or CD45+/CD11b+CD86+ inflammatory macrophages for the first 3â¯days following infarct. Further, HDAC inhibition does not change the high expression level of the inflammatory cytokines in the first days following MI. However, by day 7, there was a significant reduction in the levels of CD45+/Cd11b+ and CD45+/CD11b+/CD86+ cells with HDAC inhibition. Remarkably, HDAC inhibition resulted in the dramatic increase in the recruitment of CD45+/CD11b+/CD206+ alternatively activated macrophages as early as 1â¯day which remained significantly elevated until 5â¯days post-MI. qRT-PCR revealed that HDAC inhibitor treatment shifts the cytokine and chemokine environment towards an M2 phenotype with upregulation of M2 markers at 1 and 5â¯days post-MI. Importantly, HDAC inhibition correlates with significant preservation of both LV ejection fraction and end-diastolic volume and is associated with a significant increase in micro-vessel density in the border zone at 14â¯days post-MI. CONCLUSION: Inhibition of HDAC activity result in the early recruitment of reparative CD45+/CD11b+/CD206+ macrophages in the post-MI heart and correlates with improved ventricular function and remodeling. This work identifies a very promising therapeutic opportunity to manage macrophage phenotype and enhance resolution of inflammation in the post-MI heart.
Assuntos
Histona Desacetilase 1/genética , Inibidores de Histona Desacetilases/administração & dosagem , Inflamação/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Cicatrização/genética , Animais , Antígeno B7-2/metabolismo , Antígeno CD11b/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/crescimento & desenvolvimento , Coração/fisiopatologia , Histona Desacetilase 1/antagonistas & inibidores , Humanos , Inflamação/genética , Inflamação/fisiopatologia , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/metabolismo , Macrófagos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/genética , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/genética , Cicatrização/efeitos dos fármacosRESUMO
Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD.
Assuntos
Morte Encefálica/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Transplante de Pulmão/efeitos adversos , Receptores de Complemento/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Doadores de Tecidos , Administração por Inalação , Animais , Rejeição de Enxerto/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/etiologiaRESUMO
We present the unique case of a 15-month-old male born with biliary atresia and situs inversus totalis and disrupted inferior vena cava who underwent a successful liver transplantation. The patient had previously undergone a failed Kasai procedure and presented with persistent hyperbilirubinemia. The patient was transplanted with a left lateral segment donor having standard arterial anatomy. Technical considerations included identifying completely replaced arterial anatomy in the recipient from the superior mesenteric artery and creating a branch patch between the gastroduodenal artery and HA, anastomosing the donor left hepatic vein to confluences of the donor left, middle, and right hepatic veins, using a "lazy-S" configuration of portal vein anastomosis, and suspending the allograft to the abdominal wall. Post-operatively, his liver function tests and total bilirubin normalized and he progressed to tolerating an oral diet with tube-feed supplementation.
Assuntos
Anormalidades Múltiplas/cirurgia , Atresia Biliar/cirurgia , Transplante de Fígado , Situs Inversus/cirurgia , Veia Cava Inferior/anormalidades , Humanos , Lactente , MasculinoRESUMO
In this study, we examined the thickness of the electrical double layer (EDL) in ionic liquids using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. We focused on BF4- anion adsorption from the 1-ethyl-3-methylimidazolium tetrafluoroborate (EMImBF4) ionic liquid on the Au(111) surface. At both DFT and MD levels, we evaluated the capacitance-potential dependence for the Helmholtz model of the interface. Using MD simulations, we also explored a more realistic, multilayer EDL model accounting for the ion layering. Concurrent analysis of the DFT and MD results provides a ground for thinking whether the electrical double layer in ionic liquids is one- or multi-ionic-layer thick.
RESUMO
Left ventricular dysfunction resulting in cardiogenic shock occurs infrequently following organ reperfusion in liver transplantation. The etiology of the cardiogenic shock is often multifactorial and difficult to manage due to the complex nature of the procedure and the patient's baseline physiology. Traditionally, this hemodynamic instability is managed medically using inotropic agents and vasopressor support. If medical treatment is insufficient, the use of an intra-aortic balloon pump for counterpulsation may be employed to improve the hemodynamics and stabilize the patient. Here, we analyze three cases and review the literature.
Assuntos
Balão Intra-Aórtico/métodos , Transplante de Fígado/efeitos adversos , Choque Cardiogênico/terapia , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Choque Cardiogênico/etiologiaRESUMO
BACKGROUND: Allograft arteriopathy is still a leading cause of late organ failure. The aortic allograft model in mice has been used to study chronic rejection and has given useful information in the development of graft arteriosclerosis. However, the technical difficulties of small vessel anastomoses still continue to limit its widespread use. We introduce a new simple method for aortic transplantation in mice. METHODS: The descending aorta or infrarenal aorta from the donor mouse was anastomosed to the infrarenal aorta using a cuff technique. Aortic transplantation was performed in 30 mice, 10 isografts and 20 allografts. No immunosuppression was administered, and the recipients were sacrificed at day 28. The grafts were histologically analyzed. RESULTS: Implantation of grafts could be completed in an average of 23 min. There was no technical failure in all 60 anastomoses. The overall survival rate was 93.3%. Histology of aortas revealed typical aspects of chronic rejection in the allografts at day 28. No significant lesion was observed in isografts. CONCLUSIONS: We have developed an innovative, stable, and simple aortic transplantation model in mice, which is useful for vascular research in transplantation and beyond.
Assuntos
Aorta Abdominal/transplante , Aorta Torácica/transplante , Camundongos Endogâmicos BALB C/cirurgia , Camundongos Endogâmicos C57BL/cirurgia , Modelos Animais , Aloenxertos/patologia , Aloenxertos/transplante , Anastomose Cirúrgica , Animais , Aorta Abdominal/patologia , Aorta Torácica/patologia , Rejeição de Enxerto/patologia , Isoenxertos/patologia , Isoenxertos/transplante , Masculino , Camundongos , Transplante Homólogo/métodos , Transplante Isogênico/métodosRESUMO
OIs present significant risks to patients following solid organ transplantation. The purpose of this study was to identify risk factors for the development of OIs after kidney transplantation in pediatric patients and to evaluate the impact of OIs on outcomes in this patient population. A single-center retrospective longitudinal cohort analysis including pediatric patients 21 yr of age or younger transplanted from July 1999 to June 2013 at an academic medical center was conducted. Patients were excluded if they received multi-organ transplant. A total of 175 patients were included in the study. Patients who developed OIs were more likely to be female and younger at the time of transplant. A six-factor risk model for OI development was developed. Death, disease recurrence, and PTLD development were similar between groups but trended toward increased incidence in the OI group. Incidence of rejection was significantly higher in the OI group (p = 0.04). Patients who developed OIs had several important risk factors, including younger age, EBV-negative serostatus, CMV donor (+)/recipient (-), biopsy-proven acute rejection, ANC <1000, MMF dose >500 mg/m(2), and any infection. Incidence of rejection was higher in the OI group, but rate of graft loss was not statistically different.
Assuntos
Transplante de Rim , Infecções Oportunistas/epidemiologia , Insuficiência Renal/cirurgia , Adolescente , Algoritmos , Biópsia , Criança , Feminino , Rejeição de Enxerto , Humanos , Imunossupressores/uso terapêutico , Incidência , Estudos Longitudinais , Masculino , Curva ROC , Recidiva , Insuficiência Renal/complicações , Insuficiência Renal/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
BACKGROUND: Biliary complications are a leading source of surgical morbidity following orthotopic liver transplantation (OLT). METHODS: We examined how prophylactic internal biliary stent placement during OLT affected post-transplant morbidity and mortality in a single-center retrospective cohort study of 513 recipients (2006-2012). Recipient and donor covariates were collected. Biliary complications included major and minor anastomotic leaks, strictures, or stenoses. Multivariate regression models were created to estimate how operative biliary stents affected outcomes. RESULTS: About 87.3% (n = 448) of recipients had a duct-to-duct biliary anastomosis, and 43.1% (n = 221) had biliary stents placed. The biliary complication rate was <15% at five yr, and 44.8% (n = 230) overall. Stenting was not protective from anastomotic biliary complications (p = 0.06). Stenting was associated with a 74% higher adjusted risk of needing multiple endoscopic retrograde cholangiographies (ERCs; odds ratio [OR] 1.74, p = 0.011), and trended toward a lower adjusted risk for repetitive percutaneous transhepatic cholangiography (PTCs; OR 0.56, p = 0.063). Stenting had no effect on the cumulative freedom from biliary complications (p = 0.94). Biliary complications were associated with mortality (HR 1.86, p = 0.014) and was unaffected by stenting (aHR = 0.72, p = 0.246). CONCLUSIONS: Biliary stenting during OLT does not deter biliary complications and is associated with higher risk of multiple invasive biliary interventions, particularly ERCs. Surgeons should evaluate the utility of biliary stents at OLT within this context.