RESUMO
Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.
Assuntos
Hepacivirus/genética , Hepatite C/tratamento farmacológico , Transplante de Fígado/métodos , Oligonucleotídeos/uso terapêutico , Perfusão , Replicação Viral/genética , Animais , Antivirais/uso terapêutico , Circulação Extracorpórea , Hepacivirus/isolamento & purificação , Hepatite C/genética , Hepatite C/virologia , Masculino , SuínosRESUMO
BACKGROUND: Cytomegalovirus (CMV) is a risk factor for patient and graft survival after kidney transplantation. METHODS: We retrospectively analyzed risk factors for CMV infection in 348 patients who received a kidney transplant donated after brain death (n = 232) or by living donation (n = 116) between 2008 and 2013. Of the 348 patients analyzed, 91 received a mammalian target of rapamycin inhibitor (mTORi)-based immunosuppressive regimen. A total of 266 patients were treated with standard immunosuppression (Group 1) consisting of basiliximab induction, calcineurin inhibitor (CNI), and either mycophenolic acid (MPA, n = 219) or everolimus (EVE) (n = 47). We also included 82 patients who received more intense immunosuppression (Group 2) with lymphocyte depletion, CNI, plus either MPA (n = 38) or EVE (n = 44). Only patients in the high-risk constellation received CMV prophylaxis in Group 1, while all patients in Group 2 received prophylaxis for 6 month. RESULTS: The overall rate of CMV infections was low with 10.1% in all patients. Despite the different prophylaxis strategies applied, no difference was seen in CMV infections between Group 1 (10.9%) and Group 2 (13.6%). A multivariate analysis revealed that patients on EVE had fewer CMV complications compared with patients on MPA (P = 0.013, odds ratio [OR] 4.8, confidence interval [CI] 1.4-16.5). Donor and recipient age >65 years was an independent risk factor (P = 0.002, OR 3.2, CI 1.5-6.7) for CMV infections. Patients with CMV infections had significantly worse graft function after 2 years (P = 0.001). CONCLUSION: CMV is a significant risk factor for long-term graft outcome. Patients treated with EVE developed fewer CMV complications compared to patients on MPA. The use of mTORi is useful in patients at high risk of developing CMV infections.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/isolamento & purificação , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Estudos de Coortes , Infecções por Citomegalovirus/virologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Terapia de Imunossupressão , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Estudos RetrospectivosRESUMO
We report the outcome of live donor liver transplantation (LDLT) for patients suffering from acute liver failure (ALF). From 2006 to 2013, all patients with ALF who received a LDLT (n = 7) at our institution were compared to all ALF patients receiving a deceased donor liver transplantation (DDLT = 26). Groups were comparable regarding pretransplant ICU stay (DDLT: 1 [0-7] vs. LDLT: 1 days [0-10]; p = 0.38), mechanical ventilation support (DDLT: 69% vs. LDLT: 57%; p = 0.66), inotropic drug requirement (DDLT: 27% vs. LDLT: 43%; p = 0.64) and dialysis (DDLT: 2 vs. LDLT: 0 patients; p = 1). Median evaluation time for live donors was 24 h (18-72 h). LDLT versus DDLT had similar incidence of overall postoperative complications (31% vs. 43%; p = 0.66). No difference was detected between LDLT and DDLT patients regarding 1- (DDLT: 92% vs. LDLT: 86%), 3- (DDLT: 92% vs. LDLT: 86%), and 5- (DDLT: 92% vs. LDLT: 86%) year graft and patient survival (p = 0.63). No severe donor complication (Dindo-Clavien ≥3 b) occurred after live liver donation. ALF is a severe disease with high mortality on liver transplant waiting lists worldwide. Therefore, LDLT is an attractive option since live donor work-up can be expedited and liver transplantation can be performed within 24 h with excellent short- and long-term outcomes.
Assuntos
Estado Terminal , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Doadores Vivos , Doadores de Tecidos , Adulto , Idoso , Canadá , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Current non-invasive respiratory-based methods of measuring cardiac output [Formula: see text] make doubtful assumptions and encounter significant technical difficulties. We present a new method using an iterative approach [Formula: see text], which overcomes limitations of previous methods. METHODS: Sequential gas delivery (SGD) is used to control alveolar ventilation [Formula: see text] and CO2 elimination [Formula: see text] during a continuous series of iterative tests. Each test consists of four breaths where inspired CO2 [Formula: see text] is controlled; raising end-tidal Pco2 [Formula: see text] by about 1.33 kPa (10 mm Hg) for the first breath, and then maintaining [Formula: see text] constant for the next three breaths. The [Formula: see text] required to maintain [Formula: see text] constant is calculated using the differential Fick equation (DFE), where [Formula: see text] is the only unknown and is arbitrarily assumed for the first iteration. Each subsequent iteration generates measures used for calculating [Formula: see text] by the DFE, refining the assumption of [Formula: see text] for the next test and converging it to the true [Formula: see text] when [Formula: see text] remains constant during the four test breaths. We compared [Formula: see text] with [Formula: see text] measured by bolus pulmonary artery thermodilution [Formula: see text] in seven pigs undergoing liver transplantation. RESULTS: [Formula: see text] implementation and analysis was fully automated, and [Formula: see text] varied from 0.6 to 5.4 litre min(-1) through the experiments. The bias (between [Formula: see text] and [Formula: see text]) was 0.2 litre min(-1) with 95% limit of agreement from -1.1 to 0.7 litre min(-1) and percentage of error of 32%. During acute changes of [Formula: see text], convergence of [Formula: see text] to actual [Formula: see text] required only three subsequent iterations. CONCLUSIONS: [Formula: see text] measurement is capable of providing an automated semi-continuous non-invasive measure of [Formula: see text].
Assuntos
Débito Cardíaco/fisiologia , Monitorização Fisiológica/métodos , Respiração , Animais , Gasometria/métodos , Testes Respiratórios/métodos , Dióxido de Carbono/metabolismo , Modelos Animais , Consumo de Oxigênio/fisiologia , Troca Gasosa Pulmonar/fisiologia , Reprodutibilidade dos Testes , Suínos , Termodiluição/métodos , Volume de Ventilação Pulmonar/fisiologiaRESUMO
Outcomes of living versus deceased donor liver transplantation in patients with chronic liver disease and hepatorenal syndrome (HRS) was compared using a matched pair study design. Thirty patients with HRS receiving a live donor liver transplantation (LDLT) and 90 HRS patients receiving a full graft deceased donor liver transplantation (DDLT) were compared. LDLT versus DDLT of patients with HRS was associated with decreased peak aspartate aminotransferase levels (339 ± 214 vs. 935 ± 1253 U/L; p = 0.0001), and similar 7-day bilirubin (8.42 ± 7.89 vs. 6.95 ± 7.13 mg/dL; p = 0.35), and international normalized ratio levels (1.93 ± 0.62 vs. 1.78 ± 0.78; p = 0.314). LDLT vs. DDLT had a decreased intensive care unit (2 [1-39] vs. 4 [0-93] days; p = 0.004), and hospital stay (17 [4-313] vs. 26 [0-126] days; p = 0.016) and a similar incidence of overall postoperative complications (20% vs. 27%; p = 0.62). No difference was detected between LDLT and DDLT patients regarding graft survival at 1 (80% vs. 82%), at 3 (69% vs. 76%) and 5 years (65% vs. 76%) (p = 0.63), as well as patient survival at 1 (83% vs. 82%), 3 (72% vs. 77%) and 5 years (72% vs. 77%) (p = 0.93). The incidence of chronic kidney disease post-LT (10% vs. 6%; p = 0.4) was similar between both groups. LDLT results in identical long-term outcome when compared with DDLT in patients with HRS.