Placement of removable metal biliary stent in post-orthotopic liver transplantation anastomotic stricture

Postoperative biliary strictures are the most common cause of benign biliary stricture in Western countries, secondary to either operative injury or bile duct anastomotic stricture following orthotopic liver transplantation(OLT).Surgery or endoscopic interventions are the mainstay of treatment for benign biliary strictures.We aim to report the outcome of 2 patients with refractory anastomotic biliary stricture post-OLT,who had successful temporary placement of a prototype removable covered self-expandable metal stent(RCSEMS).These 2 patients(both men,aged 44 and 53 years)were given temporary placement of a prototype RCSEMS (8.5 Fr gauge delivery system,8 mm×40 mm stent dimensions)in the common bile duct across the biliary stricture.There was no morbidity associated with stent placement and removal in these 2 cases.Clinical parameters improved after the RCSEMS placement.Longterm biliary patency was achieved in both the patients. No further biliary intervention was required within 14 and 18 mo follow-up after stent removal.

Portal vein stenting as a significant risk factor for biliary stricture in adult living donor liver transplantation

BACKGROUND: Although perioperative portal vein (PV) stent implantation is an effective treatment for steno-occlusive disease in adult living donor liver transplantation (LDLT) re-cipients, we experienced high incidence of biliary anastomotic strictures (BAS) after PV stenting. In this study, we sought to clarify the relation between BAS and PV stenting and to suggest the possible mechanism of BAS and measures to reduce its in-cidence. METHODS: We retrospectively analyzed 44 LDLT recipients who underwent PV stent implantation across the line of PV anastomosis regardless of the location of steno-occlusion (stent group) and their matched controls (non-stented LDLT recipients, n=131). RESULTS: The incidence of BAS was higher in patients in the stent group than that in the control group (43.2% vs 17.6%, P=0.001). Cumulative 6-month and 1-, 2- and 5-year BAS rates were 31.8%, 34.1%, 41.4% and 43.2%, respectively, in the stent group and 13.0%, 13.8%, 16.1% and 17.8%, respectively, in the control group (P=0.001). Multivariate analysis revealed that PV stenting was an independent risk factor for BAS. CONCLUSIONS: Although PV stent implantation is a reliable treatment modality for steno-occlusive PV in adult LDLT recipients, innovative methods to prevent the PV stent from crossing the line of PV anastomosis may be necessary to reduce the incidence of postoperative BAS.

Endoscopic therapy using a self-expandable metallic stent with an anti-migration system for postorthotopic liver transplantation anastomotic biliary stricture

BACKGROUND Endoscopic therapy using multiple plastic stents(MPSs)is the standard therapy for postorthotopic liver transplantation(p-OLT)anastomotic biliary stricture(ABS).However,this approach demands repeated procedures.Recent studies us-ing fully covered self-expandable metallic stents(FCSEMS)have shown en-couraging results,but migration occurs in 10%to 40%of cases.The objective of this retrospective study was to evaluate the efficacy of endoscopic treatment using FCSEMS with an anti-migration system(Am-FCSEMS)in patients with p-OLT ABS.AIM To evaluate the efficacy of endoscopic treatment using an Am-FCSEMS in patients with p-OLT ABS.METHODS This study was conducted in a private tertiary care centre in S?o Paulo,Brazil and was approved by our institution's Human Research Committee.From April 2018 to October 2020,regardless of previous endoscopic treatment(MPS or FCSEMS),17 patients with p-OLT ABS and indications for endoscopic therapy were included in this study.The exclusion criteria were pregnancy,nonanastomotic biliary or hilar stricture,hepatic artery stenosis/thrombosis,isolated biliary fistulae,a distance shorter than 2 cm from the stricture to the hepatic hilum,and patient refusal.The primary endpoint was the efficacy of p-OLT ABS endoscopic treatment using an Am-FCSEMS that re-mained in place for a 12-mo period.Biliary sphincterotomy was performed in patients with native papilla,and an Am-FCSEMS(10 mm in final diameter and 60 or 80 mm in length)was placed(Hanarostent TM MI Tech,Co).Balloon stricture dilation was performed only if necessary to introduce the stent.RESULTS Three patients were excluded due to loss to follow-up before stent removal.Among the 14 patients included and followed,7 were women,and the average age was 56 years(range:28-76).The average period of Am-FCSEMS placement was 362±109 d.Technical success occurred in all 14 patients(100%).There were no cases of distal stent migration.Complete resolution of the stricture occurred in 13/14 patients(92.85%).Adverse events occurred in 3/14 patients(21.42%):2 patients with mild acute pancreatitis(14.28%)and 1 patient(7.14%)with stent dysfunction(occlusion by biliary sludge and stones,which was treated endoscopically without the need for stent removal).No deaths occurred related to therapy.All stents were removed using foreign body forceps or snares without difficulty.After Am-FCSEMS removal,all 13 patients who had ABS resolution were followed-up for an average of 411±172 d,and there was no stricture recurrence or need for further endoscopic therapy.CONCLUSION In this retrospective study,endoscopy therapy using an Am-FCSEMS for p-OLT ABS was safe and effective,with a high stricture re-solution rate that was probably due to the absence of stent migration.

Treatment of hepatic venous outflow stenosis after living donor liver transplantation by insertion of an expandable metallic stent

BACKGROUND: Hepatic venous outflow stenosis is an uncommon but serious complication after right lobe living donor liver transplantation (LDLT). Failure to recognize and treat this complication early can result in graft failure and even death. The early diagnosis and management of hepatic venous outflow stenosis has become an important issue. METHOD: We report a case with this complication treated by endovascular stent placement in the early period after right lobe LDLT and review related reports to explore the possible mechanism. RESULTS: A 44-year-old man with end-stage hepatitis B liver cirrhosis underwent right lobe LDLT. On postoperative day 13, his liver function deteriorated and he developed refractory ascites for maximal diuretic therapy. Hepatic venography showed a stenosis with an element of torsion of the venous drainage proximal to the anastomosis of the right hepatic venous orifice and inferior vena cava. The stenosis was successfully treated by insertion of an expandable metallic stent. CONCLUSIONS: The result demonstrates that stent placement for stenosis is safe and effective. We suspect that rapid hypertrophy of an asymmetric right lobe graft may result in hepatic venous outflow stenosis caused by twisting or external compression of the hepatic veins.

Safety and efficacy of Kaffes intraductal self-expanding metal stents in the management of post-liver transplant anastomotic strictures

BACKGROUND Endoscopic management is the first-line therapy for post-liver-transplant anas-tomotic strictures.Although the optimal duration of treatment with plastic stents has been reported to be 8-12 months,data on safety and duration for metal stents in this setting is scarce.Due to limited access to endoscopic retrograde cholan-giopancreatography(ERCP)during the coronavirus disease 2019 pandemic in our centre,there was a change in practice towards increased usage and length-of-stay of the Kaffes biliary intraductal self-expanding stent in patients with suitable anatomy.This was mainly due to the theoretical benefit of Kaffes stents allowing for longer indwelling periods compared to the traditional plastic stents.METHODS Adult liver transplant recipients aged 18 years and above who underwent ERCP were retrospectively identified during a 10-year period through a database query.Unplanned admissions post-Kaffes stent insertion were identified manually through electronic and scanned medical records.The main outcome was the incidence of complications when stents were left indwelling for 3 months vs 6 months.Stent efficacy was calculated via rates of stricture recurrence between patients that had stenting courses for≤120 d or>120 d.RESULTS During the study period,a total of 66 ERCPs with Kaffes insertion were performed in 54 patients throughout their stenting course.In 33 ERCPs,the stent was removed or exchanged on a 3-month interval.No pancreatitis,perfor-ations or deaths occurred.Minor post-ERCP complications were similar between the 3-month(abdominal pain and intraductal migration)and 6-month(abdominal pain,septic shower and embedded stent)groups-6.1%vs 9.1%respectively,P=0.40.All strictures resolved at the end of the stenting course,but the stenting course was variable from 3 to 22 months.The recurrence rate for stenting courses lasting for up to 120 d was 71.4%and 21.4%for stenting courses of 121 d or over(P=0.03).There were 28 patients that were treated with a single ERCP with Kaffes,21 with removal after 120 d and 7 within 120 d.There was a significant improvement in stricture recurrence when the Kaffes was removed after 120 d when a single ERCP was used for the entire stenting course(71.0%vs 10.0%,P=0.01).CONCLUSION Utilising a single Kaffes intraductal fully-covered metal stent for at least 4 months is safe and efficacious for the management of post-transplant anastomotic strictures.

Percutaneous portal venoplasty and stenting for anastomotic stenosis after liver transplantation

AIM:To review percutaneous transhepatic portal venoplasty and stenting(PTPVS)for portal vein anastomotic stenosis(PVAS)after liver transplantation (LT). METHODS:From April 2004 to June 2008,16 of 18 consecutive patients(11 male and 5 female;aged 17-66 years,mean age 40.4 years)underwent PTPVS for PVAS.PVAS occurred 2-10 mo after LT(mean 5.0 mo). Three asymptomatic patients were detected on routine screening color Doppler ultrasonography(CDUS). Fifteen patients who also had typical clinical signs of portal hypertension(PHT)were identified by contrastenhanced computerized tomography(CT)or magnetic resonance imaging.All procedures were performed under local anesthesia.If there was a PVAS<75%, the portal pressure was measured.Portal venoplasty was performed with an undersized balloon and slowly inflated.All stents were deployed immediately following the predilation.Follow-ups,including clinical course, stenosis recurrence and stent patency which were evaluated by CDUS and CT,were performed. RESULTS:Technical success was achieved in all patients.No procedure-related complications occurred. Liver function was normalized gradually and the symptoms of PHT also improved following PTPVS.In 2 of 3 asymptomatic patients,portal venoplasty and stenting were not performed because of pressure gradients<5 mmHg.They were observed with periodic CDUS or CT.PTPVS was performed in 16 patients.In 2 patients,the mean pressure gradients decreased from 15.5 mmHg to 3.0 mmHg.In the remaining 14 patients,a pressure gradient was not obtained because of>75%stenosis and typical clinical signs of PHT.In a 51-year-old woman,who suffered from massive ascites and severe bilateral lower limb edema after secondary LT,PVAS complicated hepatic vein stenosis and inferior vena cava(IVC)stenosis. Before PTPVS,a self-expandable and a balloonexpandable metallic stent were deployed in the IVC and right hepatic vein respectively.The ascites and edema resolved gradually after treatment.The portosystemic collateral vessels resulting from PHT were visualized in 14 patients.Gastroesophageal varices became invisible on poststenting portography in 9 patients.In a 28-yearold man with hepatic encephalopathy,a pre-existing meso-caval shunt was detected due to visualization of IVC on portography.After stenting,contrast agents flowed mainly into IVC via the shunt and little flowed into the portal vein.A covered stent was deployed into the superior mesenteric vein to occlude the shunt. Portal hepatopetal flow was restored and the IVC became invisible.The patient recovered from hepatic encephalopathy.A balloon-expandable Palmaz stent was deployed into hepatic artery for anastomotic stenosis before PTPVS.Percutaneous transhepatic internal-external biliary drainage was performed in 2 patients with obstructive jaundice.Portal venous patency was maintained for 3.3-56.6 mo(mean 33.0 mo) and all patients remained asymptomatic.CONCLUSION:With technical refinements,early detection and prompt treatment of complications,and advances in immunotherapy,excellent results can be achieved in LT.

Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions

Intrahepatic cholangiocarcinoma(iCCA)is a rare biliary tract cancer with high mortality rate.Complete resection of the iCCA lesion is the first choice of treatment,with good prognosis after margin-negative resection.Unfortunately,only 12%-40% of patients are eligible for resection at presentation due to cirrhosis,portal hypertension,or large tumor size.Liver transplantation(LT)offers margin-negative iCCA extirpation for patients with unresectable tumors.Initially,iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes.Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA.Another selection criterion is the tumor response to neoadjuvant therapy.Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy.Another index that helps predict the treatment outcome is the biomarker.Improved survival outcomes have also opened the door for living donor LT for iCCA.Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection.The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Liver transplantation as an alternative for the treatment of neuroendocrine liver metastasis: Appraisal of the current evidence

Background:Liver transplantation(LT)for neuroendocrine liver metastases(NELM)is still in debate.Studies comparing LT with liver resection(LR)for NELM are scarce,as patient selection is heterogeneous and experience is limited.The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM.Data sources:A scoping literature search on LT and LR for NELM was performed with PubMed,including English articles up to March 2023.Results:International guidelines recommend LR for NELM in resectable,well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies.Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival.In highly selected patients(based on the Milan criteria)with unresectable NELM,oncologic results of LT are promising.Prognostic factors include tumor biology(G1/G2)and burden,waiting time for LT,patient age and extrahepatic spread.Based on low-level evi-dence,LT for low-grade NELM within the Milan criteria resulted in improved disease-free survival and overall survival compared to LR.The benefits of LT were lost in patients beyond the Milan NELM-criteria.Conclusions:With adherence to strict selection criteria especially tumor biology,LT for NELM is becoming a valuable option providing oncologic benefits compared to LR.Recent evidence suggests even stricter selection criteria with regard to tumor biology.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Liver transplantation and resection in patients with hepatocellular cancer and portal vein tumor thrombosis: Feasible and effective?

Patients with locally advanced hepatocellular cancer(HCC)and portal vein tumor thrombosis(PVTT)have a dismal prognosis since limited treatment options are available for them.In recent years,effective systemic therapy,and advances in the understanding of technicalities and effectiveness of ablative therapies especially radiotherapy,have given some hope to prolong survival in them.This review summarized recent evidence in literature regarding the possible role of liver resection(LR)and liver transplantation(LT)in patients with locally advanced HCC and PVTT with no extrahepatic disease.Downstaging therapies have helped make curative resection or LT a reality in selected patients.This review emphasizes on the key points to focus on when considering surgery in these patients,who are usually relegated to palliative systemic therapy alone.Meticulous patient selection based on tumor biology,documented downstaging based on imaging and decrease in tumor marker levels,and an adequate waiting period to demonstrate stable disease,may help obtain satisfactory long-term outcomes post LR or LT in an intention to treat strategy in patients with HCC and PVTT.

Use of machine learning models for the prognostication of liver transplantation: A systematic review

BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.

Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma

BACKGROUND At present,liver transplantation(LT)is one of the best treatments for hepatocellular carcinoma(HCC).Accurately predicting the survival status after LT can significantly improve the survival rate after LT,and ensure the best way to make rational use of liver organs.AIM To develop a model for predicting prognosis after LT in patients with HCC.METHODS Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated.The expression levels of alphafetoprotein(AFP),des-gamma-carboxy prothrombin,Golgi protein 73,cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer.The best cutoff value of biomarkers was determined using the Youden index.Cox regression analysis was used to identify the independent risk factors.A forest model was constructed using the random forest method.We evaluated the accuracy of the nomogram using the area under the curve,using the calibration curve to assess consistency.A decision curve analysis(DCA)was used to evaluate the clinical utility of the nomograms.RESULTS The total tumor diameter(TTD),vascular invasion(VI),AFP,and cytokeratin-18 epitopes M30(CK18-M30)were identified as important risk factors for outcome after LT.The nomogram had a higher predictive accuracy than the Milan,University of California,San Francisco,and Hangzhou criteria.The calibration curve analyses indicated a good fit.The survival and recurrence-free survival(RFS)of high-risk groups were significantly lower than those of low-and middle-risk groups(P<0.001).The DCA shows that the model has better clinical practicability.CONCLUSION The study developed a predictive nomogram based on TTD,VI,AFP,and CK18-M30 that could accurately predict overall survival and RFS after LT.It can screen for patients with better postoperative prognosis,and improve longterm survival for LT patients.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be determined.This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC.Methods:Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed.The associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further studied.Results:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male donors.Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(P<0.05).Conclusions:Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients,and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival.Livers from male donors may provide the most benefit to female recipients.Our results indicate that sex should be considered as a critical factor in organ allocation.

Current status of liver transplantation for human immunodeficiency virus-infected patients in China's Mainland

According to the report from the Chinese Center for Disease Control and Prevention,the prevalence of human immunodeficiency virus(HIV)infection exceeded 1.2 million individuals by the year 2022,with an annual increase of about 80000 cases.The overall prevalence of hepatitis B surface antigen among individuals co-infected with HIV reached 13.7%,almost twice the rate of the general population in China.In addition to the well-documented susceptibility to opportunistic infections and new malignancies,HIV infected patients frequently experience liver-related organ damage,with the liver and kidneys being the most commonly affected.This often leads to the development of end-stage liver and kidney diseases.Therefore,organ transplantation has emerged as an important part of active treatment for HIV infected patients.However,the curative effect is not satisfactory.HIV infection has been considered a contraindication for organ transplantation.Until the emergence of highly active anti-retroviral therapy in 1996,the once intractable replication of retrovirus was effectively inhibited.With prolonged survival,the failure of important organs has become the main cause of death among HIV patients.Therefore,transplant centers worldwide have resu-med exploration of organ transplantation for HIV-infected individuals and reached a positive conclusion.This study provides an overview of the current landscape of HIV-positive patients receiving liver transplantation(LT)in main-land China.To date,our transplant center has conducted LT for eight end-stage liver disease patients co-infected with HIV,and all but one,who died two months postoperatively due to sepsis and progressive multi-organ failure,have survived.Comparative analysis with hepatitis B virus-infected patients during the same period revealed no statistically significant differences in acute rejection reactions,cytomegalovirus infection,bacteremia,pulmonary infections,acute kidney injury,new-onset cancers,or vascular and biliary complications.

Advancing immunosuppression in liver transplantation: A narrative review

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

HSP110 aggravates ischemia-reperfusion injury after liver transplantation by promoting NF-κB pathway

Background:Ischemia-reperfusion injury(IRI)poses a significant challenge to liver transplantation(LT).The underlying mechanism primarily involves overactivation of the immune system.Heat shock protein 110(HSP110)functions as a molecular chaperone that helps stabilize protein structures.Methods:An IRI model was established by performing LT on Sprague-Dawley rats,and HSP110 was silenced using siRNA.Hematoxylin-eosin staining,TUNEL,immunohistochemistry,ELISA and liver enzyme analysis were performed to assess IRI following LT.Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular changes.Results:Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT(P<0.05).However,when rats were injected with siRNAHSP110,IRI subsequent to LT was notably reduced(P<0.05).Additionally,the levels of liver enzymes and inflammatory chemokines in rat serum were significantly reduced(P<0.05).Silencing HSP110 with siRNA resulted in a marked decrease in M1-type polarization of Kupffer cells in the liver and downregulated the NF-κB pathway in the liver(P<0.05).Conclusions:HSP110 in the liver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer cells.Targeting HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.

Cellular strategies to induce immune tolerance after liver transplantation:Clinical perspectives

Liver transplantation(LT)has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management.However,long-term side-effects of immunosuppressants,like infection,metabolic disorders and malignant tumor are gaining more attention.Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants,but the liver function and intrahepatic histology maintain normal.The approaches to achieve immune tolerance after transplantation include spontaneous,operational and induced tolerance.The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up.No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation.With the understanding to the underlying mechanisms of immune tolerance,many strategies have been developed to induce tolerance in LT recipients.Cellular strategy is one of the most promising methods for immune tolerance induction,including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells.The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials,while obstacles still exist before translating into clinical practice.Here,we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.