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1.
Am J Transplant ; 18(10): 2513-2522, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29963780

RESUMO

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Transplante de Fígado/métodos , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/virologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Recidiva , Transplantados
2.
J Hepatol ; 69(3): 626-634, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29709679

RESUMO

BACKGROUND & AIMS: Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. METHODS: All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. RESULTS: Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. CONCLUSIONS: A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. LAY SUMMARY: A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time.


Assuntos
Perfilação da Expressão Gênica/métodos , Rejeição de Enxerto , Inflamação , Transplante de Fígado , Fígado , Efeitos Adversos de Longa Duração , Linfócitos T , Adulto , Doenças Assintomáticas , Biópsia/métodos , Correlação de Dados , Progressão da Doença , Feminino , Fibrose/imunologia , Fibrose/patologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Fígado/imunologia , Fígado/patologia , Testes de Função Hepática/métodos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Efeitos Adversos de Longa Duração/imunologia , Efeitos Adversos de Longa Duração/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/patologia
3.
Hepatology ; 67(5): 1683-1694, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28960366

RESUMO

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). CONCLUSION: In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Hipertensão Portal/diagnóstico , Cirrose Hepática/patologia , Resposta Viral Sustentada , Idoso , Técnicas de Imagem por Elasticidade/métodos , Feminino , Seguimentos , Hepacivirus , Hepatite C/complicações , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/virologia , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/virologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pressão na Veia Porta/fisiologia , Recidiva , Taxa de Sobrevida
4.
Liver Transpl ; 23(5): 645-651, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28188668

RESUMO

There is a lack of data on incidental hepatocellular carcinoma (iHCC) in the setting of liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients. This study aims to describe the frequency, histopathological characteristics, and outcomes of HIV+ LT recipients with iHCC from a Spanish multicenter cohort in comparison with a matched cohort of LT patients without HIV infection. A total of 15 (6%) out of 271 patients with HIV infection who received LT in Spain from 2002 to 2012 and 38 (5%) out of the 811 HIV- counterparts presented iHCC in liver explants (P = 0.58). Patients with iHCC constitute the present study population. All patients also had hepatitis C virus (HCV)-related cirrhosis. There were no significant differences in histopathological features of iHCC between the 2 groups. Most patients showed a small number and size of tumoral nodules, and few patients had satellite nodules, microvascular invasion, or poorly differentiated tumors. After a median follow-up of 49 months, no patient developed hepatocellular carcinoma (HCC) recurrence after LT. HIV+ LT recipients tended to have lower survival than their HIV- counterparts at 1 (73% versus 92%), 3 (67% versus 84%), and 5 years (50% versus 80%; P = 0.06). There was also a trend to a higher frequency of HCV recurrence as a cause of death in the former (33% versus 10%; P = 0.097). In conclusion, among LT recipients for HCV-related cirrhosis, the incidence and histopathological features of iHCC in HIV+ and HIV- patients were similar. However, post-LT survival was lower in HIV+ patients probably because of a more aggressive HCV recurrence. Liver Transplantation 23 645-651 2017 AASLD.


Assuntos
Carcinoma Hepatocelular/complicações , Infecções por HIV/complicações , Falência Hepática/complicações , Neoplasias Hepáticas/complicações , Transplante de Fígado/mortalidade , Adulto , Feminino , Humanos , Falência Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espanha/epidemiologia
5.
J Antimicrob Chemother ; 71(11): 3195-3201, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27402009

RESUMO

OBJECTIVES: IFN-based therapy against hepatitis C recurrence after liver transplantation (LT) has poor effectiveness and tolerability. In HIV/HCV-coinfected liver transplant recipients, the results are even poorer. Here, we report our experience using direct antiviral agents (DAAs) in 11 consecutive coinfected patients within the LT setting. METHODS: Four patients with compensated cirrhosis and hepatocellular carcinoma were treated while awaiting LT and seven patients received antiviral therapy due to severe hepatitis C recurrence after LT [fibrosing cholestatic hepatitis (n = 1), fibrosis stage ≥F3 (n = 2) and decompensated cirrhosis (n = 4)]. Patients were treated with different sofosbuvir-based regimens with or without ribavirin for 12 or 24 weeks. RESULTS: Sustained virological response (SVR) was achieved in all patients. Two of the four patients treated while awaiting LT reached the time of transplant with undetectable HCV-RNA that remained undetectable 12 weeks after LT, one patient had detectable HCV-RNA at the time of transplant but achieved SVR after completing 12 weeks of therapy after LT and the last patient is still on the waiting list. Seven patients with severe post-LT hepatitis C recurrence were treated within 11-120 months after LT. In these patients, viral eradication was associated with an improvement in liver function and clinical decompensation. Tolerance to antiviral therapy was good and only four patients reported mild adverse events. CONCLUSIONS: IFN-free regimens are effective and well tolerated in HIV/HCV-coinfected patients within the LT setting, but more data are needed to confirm our promising results and to establish the best treatment option in this population.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/complicações , Hepatite C/tratamento farmacológico , Transplante de Fígado , Transplantados , Adulto , Antivirais/efeitos adversos , Coinfecção/prevenção & controle , Feminino , Hepatite C/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento
6.
Immunobiology ; 221(5): 595-603, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26850323

RESUMO

The mayor goal still outstanding into the solid organ transplantation field involves the search of surrogate biomarkers able to predict several clinical events, such as acute rejection (AR) or opportunistic infection. In the present multicenter study, a series of interesting surface antigens with important activator or inhibitory immune functions on cultured peripheral T cells were monitored in liver transplant recipients drawn at baseline and up to one year after transplantation. Sixty-four patients were included in the multicenter study during 3 years. Pre- and post-transplantation surface antigens levels displayed significant differences between AR and non acute rejection (NAR) groups, and also this differential expression was used to construct a risk predictive model based on a composite panel of outcome biomarkers (CD38, CD69, CD95 and CD154). The model was able to stratify these patients at high risk of AR. These preliminary results could provide basic information to improve the immunosuppressive treatment and it might better help to predict AR episodes.


Assuntos
Aloenxertos/imunologia , Antígenos CD/metabolismo , Rejeição de Enxerto/imunologia , Transplante de Fígado , Linfócitos T/imunologia , Linfócitos T/metabolismo , ADP-Ribosil Ciclase 1 , Adulto , Idoso , Aloenxertos/metabolismo , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T , Biomarcadores , Ligante de CD40 , Células Cultivadas , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/metabolismo , Humanos , Imunofenotipagem , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lectinas Tipo C , Transplante de Fígado/efeitos adversos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Prognóstico , Curva ROC , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem , Receptor fas
7.
Hepatology ; 63(2): 488-98, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26516761

RESUMO

UNLABELLED: The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV-infected patients undergoing LT for HCC (2002-2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non-HIV-infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy-four HIV-infected patients and 222 non-HIV-infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV-infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non-HIV-infected patients. No significant differences were detected between HIV-infected and non-HIV-infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV-infected versus non-HIV-infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07-56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02-2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV-infected patients (16%) and 32 non-HIV-infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34-8.64) was the only factor independently associated with HCC recurrence. CONCLUSIONS: HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV-infected patients with HCC.


Assuntos
Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Infecções por HIV/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
8.
Biomed Res Int ; 2015: 794287, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26543868

RESUMO

Ischemia reperfusion injury (IRI) leads to significant tissue damage in liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proved their effectiveness against IRI. The objective of our study was to investigate the potential protective effects of intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) in steatotic livers subjected to cold ischemia reperfusion. In this study, we used isolated perfused rat liver model to assess the effects of PEG 35 intravenous administration after prolonged cold ischemia (24 h, 4°C) and after reperfusion (2 h, 37°C). Liver injury was measured by transaminases levels and mitochondrial damage was determined by confocal microscopy assessing mitochondrial polarization (after cold storage) and by measuring glutamate dehydrogenase activity (after reperfusion). Also, cell signaling pathways involved in the physiopathology of IRI were assessed by western blot technique. Our results show that intravenous administration of PEG 35 at 10 mg/kg ameliorated liver injury and protected the mitochondria. Moreover, PEG 35 administration induced a significant phosphorylation of prosurvival protein kinase B (Akt) and activation of cytoprotective factors e-NOS and AMPK. In conclusion, intravenous PEG 35 efficiently protects steatotic livers exposed to cold IRI.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Mitocôndrias Hepáticas/patologia , Polietilenoglicóis/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Administração Intravenosa , Animais , Isquemia Fria , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Mitocôndrias Hepáticas/ultraestrutura , Peso Molecular , Ratos , Traumatismo por Reperfusão/fisiopatologia , Transaminases/metabolismo
9.
J Hepatol ; 62(3): 701-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25450714

RESUMO

Liver transplantation is increasingly performed in selected HIV-infected patients in most developed countries, with excellent results reported in patients with liver diseases unrelated to HCV. In contrast, survival in HCV/HIV-coinfected liver recipients is poorer than in HCV-monoinfected patients, due to more aggressive recurrence of HCV and consequent graft loss and death. Results from American, French, and Spanish cohort studies showed a 5-year survival rate of only 50-55%. Therefore, it is debated whether liver transplantation should be offered to HCV/HIV-coinfected patients. Studies have shown that the variables more consistently associated with poor outcome are: (1) the use of old or HCV-positive donors, (2) dual liver-kidney transplantation, (3) recipients with very low body mass index and (4) less site experience. However, the most effective factor influencing transplantation outcome is the successful treatment of HCV recurrence with anti-HCV. Survival is 80% in patients whose HCV infection resolves. Unfortunately, the rates of sustained virological response with pegylated-interferon plus ribavirin in coinfected recipients are low, particularly for genotype 1 (only 10%). Here we present a non-systematic review of the literature based on our own experience in different liver transplant scenarios. This review covers selection criteria in HIV-infected patients, pre- and post-LT management, donor selection, anti-HCV treatment, drug interactions with antiretrovirals and anti-HCV direct antiviral agents, hepatocellular carcinoma, and liver retransplantation. Recommendations are rated. Finally, we explain how the introduction of new effective and more tolerable direct antiviral agents may improve significantly the outcome of HCV/HIV-coinfected liver recipients.


Assuntos
Coinfecção/terapia , Infecções por HIV/complicações , Infecções por HIV/terapia , Hepatite C/complicações , Hepatite C/terapia , Transplante de Fígado , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Coinfecção/cirurgia , Seleção do Doador , Infecções por HIV/cirurgia , Hepatite C/cirurgia , Humanos , Seleção de Pacientes , Prognóstico , Resultado do Tratamento , Listas de Espera
10.
J Hepatol ; 62(1): 92-100, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25127748

RESUMO

BACKGROUND & AIMS: The aim of this study was to evaluate the results of treatment with pegylated interferon and ribavirin for the recurrence of hepatitis C after liver transplantation in HCV/HIV-coinfected patients. METHODS: This was a prospective, multicentre cohort study, including 78 HCV/HIV-coinfected liver transplant patients who received treatment for recurrent hepatitis C. For comparison, we included 176 matched HCV-monoinfected patients who underwent liver transplantation during the same period of time at the same centres and were treated for recurrent hepatitis C. RESULTS: Antiviral therapy was discontinued prematurely in 56% and 39% (p = 0.016), mainly because of toxicity (22% and 11%, respectively; p=0.034). Sustained virological response (SVR) was achieved in 21% of the coinfected patients and in 36% of monoinfected patients (p = 0.013). For genotype 1, SVR rates were 10% and 33% (p = 0.002), respectively; no significant differences were observed for the other genotypes. A multivariate analysis based on the whole series identified HIV-coinfection as an independent predictor of lack of SVR (OR, 0.17; 95% CI, 0.06-0.42). Other predictors of SVR were donor age, pretreatment HCV viral load, HCV genotype, and early virological response. SVR was associated with a significant improvement in survival: 5-year survival after antiviral treatment was 79% for HCV/HIV-coinfected patients with SVR vs. 43% for those without (p = 0.02) and 92% vs. 60% in HCV-monoinfected patients (p < 0.001), respectively. CONCLUSIONS: The response to pegylated interferon and ribavirin was poorer in HCV/HIV-coinfected liver recipients, particularly those with genotype 1. However, when SVR was achieved, survival of coinfected patients increased significantly.


Assuntos
Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Transplante de Fígado , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/administração & dosagem , Coinfecção , Portadores de Fármacos , Quimioterapia Combinada , Feminino , Seguimentos , HIV/genética , Infecções por HIV/virologia , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/genética , Proteínas Recombinantes/administração & dosagem , Recidiva , Resultado do Tratamento , Carga Viral
11.
World J Gastroenterol ; 20(43): 16203-14, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25473175

RESUMO

AIM: To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts. METHODS: Sprague-Dawley rat livers were stored in University of Wisconsin preservation solution and then washed with different rinse solutions (Ringer's lactate solution and a new rinse solution enriched with PEG-35 at either 1 or 5 g/L) before ex vivo perfusion with Krebs-Heinseleit buffer solution. We assessed the following: liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity), liver function (bile output and vascular resistance), oxidative stress (malondialdehyde), nitric oxide, liver autophagy (Beclin-1 and LCB3) and cytoskeleton integrity (filament and globular actin fraction); as well as levels of metalloproteinases (MMP2 and MMP9), adenosine monophosphate-activated protein kinase (AMPK), heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1). RESULTS: When we used the PEG-35 rinse solution, reduced hepatic injury and improved liver function were noted after reperfusion. The PEG-35 rinse solution prevented oxidative stress, mitochondrial damage, and liver autophagy. Further, it increased the expression of cytoprotective heat shock proteins such as HO-1 and HSP70, activated AMPK, and contributed to the restoration of cytoskeleton integrity after IRI. CONCLUSION: Using the rinse solution containing PEG-35 was effective for decreasing liver graft vulnerability to IRI.


Assuntos
Isquemia Fria , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Soluções para Preservação de Órgãos/farmacologia , Preservação de Órgãos/métodos , Polietilenoglicóis/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Adenosina/farmacologia , Alopurinol/farmacologia , Animais , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Citoproteção , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Modelos Animais de Doenças , Glutationa/farmacologia , Hepatectomia , Insulina/farmacologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Estresse Oxidativo/efeitos dos fármacos , Rafinose/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
12.
Gastroenterol Hepatol ; 37(8): 480-91, 2014 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-25060591

RESUMO

Renal failure is a frequent complication in liver transplant recipients and is associated with increased morbidity and mortality. A variety of risk factors for the development of renal failure in the pre- and post-transplantation periods have been described, as well as at the time of surgery. To reduce the negative impact of renal failure in this population, an active approach is required for the identification of those patients with risk factors, the implementation of preventive strategies, and the early detection of progressive deterioration of renal function. Based on published evidence and on clinical experience, this document presents a series of recommendations on monitoring RF in LT recipients, as well as on the prevention and management of acute and chronic renal failure after LT and referral of these patients to the nephrologist. In addition, this document also provides an update of the various immunosuppressive regimens tested in this population for the prevention and control of post-transplantation deterioration of renal function.


Assuntos
Transplante de Fígado , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/terapia , Insuficiência Renal/diagnóstico , Insuficiência Renal/terapia , Doença Aguda , Algoritmos , Doença Crônica , Diagnóstico Precoce , Humanos , Testes de Função Renal , Complicações Pós-Operatórias/prevenção & controle , Guias de Prática Clínica como Assunto , Insuficiência Renal/prevenção & controle , Fatores de Risco
13.
Transplant Rev (Orlando) ; 28(2): 84-91, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24602805

RESUMO

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.


Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Transplante de Órgãos/efeitos adversos , Prevenção Primária/métodos , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Humanos , Hospedeiro Imunocomprometido , Incidência , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Masculino , Transplante de Órgãos/métodos , Prognóstico , Análise de Sobrevida
14.
Transpl Int ; 27(5): 493-503, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24472096

RESUMO

Ischemia-reperfusion (IR) injury is an important problem in liver surgery especially when steatosis is present. Ischemic preconditioning (PC) is the only surgical strategy that has been applied in patients with steatotic livers undergoing warm ischemia. Silent information regulator 1 (SIRT1) is a histone deacetylase that regulates various cellular processes. This study evaluates the SIRT1 implication in PC in fatty livers. Homozygous (Ob) Zucker rats were subjected to IR and IR + PC. An additional group treated with sirtinol or EX527 (SIRT1 inhibitors) before PC was also realized. Liver injury and oxidative stress were evaluated. SIRT1 protein levels and activity, as well as other parameters involved in PC protective mechanisms (adenosine monophosphate protein kinase, eNOS, HSP70, MAP kinases, apoptosis), were also measured. We demonstrated that the protective effect of PC was due in part to SIRT1 induction, as SIRT1 inhibition resulted in increased liver injury and abolished the beneficial mechanisms of PC. In this study, we report for the first time that SIRT1 is involved in the protective mechanisms induced by hepatic PC in steatotic livers.


Assuntos
Fígado Gorduroso/complicações , Precondicionamento Isquêmico , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Sirtuína 1/fisiologia , Animais , Apoptose , Proteínas de Choque Térmico HSP70/fisiologia , Fígado/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/fisiologia , Estresse Oxidativo , Ratos , Ratos Zucker , Sirtuína 1/análise
15.
J Pharm Pharmacol ; 66(1): 62-72, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24127984

RESUMO

OBJECTIVES: The aim of this study is to investigate the protective mechanisms induced by bortezomib added to Institut George Lopez (IGL)-1 preservation solution to protect steatotic livers against cold ischaemia reperfusion injury and to examine whether these mechanisms occur through the activation of adenosine monophosphate activated protein kinase (AMPK), Akt/mTOR pathways. METHODS: Steatotic livers from obese rats were preserved for 24 h (at 4 °C) in IGL-1 solution with or without bortezomib (100 nM) or pretreated with AMPK inhibitor adenine 9-α-D-arabinofuranoside and preserved in IGL-1 + bortezomib. Livers were then perfused for 2 h at 37 °C. Liver injury (alanine aminotransferase/aspartate aminotransferase) and function (bile production and vascular resistance) were measured. Also, Akt/mTOR, phosphorylated AMPK (pAMPK) and apoptosis were determined by Western blot analyses. KEY FINDINGS: Bortezomib addition to IGL-1 solution significantly reduced steatotic liver injury, improved graft function and decreased liver apoptosis. These benefits were diminished by the pretreatment of obese rats with AMPK inhibitor Ara. Western blot analyses showed a significant increase in pAMPK after ischaemia and reperfusion. We also observed a significant phosphorylation of Akt in IGL-1 +bortezomib group that, in turn, induced the phosphorylation of mTOR and glycogen synthase kinase 3ß. CONCLUSIONS: Bortezomib, at low and non toxic concentration, is a promising additive to IGL-1 solution for steatotic liver preservation. Its protective effect is due to the activation of AMPK and Akt/mTOR pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Borônicos/farmacologia , Fígado Gorduroso/metabolismo , Soluções para Preservação de Órgãos/farmacologia , Preservação de Órgãos/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Bortezomib , Fígado/metabolismo , Ratos , Ratos Zucker , Traumatismo por Reperfusão/metabolismo , Soluções/farmacologia
16.
Liver Transpl ; 19(2): 199-206, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23404861

RESUMO

In this descriptive study, we examined the role of single-operator cholangioscopy (SOC) in the evaluation of biliary complications after liver transplantation (LT). We prospectively included adult recipients of deceased donor LT who were referred for endoscopic retrograde cholangiopancreatography between June 2009 and July 2011. All patients underwent SOC with biopsy of the biliary anastomosis. Sixteen patients were included: 12 with biliary anastomotic strictures (ASs), 2 with common bile duct stones, 1 with a bile leak, and 1 with sphincter of Oddi dysfunction. Patients with ASs displayed 1 of 2 patterns: (A) mild erythema (n = 9) or (B) edema, ulceration, and sloughing (n = 3). Those without ASs displayed a pale mucosa with mild edema at the anastomosis. Patients with ASs and pattern B required a longer period of stenting than patients with pattern A (457 versus 167 days, P = 0.02). In addition, patients with pattern A had a better response and better resolution of their strictures with endoscopic therapy than those with pattern B (66% versus 33%, P = 0.13). Histological examinations of ASs showed nonspecific intraepithelial inflammation in patients with patterns A and B. Biopsy samples from patients without ASs showed normal columnar epithelial bile duct cells. The total cholangioscopy time for all procedures was 26.8 ± 10.1 minutes. In conclusion, SOC in LT recipients is feasible and allows adequate visualization and tissue sampling of ASs and bile ducts. Two distinct visual patterns that are easily identified with SOC may help to predict the outcomes of endoscopic therapy in patients with biliary complications after LT.


Assuntos
Doenças Biliares/patologia , Sistema Biliar/patologia , Colangiopancreatografia Retrógrada Endoscópica , Transplante de Fígado/efeitos adversos , Adulto , Idoso , Fístula Anastomótica/etiologia , Fístula Anastomótica/patologia , Doenças Biliares/etiologia , Doenças Biliares/terapia , Biópsia , Distribuição de Qui-Quadrado , Colangiopancreatografia Retrógrada Endoscópica/instrumentação , Colestase/etiologia , Colestase/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , Disfunção do Esfíncter da Ampola Hepatopancreática/etiologia , Disfunção do Esfíncter da Ampola Hepatopancreática/patologia , Stents , Fatores de Tempo , Resultado do Tratamento
17.
Exp Mol Pathol ; 94(2): 352-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23305864

RESUMO

BACKGROUND: The dramatic shortage of organs leads to consider the steatotic livers for transplantation although their poor tolerance against ischemia reperfusion injury (IRI). Ubiquitin proteasome system (UPS) inhibition during hypothermia prolongs myocardial graft preservation. The role of UPS in the liver IRI is not fully understood. Bortezomib (BRZ) treatment at non-toxic doses of rats fed alcohol chronically has shown protective effects by increasing liver antioxidant enzymes. We evaluated and compared both proteasome inhibitors BRZ and MG132 in addition to University of Wisconsin preservation solution (UW) at low and non-toxic dose for fatty liver graft protection against cold IRI. EXPERIMENTAL: Steatotic and non-steatotic livers have been stored in UW enriched with BRZ (100 nM) or MG132 (25 µM), for 24h at 4°C and then subjected to 2-h normothermic reperfusion (37 °C). Liver injury (AST/ALT), hepatic function (bile output; vascular resistance), mitochondrial damage (GLDH), oxidative stress (MDA), nitric oxide (NO) (e-NOS activity; nitrates/nitrites), proteasome chymotrypsin-like activity (ChT), and UPS (19S and 20S5 beta) protein levels have been measured. RESULTS: ChT was inhibited when BRZ and MG132 were added to UW. Both inhibitors prevented liver injury (AST/ALT), when compared to UW alone. BRZ increased bile production more efficiently than MG132. Only BRZ decreased vascular resistance in fatty livers, which correlated with an increase in NO generation (through e-NOS activation) and AMPK phosphorylation. GLDH and MDA were also prevented by BRZ. In addition, BRZ inhibited adiponectin, IL-1, and TNF alpha, only in steatotic livers. CONCLUSION: MG132 and BRZ, administrated at low and non toxic doses, are very efficient to protect fatty liver grafts against cold IRI. The benefits of BRZ are more effective than those of MG132. This evidenced for the first time the potential use of UPS inhibitors for the preservation of marginal liver grafts and for future applications in the prevention of IRI.


Assuntos
Ácidos Borônicos/farmacologia , Isquemia Fria , Fígado Gorduroso/metabolismo , Leupeptinas/farmacologia , Transplante de Fígado/métodos , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Adiponectina/antagonistas & inibidores , Animais , Bortezomib , Inibidores de Cisteína Proteinase/farmacologia , Citoproteção/efeitos dos fármacos , Interleucina-1/antagonistas & inibidores , Mitocôndrias Hepáticas/metabolismo , Preservação de Órgãos , Soluções para Preservação de Órgãos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Zucker , Traumatismo por Reperfusão/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
18.
World J Surg ; 36(12): 2914-22, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22968536

RESUMO

BACKGROUND: Few studies have studied the effects of graft quality on non-urgent liver retransplantation (ReLT) outcomes. We aimed to analyze graft characteristics and survival in non-urgent ReLT and the effect of using grafts with extended criteria on survival. METHODS: Eighty non-urgent ReLT were performed from June 1988 to June 2010. The whole series was divided by identical time periods to study time-related effects. We assessed graft quality with donor risk index (DRI) and Briceño scores and recipient status with the Model for End-stage Liver Diseases and Rosen scores. Low and high-risk grafts were defined by a DRI cutoff of 1.8. RESULTS: Graft survival was similar in both periods (1-, 5-, and 10-year graft survivals: 73.5, 46.9, and 40.8 versus 71, 47.7, and 47.7%, p=0.935) although donor quality was worse in the second period (DRI: 1.35±0.32 vs. 1.66±0.34, p<0.001). In the first period high-risk grafts did worse than low-risk grafts (5-year survival: 0 vs. 54.5%, p=0.002) while in the second period outcomes were similar (5-year survival: 48.6 vs. 56.7%, p=0.660). Donor age was the only independent donor factor for graft survival, with lower survival when using grafts from donors over 60-years-old. CONCLUSIONS: Graft quality in ReLT has worsened with time mainly because of older donors but nowadays the use of high-risk grafts in non-urgent ReLT is not associated with worse graft survival because of better perioperative management. Moreover of being selective on recipient conditions, care should be taken when using grafts from donors over 60-years-old for non-urgent ReLT.


Assuntos
Seleção do Doador/normas , Sobrevivência de Enxerto , Transplante de Fígado/normas , Adulto , Fatores Etários , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Avaliação de Processos e Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais , Reoperação , Estudos Retrospectivos , Risco , Fatores de Tempo
19.
Transplant Rev (Orlando) ; 26(4): 261-79, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22902168

RESUMO

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.


Assuntos
Neoplasias , Transplante de Órgãos/normas , Complicações Pós-Operatórias , Guias de Prática Clínica como Assunto/normas , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Cuidados Pós-Operatórios/normas , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Cuidados Pré-Operatórios/normas , Fatores de Risco
20.
Liver Transpl ; 18(10): 1198-208, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22685091

RESUMO

Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver.


Assuntos
Fígado Gorduroso/metabolismo , Hepatectomia/métodos , Isquemia/complicações , Fígado/metabolismo , Reperfusão/efeitos adversos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Vitamina A/metabolismo , Animais , Modelos Animais de Doenças , Fígado Gorduroso/cirurgia , Fígado/irrigação sanguínea , Fígado/cirurgia , Regeneração Hepática/efeitos dos fármacos , Masculino , Ratos , Ratos Zucker , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Plasmáticas de Ligação ao Retinol/farmacologia , Fatores de Tempo , Vitamina A/farmacologia , Vitamina A/uso terapêutico
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