Adult Liver Transplant Patients Research Articles

Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human.

Hepatic ischemia/reperfusion injury (IRI), an inevitable antigen-independent inflammation response in cadaveric liver transplantation, correlates with poor early graft function, rejection episodes, and contributes to donor organ shortage. Sirtuin 1 (SIRT1) is a histone deacetylase that may regulate inflammatory cell activity and manage liver function in IRI, though its functional role and clinical relevance remains to be elucidated. We investigated the efficacy of SIRT1 activation in a murine liver IRI model and verified the concept of putative SIRT1-mediated hepatoprotection in clinical liver transplantation. In the experimental arm, mice were subjected to 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion with or without adjunctive SIRT1 activation in vivo (resveratrol [Res]). In parallel, bone marrow-derived macrophage (BMDM) or spleen lymphocyte cultures were treated with Res. In the clinical arm, liver biopsies from 21 adult primary liver transplant patients (2 hours after reperfusion) were divided into "low" (n = 11) versus "high" (n = 10) SIRT1 expression groups, assessed by Western blots. Treatment with Res attenuated murine liver IRI while up-regulating SIRT1, suppressing leukocyte infiltration, and decreasing proinflammatory cytokine programs. SIRT1 silencing (small interfering RNA) in BMDM cultures enhanced inflammatory cytokine programs, whereas addition of Res decreased proinflammatory response in a SIRT1-dependent manner. In addition, Res decreased interferon γ production in liver-infiltrating and spleen lymphocyte cultures. Human liver transplants with high SIRT1 levels showed improved hepatocellular function and superior survival (P = 0.04), accompanied by lower proinflammatory cytokine profile. In conclusion, our translational study is the first to identify SIRT1 as a regulator of hepatocellular function in human liver transplant recipients under ischemia/reperfusion stress. By targeting innate and adaptive immune activation, manipulation of SIRT1 signaling should be considered as a novel means to combat inflammation in liver transplantation. Liver Transplantation 23 1282-1293 2017 AASLD.

Incidental hepatocellular carcinoma after liver transplantation: Prevalence, histopathological features and prognostic impact.

BackgroundIncidental hepatocellular carcinoma (iHCC) is a histological finding after liver transplantation (LT) which relevance has been scarcely studied.Aimsto describe the histopathological features of iHCC and to determine its prognostic impact in terms of tumor recurrence and overall survival.MethodsObservational study including 451 consecutive adult LT patients (2000–2013). Patients aged<18, retransplanted or with early postoperative death were excluded. Median follow-up after LT was 58 months. Multiple Cox’s regression was used to assess the prognostic impact of iHCC on tumor recurrence and mortality while controlling for potential confounders.Results141 patients had known HCC before LT (31.3%). Among the remaining 310 patients, the prevalence of iHCC was 8.7% (n = 27). In the explanted liver, 36.2% of patients with known HCC and 25.9% of patients with iHCC trespassed Milan criteria (p = 0.30). Patients with known and iHCC had similar rates of multinodular disease (50.4% vs 55.6%; p = 0.62), macrovascular invasion (6.5% vs 3.7%; p = 0.58), microvascular invasion (12.9% vs 14.8%; p = 0.76) and moderate-poor tumor differentiation (53.9% vs 70.4%; p = 0.09). In the multivariate analysis, iHCC and known HCC had identical recurrence-free survival after controlling for histological features (RR = 1.06, 95%CI 0.36–3.14; p = 0.90). Cumulative 5-year overall survival rates were similar between patients with known and iHCC (65% vs 52.8% respectively; log rank p = 0.44), but significantly inferior as compared with patients without HCC (77.8%) (p = 0.002 and p = 0.007 respectively). Indeed, in the overall cohort, iHCC was an independent predictor of mortality (RR = 3.02; 95%CI 1.62–5.65; p = 0.001).ConclusionThe risk of tumor recurrence after LT is similar in patients with iHCC and known HCC. A close imaging surveillance is strongly recommended for patients awaiting LT in order to detect HCC prior to LT, thus allowing for an adequate selection of candidates, prioritization and indication of bridging therapies.

Clinicopathological Features and Prognosis of Intrahepatic Cholangiocarcinoma After Liver Transplantation and Resection.

BACKGROUND Intrahepatic cholangiocarcinoma (ICC) can be incidentally diagnosed after liver transplantation (LT). We investigated the clinicopathological features of LT recipients with ICC and compared prognosis with that of the control group. MATERIAL AND METHODS We identified 16 recipients with ICC in our institutional database. The propensity score-matched control group comprised 100 ICC patients who underwent hepatic resection (HR). RESULTS ICC incidence was 0.5% in all adult LT patients and 1.2% in adult recipients with primary liver cancer. Mean age was 58.0±4.8 years and 15 were male. All ICCs were diagnosed incidentally in the explanted livers. Mean ICC tumor diameter was 2.5±1.1 cm and 14 recipients had a single tumor. Tumor stages were I in 9, II in 5, and IV in 2. Concurrent second primary liver cancer was detected as hepatocellular carcinoma in 7 and combined hepatocellular carcinoma-cholangiocarcinoma in 1. Tumor recurrence and patient survival rates were 56.2% and 81.3% at 1 year and 78.1% and 52.4% at 5 years, respectively. Presence of second cancer did not affect tumor recurrence (p=0.959) or patient survival (p=0.737). All 3 patients with very early ICC did not show ICC recurrence. Compared with the control group, the tumor recurrence rate was higher after LT (p=0.024), but this difference disappeared after analysis was confined to recipients with ICC alone (p=0.121). Post-recurrence survival was not different after HR and LT (p=0.082). CONCLUSIONS ICC is rarely diagnosed after LT and half of such patients have second liver cancer. Post-transplant prognosis of ICC is poor except for very early ICC; thus, strict surveillance is mandatory.

Immunosuppression in pediatric liver transplant recipients: Unique aspects.

Pediatric liver transplantation has experienced improved outcomes over the last 50 years. This can be attributed in part to establishing optimal use of immunosuppressive agents to achieve a balance between minimizing the risks of allograft rejection and infection. The management of immunosuppression in children is generally more complex and can be challenging when compared with the use of these agents in adult liver transplant patients. Physiologic differences in children alter the pharmacokinetics of immunosuppressive agents, which affects absorption, distribution, metabolism, and drug excretion. Children also have a longer expected period of exposure to immunosuppression, which can impact growth, risk of infection (bacterial, viral, and fungal), carcinogenesis, and likelihood of nonadherence. This review discusses immunosuppressive options for pediatric liver transplant recipients and the unique issues that must be addressed when managing this population. Further advances in the field of tolerance and accommodation are needed to relieve the acute and cumulative burden of chronic immunosuppression in children. Liver Transplantation 23 244-256 2017 AASLD.

Clinicopathological Features and Prognosis of Hepatic Epithelioid Hemangioendothelioma After Liver Resection and Transplantation.

BACKGROUND Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor. We present a single-center study on hepatic EHE cases treated by hepatic resection (HR) or liver transplantation (LT). MATERIAL AND METHODS Six HR patients with hepatic EHE were identified during 5 years from 2010 to 2014; EHE represented 0.13% (6 of 4572) of all primary liver tumors. Two LT recipients were also identified during 12 years from 2003 to 2014, who represented 0.06% (2 of 3576) of all adult LT patients. RESULTS Mean age of the patients was 42.3±11.2 years and 7 were female. Preoperative diagnoses based on imaging studies were suspected liver metastasis or EHE; thus, all patients underwent liver biopsy. The extent of HR, which was determined by the location and size of tumors, consisted of right hepatectomy in two patients, right anterior sectionectomy in one, right posterior sectionectomy in one, central bisectionectomy plus partial hepatectomy in one, and right trisectionectomy plus partial hepatectomy in one. All patients recovered uneventfully from surgery. The disease-free survival rate was 83.3% at 1 year and 44.4% at 3 years in HR patients, but all patients are alive to date. Two patients underwent living-donor LT because they had multiple tumors scattered throughout the liver. Of these, one patient died from tumor recurrence at 9 months and the other is alive after 5 years without recurrence. CONCLUSIONS Hepatic EHE is often misdiagnosed as a metastatic tumor. This disease has malignant potential; thus, it requires aggressive treatment including HR, non-surgical treatment, and LT.

De Novo Donor-Specific Anti–Human Leukocyte Antigen Antibody Detection in Long-Term Adult Liver Transplantation

IntroductionInformation about the consequences of de novo donor-specific anti-human leukocyte antigen (DSA) antibody development in the long term after adult liver transplantation (LT) is scarce. We conducted a cross-sectional study in LT patients with a follow-up of at least 6 years. MethodsA total of 28 adult LT patients were included, with a median follow-up of 77 months (range, 63 to 96) and without preformed anti- human leukocyte antigen (HLA) antibodies prior to LT. The anti-HLA identification was performed with LABScreen Single Antigen, whereas the ability to fix the complement was demonstrated with C1q test (One Lambda). In both assays, a value >3.500 mean fluorescence intensity (MFI) was considered positive. The anti-HLA antibody specificities were compared with donor HLA antigens to confirm them as DSA. Hepatic fibrosis was assessed by transient elastography. ResultsIn 5 patients (17.8%), de novo DSA were detected, all them against DQ locus. In all of these cases (100%) the complement fixation was confirmed by C1q binding. The grade of hepatic fibrosis in de novo DSA patients was significantly higher compared with No-DSA patients (13.2 ± 9.2 KPa vs 7.3 ± 3.7 KPa; P = .02). It is noteworthy that in both groups of patients the levels of liver function tests (LFT) at the time of the study were normal or near the normal range with no difference between patients with or without de novo DSA. ConclusionsOur preliminary results are consistent with those previously demonstrated in pediatric LT, where de novo DSA production and humoral response could contribute to the liver fibrosis observed in the long term after LT in pediatric patients with normal or near-normal LFT.

Limited Sampling Strategy for the Estimation of Tacrolimus Area Under the Concentration-Time Curve in Chinese Adult Liver Transplant Patients

Objectives: Limited sampling strategies (LSS) have been proposed as an alternative method for estimating area under concentration-time curve (AUC) of immunosuppressive agent tacrolimus (TAC). In this study, we aimed to develop the LSS models for predicting AUC of TAC in Chinese liver transplant patients. Methods: Twenty-eight adult liver transplant patients receiving immunosuppressive regimen including TAC were enrolled. A total of 47 pharmacokinetic profiles were obtained after 1 or 3 weeks therapy. TAC concentrations were determined before dose (0 h) and at 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after dosing by LC-MS/MS assay. Optimal subset regression analysis was used to establish the models for estimating TAC AUC_0-12. Prediction error (PE) and absolute PE were calculated. The agreement between predicted and measured AUC_0-12 was investigated by Bland-Altman analysis. The obtained models were validated by bootstrap analysis. The prediction performance among various CYP3A5 and ABCB1 genotypes was compared. The models selected from previous published studies were also validated using our data. Results: Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r² = 0.653-0.979). The best model for prediction of TAC AUC_0-12 was 0.81 + 1.73C₁ + 1.32C₂ + 3.87C₄ + 3.75C₈ (r² = 0.979). Forty profiles (85.1%) had estimated TAC AUC_0-12 within ±15% of observed TAC AUC_0-12. Model with C₀-C₂ (r² = 0.880) can be used for outpatients who need monitoring to be carried out in a short period. We also found that ABCB1 genotype may be a reason of variation in the prediction performance. There was good correlation between predicted and measured AUC_0-12 (r² = 0.880-0.928) by using models from previous studies with sample collected within 4 h post dose. Conclusion: The LSS is an effective approach for estimation of full TAC AUC_0-12 in Chinese liver transplant patients.

De Novo Gastric Cancer After Liver Transplantation.

BACKGROUND In South Korea, which has a high incidence of gastric cancer, the most common de novo malignancy associated with liver transplantation is gastric cancer. This study sought to identify clinicopathologic characteristics in gastric cancer patients after liver transplantation, and to help manage these cases. MATERIAL AND METHODS We investigated gastric cancer patients after liver transplantation at Asan Medical Center. We analyzed sex, age, cause of liver transplantation, initiating immunosuppressant, pre-transplantation gastric fibroscopy findings, time interval between transplantation and gastric cancer occurrence, follow-up period, existence of gastric cancer screening, Helicobacter pylori infection, family cancer history, gastric cancer treatment, cancer location, size of tumor, macroscopic gross type, WHO histologic type, Lauren's classification, TNM stage, and survival. RESULTS Of 2968 adult liver transplantation patients at our hospital, 19 were diagnosed with gastric cancer. The mean age at the time of gastric cancer diagnosis was 60.2±6.8 (46-71) years and mean time interval between liver transplantation and diagnosis of gastric cancer was 56.0±30.7 (3.20-113) months. Endoscopic submucosal dissection was done for 10 patients, 4 of whom underwent surgical resection. Surgical resection as an initial treatment was done in 8 patients. One patient received chemotherapy first. The standard incidence ratio of gastric cancer in these patients was 1036 per 100 000 persons (95% CI, 623.7-1,619) in men and 318.9 per 100 000 (95% CI, 4.170-1,774) in women. CONCLUSIONS For long-term survival of liver transplant patients, early detection of de novo cancer is necessary. Therefore, annual screening for gastric cancer after liver transplantation is needed, especially in areas where the incidence of gastric cancer is high, such as South Korea.

Prospective long-term study on primary CMV infections in adult liver transplant (D+/R−) patients after valganciclovir prophylaxis

BackgroundCytomegalovirus (CMV) can cause severe infections in transplanted patients. To prevent CMV infection, most liver centers use prophylaxis for CMV-seronegative recipients receiving an organ from a seropositive donor (D+/R−). Valganciclovir is mostly given for 3–6 months after transplantation. However, the patients may develop primary CMV infection after the cessation of prophylaxis and late-onset CMV disease may occur. ObjectivesA prospective long-term follow-up of CMV (D+/R−) adult liver transplant recipients after 3 months valganciclovir prophylaxis was investigated. Study designOf 154 consecutive adult liver recipients transplanted from 2006 to 2009, 20 (13%) were CMV D+/R− and received antiviral prophylaxis up to 3 months after transplantation. After excluding the recipients with incomplete prophylaxis or monitoring, 13 (D+/R−) patients with follow-up of >4 years after the 3-month period of valganciclovir prophylaxis were included in the study.The patients were monitored for CMV by real-time quantitative plasma PCR. ResultsNo break-through CMV infections were recorded during the prophylaxis period. After cessation of valganciclovir prophylaxis 12/13 (90%) patients demonstrated CMV-DNAemia following a post transplantation mean interval of 165 days (range 95–320). Ten patients with high viral loads (peak viral load mean 81,510, range 1900–648950cps/ml) were successfully treated, 6 with valganciclovir, and 4 with ganciclovir. Two patients with low level CMV-DNAemia (<1000cps/ml) were asymptomatic and not treated. No intragraft infection was seen, but one patient developed gastrointestinal CMV infection verified from ileum biopsy. During long-term follow-up, 3 patients demonstrated low-level viral replication, but no symptomatic recurrences occurred. One patient died of bacterial sepsis, but no patient or graft was lost due to CMV. ConclusionsPrimary CMV infections after cessation of prophylaxis were common, but were successfully treated with valganciclovir or ganciclovir.

Recurrent alcoholic cirrhosis in severe alcoholic relapse after liver transplantation: a frequent and serious complication.

Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT). Recurrent alcoholic cirrhosis (RAC) after LT can occur but has not been studied. The aims of this study were to estimate the prevalence, predictive factors, and natural history of RAC after LT. All patients transplanted for ALD between 1990 and 2007 in three French centers were included. The diagnosis of RAC was based on histological evidence or a series of features combined with severe alcoholic relapse. Among 1,894 adult LT patients, 712 were transplanted for alcoholic cirrhosis and survived >6 months. After a mean follow-up of 9 years, 128 patients (mean age at LT 47.2±7.1 years old, 78.9% men) experienced severe alcoholic relapse (18.0% of cases). Severe alcoholic relapse occurred after a median delay of 25 months (range 4-157) after LT. RAC was diagnosed in 41 patients with severe relapse (32%). The diagnosis of RAC was made after a median delay of 5.1 years (range 1.8-13.9) after LT and of 4.0 years (range 1.2-11.5) after relapse. RAC was significantly associated with younger age and a shorter period of pre-LT abstinence. One-, 5-, 10-, and 15-year survival was 100, 87.6, 49.7, and 21.0%, respectively, for RAC patients vs. 100, 89.4, 69.9, and 41.1%, respectively, for the patients without RAC (P<0.001). RAC occurs in <6% of ALD transplant patients. One-third of severe alcoholic relapse patients develop RAC <5 years after transplantation with a very poor prognosis.

Acute Renal Injury Evaluation After Liver Transplantation: With RIFLE Criteria

BackgroundThe aim of this study was to identify acute renal injury (ARI) through the use of RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria and to investigate perioperative risk factors for ARI in liver transplantation (LT). MethodsWe reviewed medical records of adult LT patients retrospectively. Postoperative ARI was staged with RIFLE criteria by the 1st and 7th days of the surgery. ResultsWe analyzed 440 adult LT patients, categorized as risk (R), injury (I), or failure (F) according to the RIFLE criteria. In this study, in the first postoperative day, incidence of ARI was 7.95%; all of them were R-class, and, on the 7th day, the incidence of ARI was 7.27%, as R-class 6.59% and I-class 0.68%. Significant risk factors were detected within the first postoperative day including pre-operative hemoglobin levels <9 g/dL (P = .019), intra-operative transfusion of red blood cells (RBCs) (P = .049) and fresh-frozen plasma (FFP) (P = .049), blood loss (P = .011), and post-reperfusion syndrome (P = .023). Multivariate analysis revealed risk factors for ARI as RBCs (odds ratio [OR], 1.049; P = .247) and FFP (OR, 1.017; P = .627) transfusion and blood loss (OR, 1.000; P = .021) (blood loss OR: 0.9996952300184; 95% confidence interval: 0.9994356774026 to 0.999548500399). The only significant risk factor for the 7th postoperative day was the Model for End-Stage Liver Disease (MELD) score (>20) (P = .002). ConclusionsThis study showed that RBC and FFP transfusion, perioperative blood loss, and MELD score >20 are risk factors for LT-related ARI. Also normalization of hemoglobin levels with non-blood products in patients with preoperative low hemoglobin levels can diminish the need for RBC and that can prevent ARI.

Effects of CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients

1. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene-encoding P-glycoprotein (ABCB1), on the PK parameters in Chinese adult liver transplant recipients.2. Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs.3. A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6 L/h and 225 L, respectively. The absorption rate constant (Ka) was fixed at 4.48 h−1. The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F.4. Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.

Major complications of adult right lobe living liver donors

The right lobe of the liver is generally preferred for living donor liver transplantation in adult patients with end-stage liver disease. It is important to know the preoperative factors relating to the major postoperative complications. We therefore evaluated the possible risk factors for predicting postoperative complications in right lobe liver donors. Data from 378 donors who had undergone right lobe hepatectomy at our center were evaluated retrospectively. The factors we evaluated included donor age, gender, body mass index (BMI), remnant liver volume, operation time, history of previous abdominal surgery, inclusion of the middle hepatic vein and variations in the portal and bile systems. Of the 378 donors, 219 were male and 159 female. None of the donors died, but 124 (32.8%) donors experienced complications including major complications (Clavien scores III and IV) in 27 (7.1%). Univariate analysis showed that complications were significantly associated with male gender and higher BMI (P<0.05), but not with donor age, remnant liver volume, operation time, graft with middle hepatic vein, variations in the portal and bile systems and previous abdominal surgery (P<0.05). Multivariate logistic regression analysis showed that major complications were significantly associated with male gender (P=0.005) and higher BMI (P=0.029). Moreover, the Chi-square test showed that there were significant relationships between major complications and male gender (P=0.010, X2=6.614, df=1) and BMI >25 kg/m2 (P=0.031, X2=8.562, df=1). Of the 96 male donors with BMI >25 kg/m2, 14 (14.6%) with major complications had significantly smaller mean remnant liver volume than those (82, 85.4%) without major complications (32.50%+/-4.45% vs 34.63%+/-3.11%, P=0.029). Male donors with BMI >25 kg/m2 and a remnant liver volume ≤32.50% had a significantly increased risk for major complications.

Seizure as a neurologic complication after liver transplant.

Seizure is a common complication after liver transplant and has been reported to occur in up to 42% of patients in different case series. Multiple factors can trigger seizures, including immunosuppressive toxicity, sepsis, metabolic imbalance, and structural brain lesions. The aim of this retrospective study was to evaluate seizure types and associated factors in adult liver transplant patients. We retrospectively evaluated the medical records of 142 adult patients who received a liver transplant between 2005 and 2013. We recorded demographic data, immunosuppressive treatment, seizure type, cause, recurrence, and treatment. Of the 146 patients, 23 (15.7%) had a seizure after the liver transplant. This group included 10 females and 13 males, with ages ranging between 18 and 63 (39.9 ± 14.8 y). Generalized tonic-clonic seizures were the most common, occurring in 20 patients (87%). We observed complex partial seizure and status epilepticus in 1 and 2 patients. Immunosuppressive drug-related seizure occurred in 8 patients (34.8%) with normal drug blood levels, and all but 1 of these patients experienced seizure within the first week after transplant. Multiple factors (26.1%), metabolic imbalance (17.4%), structural lesion (13%), and sepsis (8.7%) were the other factors identified as underlying conditions. In conclusion, seizure occurred in a significant proportion of patients who underwent liver transplant. Immunosuppressive drugs were the most common factor associated with seizure occurrence and drug cessation prevented seizure recurrence.

Weight gain, overweight and obesity in solid organ transplantation--a study protocol for a systematic literature review.

BackgroundOverweight and obesity, which have a substantial impact on health in the general population, have similar prevalence in solid organ transplant recipients but carry even more serious ramifications. As this group’s use of immunosuppressive medication increases the risk for comorbidities, e.g. metabolic syndrome and cardiovascular disease, the prevention of additional risk factors is vital. This systematic review will be the first to summarize the issue of weight gain, overweight and obesity concurrently within and across solid organ transplantation. The three research questions relating to solid organ transplantation are the following: (1) What are the prevalence and evolution of overweight and obesity from pre- to post-transplant?; (2) Which pre- and post-transplant risk factors are associated with post-transplant weight gain, overweight or obesity? and (3) Which post-transplant patient outcomes and comorbidities are associated with pre- and post-transplant weight gain, overweight and obesity?Methods/DesignMEDLINE via PubMed, The Cochrane Library, Cumulative Index to Nursing and Allied Health (CINAHL), PsycINFO and Excerpta Medica DataBase (EMBASE) will be searched for original quantitative studies in adult liver, heart, lung or kidney transplant patients. Topics of interest will be the prevalence and evolution of overweight and obesity over time, risk factors associated with changes in weight or body mass index (BMI), overweight and obesity, and the relationship of weight or BMI with post-transplant outcomes and comorbidities. Screening of titles and abstracts, full-text reading and data extraction will be divided between three researchers. Researchers will cross-check one another’s screening decisions for random samples of studies to adhere as closely as possible to the recommendations of The Cochrane Collaboration. For quality assessment, a purpose-adapted 19-item instrument will be used. Effect sizes will be calculated for relationships investigated in a minimum of five studies. Random effects meta-analysis with moderator analyses will be conducted if applicable.DiscussionThis systematic review will comprehensively synthesize the existing evidence concerning weight gain, overweight and obesity in solid organ transplantation in view of magnitude, influencing factors and associations with patient outcomes and comorbidities. The results can fuel the development of interventions to prevent weight gain in the solid organ transplant population.Systematic review registrationPROSPERO CRD42014009151Electronic supplementary materialThe online version of this article (doi:10.1186/2046-4053-4-2) contains supplementary material, which is available to authorized users.

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients.

We examined the influence of the cytochrome P450 3A5 (CYP3A5) genes in both donors and recipients on the concentration-dosage ratio (C/D) of tacrolimus in Chinese liver transplant patients. Fifty-one adult liver transplant patients who received tacrolimus were included in this study. The CYP3A5 polymorphism in donors and recipients was determined at the time of transplantation, and tacrolimus-based immunosuppressive therapy was started based on each patient's genetic constitution. The relationship between the C/D of tacrolimus for 3 months after surgery and the CYP3A5 genotype was analyzed. A stepwise regression model was used to analyze the relationship between C/D of tacrolimus and genotype, time course, age, and liver weight in liver transplant patients. Three months after liver transplantation, C/D was both affected by the CYP3A5 genotype of both the donors and the recipients. The C/D of tacrolimus in patients with the CYP3A5*1 allele or carrying CYP3A5*1 allele in the liver was lower than that in CYP3A5*3/*3 patients with the CYP3A5*3/*3 genotype in the liver (P < 0.01). The CYP3A5*1 genotype in donors as well as in patients both contributes to interindividual variation in the C/D of tacrolimus in adult liver transplantation.

Utility of liver biopsy in predicting clinical outcomes after percutaneous angioplasty for hepatic venous obstruction in liver transplant patients.

To determine utility of transplant liver biopsy in evaluating efficacy of percutaneous transluminal angioplasty (PTA) for hepatic venous obstruction (HVOO). Adult liver transplant patients treated with PTA for HVOO (2003-2013) at a single institution were reviewed for pre/post-PTA imaging findings, manometry (gradient with right atrium), presence of HVOO on pre-PTA and post-PTA early and late biopsy (EB and LB, < or > 60 d after PTA), and clinical outcome, defined as good (no clinical issues, non-HVOO-related death) or poor (surgical correction, recurrent HVOO, or HVOO-related death). Fifteen patients meeting inclusion criteria underwent 21 PTA, 658 ± 1293 d after transplant. In procedures with pre-PTA biopsy (n = 19), no difference was seen between pre-PTA gradient in 13/19 procedures with HVOO on biopsy and 6/19 procedures without HVOO (8 ± 2.4 mmHg vs 6.8 ± 4.3 mmHg; P = 0.35). Post-PTA, 10/21 livers had EB (29 ± 21 d) and 9/21 livers had LB (153 ± 81 d). On clinical follow-up (392 ± 773 d), HVOO on LB resulted in poor outcomes and absence of HVOO on LB resulted good outcomes. Patients with HVOO on EB (3/7 good, 4/7 poor) and no HVOO on EB (2/3 good, 1/3 poor) had mixed outcomes. Negative liver biopsy greater than 60 d after PTA accurately identifies patients with good clinical outcomes.

Effects of Combinational CYP3A5 6986A&gt;G Polymorphism in Graft Liver and Native Intestine on the Pharmacokinetics of Tacrolimus in Liver Transplant Patients

Many studies have reported reduced tacrolimus dose-adjusted exposure in individuals expressing the CYP3A5*1 allele. A meta-analyses of the current data may help characterize the extent of impact this polymorphism has on tacrolimus pharmacokinetics in adult liver transplant recipients and whether donor or recipient genotype is the most influential factor. Structured searches, of studies that evaluated the association between CYP3A5*1 allele and tacrolimus pharmacokinetics in adult liver transplant recipients, were conducted using Embase and Medline. A meta-analysis comparing tacrolimus daily dose, trough concentrations (C0), and dose-adjusted trough concentrations (C0/dose) across the donor and recipient genotype pairs was conducted using a random effects model. Eight studies, involving a total of 694 adult liver transplant recipients, were included. Dose-adjusted tacrolimus trough concentrations were significantly lower in those in whom the donor or recipient expressed a *1 allele compared with those in whom neither the donor nor recipient expressed this allele at 7 days and 2, 3, 6, and 12 months after transplant [standardized mean differences between expressers and nonexpressers of -1.98, -2.12, -2.39, -3.68, and -3.26 (ng/mL)/(mg·kg·d), respectively]. Results of the meta-analysis demonstrated that, in adult liver transplant patients, CYP3A5 expression in either the donor or recipient resulted in a need for a higher mean tacrolimus daily dose to achieve the target drug exposure. In the immediate posttransplant period, recipient expression of a CYP3A5*1 allele seemed to have the greatest influence on tacrolimus pharmacokinetics with donor expression of a CYP3A5*1 allelle possibly becoming more important with increasing time after transplant.

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients

Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability. Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection. Non-linear mixed effects modelling was used to analyze the concentration-time data and evaluate demographic and transplant-related covariates. A two compartment model with first order absorption best described the data. Given the range of body sizes, clearance and volume of distribution terms were scaled using standard weight-based allometric exponents. Creatinine clearance was included on apparent oral clearance. Final estimates in a standard 70 kg individual for apparent oral clearance, central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.5 l h(-1) , 87.5 l, 4.80 l h(-1) and 42.6 l, respectively. The median terminal half-life for kidney, liver and lung transplant recipients was 9.4, 9.5 and 8.2 h, respectively. Median exposure (i.e. AUC(0,∞) in subjects taking valganciclovir 900 mg or 450 mg once daily was 57.4 and 34.3 μg ml(-1) h, respectively. Allometric scaling allowed simultaneous analysis of data from children and adults. Ganciclovir pharmacokinetics were similar among kidney, liver and lung transplant recipients. Ganciclovir exposure after valganciclovir 450 mg once daily may be suboptimal in some individuals and requires evaluation along with virologic outcomes data.

Perioperative complications in liver transplantation using donation after cardiac death grafts: A propensity-matched study

Donation after cardiac death (DCD) is an important source for expanding the donor pool for liver transplantation (LT). Although the long-term outcomes of LT using DCD grafts have been extensively studied, perioperative complications related to DCD grafts are rarely reported. The aim of this study was to determine whether DCD grafts were associated with a higher incidence of postreperfusion complications and worse outcomes in adult LT patients. After institutional review board approval, the medical records of all adult patients who underwent LT at our medical center between 2004 and 2011 were reviewed. Postreperfusion complications and posttransplant outcomes were compared between patients receiving DCD grafts and patients receiving donation after brain death (DBD) grafts. In all, 74 patients received DCD grafts during the study period, and 1369 patients received DBD grafts. An initial comparison showed that many preoperative, prereperfusion, and donor variables in the DCD group differed significantly from those in the DBD group. Propensity matching was chosen so that adjustments could be made for the differences. A postmatching analysis showed that the preoperative, prereperfusion, and donor variables no longer differed between the 2 groups. The postreperfusion requirements for blood products and vasopressors, the posttransplant ventilation times, the incidence of posttransplant acute renal injury, and the 30-day and 1-year patient and graft survival rates were comparable between the 2 groups. However, patients receiving DCD grafts experienced significantly higher rates of hyperkalemia (33.8% versus 18.9%, P < 0.05) and postreperfusion syndrome (PRS; 25.7% versus 12.3%, P < 0.05). In conclusion, after adjustments for preoperative and prereperfusion risks via propensity matching, DCD grafts remained a risk factor for postreperfusion hyperkalemia and PRS. A prophylactic regimen aimed at decreasing postreperfusion hyperkalemia and PRS is recommended for the management of LT using DCD grafts.