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1.
Transpl Int ; 36: 11729, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37841645

RESUMO

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.


Assuntos
Colangite Esclerosante , Doenças Inflamatórias Intestinais , Transplante de Fígado , Humanos , Colangite Esclerosante/complicações , Colangite Esclerosante/cirurgia , Fatores de Risco , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/cirurgia
2.
Am J Transplant ; 17(3): 754-760, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27545327

RESUMO

The increased prevalence of obesity worldwide threatens the pool of living liver donors. Although the negative effects of graft steatosis on liver donation and transplantation are well known, the impact of obesity in the absence of hepatic steatosis on outcome of living donor liver transplantation (LDLT) is unknown. Consequently, we compared the outcome of LDLT using donors with BMI <30 versus donors with BMI ≥30. Between April 2000 and May 2014, 105 patients received a right-lobe liver graft from donors with BMI ≥30, whereas 364 recipients were transplanted with grafts from donors with BMI <30. Liver steatosis >10% was excluded in all donors with BMI >30 by imaging and liver biopsies. None of the donors had any other comorbidity. Donors with BMI <30 versus ≥30 had similar postoperative complication rates (Dindo-Clavien ≥3b: 2% vs. 3%; p = 0.71) and lengths of hospital stay (6 vs. 6 days; p = 0.13). Recipient graft function, assessed by posttransplant peak serum bilirubin and international normalized ratio was identical. Furthermore, no difference was observed in recipient complication rates (Dindo-Clavien ≥3b: 25% vs. 20%; p = 0.3) or lengths of hospital stay between groups. We concluded that donors with BMI ≥30, in the absence of graft steatosis, are not contraindicated for LDLT.


Assuntos
Índice de Massa Corporal , Transplante de Fígado/métodos , Doadores Vivos , Seleção de Pacientes , Complicações Pós-Operatórias , Obtenção de Tecidos e Órgãos/métodos , Adulto , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco
3.
Am J Transplant ; 17(4): 970-978, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27805315

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 , Suínos
4.
Am J Transplant ; 16(12): 3512-3521, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27088432

RESUMO

Liver transplantation (LT) is the treatment of choice for end-stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first-degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty-three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post-LT follow-up, were included in this study. Of these, 72 (27%) received a graft from a first-degree living-related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first-degree living-related, living-unrelated, or deceased-donor LT. Similarly, time to recurrence, recurrence-related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first-degree living-related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence.


Assuntos
Doenças Autoimunes/cirurgia , Família , Rejeição de Enxerto/etiologia , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Complicações Pós-Operatórias/etiologia , Adulto , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Fatores de Risco
5.
J Viral Hepat ; 23(5): 340-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26710754

RESUMO

The outcome of triple therapy with protease inhibitors (PI) depends on the intrinsic response to interferon. Interferon-stimulated gene (ISG) expression differs by cell type in the liver and is a strong predictor of interferon responsiveness. Patients who respond well to interferon have low/absent ISG expression in hepatocytes but significant ISG expression in macrophages. Nonresponders (NRs) show the opposite pattern. We aimed to determine the association between cell-type-specific ISG staining and treatment outcome with PI-based triple therapy. Liver biopsy tissue from consecutive patients treated with boceprevir or telaprevir with peginterferon and ribavirin was stained for myxovirus A (MxA). Staining was scored 0-3 in macrophages (M-MxA) and hepatocytes (H-MxA), and IL28B genotyping was performed. Of 56 patients included 41 achieved SVR (73%) (sustained virological response), 2 (4%) relapsed, 10 (18%) were NRs, and 3 (5%) were lost to follow-up. Median M-MxA staining was stronger and H-MxA staining was weaker in patients who achieved SVR. MxA staining correlated with IL28B genotype and with the HCV RNA decline during lead-in phase. However, unlike with dual therapy, the negative predictive value (NPV) of absent or weak M-MxA staining was poor (42%), while the positive predictive value improved (93%). Although by multivariable logistic regression M-MxA staining was significantly associated with SVR (OR 4.35, 1.32-14.28, P = 0.012), the predictive ability was inadequate to withhold therapy. The interaction between macrophages and hepatocytes plays a critical role in interferon responsiveness; however, the addition of a PI at least partially overcomes the interferon nonresponse phenotype making the predictive ability of ISG staining less clinically useful.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Interferon-alfa/uso terapêutico , Inibidores de Proteases/uso terapêutico , Adulto , Idoso , Biópsia , Feminino , Perfilação da Expressão Gênica , Hepatócitos/imunologia , Humanos , Interferon-alfa/imunologia , Fígado/patologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Ribavirina/uso terapêutico , Coloração e Rotulagem
6.
Am J Transplant ; 15(6): 1591-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25799890

RESUMO

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 Tratamento
7.
Am J Transplant ; 14(12): 2788-95, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25277134

RESUMO

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.


Assuntos
Rejeição de Enxerto/epidemiologia , Síndrome Hepatorrenal/cirurgia , Falência Renal Crônica/epidemiologia , Transplante de Fígado , Doadores Vivos , Complicações Pós-Operatórias , Adulto , Cadáver , Estudos de Casos e Controles , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Humanos , Incidência , Falência Renal Crônica/mortalidade , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
8.
Am J Transplant ; 13(6): 1441-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23668775

RESUMO

We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts.


Assuntos
Doenças dos Ductos Biliares/prevenção & controle , Morte Encefálica , Transplante de Fígado , Preservação de Órgãos/métodos , Perfusão/métodos , Traumatismo por Reperfusão/prevenção & controle , Angiografia , Animais , Doenças dos Ductos Biliares/diagnóstico por imagem , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão/diagnóstico por imagem , Suínos , Temperatura , Tomografia Computadorizada por Raios X
9.
Ann Med Surg (Lond) ; 77: 103645, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35637985

RESUMO

Background: Curative-intent therapies for hepatocellular carcinoma (HCC) include radiofrequency ablation (RFA), liver resection (LR), and liver transplantation (LT). Controversy exists in treatment selection for early-stage tumours. We sought to evaluate the oncologic outcomes of patients who received either RFA, LR, or LT as first-line treatment for solitary HCC ≤ 3 cm in an intention-to-treat analysis. Materials and methods: All patients with solitary HCC ≤ 3 cm who underwent RFA, LR, or were listed for LT between Feb-2000 and Nov-2018 were analyzed. Cox regression analysis was then performed to compare intention-to-treat (ITT) survival by initial treatment allocation and disease-free survival (DFS) by treatment received in patients eligible for all three treatments. Results: A total of 119 patients were identified (RFA n = 83; LR n = 25; LT n = 11). The overall intention-to-treat survival was similar between the three groups. The overall DFS was highest for the LT group. This was significantly higher than RFA (p = 0.02), but not statistically significantly different from LR (p = 0.14). After multivariable adjustment, ITT survival was similar in the LR and LT groups relative to RFA (LR HR:1.13, 95%CI 0.33-3.82; p = 0.80; LT HR:1.39, 95%CI 0.35-5.44; p = 0.60). On multivariable DFS analysis, only LT was better relative to RFA (LR HR:0.52, 95%CI 0.26-1.02; p = 0.06; LT HR:0.15, 95%CI 0.03-0.67; p = 0.01). Compared to LR, LT was associated with a numerically lower hazard on multivariable DFS analysis, though this did not reach statistical significance (HR 0.30, 95%CI 0.06-1.43; p = 0.13). Conclusion: For treatment-naïve patients with solitary HCC ≤ 3 cm who are eligible for RFA, LR, and LT, adjusted ITT survival is equivalent amongst the treatment modalities, however, DFS is better with LR and LT, compared with RFA. Differences in recurrence between treatment modalities and equipoise in ITT survival provides support for a future prospective trial in this setting.

10.
Scand J Rheumatol ; 40(4): 269-78, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21469939

RESUMO

OBJECTIVE: Fibrin deposition is integral to the pathogenesis of collagen-induced arthritis (CIA), an experimental model of rheumatoid arthritis (RA). Membrane-associated fibrinogen-like protein 2 (mFGL2), a novel inducible prothrombinase, generates fibrin by an alternate pathway and has been reported to be involved in the pathogenesis of a number of immune-mediated diseases. We hypothesized that expression of mFGL2 in inflamed synovium contributes to the fibrin deposition and subsequent inflammation in arthritis. METHODS: DBA/1 mice were immunized with 100 µg bovine collagen type II (CII) emulsified in complete Freund's adjuvant (CFA) followed by lipopolysaccharide (LPS) injection. Expression of mFGL2 prothrombinase in association with fibrin deposition was examined in mice with CIA and CD200-treated mice following induction of CIA. To directly assess the contribution of mFGL2, fgl2(-/-) mice were injected with antibody to CII (anti-CII). RESULTS: Levels of fgl2 mRNA transcripts and mFGL2 protein were markedly up-regulated in joints of mice that developed CIA. Fibrin deposition was prominent within the synovial lining and articular joint space associated with expression of mFGL2. Inhibition of CIA by the immunosuppressant CD200 was associated with decreased expression of fgl2 mRNA and mFGL2 protein and absence of fibrin deposition. Following injection of anti-CII, all fgl2(+/+) mice developed severe arthritis with clinical and histological manifestations characteristic of RA, whereas fgl2(-/-) mice failed to develop any clinical manifestation or histological evidence of arthritis. CONCLUSIONS: This study demonstrates that the prothrombinase activity of mFGL2 contributes to the pathogenesis of experimental arthritis. These studies may have therapeutic implications for patients with RA.


Assuntos
Artrite Experimental/etiologia , Artrite Experimental/fisiopatologia , Fibrinogênio/fisiologia , Tromboplastina/fisiologia , Animais , Antígenos CD/farmacologia , Modelos Animais de Doenças , Fibrina/metabolismo , Fibrinogênio/genética , Imunossupressores/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Transdução de Sinais/fisiologia , Membrana Sinovial/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
11.
Am J Transplant ; 10(2): 364-71, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20415904

RESUMO

Right lobe living donor liver transplantation is an effective treatment for selected individuals with end-stage liver disease. Although 1 year donor morbidity and mortality have been reported, little is known about outcomes beyond 1 year. Our objective was to analyze the outcomes of the first 202 consecutive donors performed at our center with a minimum follow-up of 12 months (range 12-96 months). All physical complications were prospectively recorded and categorized according to the modified Clavien classification system. Donors were seen by a dedicated family physician at 2 weeks, 1, 3 and 12 months postoperatively and yearly thereafter. The cohort included 108 males and 94 females (mean age 37.3 +/- 11.5 years). Donor survival was 100%. A total of 39.6% of donors experienced a medical complication during the first year after surgery (21 Grade 1, 27 Grade 2, 32 Grade 3). After 1 year, three donors experienced a medical complication (1 Grade 1, 1 Grade 2, 1 Grade 3). All donors returned to predonation employment or studies although four donors (2%) experienced a psychiatric complication. This prospective study suggests that living liver donation can be performed safely without any serious late medical complications and suggests that long-term follow-up may contribute to favorable donor outcomes.


Assuntos
Transplante de Fígado , Doadores Vivos , Doadores de Tecidos , Adulto , Feminino , Humanos , Fígado/cirurgia , Falência Hepática/cirurgia , Masculino , Morbidade , Estudos Prospectivos , Resultado do Tratamento , Universidades
14.
J Cyst Fibros ; 17(1): e1-e4, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28549610

RESUMO

Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF.


Assuntos
Fibrose Cística , Transplante de Fígado/métodos , Transplante de Pulmão/métodos , Transplante de Pâncreas/métodos , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Fibrose Cística/cirurgia , Progressão da Doença , Humanos , Fígado/fisiopatologia , Fígado/cirurgia , Pulmão/fisiopatologia , Pulmão/cirurgia , Masculino , Pâncreas/fisiopatologia , Pâncreas/cirurgia , Assistência Perioperatória/métodos , Resultado do Tratamento , Adulto Jovem
15.
Aliment Pharmacol Ther ; 26(2): 305-11, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17593076

RESUMO

BACKGROUND: The (13)C-methacetin breath test (MBT) has been proposed for the non-invasive evaluation of hepatic microsomal activity. AIM: To test a new continuous breath analysis system (BreathID) in comparison with gold-standard isotopic ratio mass spectrometry (IRMS) in patients with chronic hepatitis C infection and to assess the diagnostic performance of these validation data compared with liver biopsy for the quantification of liver fibrosis. METHODS: Fifty patients at different METAVIR stages received 75 mg of (13)C-methacetin. Breath isotopic ratio was analysed over 90 min by BreathID (one sample/3 min; BreathID) and IRMS (one sample/10 min). Results were expressed as delta over baseline [DOB (%)] at each time interval and maximal DOB [DOB(max)(%)]. RESULTS: A high linear association between both methods was observed (R(2) = 0.95, P < 0.001). For all DOB and DOB(max), the limits of agreement by Bland-Altman analysis were within the predefined maximal width of s.d. <2.5%. MBT parameters in patients with high-grade fibrosis were different from patients with low-grade fibrosis (P < 0.001). CONCLUSION: The MBT obtained by an easy to operate, automated BreathID provides results comparable with standard IRMS and differentiates fibrosis grades in patients with chronic hepatitis C infection.


Assuntos
Acetamidas , Testes Respiratórios/métodos , Hepatite C Crônica/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Isótopos de Carbono , Feminino , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática/métodos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Espectrofotometria Infravermelho/métodos
16.
Cell Death Differ ; 11 Suppl 2: S172-80, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15459753

RESUMO

Although exposure of cells to extreme hypotonic stress appears to be a purely experimental set up, it has found an application in clinical routine. For years, surgeons have washed the abdominal cavity with distilled water to lyse isolated cancer cells left after surgery. No data are available supporting this practice or evaluating the potential mechanisms of cell injury under these circumstances. Recent evidence indicates that increases in cell volume stimulate release of adenosine triphosphate and autocrine stimulation of purinergic (P2) receptors in the plasma membrane of certain epithelial cell types. Under physiological conditions, purigenic stimulation can contribute to cell volume recovery through activation of solute efflux. In addition, adenosine triphosphate-P2 receptor binding might trigger other mechanisms affecting cell viability after profound hypotonic stress. This study demonstrates a novel pathway of cell death by apoptosis in human colon cancer cells following a short hypotonic stress. This pathway is induced by transitory cell swelling which leads to extracellular release of adenosine triphosphate (ATP) and specific binding of ATP to P2 receptors (probably P2X7). Extracellular ATP induced activation of caspases 3 and 8, annexin V, release of cytochrome c, and eventually cell death. The effect of ATP can be blocked by addition of (i) apyrase to hydrolyse extracellular ATP and (ii) suramin, a P2 receptor antagonist. Finally, (iii) gadolinium pretreatment, a blocker of ATP release, reduces sensitivity of the cells to hypotonic stress. The adenosine triphosphate-P2 receptor cell death pathway suggests that autocrine/paracrine signaling may contribute to regulation of viability in certain cancer cells disclosed with this pathway.


Assuntos
Trifosfato de Adenosina/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ligação Proteica/fisiologia , Receptores Purinérgicos P2/fisiologia , Água/farmacologia , Animais , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Humanos , Soluções Hipotônicas/farmacologia , Mitocôndrias/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Fatores de Tempo
17.
Transplantation ; 72(6): 1061-5, 2001 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-11579301

RESUMO

BACKGROUND: Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function. METHODS: The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France). RESULTS: Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss. CONCLUSIONS: These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Fígado , Tacrolimo/uso terapêutico , Adulto , Ciclosporina/intoxicação , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Imunossupressores/intoxicação , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/tratamento farmacológico , Retratamento , Estudos Retrospectivos , Terapia de Salvação , Esteroides/administração & dosagem , Esteroides/uso terapêutico
18.
Transplant Proc ; 45(6): 2288-94, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23953540

RESUMO

BACKGROUND: Obesity is thought to be associated with higher rates of morbidity and mortality after liver transplantation (LT); however, its actual impact is difficult to evaluate, in part because of the confounding effects of fluid accumulation on body mass index (BMI). OBJECTIVE: We sought to define the effects of conventional BMI (cBMI) and modified BMI (mBMI; calculated by multiplying the BMI by serum albumin level to compensate for fluid accumulation), on the outcome of LT recipients overall. METHODS: A cohort of 507 patients who underwent LT from April 2000 to August 2006 were analyzed. RESULTS: Pre-LT diabetes mellitus was seen somewhat more frequently in the higher mBMI group (P = .054), whereas there was no difference across cBMI categories. The recipients at extremes of cBMI (>40 kg/m(2) and <18.5 kg/m(2)) had significantly lower patient and graft survival than other groups (P = .038 and P = .010, respectively); however, no statistically significant differences were found in overall patient and graft survival across mBMI categories. There were no differences in duration of intensive care unit stay, duration of overall hospital stay, and vascular complications after LT among mBMI categories. CONCLUSIONS: Pre-LT obesity alone, when estimated by mBMI rather than by cBMI, should not be a contraindication for LT.


Assuntos
Índice de Massa Corporal , Transplante de Fígado , Obesidade/diagnóstico , Adulto , Biomarcadores/sangue , Contraindicações , Feminino , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/sangue , Obesidade/complicações , Obesidade/mortalidade , Ontário , Seleção de Pacientes , Complicações Pós-Operatórias/mortalidade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Albumina Sérica/análise , Albumina Sérica Humana , Fatores de Tempo , Resultado do Tratamento
19.
Transplant Proc ; 45(6): 2331-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23953545

RESUMO

BACKGROUND: Liver transplantation (LT) for hepatitis C virus (HCV)-related end-stage liver disease is impaired by universal disease recurrence and suboptimal response to antiviral therapy. Inhibition of angiotensin-II signalling by angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin-II receptor blockers (ARB) decreases hepatic stellate cell activation in vitro and hepatic fibrogenesis in animal models. A single-center retrospective analysis suggested that angiotensin blockade (AB) inhibits fibrosis progression in recurrent HCV post-LT. This study assessed the effect of AB on fibrosis progression in an independent patient cohort. METHODS: Chart review of all patients who underwent transplantation in our institution for HCV-related ESLD between January 2000 and February 2008 revealed 109 patients with ≥2 protocol liver biopsies and free of antiviral therapy post-LT up to the last biopsy analyzed; 27 of 109 patients were treated with ACE-I/ARB for ≥12 months, 82 were not. Fibrosis was staged using METAVIR. RESULTS: Live-donor LT was more frequent in controls than in the AB group (25% vs 11%; P < .05). However, parameters known to affect outcome of recurrent HCV, including donor age, prevalence of diabetes, acute cellular rejection, and immunosuppression, were similar in both groups. Time between first and last biopsy (median, 23 months), stage of fibrosis, fibrosis progression rates (median 0.47 vs 0.45 unit/y; P = .46), and time to develop fibrosis stage ≥2 did not differ between groups. Results held true if deceased-donor LT were analyzed separately. CONCLUSION: Our study does not support the contention of a previous report that use of AB reduces fibrosis progression in recurrent HCV post-LT.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doença Hepática Terminal/cirurgia , Hepatite C/terapia , Cirrose Hepática/prevenção & controle , Transplante de Fígado , Adulto , Idoso , Antivirais/uso terapêutico , Biópsia , Progressão da Doença , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/virologia , Feminino , Hepatite C/complicações , Hepatite C/diagnóstico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
20.
Transplant Proc ; 44(5): 1351-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22664014

RESUMO

BACKGROUND: Routine induction therapy in living donor liver transplantation (LDLT) has not been well described. METHODS: We reviewed outcomes of induction therapy with rabbit antithymocyte globulin (rATG) or basiliximab within 1 year of LDLT. RESULTS: Between 2002 and 2007, 184 adults underwent LDLT and received induction therapy in addition to standard immunosuppression. Acute cellular rejection (ACR) developed in 17 of 130 patients (13.1%) who received rATG and 13 of 54 patients (24.1%) who received basiliximab (P = .066). The interval between transplantation and rejection as well as rejection severity was similar in patients who received rATG and those who received basiliximab. Hepatitis C (HCV) recurrence requiring initiation of antiviral therapy was more common in patients who received rATG compared with basiliximab (34.5% vs 8.7%; P = .021), and in those who received induction combined with tacrolimus as opposed to cyclosporine (38.5% vs 3.9%; P = .001). rATG and basiliximab were associated with excellent patient and graft survivals well as low rates of opportunistic infections and malignancies. CONCLUSION: Induction with rATG or basiliximab was well tolerated and highly effective at preventing ACR within 1 year of LDLT, but may be associated with a higher risk of clinically significant HCV recurrence in some patients.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Soro Antilinfocitário/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Hepatite C/complicações , Imunossupressores/efeitos adversos , Cirrose Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Proteínas Recombinantes de Fusão/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Antivirais/uso terapêutico , Basiliximab , Distribuição de Qui-Quadrado , Feminino , Rejeição de Enxerto/imunologia , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Cirrose Hepática/virologia , Transplante de Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Ontário , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ativação Viral
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