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Resumen A pesar del consenso universal sobre la necesidad de administrar profilaxis para evitar la recurrencia de la hepatitis B despues del trasplante hepatico (TH), no existen hasta el momento unas recomendaciones nacionales sobre las pautas concretas para la profilaxis y el tratamiento de la infeccion por el virus de la hepatitis B (VHB) en el TH. El objetivo de la VII Reunion de consenso organizada por la Sociedad Espanola de Trasplante Hepatico (SETH) fue unificar criterios y protocolos clinicos entre todas unidades de TH en Espana, sobre como prevenir y tratar la reinfeccion por el VHB despues del TH. La evidencia y las recomendaciones de este documento se han llevado a cabo acuerdo con el sistema Grading of Recommendations Assessment Development and Evaluation (GRADE). En el presente documento se describen las recomendaciones y su grado de evidencia para: la definicion de la recurrencia del VHB post-TH y sus factores de riesgo, la monitorizacion y la profilaxis de la recurrencia del VHB tras el TH en sus diversas etapas, el tratamiento de la hepatitis B antes y despues del TH, y la profilaxis de la infeccion por VHB los receptores de TH con donantes anti-HBc positivo.

BACKGROUND AND AIM: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. METHODS: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels =?5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. RESULTS: in the EVR + rTAC group (n?=?105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73?m2 to 86.1 [27.9] mL/min/1.73?m2) whereas it decreased in the MMF + TAC (n?=?106) group (88.4?[34.3]?mL/min/1.73 m2 to 83.2?[25.2]?mL/min/1.73 m2), with significant (p?0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. CONCLUSION: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

As with any other intervention in health, liver transplantation (LT) entails a variety of risks, including donor-transmitted cancers (DTCs). At present, 2%-4% of used deceased organ donors are known to have a current or past history of malignancy. The frequency of DTCs is consistently reported at 3-6 cases per 10 000 solid organ transplants, with a similar frequency in the LT setting. A majority of DTCs are occult cancers unknown in the donor at the time of transplantation. Most DTCs are diagnosed within 2 y after LT and are associated with a 51% probability of survival at 2 y following diagnosis. The probability of death is greatest for DTCs that have already metastasized at the time of diagnosis. The International Liver Transplantation Society-Sociedad Española de Trasplante Hepático working group on DTC has provided guidance on how to minimize the occurrence of DTCs while avoiding the unnecessary loss of livers for transplantation both in deceased and living donor LT. The group endorses the Council of Europe classification of risk of transmission of cancer from donor to recipient (minimal, low to intermediate, high, and unacceptable), classifies a range of malignancies in the liver donor into these 4 categories, and recommends when to consider LT, mindful of the risk of DTCs, and the clinical condition of patients on the waiting list. We further provide recommendations to professionals who identify DTC events, stressing the need to immediately alert all stakeholders concerned, so a coordinated investigation and management can be initiated; decisions on retransplantation should be made on a case-by-case basis with a multidisciplinary approach.

In the last few years, several studies have analyzed sex and gender differences in liver transplantation (LT), but none have performed a disaggregated analysis of both mortality and causes of death. Data from 15,998 patients, 11,914 (74.5%) males and 4,069 (25.5%) females, transplanted between 2000 and 2016 were obtained from the Liver Transplantation Spanish Registry. Survival analysis was applied to explore recipient sex as a risk factor for death. The causes of death at different follow-up duration were disaggregated by recipient sex for analysis. Short-term survival was higher in males, whereas long-term survival was higher in females. Survival at 1, 5 and 10 years post-transplant was 87.43%, 73.83%, and 61.23%, respectively, in males and 86.28%, 74.19%, and 65.10%, respectively, in females (p = 0.05). Post-LT mortality related to previous liver disease also presented sex differences. Males had 37% increased overall mortality from acute liver failure (p = 0.035) and 37% from HCV-negative cirrhosis (p < 0.001). Females had approximately 16% increased mortality when the liver disease was HCV-positive cirrhosis (p = 0.003). Regarding causes of death, non-malignancy HCV+ recurrence (6.3% vs. 3.9% of patients; p < 0.001), was more frequently reported in females. By contrast, death because of malignancy recurrence (3.9% vs. 2.2% of patients; p = 0.003) and de novo malignancy (4.8% vs. 2.5% of patients; p < 0.001) were significantly more frequent in male recipients. Cardiovascular disease, renal failure, and surgical complications were similar in both. In summary, male patients have lower short-term mortality than females but higher long-term and overall mortality. In addition, the post-LT mortality risk related to previous liver disease and the causes of mortality differ between males and females.

The purpose of the study was to build a predictive model for estimating the risk of ICU admission or mortality among patients hospitalized with COVID-19 and provide a user-friendly tool to assist clinicians in the decision-making process. The study cohort comprised 3623 patients with confirmed COVID-19 who were hospitalized in the SALUD hospital network of Aragon (Spain), which includes 23 hospitals, between February 2020 and January 2021, a period that includes several pandemic waves. Up to 165 variables were analysed, including demographics, comorbidity, chronic drugs, vital signs, and laboratory data. To build the predictive models, different techniques and machine learning (ML) algorithms were explored: multilayer perceptron, random forest, and extreme gradient boosting (XGBoost). A reduction dimensionality procedure was used to minimize the features to 20, ensuring feasible use of the tool in practice. Our model was validated both internally and externally. We also assessed its calibration and provide an analysis of the optimal cut-off points depending on the metric to be optimized. The best performing algorithm was XGBoost. The final model achieved good discrimination for the external validation set (AUC = 0.821, 95% CI 0.787–0.854) and accurate calibration (slope = 1, intercept = −0.12). A cut-off of 0.4 provides a sensitivity and specificity of 0.71 and 0.78, respectively. In conclusion, we built a risk prediction model from a large amount of data from several pandemic waves, which had good calibration and discrimination ability. We also created a user-friendly web application that can aid rapid decision-making in clinical practice.

[EN]: The Spanish Association for the Study of the Liver (AEEH) is convinced that the elimination of hepatitis C virus (HCV) in Spain is possible as long as we are able to use the resources and tools necessary for it. This document reflects the position of the AEEH regarding the elimination of HCV, establishing a wide range of recommendations that can be grouped into five categories: 1) Screening of HCV according to age, of the existence of classic acquisition risk factors of infection, active search of previously diagnosed patients and development of micro-elimination strategies in vulnerable populations; 2) Simplification of HCV diagnosis (one-step diagnosis and diagnosis at the point of patient care); 3) Simplification of patient treatment and improvement of care circuits; 4) Health policy measures, and, finally, 5) Establishment of HCV elimination indicators., [ES]: La Asociación Española para el Estudio del Hígado (AEEH) está convencida de que la eliminación de la hepatitis C en España es posible siempre y cuando seamos capaces de emplear los recursos y las herramientas necesarias para la misma. Este documento refleja la posición de la AEEH respecto a la eliminación del virus de la hepatitis C (VHC), estableciendo una amplia serie de recomendaciones que se pueden agrupar en cinco categorías: 1) cribado del VHC en función de la edad, de la existencia de factores de riesgo clásicos de adquisición de la infección, búsqueda activa de pacientes diagnosticados con anterioridad y desarrollo de estrategias de microeliminación en poblaciones vulnerables; 2) simplificación del diagnóstico del VHC (diagnóstico en un solo paso y diagnóstico en el punto de atención del paciente); 3) simplificación del tratamiento de los pacientes y mejora de los circuitos asistenciales; 4) medidas de política sanitaria, y, finalmente, 5) establecimiento de indicadores de eliminación del VHC.

Background Direct-acting antivirals (DAAs) show high efficacy and safety in HCV-cirrhotic patients, but most maintain clinically significant portal hypertension after sustained virological response (SVR). Non-invasive Baveno and expanded-Baveno criteria can identify patients without high-risk gastroesophageal varices (GEV) who have no need for endoscopic surveillance. However, data after SVR are scarce. We performed a multicenter study to evaluate SVR effects over GEV and diagnostic accuracy of non-invasive criteria after SVR. Methods HCV-cirrhotic patients receiving DAAs and baseline endoscopic evaluation were included (November 2014-October 2015). GEV were classified as low risk (LR-GEV) (< 5 mm) or high risk (HR-GEV) (>= 5 mm or with risk signs). Transient elastography (TE) and endoscopy were performed during follow-up. Results SVR was achieved in 230 (93.1%) of 247 included patients, 151 (65.7%) with endoscopic follow-up. Among 64/151 (42.4%) patients without baseline GEV, 8 (12.5%) developed GEV after SVR. Among 50/151 (33.1%) with baseline LR-GEV, 12 (24%) developed HR-GEV. Patients with GEV progression showed TE >= 25 kPa before treatment (64.7%) or >= 20 kPa after SVR (66.7%). Only 6% of patients without GEV and LSM < 25 kPa before treatment, and 10% of those with baseline LSM < 25 kPa and LSM < 20 kPa after SVR showed GEV progression after 36 months. The negative predictive value of Baveno and expanded-Baveno criteria to exclude HR-GEV was maintained after SVR (100% and 90.7%, respectively). Conclusions HCV-cirrhotic patients can develop HR-GEV after SVR. Surveillance is especially recommended in those with GEV before antiviral treatment. Baveno and expanded-Baveno criteria can be safely applied after SVR. : NCT02758509.

The liver stem cell niche is a specialized and dynamic microenvironment with biomechanical and biochemical characteristics that regulate stem cell behavior. This is feasible due to the coordination of a complex network of secreted factors, small molecules, neural, blood inputs and extracellular matrix (ECM) components involved in the regulation of stem cell fate (self-renewal, survival, and differentiation into more mature phenotypes like hepatocytes and cholangiocytes). In this review, we describe and summarize all the major components that play essential roles in the liver stem cell niche, in particular, growth factor signaling and the biomechanical properties of the ECM.

A comparison between pandemic waves could help to understand the evolution of this disease. The objective of this work was to study the evolution of COVID-19 hospitalized patients on different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of hospitalized patients (5,220) with SARS-CoV-2 infection from February to September in Aragon, Spain. In a comparative way, we analyzed ICU admission and 30-day mortality, clinical characteristics and risk factors, of first and second waves. SARS-CoV-2 virus genome were analyzed in 236 samples. Patients in the first wave (n=2,547) were older (74 y, IQR: 60-86 vs. 70 y, IQR: 53-85; p

Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months, p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months, p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months, p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months, p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response.

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/mu L. HIV-RNA was

A series of 2- or 3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indole derivatives were synthesized, characterized, and evaluated for their in vitro antibacterial and antifungal activities. Additionally, the synthesized compounds were docked into the II DNA gyrase B active site, and their predicted binding modes were inspected. Inhibitory activity were tested against two species of Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), two species of Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes) and two fungi (Candida albicans, Aspergillus niger) using the broth microdilution method. The fluorine-substituted 2-(2-imidazolyl)indole 2b was found to be the most potent antibacterial compound against E. coli and S. aureus strains (MIC value 80 μg/mL). Compounds showed better activity against Gram-positive bacteria compared to Gram-negative bacteria. The docking results predicted that the imidazoline-indole hybrid moiety bind to the active site protein ATP-binding pocket from E. coli and S. aureus with good interaction energy scores. The significant loss of antibacterial activity for some imidazoline-indole analogs could be attributed to several nonoptimal enzyme interactions, including poor hydrogen bonds provided by Asp73 (E. coli gyrase numbering) or Asp81 (S. aureus gyrase numbering) and an associated water molecule.

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Health disparities between men and women have become apparent in recent years in many fields, including the transplant setting. In this chapter, we address gender inequities in liver transplantation, including the type of liver diseases that leads to the need of transplantation, the referral pattern to transplant centers, access to waiting lists, and transplantation itself as well as posttransplant outcome. An analysis and literature search that integrates sociocultural, biological, and physiopathological perspectives is included in each of these different steps. Furthermore, recommendations regarding specific strategies that can be developed to reduce gender disparities in liver transplant care are also suggested. Particularly, changes in the liver allocation system and a consideration for a greater use of live donors and split livers are potential means to improving access to liver transplantation for women.

Orthotopic liver transplantation is the only definitive cure for patients with an end-stage liver disease. However, donor organs are limited and many patients die of liver failure before a suitable donor is found. Liver tissue engineering and regenerative medicine are promising technologies that can reduce the burden of liver shortage by increasing the number of organs available for transplantation. These technologies can also help in the development of novel and consistent biologic surrogates for drug discovery, toxicology, and cancer research. In this chapter, we focus attention on various aspects of liver bioengineering. In the first section, we describe the most representative two- and three-dimensional liver models used in liver tissue engineering, including decellularized and recellularized whole-liver scaffolds. In the second part, we highlight the importance of other hepatic three-dimensional culture models (organoids and spheroids) and bioreactor systems in liver disease and transplantation. Finally, we define its increasing use and applications by the pharmaceutical industry and research laboratories in cancer and drug discovery.

La Asociación Española para el Estudio del Hígado (AEEH) está convencida de que la eliminación de la hepatitis C en España es posible siempre y cuando seamos capaces de emplear los recursos y las herramientas necesarias para la misma. Este documento refleja la posición de la AEEH respecto a la eliminación del virus de la hepatitis C (VHC), estableciendo una amplia serie de recomendaciones que se pueden agrupar en cinco categorías: 1) cribado del VHC en función de la edad, de la existencia de factores de riesgo clásicos de adquisición de la infección, búsqueda activa de pacientes diagnosticados con anterioridad y desarrollo de estrategias de microeliminación en poblaciones vulnerables; 2) simplificación del diagnóstico del VHC (diagnóstico en un solo paso y diagnóstico en el punto de atención del paciente); 3) simplificación del tratamiento de los pacientes y mejora de los circuitos asistenciales; 4) medidas de política sanitaria, y, finalmente, 5) establecimiento de indicadores de eliminación del VHC. The Spanish Association for the Study of the Liver (AEEH) is convinced that the elimination of hepatitis C virus (HCV) in Spain is possible as long as we are able to use the resources and tools necessary for it. This document reflects the position of the AEEH regarding the elimination of HCV, establishing a wide range of recommendations that can be grouped into five categories: 1) Screening of HCV according to age, of the existence of classic acquisition risk factors of infection, active search of previously diagnosed patients and development of microelimination strategies in vulnerable populations; 2) Simplification of HCV diagnosis (one-step diagnosis and diagnosis at the point of patient care); 3) Simplification of patient treatment and improvement of care circuits; 4) Health policy measures, and, finally, 5) Establishment of HCV elimination indicators.

Appropriate post-transplant immunosuppressive regimens that avoid acute rejection, while reducing risk of viral reactivation, have been sought, but remain a chimera. Recent evidence suggesting potential regulatory and antiviral effects of mammalian target of rapamycin inhibitors (mTORi) is of great interest. Although the concept of an immunosuppressive drug with antiviral properties is not new, little effort has been made to put the evidence together to assess the management of immunosuppressive therapy in the presence of a viral infection. This review was developed to gather the evidence on antiviral activity of the mTORi against the viruses that most commonly reactivate in adult solid organ recipients: cytomegalovirus (CMV), polyomavirus, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and hepatitis C virus (HCV). A rapid review methodology and evaluation of quality and consistency of evidence based on the GRADE system was used. The existing literature was variable in nature, although indicating a potential advantage of mTORi in CMV, polyomavirus, and HHV8 infection, and a most doubtful relation with EBV and HCV infection. Several recommendations about the management of these infections are presented that can change certain current patterns of immunosuppression and help to improve the prognosis of the direct and indirect effects of viral infection in solid organ recipients.

Background The aim of this study was to compare fourteen non-invasive indexes/scores: AAR, APRI, Fibroindex, MODEL3, Forns index, FIB4, GUCI, FI, FCI, Pohl score, AP index, CDS, HGM-1 and HGM-2, in order to diagnose the hepatic fibrosis stage in a survey of patients with chronic hepatitis C. Methods 84 patients with chronic hepatitis C were studied. Liver fibrosis was staged according to the Scheuer scoring system. The diagnostic accuracy of these indexes/scores was evaluated by AUROC, contingency tables and logistic regression analysis. Results The best AUROCs (> 0.9) to discriminate cirrhosis (F = 4), were observed for CDS, FI, AAR, MODEL3, FIB4, HGM-2 and FCI. To discriminate at least advance fibrosis (F ≥ 3), the best AUROCs (> 0.89) were for CDS, FI, FIB4, HGM2-2, MODEL3 and FCI. To discriminate at least significant fibrosis (F ≥ 2), the best AUROCs (> 0.8) were for FIB4, GUCI, APRI, FI, Forns index, HGM-2 and FCI. Contingency tables and logistic regression analysis supported the results obtained by AUROC. Conclusions This study compares the diagnostic performance of fourteen indexes for the diagnosis of liver fibrosis stage in the same group of CHC patients. These results allow the selection of the best indexes for further studies in larger populations, in order to build diagnostic algorithms as an alternative to liver biopsy for fibrosis staging in patients with chronic HCV infection. These algorithms would allow to take therapeutical decisions and the continuous follow-up of hepatic fibrosis in these patients.

Naturally-derived biomaterials have been used for decades in multiple regenerative medicine applications. From the simplest cell microcarriers made of collagen or alginate, to highly complex decellularized whole-organ scaffolds, these biomaterials represent a class of substances that is usually first in choice at the time of electing a functional and useful biomaterial. Hence, in this chapter we describe the several naturally-derived biomaterials used in tissue engineering applications and their classification, based on composition. We will also describe some of the present uses of the generated tissues like drug discovery, developmental biology, bioprinting and transplantation.

RESUMEN Introducción: existen diversos indicadores para la valoración de la supervivencia del injerto hepático (DRI americano y ET-DRI europeo, entre otros), pero existen diferencias importantes entre los programas de trasplante de los diferentes países y podría ser que dichos indicadores no sean válidos en nuestro medio. Objetivos: el objetivo de este estudio es describir un nuevo indicador nacional de riesgo del injerto hepático a partir de los resultados del Registro Español de Trasplante Hepático (RETH) y validar el DRI y el ET-DRI. Metodología: el RETH incluye un análisis de Cox de los factores relacionados con la supervivencia del injerto. En base a sus resultados se define el indicador graft risk index (GRI). Las variables que contempla dependen del proceso de donación: edad, causa de muerte, compatibilidad sanguínea y tiempo de isquemia fría; y del receptor: edad, enfermedad de base, virus C, número de trasplante, estado UNOS y técnica quirúrgica. Se obtuvo la curva de la regresión logística y se calcularon las curvas de supervivencia del injerto por estratificación. La precisión se evaluó mediante el área ROC. Resultados: un GRI de 1 se corresponde con una probabilidad de pérdida del injerto del 23,25%; cada punto de aumento del GRI supone que la probabilidad se multiplica por 1,33. El GRI mostró la mejor discriminación por estratificación. El área ROC del DRI fue 0,54 (95% IC, 0,50-0,59) y del ET-DRI, 0,56 (95% IC, 0,51-0,61), frente al GRI 0,70 (95% IC, 0,65-0,73) (p < 0,0001). Conclusiones: el DRI y el ET-DRI no parecen útiles en nuestro medio y sería necesario disponer de un indicador propio. El GRI requiere un estudio nacional que perfile más el indicador y realice una validación más amplia. ABSTRACT Introduction: several indicators are available to assess liver graft survival, including the American DRI and the European ET-DRI. However, there are significant differences between transplant programs of different countries, and the previously mentioned indicators might be not valid in our setting. Objectives: the aim of the study was to describe a new national liver graft risk indicator based on the results obtained from the Registro Español de Trasplante Hepático (RETH) and to validate the DRI and ET-DRI indicators. Methods: the RETH includes a Cox analysis of factors associated with graft survival; the graft risk index (GRI) indicator was defined based on these results. The variables considered are dependent upon the donation conditions (age, cause of death, blood compatibility and cold ischemia time) and the transplant recipient (age, underlying disease, hepatitis C virus, transplant number, UNOS status and surgical technique). A logistic regression curve was obtained and graft survival curves were calculated by stratification. Precision was assessed using the ROC analysis. Results: a GRI of 1 represents a probability of graft loss of 23.25%; each point increase in the GRI score multiplies this probability by 1.33. The best discrimination of GRI was obtained by stratification. The DRI ROC area was 0.54 (95% CI, 0.50-0.59) and the ET-DRI ROC area was 0.56 (95% CI, 0.51-0.61), compared to 0.70 (95% CI, 0.65-0.73) (p < 0.0001) for the GRI. Conclusions: both the DRI and ET-DRI do not seem to be useful in our setting. Hence a national indicator is more desirable. The GRI requires a national study in order to further streamline and assess this indicator.

Introduction: chronic kidney disease is a frequent complication after liver transplantation. The use of calcineurin inhibitors is one of the causes of this complication. Current immunsuppression regimens that reduce the use of calcineurin inhibitors may be associated with an improved preservation of renal function. Objective: the study aimed to assess the evolution of renal function after liver transplantation in the current routine clinical practice. Methods: an observational, prospective, multicenter study in adult liver transplant recipients was performed. Two hundred and thirty patients with a good renal function before transplantation were assessed six months post-transplantation (baseline) and every six months until month 30. Results: at baseline, 32% of the patients had a reduction in the glomerular filtration rate below 60 ml/min/1.73 m2. The mean glomerular filtration rate increased from 72.3 to 75.6 ml/min/1.73 m2 at baseline and month 30 respectively (p < 0.01). The mean serum creatinine levels (mg/dl) decreased from 1.13 to 1.09 (p < 0.01). The percentage of patients with stage 3 chronic kidney disease decreased from 31.7% to 26.4%, whereas the percentage of patients with stage 4 remained unchanged (0.4% at baseline and 0.5% at month 30). No patients progressed to end-stage kidney disease that required dialysis or renal transplantation. Conclusion: in the routine clinical practice, a moderate deterioration of renal function is frequent after liver transplantation. However, advanced chronic kidney disease is infrequent in patients with a good pre-transplant renal function.

Resumen Determinar el estadio de fibrosis hepatica es esencial en el manejo de la enfermedad hepatica en pacientes con hepatitis cronica por virus C. La biopsia hepatica ha sido considerada el gold standard para diagnosticar la enfermedad, la actividad necroinflamatoria y el estadio de fibrosis, pero tiene algunas limitaciones tecnicas y riesgos. Teniendo en cuenta estas limitaciones, existe cierta exigencia en introducir biomarcadores sericos no invasivos para el diagnostico de fibrosis que podrian ser capaces de reemplazar parcialmente a la biopsia hepatica. El biomarcador serico ideal deberia ser especifico para el higado y facil de determinar. Los marcadores sericos se dividen en directos e indirectos. Los directos reflejan el recambio de la matriz extracelular, mientras que los indirectos reflejan alteraciones en la funcion hepatica. Aunque todavia esta limitado el grado de implementacion de los test no invasivos de fibrosis hepatica, esta revision es una vision de conjunto de los biomarcadores, indices y algoritmos diagnosticos de fibrosis hepatica estudiados en hepatitis cronica C pero con un interes potencial en otras hepatopatias cronicas.

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2)) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (

Resumen Introduccion GIDEON es un estudio internacional prospectivo, no intervencionista, que evaluo la seguridad de sorafenib en pacientes con carcinoma hepatocelular (CHC) no resecable en la practica clinica diaria, incluidos pacientes Child-Pugh B. Objetivos Analisis de datos recogidos en Espana sobre seguridad y efectividad de sorafenib y los patrones de tratamiento. Metodos Se recogieron los datos demograficos y de la enfermedad, la dosis inicial usada, los acontecimientos adversos emergentes del tratamiento (AA) y las modificaciones de dosis a lo largo del seguimiento. Se valoraron la supervivencia global y el tiempo hasta la progresion de la enfermedad. La eficacia y la seguridad se analizaron en funcion de la clasificacion Child-Pugh y la dosis inicial. Resultados Se incluyo a 143 pacientes de 19 hospitales espanoles. El 24,5% eran pacientes Child-Pugh B. El 90,9% de los pacientes recibio una dosis inicial de 400 mg/12 h. En pacientes Child-Pugh A se modifico mas frecuentemente la dosis y la duracion del tratamiento fue mas larga. La incidencia de AA y de aquellos relacionados con el farmaco fue similar en los pacientes Child-Pugh A y B, aunque los AA graves fueron mas frecuentes en los pacientes Child-Pugh B. Los mas frecuentes fueron diarrea, fatiga y eritrodisestesia palmo-plantar. La mediana de supervivencia global fue de 384 dias, y superior en pacientes Child-Pugh A (593 vs. 211 dias en Child-Pugh B); la mediana hasta la progresion de la enfermedad fue de 177 dias, similar en ambos subgrupos. Conclusion El perfil de seguridad de sorafenib en pacientes espanoles con CHC no resecable es independiente de la funcion hepatica. El estado Child-Pugh no parece influir en el enfoque de dosificacion de sorafenib ni en el tiempo hasta la progresion, pero si parece ser un fuerte predictor de la supervivencia.

The development of novel and consistent biologic surrogates for drug discovery, toxicology, and cancer research is presently intense and involves a growing number of research groups and institutions around the world. The Twilight of the days of immortalized cell lines as the workhorse of most of our drug development and cancer research efforts seem now to be heading to their end with the introduction of body-on-a-chip platforms, bioengineered tissues and stem cell organoids. In this chapter, we describe the fundamental work and the different strategies that lead to some of the breakthroughs in the generation of hepatic tissue ex vivo. Lastly, we define its increasing use and applications by pharmaceutical industry and research laboratories.

BACKGROUND Diabetes mellitus is a chronic illness with great impact on long-term outcome after liver transplantation (LT). Despite this, the current level of glycemic control and quality of screening strategies for diabetes-associated conditions that are being provided to liver transplant recipients with diabetes have not yet been assessed. METHODS We performed a cross-sectional, multicenter study that included 344 liver transplant recipients and examined the level of glycemic control and its associated factors, as well as the quality of screening strategies for diabetes-associated conditions. RESULTS Seventy-five patients (21.8%) suffered from diabetes before transplantation, and 82 (23.8%) developed diabetes mellitus after transplantation. Adequate glycemic control (HbA1c < 7%) was achieved in 66.7% of the patients. Forty-eight percent of patients underwent regular screening for retinopathy, 47.1% for nephropathy, 4.5% for neuropathy, and 5.7% for foot ulcers. Diabetes was associated with higher frequency of cardiovascular disease and dyslipidemia both before and after LT. Multivariate analysis revealed association between poor glycemic control and arterial hypertension, presence of diabetes before transplantation, elevated GGT, and insulin use. CONCLUSIONS Glycemic control was inadequate in 33.3% of LT recipients with diabetes, and screening protocols for diabetes-associated conditions did not meet the standards for medical care set by the American Diabetes Association in any of the participating centers. Consequently, this study reveals a clear deficiency in the quality of diabetes care provided to patients after LT and, hence, we predict that future progress in this area will have a significant impact on medium-term to long-term outcome of these patients.

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.

Presentation Poster

Efficient cryopreservation of human hepatocytes is essential for their use in cell therapy. This study investigated the effects of adding melatonin and/or dimethyl sulfoxide (DMSO) to pre-incubation and/or freezing solutions on the viability and function of thawed human hepatocytes.Isolated human hepatocytes were pre-incubated for 90 min at 4°C in Williams' Medium E (WEM), WEM containing 5 mM melatonin dissolved in DMSO, or WEM containing the equivalent amount of DMSO (1%). The hepatocytes were frozen in University of Wisconsin solution (UW) and 10% DMSO, with or without 5 mM melatonin. After thawing, viability, plating efficiency, mitochondrial dehydrogenase activity (MTT), and albumin and urea production were analyzed.Viability and plating efficiency were not affected by melatonin or DMSO in pre-incubation media. Unexpectedly, hepatocytes pre-incubated with DMSO had significantly higher MTT (29.7% vs. control, p0.01), albumin (82.8% vs. control, p0.05), and urea amounts (26.2% vs. control, p=0.06) than those incubated only with WEM. Hepatocytes pre-incubated in media containing melatonin had amounts between those of cells incubated with DMSO or only with WEM (p0.05 for MTT and p0.05 for albumin and urea values). Also, the addition of melatonin to the freezing media did not significantly improve any of the studied parameters (p0.05).Adding 1% DMSO to pre-incubation media prior to the cryopreservation of human hepatocytes preserves hepatocyte function after thawing. These findings could be considered in current hepatocyte cryopreservation protocols.

BACKGROUND: Increased blood pressure (BP) is common after liver transplantation. However, there is scarce information on its control. METHODS: In this prospective, cross-sectional, multicenter study, we determined BP according to the recommended international standards in 921 liver transplant patients during one routine outpatient visit to assess their grade of control of BP. At the time of the study, 490 patients had been previously diagnosed with arterial hypertension and were receiving antihypertensive treatment, and 431 were not previously diagnosed as hypertensive. RESULTS: In the hypertensive group, arterial hypertension was uncontrolled (BP >140/90 mm Hg [>130/80 in diabetics]) in 158 (32%) patients and controlled in 332 (68%) patients. In a multivariate analysis, only diabetes was identified as a significant predictor of uncontrolled hypertension. Among patients not previously diagnosed as hypertensive, BP was increased in 106 (25%) and normal in 325 (75%). On multivariate analysis, the only variable independently associated with increased BP in this group was metabolic syndrome. CONCLUSION: BP is not adequately controlled in a noticeable percentage of liver transplant patients, especially in subjects with diabetes or metabolic syndrome.

Information about infections unrelated to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)-infected liver recipients is scarce. The aims of this study were to describe the prevalence, clinical characteristics, time of onset, and outcomes of bacterial, viral, and fungal infections in HIV/hepatitis C virus (HCV)-coinfected orthotopic liver transplant recipients and to identify risk factors for developing severe infections. We studied 84 consecutive HIV/HCV-coinfected patients who underwent liver transplantation at 17 sites in Spain between 2002 and 2006 and were followed until December 2009. The median age was 42 years, and 76% were men. The median follow-up was 2.6 years (interquartile range = 1.25-3.53 years), and 54 recipients (64%) developed at least 1 infection. Thirty-eight (45%) patients had bacterial infections, 21 (25%) had cytomegalovirus (CMV) infections (2 had CMV disease), 13 (15%) had herpes simplex virus infections, and 16 (19%) had fungal infections (7 cases were invasive). Nine patients (11%) developed 10 opportunistic infections with a 44% mortality rate. Forty-three of 119 infectious episodes (36%) occurred in the first month after transplantation, and 53 (45%) occurred after the sixth month. Thirty-six patients (43%) had severe infections. Overall, 36 patients (43%) died, and the deaths were related to severe infections in 7 cases (19%). Severe infections increased the mortality rate almost 3-fold [hazard ratio (HR) = 2.9, 95% confidence interval (CI) = 1.5-5.8]. Independent factors for severe infections included a pretransplant Model for End-Stage Liver Disease (MELD) score >15 (HR = 3.5, 95% CI = 1.70-7.1), a history of AIDS-defining events before transplantation (HR = 4.0, 95% CI = 1.9-8.6), and non-tacrolimus-based immunosuppression (HR = 2.5, 95% CI = 1.3-4.8). In conclusion, the rates of severe and opportunistic infections are high in HIV/HCV-coinfected liver recipients and especially in those with a history of AIDS, a high MELD score, or non-tacrolimus-based immunosuppression.