Evaluación de la eficacia de la administración del antioxidante n-acetilcisteína en pacientes trasplantados de hígado

El trasplante hepático(TH) es el tratamiento de elección en las enfermedades hepáticas en estadio terminal, sin embargo, el desequilibrio entre el número de donantes y pacientes en lista de espera ha conducido a las diferentes unidades de trasplante a la utilización de injertos procedentes de donantes con criterios extendidos. Esta práctica, se ha traducido en una reducción de la tasa de mortalidad entre los pacientes en lista de espera, a expensas de un aumento de las complicaciones post-trasplante, como la disfunción temprana del injerto. Dicha complicación influye negativamente tanto en la evolución del paciente como del injerto después del traplante. Sin embargo, sigue sin existir actualmente una solución para disminuir la incidencia de la disfunción del injerto, incidencia que se relaciona directamente con la calidad de hígado donante. La isquemia/reperfusión (IR) producida durante la conservación del injerto hepático es la clave para la disfunción inicial del injerto después del trasplante. Desafortunadamente, la utilización de hígados marginales produce efectos negativos en la función inicial del injerto, condicionando un daño por IR, que es la principal causa de la disfunción del injerto. La fisiopatología de la isquemia resperfusión se debe principalmente al efecto del estrés oxidativo (OS) y la citotoxicidad derivados del desequilibrio entre oxidantes y antioxidantes. El glutation es la principal fuente endógena de antioxidantes, siendo el hígado el principal productor. La depleción de glutation, debido a las condiciones del donante previamente a la donación, junto con el efecto del período de la isquemia pueden dejar al hígado en condiciones desfavorables para vencer al OS durante la reperfusión. La síntesis hepática de glutation es un proceso complejo que depende de compuestos como la cisteína y la metionina, un proceso que se encuentra estrechamente vinculado a su introducción en la dieta o a la de sus precursores. El antioxidante n-acetilcisteína (NAC), es un precursor acetilado de ambos aminoácidos L-cisteína y de glutation reducido (GSH). Múltiples modelos de experimentación animal han demostrado un impacto positivo de la adición de NAC o de infusiones de GSH, disminuyendo el daño por IR durante la preservación hepática. La NAC se utiliza habitualmente en la práctica clínica como agente mucolítico para la enfermedad respiratoria crónica, como antídoto en casos de hepatotoxicidad por sobredosis de acetaminofén y como profilaxis en el daño renal debido a los productos de contraste. La NAC posee un amplio perfil de seguridad y no se han documentado efectos secundarios en función de su dosis. El cuerpo de esta tesis se basa en una revisión sistemática de la literatura publicada sobre el impacto de la NAC en el hígado y en los resultados de un ensayo clínico fase III, unicéntrico, aleatorizado, controlado, de grupos paralelos a fin de valorar la eficacia de la adición de NAC durante la preservación hepática, en el período post-trasplante. Entre noviembre del año 2011 y junio del año 2015, se realizaron 214 trasplantes en pacientes adultos con enfermedad hepática incluidos por primera vez en lista de espera de trasplantes, los cuales fueron asignados de acuerdo con un protocolo informatizado de asignación aleatoria a razón de 1/1: NAC SÍ (113 pacientes) o al protocolo estándar NAC NO (101 pacientes). El protocolo NAC incluía la infusión de NAC por vía periférica 30 mg/kg de NAC solución inyectable al 10%, 300 mg de NAC en la vena mesentérica inferior y en el primer litro de solución de preservación Celsior® por vía portal se añadía una última ampolla de NAC (300 mg). El obejtivo primario de estudio fue la disfunción primaria del injerto definida por K.Olthoff. Biomarcadores de OS determinados por análisis metabolómico fueron analizados.Liver transplantation (LT) has become the effective treatment for end-stage liver disease, however, the imbalance between the number of donors and patients on waiting list has led transplant units to use liver grafts from extended donor criteria. This practice has resulted in lower mortality rates among patients on waiting list at the expenses of an increasing post-transplant complications, such as early allograft dysfunction. This complication dramatically influences graft and patient outcome after LT. Nowadays, a reliable solution to diminish the incidence of early allograft dysfunction is still lacking, and its incidence is strongly determined by donor liver quality. Ischemia/reperfusion injury (IRI) during the conventional cold storage and preservation of donated livers is a key determinant of early graft function after LT. Unfortunately, the use of marginal livers may have negative effects on initial graft function, with prolonged IRI being the main source of graft dysfunction. The pathophysiology of IRI is mainly due to the antioxidative stress and cytotoxicity arising from the imbalance between oxidants and antioxidants. Glutathione is the main endogenous antioxidant, and the liver is the main organ producing glutathione under normal conditions. Glutathione depletion, because of the donor´s stay in the intensive care units and the period of ischemia, can lead to the liver being less able to overcome reperfusion oxidative stress. Hepatic glutathione synthesis is a cysteine/methionine-dependent process strictly linked to the dietary introduction of its precursors. The antioxidant n-acetylcysteine (NAC) is the acetylated precursor of the both amino acid L-cysteine and reduced glutathione. Experimental animal models have shown a potential positive impact of NAC or glutathione infusions in decreasing IRI during cold storage preservation. NAC is commonly used in clinical practice as a mucolytic agent for chronic respiratory illness, as an antidote for hepatotoxicity due to acetaminophen overdose, and as prophylaxis against renal injury due to radiocontrast agents. NAC has a very good safety profile, and there is no documented evidence of dose dependent side effects. This doctoral dissertation is based on a systematic review the effect of NAC on hepatic function and post-LT outcomes of a prospective, randomized, single institution study to test the impact of infusions of NAC during liver procurement. Between November 2011 and June 2015, 214 grafts were transplanted into adult candidates with liver disease who were listed for first LT, and according to a sequential procedure, these patients were randomly assigned in a 1/1 ratio to a NAC protocol (113 patients) or to the standard protocol without NAC, the control group (101 patients). The NAC protocol included a systemic NAC (10%) infusion (30 mg/kg) at the beginning of liver procurement, a locoregional NAC infusion (300 mg through the portal vein) and 300 mg of NAC in the first litre of Celsior® solution through portal vein. The primary endpoint was early allograft dysfunction proposed by K. Olthoff. Metabolomics biomarkers of oxidative stress were analyzed

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case-control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p <.001) and at 6 months (63.4% vs. 90.1%, p <.001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p =.001) and 6 months (p <.001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17-83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03-1.36), and therapy with renin-angiotensin-aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47-34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline

Liver transplantation in elderly patients: a systematic review and first meta-analysis

BACKGROUND: Elderly recipients are frequently discussed by the scientific community but objective indication for this parameter has been provided. The aim of this study was to synthesize the available evidence on liver transplantation for elderly patients to assess graft and patient survival. METHODS: A literature search of the Medline, EMBASE, and Scopus databases was carried out from January 2000 to August 2018. Clinical studies comparing the outcomes of liver transplantation in adult younger (65 years) populations were analyzed. The primary outcomes were patient mortality and graft loss rates. This review was registered (Number CRD42017058261) as required in the international prospective register for systematic review protocols (PROSPERO). RESULTS: Twenty-two studies were included involving a total of 242,487 patients (elderly: 23,660 and young: 218,827) were included in this study. In the meta-analysis, the elderly group had patient mortality (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.97-1.63; P = 0.09; I2 = 48%) and graft (HR: 1.09; 95% CI: 0.81-1.47; P = 0.59; I2 = 12%) loss rates comparable to those in the young group. CONCLUSIONS: Elderly patients have similar long-term survival and graft loss rates as young patients. Liver transplantation is an acceptable and safe curative option for elderly transplant candidates

Low Total Dose of Anti-Human T-Lymphocyte Globulin (ATG) Guarantees a Good Glomerular Filtration Rate after Liver Transplant in Recipients with Pretransplant Renal Dysfunction

We aimed to evaluate the safety and efficacy of low doses of anti-T-lymphocyte globulin (ATG)-based immunosuppression in preserving renal function and preventing liver rejection in liver transplant (LT) recipients with pretransplant renal dysfunction. We designed a prospective single-center cohort study analyzing patients with pre-LT renal dysfunction defined as eGFR<60 mL/min/1.73m2, who underwent induction therapy with ATG (ATG group, n=20). This group was compared with a similar retrospective cohort treated with basiliximab (BAS group, n=20). An economic analysis between both induction therapies was also undertaken. In the ATG group, 45% and 50% of patients had recovered their renal function without acute cellular rejection (ACR) episodes at day 7 and 1 month after LT, respectively, versus 40% and 55% of patients in the BAS group (p=1). Renal function improved in both groups over time and no differences between groups were observed regarding one-year eGRF and one-year probability of ACR. Cost per patient of the ATG course was 403€ (r: 126-756) versus 2,524€ of the basiliximab course (p=0.001). In conclusion, induction with low dose of ATG or basiliximab in patients with pretransplant renal dysfunction is a good strategy for preserving posttransplant renal function; however the use of low-dose ATG resulted in a substantial reduction in drug costs. This trail is registered with ClinicalTrials.gov number: NCT01453218

Early Changes in Blood Urea Nitrogen (BUN) Can Predict Mortality in Acute Pancreatitis: Comparative Study between BISAP Score, APACHE-II, and Other Laboratory Markers—A Prospective Observational Study

Background. Changes in BUN have been proposed as a risk factor for complications in acute pancreatitis (AP). Our study aimed to compare changes in BUN versus the Bedside Index for Severity in Acute Pancreatitis (BISAP) score and the Acute Physiology and Chronic Health Evaluation-II score (APACHE-II), as well as other laboratory tests such as haematocrit and its variations over 24 h and C-reactive protein, in order to determine the most accurate test for predicting mortality and severity outcomes in AP. Methods. Clinical data of 410 AP patients, prospectively enrolled for study at our institution, were analyzed. We define AP according to Atlanta classification (AC) 2012. The laboratory test’s predictive accuracy was measured using area-under-the-curve receiver-operating characteristics (AUC) analysis and sensitivity and specificity tests. Results. Rise in BUN was the only score related to mortality on the multivariate analysis (p=0.000, OR: 12.7; CI 95%: 4.2−16.6). On the comparative analysis of AUC, the rise in BUN was an accurate test in predicting mortality (AUC: 0.842) and persisting multiorgan failure (AUC: 0.828), similar to the BISAP score (AUC: 0.836 and 0.850) and APACHE-II (AUC: 0.756 and 0.741). The BISAP score outperformed both APACHE-II and rise in BUN at 24 hours in predicting severe AP (AUC: 0.873 vs. 0.761 and 0.756, respectively). Conclusion. Rise in BUN at 24 hours is a quick and reliable test in predicting mortality and persisting multiorgan failure in AP patients

The impact of advanced patient age in liver transplantation: a European Liver Transplant Registry propensity-score matching study.

BACKGROUND The futility of liver transplantation in elderly recipients remains under debate in the HCV eradication era. METHODS The aim was to assess the effect of older age on outcome after liver transplantation. We used the ELTR to study the relationship between recipient age and post-transplant outcome. Young and elderly recipients were compared using a PSM method. RESULTS A total of 10,172 cases were analysed. Recipient age >65 years was identified as an independent risk factor associated with reduced patient survival (HR:1.42 95%CI:1.23-1.65,p  0.05) between groups. CONCLUSION Liver transplantation is an acceptable and safe curative option for elderly transplant candidates, with worse long-term outcomes compare to young candidates. The underlying liver disease for liver transplantation has a significant impact on the selection of elderly patients

Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosis

Background & Aims: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. Methods: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021. Results: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14–24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all-cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001). Conclusions: Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed. Impact and implications: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation. Results of this international, multicenter analysis may be used to guide clinical decisions in transplant candidates with complex PVT. Extra-anatomical portal vein anastomoses that allow for at least some recipient splanchnic blood flow to the transplant allograft offer acceptable results. On the other hand, anastomoses that deliver only systemic blood flow to the allograft fail to resolve portal hypertension and should not be performed

The role of liver steatosis as measured with transient elastography and transaminases on hard clinical outcomes in patients with COVID-19

Liver injury has been widely described in patients with Coronavirus disease 2019 (COVID-19). We aimed to study the effect of liver biochemistry alterations, previous liver disease, and the value of liver elastography on hard clinical outcomes in COVID-19 patients. We conducted a single-center prospective observational study in 370 consecutive patients admitted for polymerase chain reaction (PCR)-confirmed COVID-19 pneumonia. Clinical and laboratory data were collected at baseline and liver parameters and clinical events recorded during follow-up. Transient elastography [with Controlled Attenuation Parameter (CAP) measurements] was performed at admission in 98 patients. All patients were followed up until day 28 or death. The two main outcomes of the study were 28-day mortality and the occurrence of the composite endpoint intensive care unit (ICU) admission and/or death. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at admission in 130 patients (35%) and 167 (45%) patients, respectively. Overall, 14.6% of patients presented the composite endpoint ICU and/or death. Neither ALT elevations, prior liver disease, liver stiffness nor liver steatosis (assessed with CAP) had any effect on outcomes. However, patients with abnormal baseline AST had a higher occurrence of the composite ICU/death (21% versus 9.5%, p = 0.002). Patients ⩾65 years and with an AST level > 50 U/ml at admission had a significantly higher risk of ICU and/or death than those with AST ⩽ 50 U/ml (50% versus 13.3%, p < 0.001). In conclusion, mild liver damage is prevalent in COVID-19 patients, but neither ALT elevation nor liver steatosis influenced hard clinical outcomes. Elevated baseline AST is a strong predictor of hard outcomes, especially in patients ⩾65 year