Quimerismo leucocitario en el trasplante hepático. Hacia la utopía de la inmunotolerancia y la no inmunosupresión

El término quimérico se emplea en medicina para designar a un organismo que contiene poblaciones celulares que proceden de individuos genéticamente distintos de la misma o distinta especie. En el campo del trasplante de médula ósea el quimerismo es de especial importancia, de forma que cuando un trasplante de médula ósea tiene éxito se produce una quimera hematopoyética completa en la que todas las células linfohematopoyéticas presentes en el receptor proceden del donante, aunque a veces se puede encontrar una quimera mixta en la que una pequeña parte de las células son del receptor. Es muy importante el estudio del quimerismo, porque una pérdida de quimera del donante se asocia con una recaída de la enfermedad hematológica (ej. leucemia). En el campo del trasplante de órganos sólidos, y del trasplante hepático, se da una situación inversa en la que una pequeña parte de los leucocitos circulantes en el receptor proceden del donante. Existe la teoría de que la existencia de quimerismo leucocitario del donante en el receptor de un trasplante hepático se asocia con la tolerancia inmunológica al injerto a largo plazo..

Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation

[Background & Aims] Although there is increasing interest in its use, definitive evidence demonstrating a benefit for postmortem normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation is lacking. The aim of this study was to compare results of cDCD liver transplants performed with postmortem NRP vs. super-rapid recovery (SRR), the current standard for cDCD.[Methods] This was an observational cohort study including all cDCD liver transplants performed in Spain between June 2012 and December 2016, with follow-up ending in December 2017. Each donor hospital determined whether organ recovery was performed using NRP or SRR. The propensity scores technique based on the inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups; logistic and Cox regression models were used for binary and time-to-event outcomes.[Results] During the study period, there were 95 cDCD liver transplants performed with postmortem NRP and 117 with SRR. The median donor age was 56 years (interquartile range 45–65 years). After IPTW analysis, baseline covariates were balanced, with all absolute standardised differences <0.15. IPTW-adjusted risks were significantly improved among NRP livers for overall biliary complications (odds ratio 0.14; 95% CI 0.06–0.35, p <0.001), ischaemic type biliary lesions (odds ratio 0.11; 95% CI 0.02–0.57; p = 0.008), and graft loss (hazard ratio 0.39; 95% CI 0.20–0.78; p = 0.008).[Conclusions] The use of postmortem NRP in cDCD liver transplantation appears to reduce postoperative biliary complications, ischaemic type biliary lesions and graft loss, and allows for the transplantation of livers even from cDCD donors of advanced age.[Lay summary] This is a propensity-matched nationwide observational cohort study performed using livers recovered from donors undergoing cardiac arrest provoked by the intentional withdrawal of life support (controlled donation after circulatory death, cDCD). Approximately half of the livers were recovered after a period of postmortem in situ normothermic regional perfusion, which restored warm oxygenated blood to the abdominal organs, whereas the remainder were recovered after rapid preservation with a cold solution. The study results suggest that the use of postmortem normothermic regional perfusion helps reduce rates of post-transplant biliary complications and graft loss and allows for the successful transplantation of livers from older cDCD donors.Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Biliary Complications After Liver Transplantation From Uncontrolled Donors After Circulatory Death: Incidence, Management, and Outcome

The utilization of livers from donation after uncontrolled circulatory death (uDCD) increases the availability of liver grafts, but it is associated with a higher incidence of biliary complications (BCs) and lower graft survival than those organs donated after brain death. From January 2006 to December 2016, we performed 75 orthotopic liver transplantations (OLTs) using uDCD livers. To investigate the relationship of BCs with the use of uDCD OLT, we compared patients who developed BCs (23 patients) with those who did not (non-BC group, 43 patients) after excluding cases of hepatic artery thrombosis (a known cause of BC) and primary nonfunction. The groups had similar uDCD donor maintenance, donor and recipient characteristics, and perioperative morbidity/mortality rates, but we observed a higher rate of hepatocellular carcinoma and hepatitis C virus in the non-BC group. Percutaneous transhepatic biliary dilation, endoscopic retrograde cholangiopancreatography dilation, Roux-en-Y hepaticojejunostomy (HJ), a T-tube, and retransplantation were used for BC management. In the BC group, 1-, 3-, and 5-year patient survival rates were 91.3%, 69.6%, and 65.2%, respectively, versus 77.8%, 72.9%, and 72.9%, respectively, in the non-BC group (P = 0.89). However, 1-, 3-, and 5-year graft survival rates were 78.3%, 60.9%, and 56.5%, respectively, in the BC group versus 77.8%, 72.9%, and 72.9%, respectively, in the non-BC group (P = 0.38). Multivariate analysis did not indicate independent risk factors for BC development. In conclusion, patient and graft survival rates were generally lower in patients who developed BCs but not significantly so. These complications were managed in the majority of patients through radiological dilation, endoscopic dilation, or Roux-en-Y HJ. Retransplantation is necessary in rare cases after the failure of biliary dilation or surgical procedures.Depto. de CirugíaFac. de MedicinaTRUEpu

Liver Transplantation Using Uncontrolled Donors After Circulatory Death: A 10-year Single-center Experience.

Background: One method for increasing the donor pool for orthotopic liver transplantations (OLTs) is to use uncontrolled donation after circulation death (uDCDs). Methods: From January 2006 to December 2016, we performed 75 OLTs using uDCD livers. The control group comprised a sample of 265 OLTs using livers of donations after brain death (DBDs). A comparative study was performed. Results: Of 256 potential uDCD donors cannulated, 75 (29.3%) livers were accepted for OLT. The amount of hemoderivatives transfused was significantly higher in the uDCD group. The rate of primary nonfunction was also significantly higher (P = 0.031) in uDCD recipients (8%) than DBD recipients (1.5%). The overall rate of biliary complications was significantly higher (P = 0.001) in uDCD recipients (23 cases, 30.6%) than DBD recipients (28 cases, 10.6%). In the uDCD group, 1-, 3-, and 5-year patient survival rates were 82.7%, 73%, and 71.5%, respectively; in the DBD group, they were 89%, 83.7%, and 78.8%, respectively (P = 0.180). In the uDCD group, 1-, 3-, and 5-year graft survival rates were 73.3%, 65.1%, and 63.6%, respectively; in the DBD group, they were 87.1%, 81.9%, and 76.5%, respectively (P = 0.013). Multivariate analysis showed that independent risk factors for patient and graft survival were intraoperative transfusion of >6 units of packed red blood cell concentrates and recipients who were older than 60 years. Conclusions: Although graft survival is significantly lower using uDCD livers, 5-year patient survival in recipients of DBD and uDCD livers is similar. After careful selection, the livers of uDCD can be selectively used for OLT.Depto. de CirugíaFac. de MedicinaTRUEpu

Liver transplantation as treatment of familial amyloid polyneuropathy in patients older than 60 years

Background and objective: Familial amyloid polyneuropathy (FAP) is the most prevalent type of hereditary systemic amyloidosis. It is an autosomal dominant disease characterized by the deposition of an abnormal variant transthyretin. It has a worldwide distribution, with localized endemic areas in Portugal, Sweden and Japan. In Spain there is an endemic focus, located in Mallorca. Liver transplantation is the only curative option for patients with FAP. The aim of this study was to describe the clinical and demographic characteristics of patients transplanted with a diagnosis of PAF. Material and method: Six patients with PAF underwent liver transplantation between April 1986 and December 2012. Results: The mean age was 57.7+16 years, patients of Spanish origin were older than 60 years. All patients had progressive symptoms as mixed polyneuropathy. In 2 patients, combined heart-liver transplants sequentially were performed. Patient survival and graft was 80% at one, 3 and 5 years. Conclusions: The only effective treatment for etiologic PAF is liver transplantation. Early detection is the key to the treatment and control, avoiding the irreversible organ damage.Depto. de CirugíaFac. de MedicinaTRUEpu

Trasplante hepático como tratamiento de la polineuropatía amiloidótica familiar en pacientes mayores de 60 años.

Fundamento y objetivo La polineuropatía amiloidótica familiar (PAF) constituye el tipo más prevalente de amiloidosis sistémica hereditaria. Es una enfermedad autosómica dominante que se caracteriza por el depósito de una variante anómala de la transtiretina. Tiene una distribución mundial, con zonas endémicas localizadas en Portugal, Suecia y Japón. En España hay un foco endémico, localizado en Mallorca. El trasplante hepático es la única opción curativa para los pacientes con PAF. El objetivo de este estudio fue describir las características clínicas y demográficas de los pacientes trasplantados con diagnóstico de PAF. Material y método Se evaluaron 6 pacientes trasplantados por PAF entre abril de 1986 y diciembre de 2012. Resultados La edad media fue de 57,7+16 años, los pacientes de origen español eran mayores de 60 años. Todos los pacientes presentaban síntomas progresivos en forma de polineuropatía mixta. En 2 pacientes se realizó un doble trasplante hepatocardiaco secuencial, efectuándose en primer lugar el trasplante hepático. La supervivencia del paciente y del injerto fue del 80% a los uno, 3 y 5 años. Conclusiones El único tratamiento etiológico eficaz para la PAF es el trasplante hepático. Una detección temprana es la clave para el tratamiento y el control, evitándose el daño orgánico irreversible.Depto. de CirugíaFac. de MedicinaTRUEpu