BACKGROUND Gastroesophageal reflux is associated with poorer outcomes after lung transplant,likely through recurrent aspiration and allograft injury.Although prior studies have demonstrated a relationship between impe...BACKGROUND Gastroesophageal reflux is associated with poorer outcomes after lung transplant,likely through recurrent aspiration and allograft injury.Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes,the role of esophageal manometry in the assessment of lung transplant patients remains debated,and the impact of esophageal dysmotility on transplant outcomes is unclear.Of particular interest is ineffective esophageal motility(IEM)and its associated impact on esophageal clearance.AIM To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation.METHODS This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018.Patients with pre-transplant anti-reflux surgery were excluded.Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing.Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection,defined histologically per International Society of Heart and Lung Transplantation guidelines.Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery,last clinic visit,or death.Fisher’s exact test for binary variables and student’s t-test for continuous variables were performed to assess for differences between groups.RESULTS Of 184 subjects(54%men,mean age:58,follow-up:443 person-years)met criteria for inclusion.Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis(41%).During the follow-up period,60 subjects(33.5%)developed acute rejection.The all-cause mortality was 16.3%.Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection[hazard ratio(HR):1.984,95%CI:1.03-3.30,P=0.04],confirmed on Kaplan-Meier curve.On multivariable analysis,IEM remained independently associated with acute rejection,even after controlling for potential confounders such as the presence of acid and nonacid reflux(HR:2.20,95%CI:1.18-4.11,P=0.01).Nonacid reflux was also independently associated with acute rejection on both univariate(HR:2.16,95%CI:1.26-3.72,P=0.005)and multivariable analyses(HR:2.10,95%CI:1.21-3.64,P=0.009),adjusting for the presence of IEM.CONCLUSION Pre-transplant IEM was associated with acute rejection after transplantation,even after controlling for acid and nonacid reflux.Esophageal motility testing may be considered in lung transplant to predict outcomes.展开更多
Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors pl...Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.展开更多
Background:Translationally controlled tumor protein(TCTP),which has been verified to have a proinflammatory activity,plays an important role in allergy.However,it remains unclear whether TCTP has an impact on the acut...Background:Translationally controlled tumor protein(TCTP),which has been verified to have a proinflammatory activity,plays an important role in allergy.However,it remains unclear whether TCTP has an impact on the acute rejection(AR)after liver transplantation.Methods:Three protocols were used to delineate the role of TCTP in AR after liver transplantation.First,in rat orthotopic liver transplantation(OLT),the expression of TCTP was measured by enzyme-linked immunosorbent assay(ELISA),real-time PCR,Western blot and immunofluorescence assays.Second,in mixed lymphocyte reaction(MLR),the role of TCTP in lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester(CFSE)labeling and the impact of TCTP on inflammatory factor release was detected by cytokine arrays.Third,in human OLT,the level of serum TCTP was detected by ELISA,and the relationship between TCTP and model for early allograft function(MEAF)score was assessed by Spearman's correlation.Results:In rat OLT,AR resulted in great harm to allografts,manifesting as deterioration of liver function,increasing inflammatory factors and infiltrating lymphocytes.Meanwhile,TCTP was overexpressed in serum and allografts.Higher level of TCTP was associated with higher rejection activity index(RAI).In an MLR protocol,TCTP knockdown inhibited the proliferation of mixed inflammatory cells and significantly suppressed the release of 15 cytokines and chemokines.In human OLT,the serum TCTP was up-regulated within a week after operation.Additionally,the increasing speed of serum TCTP positively correlated with MEAF scores(r=0.449;P=0.0088).展开更多
Objective To explore the diagnositc role of heat shock protein ( HSP) 70 in acute rejection after pancreatioduodenal transplantation in rats. Methods Groups of Wistar rats underwent total pancreatioduodenal transplant...Objective To explore the diagnositc role of heat shock protein ( HSP) 70 in acute rejection after pancreatioduodenal transplantation in rats. Methods Groups of Wistar rats underwent total pancreatioduodenal transplantation from allogeneic SD or syngeneic Wistar rats. The grafts were harvested on the posttransplantation day 3,5 and 7 and were used to detect the expression of HSP70 by immunohistochemistry and Western Blotting quantitative methods. The correlation between HSP70 expression and pathological findings was observed. Results The level of HSP70 in the isografts did not change greatly( P 】 0.05); the level of HSP70 in the allografts was increased progressively on the posttransplantation day3, 5 and 7 ( P 【 0.01). There was a significant correlation between HSP70 and pathological score in the allograft group (P 【 0.01, r = 0.934). Conclusion HSP70 involved in pancreas allograft rejection and could be useful for early diagnosis of acute rejection following pancreas transplantation. 8 refs,2 tabs.展开更多
To observe the effect of gene transfer of huCTLA4-Ig to inhibit the acute rejection of liver allograft in rats.Methods With AdEasy vector system,the recombinant adenovirus containing huCTLA4-Ig gene was constructed.Us...To observe the effect of gene transfer of huCTLA4-Ig to inhibit the acute rejection of liver allograft in rats.Methods With AdEasy vector system,the recombinant adenovirus containing huCTLA4-Ig gene was constructed.Using ex vivo gene transfer technique,exogenous gene was introduced to the liver graft during cold preservation and expressed locally in the graft.The effect of inhibition of acute rejection and inducing liver graft tolerance was observed.Results No recipients in group A (without any treatment,n=5) or group B (treated with Ad-GFP,n=4) died within 3 weeks after transplantation and severe acute rejection (massive periportal infiltration,endothelilitis,damage to biliary epithelium and severe tissue destruction) was confirmed pathologically in the graft.In contrast,all recipients in group C (treated with Ad-huCTLA4-Ig,n=5) achieved long-term liver allograft survival (>150 days).Histological examination of Ad-huCTLA4-Ig transduced allografts demonstrated a mild to moderate periportal inflammation and mild injury to liver graft on day 8 posttransplant.A mild mononuclear infiltration was observed;however,there was complete preservation of the bild ducts and no evidence of vascular injury on day 150 posttransplant.The mean IL-2 concentration in serum was (362.09±45.84) ng/L at day 1 pretransplant.In control animals (groups A and B),serum IL-2 concentration was elevated to a high level within 7 days posttransplant,which was about 1.5 to 2.5 times as much as that before transplant.In contrast,in huCTLA4-Ig-treated animals (groups C),IL-2 concentration in serum was maintained at a relative low level,which was near or less than that before transplant (P<0.01).Conclusion Using ex vivo gene transfer technique,huCTLA4-Ig gene can be introduced to the liver graft during cold preservation.The modified graft can express and excrete immunoregulatory protein locally,which can suppress acute alloimmune response and is responsible for prolongation of graft survival without using routine immunosuppressive drugs.These findings provide some experimental evidence that gene delivery of sequences encoding immunoregulatory proteins can be applied to clinical liver transplantation for inhibiting the acute alloimmune response and achieving graft tolerance.7 refs,2 tabs.展开更多
A patient with steroid-resistant acute rejection 50 days after ABO-compatible orthotopic liver transplantation(LT)received regular infusion of allogeneic mesenchymal stem cells(MSCs)after three sessions of steroid pul...A patient with steroid-resistant acute rejection 50 days after ABO-compatible orthotopic liver transplantation(LT)received regular infusion of allogeneic mesenchymal stem cells(MSCs)after three sessions of steroid pulse therapy which failed to control the pathogenetic condition as shown by biopsy.Liver function improved gradually after intravenous injection of MSCs once weekly for 10 weeks(as confirmed by biopsy)and remained stable under administration of conventional immunosuppressive agents.There was no evidence of neoplasms 5 years after treatment.MSCs infusion appears to successfully reverse resistance to immunosuppressive agents and may be a useful treatment for post-liver transplant steroid-resistant rejection.展开更多
Anti-thymocyte globulin(ATG)is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients.Commercially available as Th...Anti-thymocyte globulin(ATG)is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients.Commercially available as Thymoglobulin(rabbit-derived,Sanofi,United States),ATG-Fresenius S(rabbit-derived),and ATGAM(equine-derived,Pfizer,United States),these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells,imparting immunosuppressive effects.Although the prevailing mechanism predominantly involves T-cell depletion via the complement-mediated pathway,alternate mechanisms have been elucidated.Optimal dosing and treatment duration of ATG have exhibited variance across randomised trials and clinical reports,rendering the establishment of standardized guidelines a challenge.The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever,chills,and skin rash in the acute phase to long-term concerns related to immunosuppression,including susceptibility to infections and malignancies.This comprehensive review aims to provide a thorough exploration of the current understanding of ATG,encompassing its mechanism of action,clinical utility in the treatment of acute renal graft rejections,specifically steroid-resistant cases,efficacy in rejection episode reversal,and a synthesis of findings from different eras of maintenance immunosuppression.Additionally,it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function.Furthermore,the review underscores the existing gaps in evidence,particularly in the context of the Banff classification of rejections,and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.展开更多
BACKGROUND The liver has traditionally been regarded as resistant to antibody-mediated rejection(AMR).AMR in liver transplants is a field in its infancy compared to kidney and lung transplants.In our case we present a...BACKGROUND The liver has traditionally been regarded as resistant to antibody-mediated rejection(AMR).AMR in liver transplants is a field in its infancy compared to kidney and lung transplants.In our case we present a patient with alpha-1-antitrypsin disease who underwent ABO compatible liver transplant complicated by acute liver failure(ALF)with evidence of antibody mediated rejection on allograft biopsy and elevated serum donor-specific antibodies(DSA).This case highlights the need for further investigations and heightened awareness for timely diagnosis.CASE SUMMARY A 56 year-old woman with alpha-1-antitrypsin disease underwent ABO compatible liver transplant from a deceased donor.The recipient MELD at the time of transplant was 28.The flow cytometric crossmatches were noted to be positive for T and B lymphocytes.The patient had an uneventful recovery postoperatively.Starting on postoperative day 5 the patient developed fevers,elevated liver function tests,distributive shock,renal failure,and hepatic encephalopathy.She went into ALF with evidence of antibody mediated rejection with portal inflammation,bile duct injury,endothelitis,and extensive centrizonal necrosis,and C4d staining on allograft biopsy and elevated DSA.Despite various interventions including plasmapheresis and immunomodulating therapy,she continued to deteriorate.She was relisted and successfully underwent liver retransplantation.CONCLUSION This very rare case highlights AMR as the cause of ALF following liver transplant requiring retransplantation.展开更多
Objective:To explore the expression profile of miRNA in peripheral blood of patients with acute T cell mediated rejection after kidney transplantation.Method:4 patients with acute T cell mediated rejection(TCMR)after ...Objective:To explore the expression profile of miRNA in peripheral blood of patients with acute T cell mediated rejection after kidney transplantation.Method:4 patients with acute T cell mediated rejection(TCMR)after kidney transplantation were collected as experimental group.Meanwhile,4 patients under stable condition after kidney transplantation were collected as control group.The elbow blood was taken from two groups.The next generation sequencing was used to study miRNA libraries.Then,they were analyzed of variance by R language software.Results:14 miRNAs were differently expressed in the experimental group and control group,including 5 up-regulated miRNAs(P<0.05)and 9 down-regulated miRNAs(P<0.05).Conclusions:Peripheral blood miRNAs expression variations might be ideal biomarkers and reveal mechanisms for acute TCMR.展开更多
Kidney transplantation is the best option for kidney replacement therapy,even considering that most of the times the grafts do not survive as long as their recipients.In the Khalil et al's experience,published in ...Kidney transplantation is the best option for kidney replacement therapy,even considering that most of the times the grafts do not survive as long as their recipients.In the Khalil et al's experience,published in this issue of the Journal,they analyze their second kidney graft survival and describe those significant predictors of early loss.This editorial comments on the results and put in perspective that most of the times,long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason,and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.展开更多
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 i...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.展开更多
Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells ...Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells in the complex milieu of the liver.In this section,we will comment on the importance of donorspecific anti-human leukocyte antigen(HLA)antibodies(DSA)as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor(KIR)genotypes in the evolution of liver transplantation.Thus,HLA compatibility,viral infections,and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival.There have been reports of increased risk of acute and chronic rejection with ductopenia,faster graft fibrosis,biliary problems,poorer survival,and even de novo autoimmune hepatitis when DSAs are present in the recipient.Higher mean fluorescence intensity(MFI)values of the DSAs and smaller graft size were associated with poorer patient outcomes,implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods,according to the investigators.Similarly,in a combined kidney-liver transplant,a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment.The renal graft was lost owing to antibody-mediated rejection(AMR).The HLA antigens expressed by the transplanted liver graft influenced antibody elimination.Pathologists are increasingly diagnosing AMR in liver transplants,and desensitization therapy has even been employed in situations of AMR,particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex.In conclusion,after revealing the negative impacts of DSAs with high MFI,pretransplant virtual crossmatch techniques may be appropriate to improve evolution;however,they may extend cold ischemia periods by requiring the donor to be typed.展开更多
BACKGROUND The outcomes of liver transplantation(LT)from different grafts have been studied individually and in combination,but the reports were conflicting with some researchers finding no difference in both short-te...BACKGROUND The outcomes of liver transplantation(LT)from different grafts have been studied individually and in combination,but the reports were conflicting with some researchers finding no difference in both short-term and long-term outcomes between the deceased donor split LT(DD-SLT)and living donor LT(LDLT).AIM To compare the outcomes of DD-SLT and LDLT we performed this systematic review and meta-analysis.METHODS This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.The following databases were searched for articles comparing outcomes of DD-SLT and LDLT:PubMed;Google Scholar;Embase;Cochrane Central Register of Controlled Trials;the Cochrane Database of Systematic Reviews;and Reference Citation Analysis(https://www.referencecitationanalysis.com/).The search terms used were:“liver transplantation;”“liver transplant;”“split liver transplant;”“living donor liver transplant;”“partial liver transplant;”“partial liver graft;”“ex vivo splitting;”and“in vivo splitting.”RESULTS Ten studies were included for the data synthesis and meta-analysis.There were a total of 4836 patients.The overall survival rate at 1 year,3 years and 5 years was superior in patients that received LDLT compared to DD-SLT.At 1 year,the hazard ratios was 1.44(95%confidence interval:1.16-1.78;P=0.001).The graft survival rate at 3 years and 5 years was superior in the LDLT group(3 year hazard ratio:1.28;95%confidence interval:1.01-1.63;P=0.04).CONCLUSION This meta-analysis showed that LDLT has better graft survival and overall survival when compared to DD-SLT.展开更多
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...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.展开更多
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 retro...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.展开更多
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...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.展开更多
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 clinic...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.展开更多
文摘BACKGROUND Gastroesophageal reflux is associated with poorer outcomes after lung transplant,likely through recurrent aspiration and allograft injury.Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes,the role of esophageal manometry in the assessment of lung transplant patients remains debated,and the impact of esophageal dysmotility on transplant outcomes is unclear.Of particular interest is ineffective esophageal motility(IEM)and its associated impact on esophageal clearance.AIM To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation.METHODS This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018.Patients with pre-transplant anti-reflux surgery were excluded.Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing.Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection,defined histologically per International Society of Heart and Lung Transplantation guidelines.Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery,last clinic visit,or death.Fisher’s exact test for binary variables and student’s t-test for continuous variables were performed to assess for differences between groups.RESULTS Of 184 subjects(54%men,mean age:58,follow-up:443 person-years)met criteria for inclusion.Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis(41%).During the follow-up period,60 subjects(33.5%)developed acute rejection.The all-cause mortality was 16.3%.Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection[hazard ratio(HR):1.984,95%CI:1.03-3.30,P=0.04],confirmed on Kaplan-Meier curve.On multivariable analysis,IEM remained independently associated with acute rejection,even after controlling for potential confounders such as the presence of acid and nonacid reflux(HR:2.20,95%CI:1.18-4.11,P=0.01).Nonacid reflux was also independently associated with acute rejection on both univariate(HR:2.16,95%CI:1.26-3.72,P=0.005)and multivariable analyses(HR:2.10,95%CI:1.21-3.64,P=0.009),adjusting for the presence of IEM.CONCLUSION Pre-transplant IEM was associated with acute rejection after transplantation,even after controlling for acid and nonacid reflux.Esophageal motility testing may be considered in lung transplant to predict outcomes.
文摘Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.
基金supported by grants from the National Key Research and Development Program Funded Projects(2017YFC1103703)National Basic Research Program of China(2015CB554100)National Natural Science Foundation(81870446,81670593and 81900571)。
文摘Background:Translationally controlled tumor protein(TCTP),which has been verified to have a proinflammatory activity,plays an important role in allergy.However,it remains unclear whether TCTP has an impact on the acute rejection(AR)after liver transplantation.Methods:Three protocols were used to delineate the role of TCTP in AR after liver transplantation.First,in rat orthotopic liver transplantation(OLT),the expression of TCTP was measured by enzyme-linked immunosorbent assay(ELISA),real-time PCR,Western blot and immunofluorescence assays.Second,in mixed lymphocyte reaction(MLR),the role of TCTP in lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester(CFSE)labeling and the impact of TCTP on inflammatory factor release was detected by cytokine arrays.Third,in human OLT,the level of serum TCTP was detected by ELISA,and the relationship between TCTP and model for early allograft function(MEAF)score was assessed by Spearman's correlation.Results:In rat OLT,AR resulted in great harm to allografts,manifesting as deterioration of liver function,increasing inflammatory factors and infiltrating lymphocytes.Meanwhile,TCTP was overexpressed in serum and allografts.Higher level of TCTP was associated with higher rejection activity index(RAI).In an MLR protocol,TCTP knockdown inhibited the proliferation of mixed inflammatory cells and significantly suppressed the release of 15 cytokines and chemokines.In human OLT,the serum TCTP was up-regulated within a week after operation.Additionally,the increasing speed of serum TCTP positively correlated with MEAF scores(r=0.449;P=0.0088).
文摘Objective To explore the diagnositc role of heat shock protein ( HSP) 70 in acute rejection after pancreatioduodenal transplantation in rats. Methods Groups of Wistar rats underwent total pancreatioduodenal transplantation from allogeneic SD or syngeneic Wistar rats. The grafts were harvested on the posttransplantation day 3,5 and 7 and were used to detect the expression of HSP70 by immunohistochemistry and Western Blotting quantitative methods. The correlation between HSP70 expression and pathological findings was observed. Results The level of HSP70 in the isografts did not change greatly( P 】 0.05); the level of HSP70 in the allografts was increased progressively on the posttransplantation day3, 5 and 7 ( P 【 0.01). There was a significant correlation between HSP70 and pathological score in the allograft group (P 【 0.01, r = 0.934). Conclusion HSP70 involved in pancreas allograft rejection and could be useful for early diagnosis of acute rejection following pancreas transplantation. 8 refs,2 tabs.
文摘To observe the effect of gene transfer of huCTLA4-Ig to inhibit the acute rejection of liver allograft in rats.Methods With AdEasy vector system,the recombinant adenovirus containing huCTLA4-Ig gene was constructed.Using ex vivo gene transfer technique,exogenous gene was introduced to the liver graft during cold preservation and expressed locally in the graft.The effect of inhibition of acute rejection and inducing liver graft tolerance was observed.Results No recipients in group A (without any treatment,n=5) or group B (treated with Ad-GFP,n=4) died within 3 weeks after transplantation and severe acute rejection (massive periportal infiltration,endothelilitis,damage to biliary epithelium and severe tissue destruction) was confirmed pathologically in the graft.In contrast,all recipients in group C (treated with Ad-huCTLA4-Ig,n=5) achieved long-term liver allograft survival (>150 days).Histological examination of Ad-huCTLA4-Ig transduced allografts demonstrated a mild to moderate periportal inflammation and mild injury to liver graft on day 8 posttransplant.A mild mononuclear infiltration was observed;however,there was complete preservation of the bild ducts and no evidence of vascular injury on day 150 posttransplant.The mean IL-2 concentration in serum was (362.09±45.84) ng/L at day 1 pretransplant.In control animals (groups A and B),serum IL-2 concentration was elevated to a high level within 7 days posttransplant,which was about 1.5 to 2.5 times as much as that before transplant.In contrast,in huCTLA4-Ig-treated animals (groups C),IL-2 concentration in serum was maintained at a relative low level,which was near or less than that before transplant (P<0.01).Conclusion Using ex vivo gene transfer technique,huCTLA4-Ig gene can be introduced to the liver graft during cold preservation.The modified graft can express and excrete immunoregulatory protein locally,which can suppress acute alloimmune response and is responsible for prolongation of graft survival without using routine immunosuppressive drugs.These findings provide some experimental evidence that gene delivery of sequences encoding immunoregulatory proteins can be applied to clinical liver transplantation for inhibiting the acute alloimmune response and achieving graft tolerance.7 refs,2 tabs.
基金This work was supported by the grants from the National Natural Science Foundation of China(No.81370575,81570593)Guangdong Natural Science Foundation(2015A030312013),Scitech Research Development Program of Guangdong province(2017A020215023)+2 种基金Sci-tech Research Development Program of Guangzhou city(No.158100076,201400000001-3)Sun Yat-sen University Clinical Research 5010 Program(2014006)Young teacher development program of Sun Yat-sen University(17ykpy57).
文摘A patient with steroid-resistant acute rejection 50 days after ABO-compatible orthotopic liver transplantation(LT)received regular infusion of allogeneic mesenchymal stem cells(MSCs)after three sessions of steroid pulse therapy which failed to control the pathogenetic condition as shown by biopsy.Liver function improved gradually after intravenous injection of MSCs once weekly for 10 weeks(as confirmed by biopsy)and remained stable under administration of conventional immunosuppressive agents.There was no evidence of neoplasms 5 years after treatment.MSCs infusion appears to successfully reverse resistance to immunosuppressive agents and may be a useful treatment for post-liver transplant steroid-resistant rejection.
文摘Anti-thymocyte globulin(ATG)is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients.Commercially available as Thymoglobulin(rabbit-derived,Sanofi,United States),ATG-Fresenius S(rabbit-derived),and ATGAM(equine-derived,Pfizer,United States),these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells,imparting immunosuppressive effects.Although the prevailing mechanism predominantly involves T-cell depletion via the complement-mediated pathway,alternate mechanisms have been elucidated.Optimal dosing and treatment duration of ATG have exhibited variance across randomised trials and clinical reports,rendering the establishment of standardized guidelines a challenge.The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever,chills,and skin rash in the acute phase to long-term concerns related to immunosuppression,including susceptibility to infections and malignancies.This comprehensive review aims to provide a thorough exploration of the current understanding of ATG,encompassing its mechanism of action,clinical utility in the treatment of acute renal graft rejections,specifically steroid-resistant cases,efficacy in rejection episode reversal,and a synthesis of findings from different eras of maintenance immunosuppression.Additionally,it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function.Furthermore,the review underscores the existing gaps in evidence,particularly in the context of the Banff classification of rejections,and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.
基金Corresponding author:Lena Sibulesky,MD,Associate Professor,Surgeon,Department of Surgery,University of Washington Medical Center,UWMC 1959 NE Pacific St,Box 356410 Seattle,Seattle,WA 98195,United States.lenasi@uw.edu。
文摘BACKGROUND The liver has traditionally been regarded as resistant to antibody-mediated rejection(AMR).AMR in liver transplants is a field in its infancy compared to kidney and lung transplants.In our case we present a patient with alpha-1-antitrypsin disease who underwent ABO compatible liver transplant complicated by acute liver failure(ALF)with evidence of antibody mediated rejection on allograft biopsy and elevated serum donor-specific antibodies(DSA).This case highlights the need for further investigations and heightened awareness for timely diagnosis.CASE SUMMARY A 56 year-old woman with alpha-1-antitrypsin disease underwent ABO compatible liver transplant from a deceased donor.The recipient MELD at the time of transplant was 28.The flow cytometric crossmatches were noted to be positive for T and B lymphocytes.The patient had an uneventful recovery postoperatively.Starting on postoperative day 5 the patient developed fevers,elevated liver function tests,distributive shock,renal failure,and hepatic encephalopathy.She went into ALF with evidence of antibody mediated rejection with portal inflammation,bile duct injury,endothelitis,and extensive centrizonal necrosis,and C4d staining on allograft biopsy and elevated DSA.Despite various interventions including plasmapheresis and immunomodulating therapy,she continued to deteriorate.She was relisted and successfully underwent liver retransplantation.CONCLUSION This very rare case highlights AMR as the cause of ALF following liver transplant requiring retransplantation.
基金Hainan Provincial Natural Science Foundation of China(No.820QN404)Project of the Second Affliated Hospital of Hainan Medical University(2019)。
文摘Objective:To explore the expression profile of miRNA in peripheral blood of patients with acute T cell mediated rejection after kidney transplantation.Method:4 patients with acute T cell mediated rejection(TCMR)after kidney transplantation were collected as experimental group.Meanwhile,4 patients under stable condition after kidney transplantation were collected as control group.The elbow blood was taken from two groups.The next generation sequencing was used to study miRNA libraries.Then,they were analyzed of variance by R language software.Results:14 miRNAs were differently expressed in the experimental group and control group,including 5 up-regulated miRNAs(P<0.05)and 9 down-regulated miRNAs(P<0.05).Conclusions:Peripheral blood miRNAs expression variations might be ideal biomarkers and reveal mechanisms for acute TCMR.
文摘Kidney transplantation is the best option for kidney replacement therapy,even considering that most of the times the grafts do not survive as long as their recipients.In the Khalil et al's experience,published in this issue of the Journal,they analyze their second kidney graft survival and describe those significant predictors of early loss.This editorial comments on the results and put in perspective that most of the times,long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason,and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.
文摘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.
基金Instituto de Salud Carlos III,Spanish Ministry of Economy and Competitiveness,No.PI15/01370 and P19/01194and the European Union with the European Fund of Regional Development with the principle of“A manner to build Europe”.
文摘Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells in the complex milieu of the liver.In this section,we will comment on the importance of donorspecific anti-human leukocyte antigen(HLA)antibodies(DSA)as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor(KIR)genotypes in the evolution of liver transplantation.Thus,HLA compatibility,viral infections,and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival.There have been reports of increased risk of acute and chronic rejection with ductopenia,faster graft fibrosis,biliary problems,poorer survival,and even de novo autoimmune hepatitis when DSAs are present in the recipient.Higher mean fluorescence intensity(MFI)values of the DSAs and smaller graft size were associated with poorer patient outcomes,implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods,according to the investigators.Similarly,in a combined kidney-liver transplant,a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment.The renal graft was lost owing to antibody-mediated rejection(AMR).The HLA antigens expressed by the transplanted liver graft influenced antibody elimination.Pathologists are increasingly diagnosing AMR in liver transplants,and desensitization therapy has even been employed in situations of AMR,particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex.In conclusion,after revealing the negative impacts of DSAs with high MFI,pretransplant virtual crossmatch techniques may be appropriate to improve evolution;however,they may extend cold ischemia periods by requiring the donor to be typed.
文摘BACKGROUND The outcomes of liver transplantation(LT)from different grafts have been studied individually and in combination,but the reports were conflicting with some researchers finding no difference in both short-term and long-term outcomes between the deceased donor split LT(DD-SLT)and living donor LT(LDLT).AIM To compare the outcomes of DD-SLT and LDLT we performed this systematic review and meta-analysis.METHODS This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.The following databases were searched for articles comparing outcomes of DD-SLT and LDLT:PubMed;Google Scholar;Embase;Cochrane Central Register of Controlled Trials;the Cochrane Database of Systematic Reviews;and Reference Citation Analysis(https://www.referencecitationanalysis.com/).The search terms used were:“liver transplantation;”“liver transplant;”“split liver transplant;”“living donor liver transplant;”“partial liver transplant;”“partial liver graft;”“ex vivo splitting;”and“in vivo splitting.”RESULTS Ten studies were included for the data synthesis and meta-analysis.There were a total of 4836 patients.The overall survival rate at 1 year,3 years and 5 years was superior in patients that received LDLT compared to DD-SLT.At 1 year,the hazard ratios was 1.44(95%confidence interval:1.16-1.78;P=0.001).The graft survival rate at 3 years and 5 years was superior in the LDLT group(3 year hazard ratio:1.28;95%confidence interval:1.01-1.63;P=0.04).CONCLUSION This meta-analysis showed that LDLT has better graft survival and overall survival when compared to DD-SLT.
文摘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.
文摘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.
文摘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.
基金Supported by the Croatian Science Foundation,Emerging and Neglected Hepatotropic Viruses after Solid Organ and Hematopoietic Stem Cell Transplantation(to Mrzljak A),No.IP-2020-02-7407.
文摘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.
