Is biliary bile acid a good predictor for acute cellular rejection in living donor liver transplantation?

BACKGROUND:In liver transplantation,acute cellular rejection(ACR)is still a major complication that can lead to mortality.Bile secretion has been considered as a marker of early graft function. METHODS:The study included 41 adults who received living donor liver transplantation(LDLT)at Kyoto University Hospital between April 2007 and February 2008. The patients were stratified according to the presence or absence of ACR.Bile samples were collected from donors once and from recipients every other day for the first 2 weeks after transplantation.Total bile acid(BA)and taurine-conjugated bile acid(TCBA)in bile were measured by magnetic resonance spectroscopy.The recipient/donor (R/D)BA ratio and R/D TCBA ratio were calculated. RESULTS:The ACR group(n=12)showed a greater decrease in BA post-transplantation than the non-ACR group,but this difference was not statistically significant. On both day 7 and day 9 post-transplantation the R/D TCBA was significantly different between the two groups (P=0.038 on day 7 and P=0.036 on day 9).The R/D TCBA ratio≥0.5 on days 7 and 9,and≥0.38 on day 11 post- transplantation were associated with better ACR-free survival. CONCLUSION:The recipient/donor TCBA ratio can be a predictor for ACR after LDLT as early as post- transplantation day 7.

Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients

BACKGROUND: Although many human inflammatory and autoimmune diseases were previously considered to be mediated by T helper type 1 (Th1) cells, the recently described Th17 cells play dominant roles in several of these diseases. We and others speculated that allograft rejection after organ transplantation may also involve Th17 cells. Episodes of acute rejection occur in 30% of liver transplants. This study aimed to determine the frequency of circulating Th17 cells in patients who had received liver transplants for benign end-stage liver disease and to identify any association between acute rejection episodes and levels of Th17 cells in the peripheral blood. METHODS: A prospective study compared Th17 cells from 76 consecutive benign end-stage liver disease patients who had undergone orthotopic liver transplantation from 2007 to 2011 with those from 20 age-matched healthy individuals. Peripheral blood samples were collected at different time points within one year after transplant. Blood samples and liver biopsies were also collected at the diagnosis of acute rejection. Percentages of circulating CD4+ IL-17+ cells were measured by flow cytometry The transplant patients were classified into two groups: a rejection group consisting of 17 patients who had an episode of acute rejection, and a non-rejection group comprising the remaining 59 patients with no acute rejection episodes Percentages of circulating Th17 cells were compared between the two groups and controls. RESULTS: The levels of circulating CD4+ IL-17+ T cells in the rejection group were higher during acute rejection than those in the non-rejection group (2.56±0.43% versus 1.79±0.44% P<0.001). The frequency of CD4+ IL-17+ cells in peripheral blood was positively correlated with the rejection activity index (r=0.79, P=0.0002).CONCLUSION: Circulating Th17 cells may be useful as a surrogate marker for predicting acute rejection in liver transplant recipients.

Efficacy of ursodeoxycholic acid as an adjuvant treatment to prevent acute cellular rejection after liver transplantation: a meta-analysis of randomized controlled trials

BACKGROUND： Acute cellular rejection（ACR） after liver transplantation（LT） is one of the most common problems faced by transplant recipients in spite of advances in immunosuppressive therapy. Recently, clinical trials reported that ursodeoxycholic acid（UDCA） reduced the incidence of ACR significantly.However, others have shown contradictory conclusion. Therefore,we performed a meta-analysis of rigorous randomized controlled trials（RCTs） to determine the efficacy of UDCA in reducing ACR after LT.DATA SOURCES： All RCTs that evaluated efficacy of UDCA as an adjuvant treatment to prevent ACR after LT were searched from PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect databases and Web of Science（from January 1981 to March 2012）. There was no language limitation in these searches. Relevant abstracts of international meetings were also searched. References of each included study were searched manually.RESULTS： A total of 234 patients from four high-quality RCTs（Jadad score 4 to 5） were included in this meta-analysis.Prophylactic use of UDCA did not decrease the incidence of ACR（RR： 0.94, 95% CI： 0.77-1.16, P0.05）, steroid-resistant rejection（RR： 0.77, 95% CI： 0.47-1.27, P0.05） and the number of patients with the multiple episodes of ACR（RR： 0.60, 95% CI：0.28-1.30, P0.05）. Different intervention programs（high-dose vs low-dose UDCA; early vs delayed UDCA treatment） also did not alter the outcomes.CONCLUSIONS： UDCA, as an adjuvant treatment, was not ableto prevent ACR and steroid-resistant rejection after LT. Further trials should be done to determine whether higher dose of UDCA will be beneficial.

Sinusoidal endotheliitis as a histological parameter for diagnosing acute liver allograft rejection

AIMTo investigated the feasibility of using sinusoidal endotheliitis (SE) as a histological marker for liver allograft rejection.METHODSWe compared the histological features of 88 liver allograft biopsies with acute cellular rejection (ACR) and 59 cases with no evidence of ACR. SE was scored as: (1) focal linear lifting up of the endothelial cells by lymphocytes with no obvious damage to adjacent hepatocytes; (2) focal disruption of the endothelial lining by a cluster of subendothelial lymphocytes (a group of &#x0003e; 3 lymphocytes); and (3) severe confluent endotheliitis with hemorrhage and adjacent hepatocyte loss.RESULTSThe sensitivity and specificity of SE was 81% and 85%, respectively. Using SE as the only parameter, the positive predictive value for ACR (PPV) was 0.89, whereas the negative predictive value for ACR (NPV) was 0.75. The correlation between RAI and SE was moderate (R = 0.44, P &#x0003c; 0.001) (Figure 3A), whereas it became strong (R = 0.65, P &#x0003c; 0.001) when correlating SE with the venous endotheliitis activity index only.CONCLUSIONOur data suggest that SE scoring could be a reliable and reproducible supplemental parameter to the existing Banff schema for diagnosing acute liver allograft rejection.

Risk of recurrence of primary sclerosing cholangitis after liver transplantation is associated with de novo inflammatory bowel disease

AIM To evaluate risk factors for primary sclerosing cholangitis(PSC) recurrence(rPSC) after orthotopic liver transplantation(OLT) in patients with well-preserved colons. METHODS We retrospectively evaluated the medical records of all patients transplanted for PSC in our center between July 1994 and May 2015 and selected 47 with followup of at least 60 mo for further analysis based on strict inclusion and exclusion criteria. rPSC was confirmed by magnetic resonance or endoscopic retrograde cholangiopancreatography and liver biopsy. All patients were evaluated by protocolary pre-OLT colonoscopy with randomized mucosal biopsies. Colonoscopy was repeated annually after OLT. Both organ donors and recipients were human leukocyte antigen(HLA) typed by serological and/or DNA methods. All input data were thoroughly analyzed employing relevant statistical methods.RESULTS Altogether, 31 men and 16 women with a median(range) age of 36(15-68) years at the time of OLT and a median follow-up of 122(60-249) mo were included. rPSC was confirmed in 21/47(44.7%) of patients, a median 63(12-180) mo after transplantation. De novo colitis [rPSC in 11/12, P ≤ 0.05, hazard ratio(HR): 4.02, 95% confidence interval(CI): 1.58-10.98] and history of acute cellular rejection(rPSC in 14/25, P ≤ 0.05; HR: 2.66, 95%CI: 1.03-7.86) showed strong positive associations with rPSC. According to the univariate analysis, overlapping features of autoimmune hepatitis(r PSC in 5/5, P ≤ 0.05) and HLA-DRB1*07 in the donor(r PSC in 10/15, P ≤ 0.05) represent other potential risk factors for rPSC, while the HLA-DRB1*04(rPSC in 0/6, P ≤ 0.05), HLA-DQB1*03(rPSC in 1/11, P ≤ 0.05), and HLA-DQB1*07(rPSC in 0/7, P ≤ 0.05) recipient alleles may have protective roles.CONCLUSION De novo colitis and acute cellular rejection are clinical conditions significantly predisposed towards recurrence of PSC after liver transplantation.

Endoscopic retrograde cholangiopancreatography and liver biopsy in the evaluation of elevated liver function tests after liver transplantation

BACKGROUND Abnormal liver function tests(LFTs)in post-liver transplant(LT)patients pose a challenge in the timing and selection of diagnostic modalities.There are little data regarding the accuracy of endoscopic retrograde cholangiopancreatography(ERCP)and liver biopsy(LB)in diagnosing post-transplant complications.AIM To evaluate the diagnostic performance of ERCP and LB in patients with nonvascular post-LT complications.METHODS This single-center retrospective study evaluated patients undergoing both ERCP and LB for evaluation of elevated LFTs within 6 mo of LT from 2000 to 2017.Diagnostic operating characteristics including accuracy,sensitivity and specificity for various diagnoses were calculated for ERCP and LB.The R factor(ratio of alkaline phosphatase to alanine aminotransferase)was also calculated for each patient.RESULTS Of the 1284 patients who underwent LT,91 patients(74.7%males,mean age of 51)were analyzed.Anastomotic strictures(AS,24.2%),acute cellular rejection(ACR,11%)and concurrent AS/ACR(14.3%)were the most common diagnoses.ERCP carried an accuracy of 79.1%(95%CI:69.3-86.9),LB had an accuracy of 93.4%(95%CI:86.2-97.5),and the combination of the two had an accuracy of 100%(95%CI:96-100).There was no difference between patients with AS and ACR in mean R factor(AS:1.9 vs ACR:1.1,P=0.24).Adverse events did not differ between the two tests(ERCP:3.1%vs LB:1.1%,P=0.31).CONCLUSION In patients with abnormal LFTs after LT without vascular complications,the combination of LB and ERCP carries low risk and improves diagnostic accuracy over either test alone.

Recurrent hepatitis C after liver transplant

End stage liver disease from hepatitis C is the most common indication for liver transplantation in many parts of the world accounting for up to 40% of liver transplants. Antiviral therapy either before or after liver transplantation is challenging due to side effects and lower efficacy in patients with cirrhosis and liver transplant recipients, as well as from drug interactions with immunosuppressants. Factors that may affect recurrent hepatitis C include donor age, immunosuppression, IL28 B genotype, cytomegalovirus infection, and metabolic syndrome. Older donor age has persistently been shown to have the greatest impact on recurrent hepatitis C. After liver transplantation, distinguishing recurrent hepatitis C from acute cellular rejection may be difficult, although the development of molecular markers may help in making the correct diagnosis. The advent of interferon free regimens with direct acting antiviral agents that include NS3/4A protease inhibitors, NS5 B polymerase inhibitors and NS5 A inhibitors holds great promise in improving outcomes for liver transplant candidates and recipients.

Pretransplantation fetal-maternal microchimerism in pediatric liver transplantation from mother

AIM To investigate the rates of pretransplantation fetalmaternal microchimerism(MC) and its effect on rejection in children receiving maternal liver grafts. METHODS DNA or blood samples before liver transplantation(LT) were available in 45 pediatric patients and their mothers. The presence of pretransplantation MC to non-inherited maternal antigens(NIMAs)(NIMA-MC) in the peripheral blood was tested using nested PCRsingle-strand conformation polymorphism analysis for the human leukocyte antigen(HLA)-DRB1 alleles. NIMA-MC was successfully evaluated in 26 of the 45 children. Among these 45 pediatric LT recipients,23 children(51.1%) received transplants from maternal donors and the other 22 from non-maternal donors.RESULTS Among these 26 children,pretransplantation NIMAMC was detected in 23.1%(n = 6),6.1(range,0.8-14) years after birth. Among the children with a maternal donor,the rate of biopsy-proven cellular rejection(BPCR) was 0% in patients with NIMA-MC positivity(0/3) and those with HLA-DR identity with the mother(0/4),but it was 50% in those with NIMA-MC negativity(5/10). Patients with NIMA-MC positivity or HLA-DR identity with the mother showed significantly lower BPCR rate compared with NIMA-MC-negative patients(0% vs 50%,P = 0.04). NIMA-MC-positive patients tended to show lower BPCR rate compared with NIMAMC-negative patients(P = 0.23). CONCLUSION The presence of pretransplantation NIMA-MC or HLADR identity with the mother could be associated with BPCR-free survival in pediatric recipients of LT from maternal donors.

Combined liver and kidney transplantation in children and long-term outcome

Combined liver-kidney transplantation(CLKT)is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual(usually a cadaver)to the same recipient during a single surgical procedure.Most common indications for CLKT in children are autosomal recessive polycystic kidney disease and primary hyperoxaluria type 1.Atypical haemolytic uremic syndrome,methylmalonic academia,and conditions where liver and renal failure co-exists may be indications for CLKT.CLKT is often preferred over sequential liver-kidney transplantation due to immunoprotective effects of transplanted liver on renal allograft;however,liver survival has no significant impact.Since CLKT is a major surgical procedure which involves multiple and complex anastomosis surgeries,acute complications are not uncommon.Bleeding,thrombosis,haemodynamic instability,infections,acute cellular rejections,renal and liver dysfunction are acute complications.The long-term outlook is promising with over 80%5-year survival rates among those children who survive the initial six-month postoperative period.

Diabetes mellitus is not associated with worse short term outcome in patients older than 65 years old post-liver transplantation

BACKGROUND Non-alcoholic fatty liver disease is a global health care challenge and a leading indication of liver transplantation(LT).Hence,more patients with diabetes mellitus(DM)are undergoing LT,especially,above the age of 65.AIM To evaluate the impact of DM on short-term outcomes post-LT in patients over the age of 65.METHODS We collected data of patients who underwent LT from January 2001 until December 2019 using our electronic medical record.We assessed the impact of DM on short-term outcomes,one-year,post-LT based on the following variables:Survival at one year;acute cellular rejection(ACR)rates;intensive care unit(ICU)and hospital length of stay;and readmissions.RESULTS Total of 148 patients who are 65 year or older underwent LT during the study period.The mean age is 68.5±3.3 years and 67.6%were male.The median Model for End-stage Liver Disease score at time of transplantation was 22(6-39),39%of patients had hepatocellular carcinoma and 77.7%underwent living donor LT.The one-year survival was similar between DM patients and others,91%.ACR occurred in 13.5%of patients(P=0.902).The median ICU stay is 4.5-day P=0.023.The rates of ICU and 90-d readmission were similar(P=0.821)and(P=0.194),respectively.CONCLUSION The short-term outcome of elderly diabetic patients undergoing LT is similar to others.The presence of DM in elderly LT candidates should not discourage physicians from transplant consideration in this cohort of patients.

Approach to persistent ascites after liver transplantation

Persistent ascites(PA)after liver transplantation(LT),commonly defined as ascites lasting more than 4 wk after LT,can be expected in up to 7%of patients.Despite being relatively rare,it is associated with worse clinical outcomes,including higher 1-year mortality.The cause of PA can be divided into vascular,hepatic,or extrahepatic.Vascular causes of PA include hepatic outflow and inflow obstructions,which are usually successfully treated.Regarding modifiable hepatic causes,recurrent hepatitis C and acute cellular rejection are the leading ones.Considering predictors for PA,the presence of ascites,refractory ascites,hepatorenal syndrome type 1,spontaneous bacterial peritonitis,hepatic encephalopathy,and prolonged ischemic time significantly influence the development of PA after LT.The initial approach to patients with PA should be to diagnose the treatable cause of PA.The stepwise approach in evaluating PA includes diagnostic paracentesis,ultrasound with Doppler,and an echocardiogram when a cardiac cause is suspected.Finally,a percutaneous or transjugular liver biopsy should be performed in cases where the diagnosis is unclear.PA of unknown cause should be treated with diuretics and paracentesis,while transjugular intrahepatic portosystemic shunt and splenic artery embolization are treatment methods in patients with refractory ascites after LT.

Exosome-derived galectin-9 may be a novel predictor of rejection and prognosis after liver transplantation

Acute cellular rejection(ACR) remains a major concern after liver transplantation.Predicting and monitoring acute rejection by non-invasive methods are very important for guiding the use of immunosuppressive drugs.Many studies have shown that exosomes and their contents are potential biomarkers for various liver diseases.Here,we identify and validate the role of exosomes and galectin-9 in ACR after liver transplantation.Exosomes were isolated from three sets of paired patients,with and without ACR,and the proteins within the exosomes were isolated and identified.Candidate proteins were then validated using a tissue microarray containing resected liver samples from 73 ACR and 63 non-rejection patients.Finally,protein expression and clinical manifestations were included in KaplanMeier survival and Cox regression analyses.Circulating exosomes were isolated from ACR and non-rejection patients and characterized using transmission electron microscopy and western blotting for CD63/CD81.Western blotting experiments revealed higher levels of galectin-9 protein in circulating exosomes from ACR recipients.Immunohistochemical analysis of the tissue microarray showed that the expression of galectin-9 in resected liver was significantly higher in the ACR group than in the non-rejection group(P<0.05).Higher levels of galectin-9 expression in resected livers were associated with poorer prognosis(P<0.05).Exosome-derived galectin-9 may be a novel predictor of rejection and prognosis after liver transplantation.

The conclusion of reducing acute rejection after liver transplantation by machine perfusion should be extrapolated with caution

There is a theory that the unavoidable graft damage caused by ischemia-reperfusion injury(IRI)during liver transplantation(LT)can lead to severe IRI-related inflammation and trigger an early activation of the innate immune response mediated by T-cells,which potentially worsening the acute cellular rejection(ACR)cascade.As a result,machine perfusion(MP)has been placed great expectations for the potential to diminish post-LT ACR and other related immune responses by alleviating IRI through removing harmful substances and restoring cellular metabolism homeostasis(1,2).However,there has been much debate about MP’s benefits on ACR as relative data is limited.