[Show abstract][Hide abstract] ABSTRACT: Activated regulatory T cells (aTregs) are nowadays a hot topic in organ transplantation to establish their role during acute rejection (AR) episodes. The aim of this multi-center study was to monitor the frequency of aTregs within the first year after transplantation in a cohort of first-time liver transplant recipients enrolled from 2010 to 2012. aTregs frequency was analyzed by means of flow cytometry. Patients who had AR showed higher levels of aTregs during first year after transplantation in comparison with patients who did not have higher levels. High levels of aTregs in liver recipients might be used as a biomarker of AR; however, further studies must be done to address the potential role of aTregs as biomarkers of AR in liver transplantation.
[Show abstract][Hide abstract] ABSTRACT: To investigate an optimal long-term prophylactic strategy for prevention of HBV recurrence after liver transplantation, we conducted a randomized study of 29 transplant recipients receiving a short course of hepatitis B immune globulin (HBIg) + lamivudine (LAM), followed by randomization to long-term prophylaxis with LAM with or without HBIg.
The efficacy and safety, and impact on survival and HBV recurrence of these 2 prophylactic regimens were compared over a mean period of 10 years. In patients with viral recurrence, the HBV quasispecies in the surface/polymerase region were studied by ultra-deep pyrosequencing (UDPS).
The 10-year survival rate was 76% and was not affected by the type of prophylaxis. Four patients had hepatitis B surface antigen (HBsAg recurrence within the first 48 months after orthotopic liver transplantation (OLT). HBsAg-positive and -negative patients showed similar mean survival times, with no differences between the 2 regimens. Low HBV DNA levels were transiently detected in 32% of HBsAg-negative patients. UDPS showed major changes after OLT in the HBV quasispecies of patients with viral recurrence, which may be explained by a "bottleneck" effect of OLT together with prophylactic therapy.
Long-term survival after OLT in end-stage chronic hepatitis B patients was good with both prophylactic strategies. However, low, transient HBV DNA levels were detected even in the absence of HBsAg, showing the importance of continuing HBV prophylaxis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Anti-inflammatory cytokines have an important role in disease, tumour and transplant processes. Alterations in the regulation of several cytokines have been implicated in a variety of inflammatory disorders, including IBD (inflammatory bowel disease) [Crohn′s disease (CD) and ulcerative colitis (UC)]. Cytokine polymorphisms are also known to affect the level of gene expression. Thus, the aim of this study was to determine the relationship between cytokine polymorphisms and the IBD pathologies in a Spanish population. Polymorphisms analysis was performed using PCR-SSOP using a microbeads luminex assay. The following polymorphisms were determined: TNFα [−238G/A (rs361525) and −308G/A (rs1800629)], IFNγ [+874A/T (rs62559044)], TGFβ [+869C/T (rs1982073) and +915G/C (rs1800471)], IL10 [−1082A/A (rs1800896), −592A/C (rs1800872), −819C/T (rs1800871)], IL6 [−174C/G (rs1800795)], IL12p40 [3′UTR −1188A/C (rs3212227)], IL1α [−889C/T (rs1800587)], IL1β [−511C/T (rs1143634) and +3962C/T (rs1143633)], IL1R [Pst-1 1970C/T] and IL1RA [Mspa-1 11100C/T]. No statistical differences in TNFα, IFNγ, TGFβ, IL10, IL6, IL1α, IL1β, IL1R and IL1Ra genotypes and allele distributions between the IBD groups and healthy controls were found. However, we observed significant differences in the 3′UTR −1188A/C polymorphism of IL12p40. So −1188A allele was increased in patients with UC and the −1188C allele (high IL12p40 production) was increased in patients with CD with respect to controls. These data are in concordance with the fact that CD has been shown to be associated with a Th1 T-cell-mediated inflammation model and high IL12/IFNγ production at histological affected sites. These data suggest that cytokine polymorphisms in TNFα, IFNγ, TGFβ, IL10, IL6 and IL1α, IL1β, IL1R and IL1Ra cytokine gene do not seem to be relevant in IBD susceptibility and IL12p40 3′UTR −1188A/C polymorphism seems to be associated with a differential IBD development.
International Journal of Immunogenetics 10/2014; 42(1). DOI:10.1111/iji.12160 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ+ in CD4+CD69+ and in CD8+CD69+ and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2+ in CD8+CD69+ also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments.
[Show abstract][Hide abstract] ABSTRACT: AimThe aim of our study was develop and validate an algorithm system based on morphological features for finding the differences between recurrent hepatitis C virus (HCV) and acute cellular rejection (ACR) in liver biopsies of HCV-transplanted patients.Methods
Two hundred and eighty-eight liver biopsies were analyzed from 121 patients transplanted for HCV. A diagnostic consensus was reached between clinicians and pathologists in 214 biopsies for the diagnosis of recurrent HCV or ACR. A random sample of 114 liver biopsies (derivation cohort) was taken to generate the diagnostic tree and was subsequently evaluated using the validation cohort in 100 liver biopsies by recursive partitioning analysis of morphological variables and time since transplantation.ResultsThe presence of endotheliitis together with a time of less than 6 weeks since LT definitely excluded recurrent HCV. After obtaining the regression tree, diagnostic accuracy was 96% and 93% in the derivation and validation cohort, respectively. Both cases surpassed the pathologist's original diagnosis, which had a diagnostic accuracy of 91% (P < 0.05, for both comparisons).ConclusionA recursive partitioning analysis of the morphological features in liver biopsies from HCV-transplanted patients may be useful for easily distinguishing between recurrent HCV and ACR.
Hepatology Research 06/2014; 45(4). DOI:10.1111/hepr.12369 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: "Anxious preoccupation" is a maladaptive coping strategy for patients with terminal chronic liver pathology causing psychopathologic emotional responses. The aim of this study was to identify "anxious preoccupation" as a coping strategy when faced with this disease and to investigate its relationship with emotional-type psychopathologic symptoms in patients awaiting a liver transplant (LT).
A total of 63 patients awaiting an LT were evaluated. The instrument used to evaluate coping style was the Mental Adjustment to Cancer questionnaire. One of the coping scales of this questionnaire is "anxious preoccupation" (9 items). An Instrument for psychopathologic assessment was used, the SA-45 questionnaire, which assessed 9 psychopathologic dimensions: somatizations, obsessions-compulsions, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.
"Anxious preoccupation" was used as an inadequate coping style by 51% of patients when faced with the disease. Five psychopathologic dimensions were associated with this coping strategy: 1) obsessive-compulsivity: 75% of patients with "anxious preoccupation" had obsessive-compulsivity symptoms compared with 29% of patients with other coping strategies (P < .001); 2) interpersonal sensitivity: 25% vs 6%, respectively (P = .044); 3) depression: 59% vs 29% (P = .015); 4) anxiety: 75% vs 32% (P = .001); and 5) phobic anxiety: 19% vs 3% (P = .050).
More than one-half of the patients on the LT waiting list used "anxious preoccupation" as a coping style for this disease. This strategy was associated with a greater presence of emotional-type psychopathologic symptoms in these patients.
[Show abstract][Hide abstract] ABSTRACT: Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc < 0.05). This -308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD.
International Journal of Immunogenetics 04/2013; 41(1). DOI:10.1111/iji.12059 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial.
KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups.
KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4).
This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.
[Show abstract][Hide abstract] ABSTRACT: Despite the improved overall outcomes of liver transplantation as a result of advances in surgical techniques and improved immunosuppressive control, biliary complications (BCs) continue to be the most common cause of morbidity in liver transplant recipients. The objectives of this study were to analyze the incidence, type, and management of BCs over a 20-year period. We performed a comparative study of two groups of liver transplant patients in our unit operated on by the same surgical team: group I consists of the first 300 liver transplant patients (1989-1992), and group II is composed of the last 300 liver transplants (2007-2011). We found no significant differences in the number of cases of biliary leakage whether or not a Kehr T-tube was used. However, there was a significant relationship between a greater number of anastomotic strictures and less use of a Kehr T-tube. In our series, there has been a decrease over the years in the number of surgical interventions required to resolve these complications and an increase in radiologic and endoscopic treatment.
[Show abstract][Hide abstract] ABSTRACT: Patients with toxic substance abuse syndrome, such as alcohol abuse, have elevated psychopathologic morbidity and mortality such as mood disorders.
To evaluate the emotional-type psychopathologic symptoms in patients with alcohol-induced hepatic cirrhosis on the liver transplant waiting list.
Patients with alcoholic liver cirrhosis who were candidates for liver transplant (n = 41) completed the SA-45 questionnaire (González y Cuevas; 88), which assesses nine dimensions: somatizations, obsessive-compulsivity, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. A control group consisted of patients with chronic nonalcoholic terminal hepatopathies (n = 22).
Seventy-six percent of patients had some kind of psychopathologic symptom compared to 68% of the patients in the control group with other nonalcoholic etiologies (P > .05). The emotional-type clinical symptoms were: (1) somatizations: 37% of patients with alcoholic cirrhosis had this type of clinical symptoms compared to 32% of the control group (P > .05); (2) obsessive-compulsivity: 56% versus 46%, respectively (P > .05); (3) interpersonal sensitivity: 19% versus 9%, respectively (P > .05); (4) depression: 54% versus 27%, respectively (P = .045); (5) anxiety: 59% versus 46%, respectively (P > .05); (6) hostility: 29% versus 5%, respectively (P = .021); (7) phobic anxiety: 10% versus 14%, respectively (P > .05); (8) paranoid Ideation: 7% versus 5%, respectively (P > .05); (9) psychoticism: 5% versus 4%, respectively (P > .05).
The patients with alcoholic liver cirrhosis on the liver transplant waiting list had elevated psychopathologic symptoms. Depressive- and hostile-type emotional alterations were most frequent in this type of patients.
[Show abstract][Hide abstract] ABSTRACT: T-tube removal in liver transplant patients can occasionally cause a massive biliary leak and may require surgical treatment for its resolution. We present our experience with a laparoscopic approach to biliary peritonitis in liver transplant patients after the removal of a T-tube.
From January 2003 until February 2010, we performed 351 liver transplantations in 313 recipients, including 135 with a T-tube. After its removal 31 biliary leaks developed (23%); 12 were massive and required surgery, which utilized a laparoscopic approach.
The mean length of the intervention was 72.9 ± 12.87 minutes (range = 55-95), without any complications during the procedure, and no need to convert to a laparotomy. Mean hospital stay after the intervention was 6.75 ± 3.88 days (range 4-18). There was no mortality from the procedure.
The laparoscopic approach for biliary leakage after T-tube removal is indicated when large diffuse acute peritonitis is established a few hours postremoval of the T-tube. This safe procedure treats the complication without the need for another laparotomy.
[Show abstract][Hide abstract] ABSTRACT: Transplant patients receiving immunosuppressant treatment suffer gastrointestinal symptoms (GIS) limiting their health-related quality of life (HRQOL) and causing dose redíuctions and discontinuations.
This observational, multicenter, cross-sectional study aims to develop and validate a questionnaire for detecting and quantifying the impact of GIS on the HRQOL of patients with functioning organ transplants. We developed a pilot version of the questionnaire SIGIT-QOL (Impact of Gastrointestinal Symptoms on Quality Of Life) and then evaluated the feasibility, validity, and reliability. We consecutively recruited 274 solid organ transplant patients from 20 hospitals. Sociodemographic and clinical data were collected. Patients completed the SIGIT-QOL and Gastrointestinal Quality of Life Index-GIQLI- questionnaires.
Mean age was 52.7 (SD, 7.59) and 181 were male; 43.4% showed an episode of GIS since transplantation (3-12 months before). Of all patients, 95.3% completed the SIGIT-QOL. Mean time of completion was 6.49 minutes. Exploratory factorial analysis identified a 1-dimensional structure (42% of total variance). Internal consistency was high (Cronbach's alpha, 0.889). A significant association was found between the SGITI-QOL and the presence of GIS (P < .01). Finally, correlation coefficients between SIGIT-QOL and GIQLI were moderate-high except for Social Function.
The brief SIGIT-QOL questionnaire can detect and quantify the GIS and their impact on the HRQOL of solid organ transplant patients.
[Show abstract][Hide abstract] ABSTRACT: Co-stimulatory factors such as CD86 and apoptotic molecules such as CD95 and CD95L required to start and to turn off the allogenic immune response may also be present as soluble proteins. To determine the role of the soluble forms of CD86 (sCD86), CD95 (sCD95) and CD95L (sCD95L) in the outcome of liver transplants, we analyzed the circulating levels of these molecules in patients subjected to liver transplantation in the pre-operative period and during the first month post-transplantation. Serum samples were obtained from sixty-nine first orthotopic liver transplants (OLT). The patients were classified into acute rejection (AR=24) and not acute rejection (NAR=45), or considering the presence of chronic active hepatitis B or C (VP=30) or other primary liver diseases (VN=39). The levels of sCD86, sCD95 and sCD95L were analyzed by solid phase sandwich enzyme-linked immunoabsorbent assays. Our results first showed that the pre-transplantation serum levels of sCD86 in the AR group were significantly higher than in the NAR group (1007±82U/mL vs. 739±46U/mL, p=0.006), and in the post-transplantation period these levels decreased sharply. Second, the levels of sCD95L and sCD95 in the pre-transplantation period did not point to statistically significant differences between the AR and NAR groups. Considering primary liver disease, the pre-transplantation levels of sCD86 and sCD95L in the VP group were significantly higher than those of the VN group (VP, 977±69U/mL vs. VN, 722±51U/mL, p<0.002, and VP, 482±78pg/mL vs. VN, 221±31pg/mL, p=0.002, respectively). Multivariate analysis revealed that only the pre-transplantation levels of sCD86 were independently associated with the development of episodes of acute rejection (p=0.005, OR=2.1, IC 95%=1.27-3.47). In conclusion, the present work shows that primary liver disease could influence the pre-transplantation levels of sCD86 and sCD95L. High pre-transplantation serum levels of sCD86 could favor the development of episodes of acute rejection.
[Show abstract][Hide abstract] ABSTRACT: The influence of HLA matching on liver transplant is still controversial, as studies have failed to demonstrate an adverse effect of HLA mismatching on transplant outcome. We examined the effect of HLA mismatching on transplant outcome in a series of 342 consecutive liver transplants (224 finally analyzed). HLA typing was performed by serological and molecular methods. HLA-A matching was associated with an increased chronic rejection incidence (P=0.04). Indeed, HLA-A match also demonstrated a significant impact on allograft survival (P=0.03), confirming previous observation concerning to rejection, as complete HLA-A mismatching favored a better liver transplant outcome. Analysis of HLA-A+B+DR matching also demonstrated a significant impact on graft survival (P<0.05). Multivariate Cox regression analysis confirmed the effect of HLA-A and DPB1 matching as independent risk factors for graft loss. Another independent factor was a positive pre-transplant crossmatch. In conclusion, liver transplant outcome has not been found to be improved by HLA matching, however a poorer HLA compatibility favored a better graft survival and decreased rejection incidence, with a special relevance for HLA-A matching.
[Show abstract][Hide abstract] ABSTRACT: Liver transplantation is the treatment of choice for various types of end-stage liver disease and the most appropriate alternative for the treatment of hepatocellular carcinoma (HCC)-associated liver cirrhosis. The aim of this study was to describe our initial experience with the use of 18-FDG positron emission tomography (PET)/computed tomography CT before and after transarterial chemoembolization (TACE) in HCC patients undergoing liver transplantation, seeking to predict the percentage of tumor necrosis achieved by TACE procedures.
From January 2007 through December 2009, 39 patients with HCC and liver cirrhosis were included in our liver transplantation program. We selected the 6 subjects who underwent 18-fluorodeoxyglucose PET/CT (18-FDG PET/CT) pre- and post-TACE.
The median SUV (standardized uptake value) in the lesions studied were 4 (range, 2.79-6.95) before TACE with a median post-TACE SUV of 0 (range, 0-4). Among patients whose post-TACE SUV decreased to <3, the percentage of necrosis after studying the hepatectomy was >80%.
Performance of an 18-FDG PET/CT before and after TACE and comparison of SUV in patients with HCC awaiting liver transplantation provided valuable information regarding the effectiveness of TACE.