RESUMEN
BACKGROUND: Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction. MATERIAL AND METHODS: Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12-84). RESULTS: Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (<6 ng/mL) TAC monotherapy (P 0.79). CONCLUSION: TAC monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population. The higher incidence of early CRR in the TAC-PL group related to the significantly higher number of patients transplanted while being on artificial organ support. In such condition, this monodrug immunosuppressive strategy needs to be adapted. TAC monotherapy strategy should lay the basis for further large scale minimization studies in liver transplantation.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Hígado , Tacrolimus/uso terapéutico , Adulto , Anciano , Colestasis Intrahepática/cirugía , Método Doble Ciego , Femenino , Humanos , Cirrosis Hepática/cirugía , Pruebas de Función Hepática , Trasplante de Hígado/inmunología , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
The aims of this work were both to validate a sensitive and specific method to quantify tacrolimus (TAC) in liver biopsies after hepatic transplantation and to evaluate the predictive value of either tissue or blood TAC concentrations for rejection in 146 adult patients under a TAC-based immunosuppression. Trough blood levels were monitored daily during the hospital stay by immunoassay. Liver biopsies were routinely performed at day 7 posttransplantation. The tissue assay was developed by liquid chromatography-mass spectrometry. The limit of quantification was 5 pg/mg, with intra- and interassay precision ranging from 3.9% to 14.3% and 4.7% to 15.9%, respectively. The extraction efficiency was approximately 80%. TAC found in liver biopsies ranged from less than 5 up to 387 pg/mg. Blood TAC levels ranged from 2.7 to 19.3 ng/mL. Tissue levels displayed excellent correlation with liver histopathologic BANFF rejection score, whereas blood levels did not. Clinically significant rejections (BANFF scores > or = 6) were characterized by mean TAC tissue and blood concentration of 13.1 pg/mg and 7.6 ng/mL, respectively, whereas these mean values became, respectively, 74.9 pg/mg (P < 0.05) and 7.1 ng/mL (not significant) for nonclinically significant rejection episodes (BANFF < 6). In this study, hepatic tissue TAC concentrations were distributed in a wider range and displayed a significantly better correlation with the severity of the organ rejection than predose blood levels. A tissue TAC concentration less than 30 pg/mg is 89% sensitive and 98% specific to discriminate clinically significant cellular rejection. Further studies are required to better understand the factors affecting TAC distribution within liver tissue (such as carrier proteins and cytochrome genetic polymorphism, liver function, age, hepatic blood flow, type of organ transplanted, time posttransplantation) and to define its value in the treatment of liver allograft rejection.
Asunto(s)
Monitoreo de Drogas/métodos , Rechazo de Injerto/metabolismo , Inmunosupresores/farmacocinética , Trasplante de Hígado , Hígado/metabolismo , Tacrolimus/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cromatografía Liquida , Femenino , Rechazo de Injerto/sangre , Humanos , Inmunosupresores/sangre , Inmunosupresores/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Espectrometría de Masa por Ionización de Electrospray , Tacrolimus/sangre , Tacrolimus/metabolismo , Distribución TisularRESUMEN
The use of livers from anti-hepatitis B core (HBc) positive donors can alleviate donor shortage. Nineteen of 367 (6%) adults receiving anti-HBc positive allografts [three were hepatitis B antigen (HBsAg) negative, hepatitis B antibody (HBsAb) positive; four were HBsAg positive and 12 were not exposed to hepatitis B viral (HBV) infection] were retrospectively reviewed. In HBsAg negative recipients, immunoprophylaxis (IP) was guided by viral serology and immunohistochemistry (IH) of day 0 and day 7 liver biopsies. If IH was negative, IP was stopped. None of three HBsAg negative, HBsAb positive recipients infected; one (replicating) of four HBsAg positive recipients reinfected and seven of eight (87.5%) HBsAg, HBsAb negative recipients, who did not receive long-term IP, infected after a median time of 2 years (range 1-5); one patient died of liver failure. Four HBsAg, HBsAb negative recipients, receiving life-long IP, remained infection free. Anti-HBc positive donor livers must be directed selectively first to HBsAg positive recipients, next to recipients having HBV antibodies and finally to HBV-naive recipients. Identification of both donor and recipient risk factors for HBV infection before transplantation allows indiscriminate use of antiviral prophylaxis. The necessity for IP therapy should be guided by HBV-DNA testing of donor liver tissue and serum. IH of early liver biopsies is an unreliable marker for predicting antiviral treatment requirements.
Asunto(s)
Antígenos del Núcleo de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/análisis , Trasplante de Hígado/inmunología , Donantes de Tejidos/estadística & datos numéricos , Adolescente , Adulto , Biopsia , Estudios de Seguimiento , Hepatitis B/prevención & control , Hepatitis B/transmisión , Humanos , Trasplante de Hígado/patología , Estudios Retrospectivos , Obtención de Tejidos y Órganos/organización & administración , Trasplante Homólogo/inmunología , Resultado del TratamientoRESUMEN
Caroli's disease (CD) or syndrome (CS) are rare inherited disorders which may cause severe, life-threatening, cholangitis or which may lead to hepatobiliary degeneration. The typical cystic biliary anomalies are often associated to congenital hepatic fibrosis (CHF) and, less frequently, to cystic renal disease especially autosomic recessive polycystic kidney disease (ARPKD). The place of liver transplantation (LT) in the treatment of CD or CS is evaluated based on our own experience of three successfully transplanted patients, the literature review of 19 patients and the European experience with 110 patients collected in the European Liver Transplant Registry. LT should be proposed as a definitive therapeutic option once severe cholangitis or (suspicion of) malignant transformation is present. The frequently used radiological, endoscopical or surgical biliary drainage procedures carry a high morbidity and mortality rate. In case of concomitant symptomatic CHF and renal failure, combined or sequential hepatorenal transplantation should be carried out, dependent on the evolution of the hepatic and renal disease. In case of associated ARPKD, renal transplantation is often indicated early on because of the more rapid progression of the renal component of the disease.
Asunto(s)
Enfermedad de Caroli/terapia , Trasplante de Hígado/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Enfermedades Renales/terapia , Hígado/patología , Hepatopatías/terapia , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND STUDY AIMS: Little information is available about long-term results after adult liver transplantation. This study analyses long-term medical complications, changes of immunosuppression, recurrence of primary disease and quality of life 10 years after liver transplantation. MATERIAL AND METHODS: During the period February 1984-April 1994, 324 LT were performed in 282 adults (>15 years). One hundred forty-seven (52%) patients survived more than 10 years. Data regarding health status of 103 patients exclusively followed-up in our institution were analyzed. RESULTS: Actual 1, 5, 10 years survival rates of the 282 recipients were 76.6%, 64.9% and 52% respectively. Forty eight (46.6%) of the 103 studied patients had normal liver tests in their tenth year of the follow-up. Seventy-one (69%) patients were on a CyA, TAC or MMF monotherapy; 31 (30%) patients had CyA levels of less than 100ng/ml. Forty five patients had recurrent allograft disease. Twenty-four (40.6%) of 59 liver biopsy available at 10th year were normal. Thirty five (34%) patients developed chronic renal failure; nine (8.7%) of them had end-stage renal disease. New onset hypertension (>140/100 mmHg) developed in 49 (47.6%) patients; fourteen (13.6%) developed diabetes (glucose blood level > 140 mg/dl) and twenty five (24.2%) patients had serious cardiovascular events. Thirteen (12.6%) patients had a BMI>28 and thirty six (35%) patients had elevated serum cholesterol (>220 mg/dl). Cataract was present in 8 (7.7%) patients. De novo malignancy developed in 23 (22.3%) patients. One patient each developed nasopharyngeal lymphoproliferative disease and myeloma. Quality of life of this patient cohort was excellent as shown by a Karnofsky score of more than 80% in 96.6% of patients. CONCLUSION: The high rate of medical complications and especially of malignant tumours in this long-term follow-up study indicate that further optimization and especially minimization of immunosuppressive therapy as well as development of newer therapies in order to prevent recurrent allograft diseases are the priority for the future development of transplant medicine.