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Background and Aims: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe., Approach and Results: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%)., Conclusions: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background & Aims: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT)., Methods: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT., Results: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates., Conclusion: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors., Impact and Implications: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Long-term immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunosuppressed patients is not well characterized. We aimed to explore the long-term natural immunity against SARS-CoV-2 in liver transplant (LT) recipients compared to the non-transplanted population (control group)., Methods: Fifteen LT recipients and 15 controls matched according to variables associated with disease severity were included at 12 months following the coronavirus disease 2019 (COVID-19) onset. Peripheral blood mononuclear cells were stimulated with peptide pools covering spike (S), nucleocapside (N), and membrane (M) proteins. Reactive CD4+ and CD8+ T cells were identified using flow cytometry, and cytokine production was evaluated in the culture supernatants using cytometric bead array. Serum anti-N and anti-S IgG antibodies were detected with chemiluminescence., Results: The percentage of patients with a positive response in both CD4+ and CD8+ T cells against each viral protein and IL2, IL10, TNF-α, and IFN-γ levels was similar between LT recipients and controls. IFN-γ levels were positively correlated with the percentage of reactive CD4+ (p = 0.022) and CD8+ (p = 0.043) T cells to a mixture of M + N + S peptide pools. The prevalence and levels of anti-N and anti-S IgG antibodies were slightly lower in the LT recipients, but the difference was not statistically significant., Conclusion: LT recipients exhibited a similar T cell response compared to non-transplanted individuals one year after COVID-19 diagnosis., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

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.

Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients., (© 2021 by the American Association for the Study of Liver Diseases.)

The aim of this study was to assess emergency room frequentation, visit causes, and unscheduled readmissions within the first year after discharge from hospital following liver transplantation. Their impact on graft and patient survival was also assessed. This was a retrospective study of the medical records of 98 patients (mean age, 55.6 ± 8.59 years, 77.6 % males) who were consecutively discharged from hospital after undergoing a first liver transplant in our institution during 2012-2015. All visits to the emergency room during the first years after transplantation were analyzed, and survival at two years after transplantation was calculated. Fifty-six of the 98 patients (57.15 %) visited the emergency room on 117 occasions within the first year post-transplantation. Fever (n = 34; 29.05 %) and digestive symptoms (n = 32; 27.35 %) were the most common causes of consultation, and resulted in over half of visits. Thirty-five of these 56 patients (62.5 %) required an urgent readmission during 50 of the 117 (42.7 %) visits. This was primarily due to infectious complications (44 %) of diverse causes (bacterial pneumonia, cholangitis, Clostridium difficile colitis) and biliary tract-related issues. The likelihood of readmission increased from 11.22 % at 30 days after discharge to 22.4 % at 90 days after discharge. Patient survival at 1 and 2 years after transplantation was lower for patients who were readmitted (88.4 % and 80.7 %, respectively) when compared to those who were not readmitted (95.56 % and 91.17 %, respectively, p = 0.002).

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., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Aims: Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking., Methods: Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis., Results: Between March 1 and June 27, 2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39 of 204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five percent of patients requiring hospitalization for COVID-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary end point was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n = 163) (96.4% vs. 89.6% P = 0.017); the SVR in genotype 3 (n = 91) was similar, even in advanced fibrosis (96.7% vs. 88%, P = 0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR = 0.376; 95% CI 0.155-0.910) and baseline MELD (HR = 1.137; 95% CI: 1.061-1.218) were predictors of death. DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response., (© 2017 Steunstichting ESOT.)

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., (© 2017 by the American Association for the Study of Liver Diseases.)

Introduction: The prevalence of portal vein thrombosis (PVT) in patients that have undergone liver transplantation (LT) is 9.7% (SD 4.5). The aim of our study was to determine the prevalence, assess the factors that are associated with PVT and clarify their association with prognosis in patients with liver cirrhosis (LC) and LT., Aims and Methods: From 2005 to 2014, laboratory, radiological and surgical data were collected from patients with LC in our center who had undergone LT for the first time., Results: One hundred and ninety-one patients were included. The mean age was 55 (SD 9), 75.4% of patients were male and 48.7% had HCV. The Child-Pugh scores were A/B/C 41.9%/35.9%/25.5% and the MELD score was 15 (SD 6). Previous decompensations were: ascites (61.4%), hepatic encephalopathy (34.4%), variceal bleeding (25.4%), hepatocellular carcinoma (48.9%) and spontaneous bacterial peritonitis (SPB) (14.3%). The mean post-transplant follow-up was 42 months (0-113). PVT was diagnosed at LT in 18 patients (9.4%). Six patients were previously diagnosed using imaging tests (33.3%): 2 patients (11.1%) by DU and 4 patients (22.2%) by CT scan. All patients with PVT had DU in a mean time of 6 months before LT (0-44) and 90 patients (47.1%) had a CT scan in a median time of 6 months before LT (0-45). PVT was significantly related to the presence of SBP (33.3% vs 12.6%; p = 0.02) and lower levels of albumin (3.1g/dl vs 3.4g/dl; p = 0.05). MELD was higher in patients with PVT (16.6 vs 14.9; p = 0.3). There were no significant differences with regard to the need for transfusion of blood components. Moreover, the surgery time was similar in both groups. PVT correlated with a higher mortality in the first 30 days (8.8% vs 16.7%; p = 0.2)., Conclusion: Prior history of SBP and lower levels of albumin were identified as factors associated with PVT. The pre-transplant diagnosis rate is very low and the presence of PVT may have implications for short-term mortality.

Liver transplantation activates the innate immune system through toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single-nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two-center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real-time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (-1237T/C and -1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02-3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49-5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01-4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy., (© 2015 American Association for the Study of Liver Diseases.)

Organ transplant recipients living in endemic regions are at increased risk of Leishmania infections. Visceral leishmaniasis is the most common kind of presentation in the Mediterranean basin. Rarely, Leishmania infantum may cause localized mucosal disease. We present the first case, to our knowledge, of a liver transplant recipient with localized mucosal leishmaniasis. Twenty-two years after transplantation, a painless, very slow growing ulcer appeared on the inner side of the patient's upper lip. A biopsy performed in the community hospital showed non-specific chronic inflammation without neoplastic signs. Because of a high suspicion of malignancy, the patient was transferred to the referral hospital to consider complete excision. The excisional biopsy revealed a granulomatous inflammatory reaction together with intracellular Leishmania amastigotes within macrophages. Leishmaniasis was confirmed by the nested polymerase chain reaction assay. The clinical and laboratory findings did not suggest visceral involvement. The patient received meglumine antimoniate for 21 days without relevant adverse effects., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Objective: Liver transplantation (LT) is a proven effective treatment of severe liver disease. The aim of this paper is to analyze the results of LT in Spain during the period 1984-2012., Patients and Method: We analyze the results of the database of Spanish Liver Transplant Registry., Results: A total of 20,288 transplants were performed in 18,568 patients. The median age of the donor and recipient increased during the analysis period: 25 years (95% confidence interval [95% CI] 18-40) and 47 years (95% CI 34-55), respectively, in the period 1984-1994 compared to 59 years (95% CI 33-65; P<.05) and 55 years (95% CI 48-61; P<.01), respectively, in the period 2010-2012. The most frequent indications were liver cirrhosis (63.18%) and hepatocellular carcinoma (19.62%). The overall patient and graft survival was respectively 85.1 and 77.8% in the first year, 72.6 and 63.5% the fifth year and 62 and 52.6% in the tenth year. First year patients and graft survival increased respectively from 77.8 and 66.3% in the period 1984-1994 to 88.5 and 83% in 2010-2012 (P<.01). Donor and recipient age, etiology of underlying disease, and hepatitis C virus serological status, were factors associated with decreased survival in univariate and multivariate analysis., Conclusions: Results of LT improved significantly over the review period, despite a progressive increase in donor and recipient age., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

Background: Chronic kidney disease (CKD) is a frequent complication in patients with liver transplantation (LT), and calcineurin inhibitor chronic nephrotoxicity, mediated by transforming growth factor beta1 (TGF-β1) is an important contributing factor. The aim of this study was to assess the influence of genetic polymorphisms of TGF-β1 in the development of CKD at 6 months after transplantation., Methods: One hundred sixty-four LT patients (63.4% male; overall mean age, 48.7 ± 11.6 years) were included in the analysis. CKD was considered at the 6th month after LT and was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) as calculated on the basis of Modification of Diet in Renal Disease 4-variable equation. TGF-β1 +869 C/T and +915 G/C polymorphisms were analyzed with the use of hybridization with fluorescent probes and analysis by means of flow cytometry with the Luminex system. The association between the presence of CKD at 6 months and these polymorphisms, as well as with other known risk factors for CKD after LT, was considered., Results: In the univariate analysis, the TT genotype of TGF-β1 +869 (P = .036; odds ratio, 2.1; 95% confidence interval, 1.1-4.2), age at LT (P < .001), pre-transplantation serum creatinine levels (P = .03), eGFR (P < .001), CKD (P = .027), and immunosuppression with cyclosporine (P = .017) were associated with CKD at 6 months after transplantation. In the multivariate analysis, TGF-β1 +869TT genotype (P = .017), immunosuppression with cyclosporine (P = .002), age at LT (P = .024), and pre-transplantation CKD (P < .001) remained as independent variables associated with the development of CKD at 6 months after transplantation., Conclusions: The genetic polymorphism TGF-β1 +869 C/T may be an independent risk factor for CKD after liver transplantation.

Introduction: New-onset diabetes mellitus after transplantation (NODAT) in patients undergoing liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis is associated with more aggressive HCV recurrence on the graft, rapid progression of fibrosis, and lower rate of sustained viral response to antiviral therapy. The CC genotype at rs12979860 of the IL28B is associated with greater rates of spontaneous clearance of HCV and response to antiviral therapy. IL28B acts on the interferon-stimulated genes through the JAK-STAT pathway, which is related to the development of insulin resistance. The aim of this study was to investigate whether IL28B rs12979860 polymorphism is associated with the development of NODAT after LT for cirrhosis owing to HCV infection., Methods: We analyzed 99 patients (age, 52.7 ± 9.4 years; 70% male) who underwent LT for HCV-related cirrhosis, with ≥1 year of follow-up and with available DNA sample. NODAT was defined starting from the sixth month after LT, according to the international consensus guidelines. Genotyping was carried out by real-time polymerase chain reaction and analysis of the melting temperature with the LightCycler 480 system., Results: Twenty-eight patients (28.3%) developed NODAT. CC genotype at rs12979860 of IL28B was associated with a lesser incidence of NODAT versus non-CC genotypes (P = .05; odds ratio, 0.31; 95% CI, 0.11-0.92). We did not find any association between NODAT and age at transplantation, gender, pretransplant body mass index, presence of hepatocellular carcinoma, type of initial immunosuppression (cyclosporine, tacrolimus or corticosteroids) or acute rejection treated with steroids., Conclusion: The CC genotype at rs12979860 of IL28B is a protective factor for NODAT in patients with LT for HCV-related cirrhosis.

Background: Liver transplantation (LT) in adult patients is associated with a higher incidence of cardiovascular risk factors (CVRF), chronic kidney disease (CKD), and cardiovascular disease mortality than the general population. Available information about these problems in adult patients with LT from a pediatric age is limited. The aim of this study was to analyze the incidence of CVRF, risk of developing CKD, and risk of 10-year coronary event in adult patients who received LT in childhood., Methods: Thirty adult patients (11 female, 19 male; mean age, 29.3 years) who underwent LT in childhood were analyzed, and CVRF, estimated glomerular filtration rate, and current immunosuppressive regimen were recordered. The risk of 10-year coronary event was calculated with the use of validated equations (Framingham and Regicor) and compared with the estimated risk in the general population., Results: None of the patients had CVRF before LT, except 1 patient who received a transplant because of familial hypercholesterolemia. Median age of patients at the time of study was 28.6 years (range, 19.3-43.1 y), and mean follow-up after LT was 17.83 ± 5.21 years. Twenty-nine patients (96.7%) were receiving a calcineurin inhibitor (69% tacrolimus, 31% cyclosporine), along with steroids in 13 of them. The average CVRF per patient was 2, and 11 patients (43.33%) had ≥3. Thirteen patients (43.33%) had CKD. The estimated risk of developing a coronary event at 10 years according to the Framingham score was 3%, higher than expected in the general population of same age and sex. With the use of the Regicor equation, adapted to the Spanish population, the estimated cardiovascular risk was 1.6%, corresponding to Spanish men without CVRF aged 50-55 years. None of the patients had cardiovascular events during the follow-up., Conclusions: Our data show a high incidence of CVRF and CKD in young adults who received LT in childhood, resulting in an increased risk of cardiovascular disease.

Background & Aims: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival., Methods: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores., Results: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48)., Conclusions: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Polymorphisms of the IL28B gene (encoding interferon-λ3) determine the spontaneous course of hepatitis C virus (HCV) infection and its response to antiviral therapy. We investigated the influence of the IL28B rs12979860 (C>T) polymorphism on the risk of severe HCV recurrence after liver transplantation., Methods: Ninety patients who underwent transplantation because of HCV cirrhosis were retrospectively analyzed; forty-one (45.6%) of them with severe HCV recurrence. Forty-eight of their paired donors were available and were also analyzed. IL28B rs12979860 was genotyped by real-time polymerase chain reaction, and evaluated for association with severe HCV recurrence, along with other variables, by univariate and multivariate analyses., Results: The risk allele rs12979860-T was more common in transplanted patients (66.7%) than reported in healthy whites, and it was significantly overrepresented among patients with severe HCV recurrence, in comparison with patients without it (82.9% vs. 53.1%, odds ratio [OR]=4.30, etiologic fraction=63.6%; P=0.0028). Furthermore, separate analysis of the recipients' genotypes indicated that the risk of severe HCV recurrence increased with the dose of the T allele (linear trend, P=0.0068). Multiple logistic regression analysis confirmed the contribution of the IL28B genotype to the risk of severe HCV recurrence (OR=4.27; P=0.014), independently of other associated factors. Allele IL28B T in the donor seemed to have an opposite effect than that in the recipient (OR=0.46), but the study was underpowered to demonstrate this unforeseen effect (P=0.1995)., Conclusions: The recipient IL28B rs12979860 genotype has a major influence on the posttransplantation course of HCV infection, being a valuable biomarker for patient care in liver transplantation.

Liver transplantation activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. The aim of this study was to evaluate the possible association of different single nucleotide polymorphisms (SNPs) in several TLR genes with the incidence of acute graft rejection in liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis. This is a single-center study of 100 adult patients who received a first whole only liver graft from deceased donors at our institution between 1988 and 2009 for cirrhosis due to HCV infection. We examined 10 SNPs in the TLR1 (S6021), TLR2 (R753Q), TLR3 (L412F), TLR4 (D299G and T399I), TLR5 (R392X), TLR6 (S249P), TLR7 (Q11L), and TLR9 (-1237T/C and -1486C/T) genes. Genotyping was carried out with the LightSNiP typing assay (TIB-MolBiol, Berlin, Germany) by analyzing the melting curves with the LightCycler 480 system (Roche Applied Science, Mannheim, Germany). Recipient allelic and genotypic distributions for each SNP were compared among patients with and without acute rejection within the first 3 months after transplantation. We found the homozygous mutant TT genotype for TLR3 L412F was associated with a lower rate of acute rejection when compared with the homozygous wild-type genotype [odds ratio (OR) = 0.1, 95% confidence interval (95% CI) = 0.01-0.86; P = .017], and showed a trend toward a lower graft rejection rate when compared with patients carrying one or two C alleles (OR = 0.15, 95% CI = 0.02-1.2, P = .05). No other associations with acute rejection rates were found for any other SNP evaluated. This preliminary study suggests an important role for SNP TLR3 L412F in acute rejection in liver transplant patients for HCV-related cirrhosis. Nevertheless, these findings must be prospectively validated in other cohorts of patients as well as in patients after liver transplantation for other etiologies than HCV., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The incidence of fungal complications is frequent among liver transplanted subjects. Between March 1986 and June 2009, we performed 670 liver transplants in 593 patients, including 61% males and an overall average age of 46. The incidence of arterial complications in our center was 5.3% (32/593 patients), including 24 (75%) thromboses, 5 (16%) pseudoaneurysms, 2 anastomotic stenoses, and 1 an iliac graft rupture owing to a mycotic aneurysm. Four patients presented arterial complications associated with Aspergillus sp. Three of them were males of mean age 50 years and 3 had an acute rejection episode. Immunosuppression was cyclosporine (CsA), steroids, and azathioprine. Four arterial complications were diagnosed: 2 thromboses and 2 pseudoaneurysm ruptures. Two patients presented biliary complications associated with the arterial complication and Aspergillus infection. Treatment was expectant in 1 patient, interventional radiology in an other, and retransplantation in the other 2. All patients infected with Aspergillus sp. diad of sepsis and multiorgan failure. Arterial complications posttransplant associated with infection by Aspergillus sp., can be an important cause of retransplantation, sepsis and death., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This open-label, randomized study compared the efficacy of a regimen of corticosteroids and tacrolimus (standard therapy group, n = 79) with a regimen of daclizumab induction therapy in combination with mycophenolate mofetil and tacrolimus (modified therapy group, n = 78) in primary liver transplant recipients. The primary endpoint was biopsy-proven acute rejection (BPAR) at 24 weeks. Secondary endpoints included time to rejection and patient and graft survival. The incidence of BPAR was significantly reduced in the modified therapy group compared to the standard therapy group (11.5% versus 26.6%, respectively, P = 0.017). The time to rejection was significantly shorter in the standard therapy group compared with the modified therapy group (P = 0.044). There was no significant difference between groups in patient or graft survival. Hepatitis C virus-positive patients exhibited no differences from hepatitis C virus-negative patients with respect to the incidence of BPAR. A steroid-sparing regimen of daclizumab, mycophenolate mofetil, and tacrolimus was effective and well tolerated in the prevention of BPAR in adult liver transplant recipients in comparison with a standard regimen of tacrolimus and steroids.

Recurrent hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) frequently causes allograft failure, because viral aggressiveness has been shown to be increased among immunosuppressed patients. Several studies have reported lower efficacy of antiviral therapy after OLT associated with worse tolerability. The aim of this study was to compare the logarithmic falls in viral loads at 4 and 12 weeks of treatment with pegylated interferon alpha and ribavirin among OLT versus immunocompetent patients. OLT patients (group 1) were recruited from 3 Spanish centers. Two age- and sex-matched controls (group 2) were randomly assigned to each case. We excluded coinfection with human immunodeficiency virus or hepatitis B or cholestatic hepatitis. Among group 1 (n = 66) were 72.7% men with an overall mean age of 52.7 +/- 10.1 years; 90.9% were genotype 1. The mean baseline viral load was 6.0 +/- 0.6 log10 IU/mL, and 19% of patients had cirrhosis. Among group 2 (n = 132) were 72.7% men with an overall mean age of 50.1 +/- 10.1 years; 92.4% were genotype 1. The mean baseline viral load was 5.9 +/- 0.5 log10 IU/mL, and 17% of patients had cirrhosis. There were no significant differences in patient characteristics between the 2 groups. The logarithmic falls in viral loads at 4 weeks of treatment were similar in groups 1 and 2: 2.3 +/- 2.1 vs 2.4 +/- 1.9 log10 IU/mL (P = .49); they were also similar at 12 weeks of treatment: 3.9 +/- 1.9 vs 3.7 +/- 2.4 log10 IU/mL (P = .66). In conclusion, in our study HCV sensitivity to combined antiviral therapy was the same among transplant versus immunocompetent patients.

Zygomycetes are among the most frequent causes of non-Aspergillus mycelial fungal infections in transplant recipients. We have described a single case of breakthrough zygomycosis. A young Japanese woman presented because of idiopathic fulminant hepatitis and renal failure. On the third day of admission, she underwent orthotopic liver transplantation. A considerable amount of red blood cells and fresh frozen plasma were transfused during surgery. On posttransplant day 2, Candida albicans was isolated from respiratory secretions; prophylactic caspofungin was prescribed. During the next 6 days, C albicans was isolated from tracheal secretions, surgical wound, and exudates and stools. Ventilator-associated pneumonia was diagnosed day 4. Her renal function did not improve during the postoperative period; the patient continued on hemodialysis. On day 28, a dark blue eschar due to zygomycosis was detected on the skin of the nose. Tracheal and nasal exudates yielded Rhizopus sp. The patient died 12 hours later due to multiorgan failure with hypothermia. The fatal evolution in this case may be related to a presumed brain infarction after progressive vessel fungal invasion. The presented case had 2 risk factors related to zygomycosis. A high index of suspicion is required in transplant recipients with risk factors for zygomycosis. Early diagnosis and surgery with appropriate systemic fungal drugs (amphotericin B) are mandatory to improve the prognosis.

Background: Hepatocellular carcinoma (HCC) represents one of the most common malignancies globally, accounting for nearly one million new cases per year. Although the treatment of extrahepatic metastases from primary liver tumors is essentially palliative, a solitary metastasis from such tumors offers a possibility of cure by surgical resection. The adrenal gland is an uncommon site for metastasis from primary liver tumors., Methods: We report a liver transplantation case of HCC and hepatitis B virus in a 23-year-old man with an excellent postoperative result. However, because an increased alpha-fetoprotein was evident and complete radiologic and blood tests were performed, all of which were normal. Three years posttransplantation, a right adrenal mass was identified by CT. PAAF was performed as well as adrenalectomy for a solitary adrenal metastasis from hepatocellular carcinoma., Results: The patient underwent adrenalectomy for the right adrenal metastasis at 3 years following liver transplantation for HCC. He is presently alive and disease-free 24 months after adrenalectomy., Conclusion: Carefully selected patients with solitary metastasis from HCC may be considered for resection.

Surgical site infections are common bacterial infections in orthotopic liver transplantation. The purpose of this study was to determine the incidence, timing, location, and risk factors, specifically antibiotic prophylaxis, for surgical site infections. A prospective study was performed that included a population of 1222 consecutive patients (73.0% males) who underwent liver transplantation in Spanish hospitals belonging to the Red de Estudio de la Infección en el Trasplante research network. One hundred seven patients developed surgical site infections. The predominant infection sites were incisional wound (53 episodes) and peritonitis (40 episodes). The timing of the organ/space surgical site infections was slightly delayed in comparison with incisional surgical site infections. Enterococcus spp., Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii were the predominant pathogens. Choledochojejunal or hepaticojejunal reconstruction (odds ratio, 4.2; 95% confidence interval, 1.6-10.7), previous liver or kidney transplant (odds ratio, 2.6; 95% confidence interval, 1.1-6.3), and more than 4 red blood cell units transfused (odds ratio, 2.0; 95% confidence interval, 1.1-3.4) were independently associated with the development of surgical site infections. Biliary reconstruction by choledochojejunostomy or hepaticojejunostomy increases the risk of surgical site infections.

Hepatitis C recurrence after liver transplantation (LT) is universal, and frequently leads to cirrhosis and death. The aim of our study was to assess the efficacy and safety of 48-weeks of full-dose peg-interferon-alpha-2a (n = 4) or alpha-2b (n = 51) plus ribavirin (>11 mg/kg/day) in a multicentric cohort of 55 patients > or =12 months after LT. All subjects had histologically proven HCV recurrence, excluding severe cholestatic recurrence. Mean age was 54.3 +/- 9.7, 77% male, 90.9% genotype 1, 32.7% cirrhotics. All but 5 patients received monotherapy with tacrolimus (54.5%), cyclosporine (30.7%) or mycophenolate mofetil (5.5%). The rates of end-of-treatment response and sustained virological response (SVR) were 66.7% and 43.6%, respectively. Low baseline HCV-RNA (p = 0.005) and a length from LT to therapy between 2-4 years (p = 0.011) were predictors of SVR. The lack of achieving a viral load decrease > or =1-log10 at week 4 and/or 2-log10 at week 12 was 100% predictive of failure. The most frequent side effects were neutropenia (76,4%), anemia (60%) and infectious complications (30.9%). Toxicity led to peg-interferon withdrawal in 16 (29%) subjects. In 15 patients with post-treatment biopsy, the histological activity index was significantly improved (p = 0.006), whereas fibrosis did not change (p = 0.14). Three patients died (cholangitis, hepatic artery thrombosis and lung cancer). In conclusion, HCV therapy after LT was very effective, although it led to a significant rate of toxicity.

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.

We evaluate 5-year results of a prospective randomized trial that compared cyclosporine microemulsion (CsA-me) and Tacrolimus (Tac) for primary immunosuppression. One hundred one adult patients undergoing liver transplantation were randomized to receive Tac (n = 50) or CsA-me (n = 51). The most frequent indication for the procedure was cirrhosis due to virus C followed by alcoholism. Survival rates at 1, 3, and 5 years were 86%, 75%, and 72%, respectively; there was no significant difference between CsA-me versus Tac arms. Acute rejection occurred in 30 cases (30%), independent of the type of primary immunosuppression. Serious adverse events were reported significantly more among patients under CsA-me (48 episodes) than under Tac (32 episodes). Nineteen patients were switched to the other calcineurin inhibitor. The switch was much more frequent from CsA-me to Tac (n = 15; 29.4%), mainly because of lack of efficacy (n = 10; 19.6%). There were no cases of chronic rejections in the Tac arm. Four patients were switched from Tac to CsA-me for side effects; only 1 remains alive, after treatment was changed from CsA-me to an antimetabolite. There were no statistical differences in renal dysfunction, diabetes, hypertension, neurologic disorders, new-onset malignancies, or infections. There were no differences in survival or rejection among the intention-to-treat groups. Serious adverse events, total patients with switch of calcineurin inhibitor, as well as switches due to lack of efficacy, were statistically more frequent under CsA-me. Tacrolimus seems to be a more appropriate drug to be used for primary immunosuppression in liver transplantation.

Introduction: Although liver transplantation is performed successfully in some patients with previous portosystemic shunts (PSS), these surgical procedures have been considered a relative contraindication for orthotopic liver transplantation (OLT). We aimed to determine whether a previous PSS worsens the prognosis of patients who undergo OLT., Patients and Methods: Between March 1986 and October 2003, 520 liver transplants were performed in 467 patients in our center. Thirteen patients had undergone a PSS before OLT. The types of PSS were: portocaval (n = 8), splenorenal (n = 3), mesocaval (n = 1), and portoatrial (n = 1). We compared patients with previous PSS (cases) and the three patients with an OLT immediately before each case (controls). We analyzed the following variables: age, Child-Pugh stage, pretransplant liver disease, surgical times, transfusion requirements, infections, intensive care unit (ICU) stay, postoperative evolution, and survival., Results: Age, Child-Pugh stage, and pretransplant liver disease were similar in both groups. There were no statistical differences in age, surgical times, ischemia time, anhepatic phase, transfusion requirements, ICU stay, infections, or hospital stay. The postoperative course was similar in both groups. Long-term survival was 84.62% in cases versus 78.5% in controls., Conclusions: Previous PSS should not be considered a contraindication for liver transplantation, even though this group of patients involves a special surgical challenge.

Introduction: Pruritus is the most disabling symptom in patients with cholestatic liver diseases. Many drug therapies have been used for the treatment of these diseases, with different outcomes. The molecular adsorbent recirculating system (MARS) has been used in the treatment of intractable pruritus in cholestatic syndromes. We report our experience with MARS in 3 patients with intractable pruritus on the waiting list: 2 liver transplant recipients and a patient with primary biliary cirrhosis., Patients and Results: Two middle-aged women and 1 middle-aged man, who were recipients of an orthotopic liver transplant for primary biliary cirrhosis, underwent three (n = 2) and two (n = 1) 6-hour sessions of MARS due to medically uncontrollable pruritus. All noted marked improvement of pruritus, with decreased bilirubin levels, but this improvement lasted only a few days in all cases. We observed no changes in transaminase or albumin levels, or prothrombin time. Complications included an episode of angina due to anemia caused by jugular catheter bleeding, and thrombocytopenia in all patients., Conclusions: MARS is an effective treatment for intractable pruritus in cholestatic liver diseases, although its beneficial effect is short. This extracorporeal liver device is safe, because most related adverse events are mild.

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Introduction: The effectiveness of chemotherapy as prophylaxis of tumor recurrence after liver transplantation in patients with advanced hepatocellular carcinoma is controversial., Aim: Our goal was to assess the outcomes of patients with advanced hepatocellular carcinoma treated with chemotherapy after liver transplant., Methods: Ten patients with liver transplants performed between 1993-2002 were men of mean age 55 years. The etiology of cirrhosis was hepatitis C in four patients, alcoholic cirrhosis in four, and cryptogenic cirrhosis in two. Immunosuppressive therapy was cyclosporine in five patients and tacrolimus in five. The chemotherapy regimen used adriamycin (20 mg/m2 weekly for 20 weeks). Six patients were stage IVA and four stage III. Hepatocellular carcinoma was known in five patients and incidental in the other five. Pathology revealed well-differentiated hepatocellular carcinoma in six patients and moderately differentiated hepatocellular carcinoma in four. Five patients had vascular invasion., Results: After a mean posttransplant follow-up of 28 months, six patients (60%) were alive without tumor recurrence, three (30%) had died from tumor recurrence and one due to P. carinii pneumonia. Disease-free survival among patients with stage III was 50% and 80% for stage IVA. Three patients with vascular invasion died of tumor recurrence, and the other two are alive and free of disease. Disease-free survival rates were 83% in patients with well-differentiated hepatocellular carcinoma and 25% in those with moderately differentiated hepatocellular carcinoma. Tolerance of chemotherapy was good with two withdrawals due to nephrotoxicity and myelotoxicity and one death from pneumonia., Conclusion: The use of adriamycin in patients undergoing liver transplant due to advanced hepatocellular carcinoma may be useful to prevent tumor recurrence; it is well tolerated. The presence of vascular tumor invasion and a lower grade of histologic differentiation were associated with a poor prognosis.

There is a direct relationship between the grade of obesity and mortality based on the increased cardiovascular diseases, cancer, etc. However, the results of studies in renal and liver allograft recipients relating obesity to morbidity and mortality are contradictory. A retrospective cohort study of 170 patients transplanted between March 1987 and July 1997 showed obesity to be identified in 77 (45.3%) patients. During the mean follow-up of 5 years posttransplantation, 16 (9.4%) patients experienced cardiovascular complications, including 10 patients with ischemic cardiac syndromes (five acute infarctions and five angina), five patients with acute cerebrovascular accidents, and one patient with intermittent lower limbs claudication. The prevalence of obesity at 1, 3, 5, 7, and 9 years after transplantation was 58.2%, 56.9%, 60.3%, 59.5%, and 66.4%, respectively. Compared with the baseline value, the BMI was increased at 1 year posttransplantation (25.78), a significant difference. No significant differences were found between the mean BMI values of patients with and without cardiovascular diseases, or overweight and morbidly obese patients compared to the normal weight population. Among liver transplant recipients, obesity was a frequent complication after transplantation, but it was not clearly associated with increased morbidity and mortality secondary to cardiovascular disease.

Introduction: Although chronic renal dysfunction (CRD) is a common complication among patients undergoing liver transplantation (OLT) its prevalence, risk factors, and impact on outcome have not been well defined. We aimed to assess the incidence of CRD, its associated risk factors and its impact on outcome., Patients and Methods: The cohort of 289 consecutive adult first liver transplant patients with posttransplant follow-up longer than 6 months received cyclosporine in 230 patients (153 oil-based and 81 microemulsion formulation), tacrolimus in 55. CRD was defined as serum creatinine levels greater than 1.3 mg/dL for more than 6 months., Results: After a mean follow-up of 67 months, 138 patients (47.8%) displayed CRD. The prevalence of CRD was 30.9%, 41.5%, and 38.9% at 1, 5, and 13 years after OLT, respectively. Twelve patients (4.1%) developed end-stage renal failure. Male gender, older recipient age, pretransplant renal dysfunction and hyperuricemia, posttransplant in-hospital renal dysfunction and hyperuricemia, and renal dysfunction during the first 6 months after OLT were each significantly associated with the development of CRD. Survival was significantly lower (63%) among liver transplant patients with CRD than those without this complication (71%, P=.024)., Conclusions: CRD is an important cause of morbidity after OLT, although end-stage renal disease is infrequent. Because early renal dysfunction is associated with the development of CRD, and decreased long-term patient survival, efforts should be made to avoid early renal dysfunction after liver transplantation.

Introduction: Prophylaxis using high-dose intravenous anti-HBV immune globulin (HBIG) is effective to prevent reinfection due to hepatitis B virus (HBV) after orthotopic liver transplantation (OLT). However, this treatment is expensive and intravenous administration is difficult during outpatient care. Our aim was to assess the effectiveness of low-dose intramuscular HBIG to prevent HBV reinfection after OLT., Patients: Six patients (all men, mean age 41 years, negative HBV DNA without hepatotropic virus coinfection) were transplanted in our institution due to HBV cirrhosis and included in a prospective noncomparative study. Intramuscular HBIG (2000 IU) was administered during the anhepatic phase of OLT, followed by daily 2000 IU doses for 7 days and then monthly. HBV antibody titers were measured every month. Reinfection was defined as the recurrence of surface HBV antigen in serum after transplantation., Results: After 1 year follow-up, none of the six patients had detectable HBV surface antigen and the liver biopsies were normal in all cases. Using 2000 IU, anti-HBs levels were: 880+/-356 IU/L at 1 month, 191+/-123 at 6 months, and 225+/-49 after 1 year. In all cases anti-HBs titers were above 100 IU/L during the follow-up., Conclusions: Monthly administration of low-dose (2000 IU) intramuscular HBIG effectively prevents recurrence of HBV infection as well as attains a protective level of anti-HBs antibodies (over 100 IU/L) for at least the first year after transplantation.

Introduction: Calcineurin inhibitors (CIs) cause substantial long-term morbidity and mortality among orthotopic liver transplantation (OLT) patients. Our aim was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) among OLT patients with CI-related side effects., Patients: Thirty three adult patients, including 29 men and 4 women of mean age 57 years, underwent OLT between 1986 and 2000 under treatment with CIs (28 cyclosporine and five tacrolimus). Mean follow-up after OLT was 59 months. Adverse effects were renal dysfunction in 26, hypertension in 23, and neurotoxicity in two. MMF was added gradually while simultaneously reducing the dosage of CI., Results: After a mean 15-months follow-up of MMF treatment, CIs had been withdrawn in 28 patients (85%). The mean time from the initiation of MMF and CI withdrawal was 5 months. During the first year of follow-up chronic renal dysfunction improved in 16 of 26 patients (61.6%) accompanied by a decreased serum creatinine and urea and an increase in creatinine clearance. Among 13/23 (56.5%) hypertensive patients, there was a significant decrease in blood pressure or the number of antihypertensive drugs (P<.05). One patient with neurotoxicity improved. Twenty-two patients (66%) displayed adverse events: five rejections (15%) including four acute episodes, controlled by CI re-introduction, and one chronic reaction. The most frequent adverse effects were herpes simplex infection in 10 patients (30%), asthenia in nine (27%), diarrhea in five (15%) and thrombocytopenia in four (12%). Nevertheless, only six patients (19%) required MMF dose reduction, namely, three patients with GI intolerance, two with repeated VHS infections, and one with anemia., Conclusions: MMF monotherapy improves renal function and blood pressure levels in more than 50% of patients with chronic renal impairment and hypertension after OLT. Many of the side effects of MMF were mild; it was safe accompanied by a low incidence of rejection reactions.

Objectives: To conduct a descriptive study with an analysis of risk factors for early infection in liver transplant patients, and to determine the resistance of the bacteria involved., Patients and Methods: The study included 149 liver transplant recipients. All cases of infection occurring 0-90 days after transplantation were considered early infection. Pre-, intra- and postoperative variables were analyzed, and isolated microorganisms were studied. Selective bowel decontamination with quinolones, and perioperative and antifungal prophylaxis were carried out in all patients., Results: The incidence of infection was 73.1%: bacterial (49.7%), viral (35.5%), fungal (10.1%) and mixed (4.5%). In the first postoperative month the most frequent infections were bacterial and in the second and third months, viral (p = 0.001). Multivariate analysis of risk factors identified the following: days of parenteral nutrition, duration of surgery > 5 hours, rejection and CMV seronegative status. Among 1278 cultures, the following microorganisms were isolated: 77.9% gram-positive cocci (GP) and 19% aerobic gram-negative bacilli (GNB). Sensitivity of Staphylococcus to vancomycin was 99.6-100% and to teicoplanin 97.9-100%. VAN resistance was observed in 1.2% of E. faecalis and 4.5% of E. faecium. Among S. aureus strains, 68.7% were MRSA. The resistance rate of GNB to quinolones was 38.8%., Conclusions: Incidence of infection was higher the first 30 days after transplantation, with bacterial infection predominating. Duration of surgery > 5 hours was the most important risk factor for acquiring bacterial infection. GP were the most frequently isolated bacteria. Empirical treatment of early bacterial infection should include vancomycin or teicoplanin. Selective bowel decontamination resulted in a low incidence of GNB infections, among which there was 38.8% resistance to quinolones.