Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation

BACKGROUND Clinical factors predicting graft survival(GS)after ABO-incompatible(ABOi)liver transplantation(LT),and differences between recipients with and without hepatocellular carcinoma(HCC)are unclear.AIM To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without(HCC)in ABOi living-donor liver transplantation(LDLT).METHODS We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT,including 47 patients with HCC.RESULTS The 1-,3-,5-,and 10-year GS rates were 85.9%,73.3%,71.4%,and 71.4%,respectively,and there were no significant differences between HCC and non-HCC recipients.In multivariate Coxregression analyses,tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT,in addition to the antibody-mediated rejection(AMR)were associated with poor-graft outcomes.In HCC patients,AMR[hazard ratio(HR)=63.20,P<0.01]and HCC recurrence(HR=20.72,P=0.01)were significantly associated with poor graft outcomes.HCCs outside Milan criteria,and tacrolimus concentrations at 4 wk post-LT>7.3 ng/mL were significant predictive factors for HCC recurrence.After propensity score matching,patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival.CONCLUSION Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence.Therefore,careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.

Severe hepatic necrosis of unknown causes following ABO-incompatible liver transplantation

Emergency ABO-incompatible (ABO-I) liver transplantations (LTx) have been performed increasingly to treat severe liver failure.Herein,we report a case of severe hepatic necrosis after ABO-I LTx.A 53-year-old man with blood group O was diagnosed as having severe hepatitis B and acute-on-chronic liver failure,and underwent an emergency liver transplantation implanting a blood-group-B liver from a cardiac-death donor.A routine anti-rejection,anti-infection and anti-virus therapy was given after operation.On post-operative day (POD) 16,the recipient had fever and erythra.Laboratory and radiographic examinations suggested a severe hepatic necrosis of unknown causes.The patient was managed with a 10-d methylprednisolone pulse therapy.He was discharged on POD 35 with stable condition,and no recurrent disease was found during the follow-up.

A modified protocol with rituximab and intravenous immunoglobulin in emergent ABO-incompatible liver transplantation for acute liver failure

BACKGROUND： The established procedure for ABO-incompatible liver transplantation（ABO-I LT） was too complicated to be used in case of emergency. We developed a protocol consisting of rituximab and intravenous immunoglobulin（IVIG） for ABO-I LT in patients with acute liver failure（ALF）.METHODS： The data from 101 patients who had undergone liver transplantation（LT） for ALF were retrospectively analyzed.The patients were divided into two groups： ABO-compatible liver transplantation group（ABO-C LT, n=66） and ABO-I LT group（n=35）. All the patients in the ABO-I LT group received a single dose of rituximab（375 mg/m2） and IVIG（0.4 g/kg per day） at the beginning of the operation. IVIG was administered for 10 consecutive days after LT. Plasma exchange, splenectomy and graft local infusion were omitted in the protocol.Quadruple immunosuppressive therapy including basiliximab,corticosteroids, tacrolimus and mycophenolatemofetil was used to reinforce immunosuppression.RESULTS： The 3-year cumulative patient survival rates in the ABO-I LT and ABO-C LT groups were 83.1% and 86.3%,respectively（P〉0.05）, and the graft survival rates were 80.0%and 86.3%, respectively（P〉0.05）. Two patients（5.7%） suffered from antibody-mediated rejection in the ABO-I LT group.Other complications such as acute cellular rejection, biliary complication and infection displayed no significant differences between the two groups.CONCLUSIONS： The simplified treatment consisting of rituximab and IVIG prevented antibody-mediated rejection for LT of blood-type incompatible patients. With this treatment, the patients did not need plasma exchange, splenectomy and graft local infusion. This treatment was safe and efficient for LT of the patients with ALF.

First successful perinatal management of pregnancy after ABO-incompatible liver transplantation

Many papers have reported on pregnancy and delivery after liver transplantation, but there have been no reports on pregnancy after ABO-incompatible liver transplantation. This paper reports the first successful pregnancy and delivery of a newborn after ABOincompatible liver transplantation for fulminant hepatic failure. The patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology. She was taking tacrolimus, methylprednisolone, and mizoribine orally for the maintenance of immunosuppression at the time of discharge. She was discharged uneventfully on postoperative day 38 without any rejection episodes. At 1 year and 6 mo after transplantation, she indicated a wish to become pregnant. Therefore, treatment with mycophenolate mofetil was interrupted at that time. After two miscarriages, she finally became pregnant and delivered transvaginally 3 years after the transplantation. All of the pregnancies were conceived naturally. The newborn was female with a birth weight of 3146 g; the Apgar scores were 9 and 10. Delivery was performed smoothly, and the newborn exhibited no malformations. The mother and the newborn were discharged uneventfully. We suggest that pregnancy is possible for recipients after ABO-incompatible liver transplantation.

Excellent long term patient and renal allograft survival after ABO-incompatible kidney transplantation:Experience of one center

AIM: To investigate the long-term results of ABOincompatible(ABOi) kidney transplantation in a single center in Greece.METHODS: Thirty consecutive ABOi kidney transplantations were performed from June 2005 to December 2013. All patients received rituximab one month prior to transplantation. Immunoadsorption therapy was performed for the removal of anti-A/B Ig G antibodies until the titer was ≤ 1:16. Additional apheresis sessions were performed post-operatively. Intravenous immunoglobulin and oral immunosuppression consisting of tacrolimus(TAC) in combination with either everolimus or mycophenolate acid was administered. We compared the long term results of our ABOi group to those of a matched group of 30 ABO compatible(ABOc) living kidney recipients with similar baseline characteristics. The ABOc recipients received an immunosuppressive regimen consisting of TAC and mycophenolate acid. All patients in both groups received induction therapy with Basiliximab or Daclizumab, whereas corticosteroids were instituted on the day of surgery. During the followup period, indication biopsies were performed and interpreted by an experienced nephropathologist. The parameters we analyzed included the following: Donor/recipient age, gender, blood type, human leukocyte antigen mismatches, panel reactive antibodies, primary cause of renal failure, mean time on dialysis, immunosuppressive regimen, patient survival, graft outcome, incidence of rejections, surgical and infectious complications.RESULTS: The mean follow-up period was 6 years(range 1 to 9 years). A mean of 5.0 ± 3.0(range 0-14) pre-transplant immunoadsorptions were required in order to reach the target titer. Patient survival in ABOi group in comparison to ABOc group at 1, 3, 5 and 8 years did not differ significantly(100% vs 100%, 96% vs 100%, 92% vs 100% and 92% vs 100%, P = ns). Additionally, graft survival was similar in the two groups at the same time points(100% vs 100%, 96% vs 96%, 92% vs 96% and 81% vs 92%, P = ns). The mean serum creatinine and the estimated glomerular filtration rate by the modification of diet in renal disease formula at 1, 3, 5 and 8 years did not differ significantly between ABOi and ABOc group. None of the patients in the ABOi group developed acute or chronic antibodymediated rejection evidenced by histological signs. Four patients(13.3%) in the ABOi group and 3(10%) in the ABOc group experienced acute cellular rejection, which was treated successfully in all cases. Bacterial and viral infections were also similar between the two groups.CONCLUSION: ABOi kidney transplantation is a safe and effective alternative that enables kidney transplantation in countries with unacceptably long deceaseddonor waiting lists.

Current protocols and outcomes of ABO-incompatible kidney transplantation

One of the principal obstacles in transplantation from living donors is that approximately 30%are immunologically incompatible because of the presence in the recipient of antibodies directed against the human leukocyte antigen system of the donor or because of the incompatibility of the ABO system.The aim of this review is to describe the more recent data from the literature on the different protocols used and the clinical outcomes of ABO-incompatible kidney transplantation.Two different strategies are used to overcome these barriers:desensitization of the recipient to remove the antibodies and to prevent their rebound after transplantation and the exchange of organs between two or more pairs.The largest part of this review is dedicated to describing the techniques of desensitization.Even if the first reports of successful renal transplantation between ABO-incompatible pairs have been published by 1980,the number of ABO-incompatible transplants increased substantially in this century because of our improved knowledge of the immune system and the availability of new drugs.Rituximab has substantially replaced splenectomy.The technique of apheresis has improved and more recently a tailored desensitization proved to be the more efficient strategy avoiding an excess of immunosuppression with the related side effects.Recent reports document outcomes for such transplantation similar to the outcomes of standard transplantation.

Feasibility of ABO-incompatible adult living donor liver transplantation for acute-on-chronic liver failure

To the Editor:In Korea,the annual number of deceased donors for or gan transplantation per million people is still less than10.Thus,approximately 40%of patients with acute liver failure or acute-on-chronic liver failure undergo living donor liver transplantation（LDLT）.;Although the use of ABO-incompatible（ABOi）living donors is an attrac tive option,ABOi LDLT has very restricted applications

Complement activation and long-term graft function in ABO-incompatible kidney transplantation

BACKGROUND ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABOincompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM To unravel the relationship between pre-transplant anti-ABO antibodies,complement activation, and long-term graft function.METHODS We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex,and transplantation date.RESULTS Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABOincompatible recipients did have a lower kidney function at three months(creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m^2, P = 0.08), due to a high rate of early rejection(33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO Ig G titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION Co-stimulation of T-cell activation by ongoing complement activation by antiABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Risk factor for ischemic-type biliary lesion after ABO-incompatible living donor liver transplantation

AIM: To evaluate the risk factors for ischemic-type biliary lesion(ITBL) after ABO-incompatible(ABO-I) adult living donor liver transplantation(ALDLT).METHODS: Among 141 ALDLTs performed in our hospital between 2008 and 2014, 27(19%) were ABO-I ALDLT and 114 were ABO-identical/compatible ALDLT. In this study, we extensively analyzed the clinico-pathological data of the 27 ABO-I recipients to determine the risk factors for ITBL after ABO-I ALDLT. All ABO-I ALDLT recipients underwent an identical B-cell depletion protocol with preoperative rituximab, plasma exchange(PE), and operative splenectomy. The median follow-up period after transplantation was 26 mo. The clinical outcomes of the 27 ABO-I ALDLT recipients were compared with those of 114 ABO-identical/compatible ALDLT recipients.RESULTS: ITBL occurred in four recipients(14.8%) between 45 and 112 d after ABO-I ALDLT. The overall survival rates were not different between ABO-I ALDLT and ABO-identical/compatible ALDLT(P = 0.303). Among the ABO-I ALDLT recipients, there was no difference between patients with ITBL and those without ITBL in terms of B-cell and T-cell count, serum isoagglutinin titers, number of PEs, operative time and transfusion, use of graft infusion therapy, or number of remnant B-cell follicles and plasma cells in the spleen. However, the perioperative NK cell counts in the blood of patients with ITBL were significantly higher than those in the patients without ITBL(P < 0.05). Preoperative NK cell count > 150/μL and postoperative NK cell count > 120/μL were associated with greater relative risks(RR) for development of ITBL(RR = 20 and 14.3, respectively, P < 0.05). CONCLUSION: High NK cell counts in a transplant recipient's blood are associated with ITBL after ABO-I ALDLT. Further research is needed to elucidate the molecular mechanism of NK cell involvement in the development of ITBL.

A comparison of desensitization methods: Rituximab with/without plasmapheresis in ABO-incompatible living donor liver transplantation

Background: Plasmapheresis is a desensitization method used prior to ABO-incompatible(ABO-I) living donor liver transplantation. However, studies on its usefulness in the rituximab era are lacking.Methods: Fifty-six adult patients underwent ABO-I living donor liver transplantation between January2012 and October 2015. A single dose of rituximab(300 mg/m~2) was administered 2 weeks before surgery with plasmapheresis in all patients until February 2014(RP group, n = 26). Patients were administered rituximab only, without plasmapheresis between March 2014 and October 2015(RO group, n = 30).Results: The 6-, 12-and 18-month overall survival rates were 92.3%, 80.8% and 76.9% in the RP group and 96.6%, 85.4% and 85.4% in the RO group, respectively(P = 0.574). When the initial isoagglutinin titers < 16, neither group showed a rebound rise of isoagglutinin titers. For patients with initial isoagglutinin titers ≥ 16, the rebound rise of isoagglutinin titers was more prominent in the RP group. There was no difference in time-dependent changes in B cell subpopulations and ABO-I-related complications.Conclusions: Sufficient desensitization for ABO-I living donor liver transplantation can be achieved using rituximab alone. This desensitization strategy does not affect the isoagglutinin titers, ABO-I-related complications and patient survival.

Stratified Analysis of Survival Benefit for ABO-incompatible Deceased-donor Liver Transplantation:Multicenter Propensity Score-matched Study

Background and Aims:Liver transplantation(LT)using ABO-incompatible(ABOi)grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation.However,concerns of the impending prognosis associated with this option,especially for patients with liver failure and higher model for end-stage liver disease(MELD)scores,who tend to be more fragile during the waiting period before LT.Methods:Recipients undergoing LT for acute-onchronic liver failure or acute liver failure were retrospectively enrolled at four institutions.Overall survival was compared and a Cox regression analysis was performed.Propensity score matching was performed for further comparison.Patients were stratified by MELD score and cold ischemia time(CIT)to determine the subgroups with survival benefits.Results:Two hundred ten recipients who underwent ABOi LT and 1,829 who underwent ABO compatible(ABOc)LT were enrolled.The 5-year overall survival rate was significantly inferior in the ABOi group compared with the ABOc group after matching(50.6%vs.75.7%,p<0.05).For patients with MELD scores≤30,using ABOi grafts achieved a comparable overall survival rate as using ABOc grafts(p>0.05).Comparison of the survival rates revealed no statistically significant difference for patients with MELD scores≥40(p>0.05).For patients with MELD scores of 31-39,the overall survival rate was significantly inferior in the ABOi group compared with the ABOc group(p<0.001);however,the rate was increased when the liver graft CIT was<8 h.Conclusions:For recipients with MELD scores≤30,ABOi LT had a prognosis comparable to that of ABOc LT and can be regarded as a feasible option.For recipients with MELD scores≥40,ABOi should be adopted with caution in emergency cases.For recipients with MELD scores of 31-39,the ABOi LT prognosis was worse.However,those patients benefited from receiving ABOi grafts with a CIT of<8 h.

Feasibility of using marginal liver grafts in living donor liver transplantation

Liver transplantation(LT) is one of the most effective treatments for end-stage liver disease caused by related risk factors when liver resection is contraindicated. Additionally,despite the decrease in the prevalence of hepatitis B virus(HBV) over the past two decades,the absolute number of HBs Ag-positive people has increased,leading to an increase in HBV-related liver cirrhosis and hepatocellular carcinoma. Consequently,a large demand exists for LT. While the wait time for patients on the donor list is,to some degree,shorter due to the development of living donor liver transplantation(LDLT),there is still a shortage of liver grafts. Furthermore,recipients often suffer from emergent conditions,such as liver dysfunction or even hepatic encephalopathy,which can lead to a limited choice in grafts. To expand the pool of available liver grafts,one option is the use of organs that were previously considered "unusable" by many,which are often labeled "marginal" organs. Many previous studies have reported on the possibilities of using marginal grafts in orthotopic LT; however,there is still a lack of discussion on this topic,especially regarding the feasibility of using marginal grafts in LDLT. Therefore,the present review aimed to summarize the feasibility of using marginal liver grafts for LDLT and discuss the possibility of expanding the application of these grafts.

Pediatric liver transplantation outcomes from a single center in Thailand

BACKGROUND Liver transplantation(LT)has become an acceptable curative method for children with several liver diseases,especially irreversible acute liver failure and chronic liver diseases.King Chulalongkorn Memorial Hospital is one of Thailand’s largest liver transplant centers and is responsible for many pediatric cases.AIM To report the experience with pediatric LT and evaluate outcomes of livingrelated vs deceased-donor grafts.METHODS This evaluation included children who underwent LT between August 2004 and November 2019.Data were retrospectively reviewed,including demographics,diagnoses,laboratory values of donors and recipients,the pediatric end-stage liver disease(PELD)or model for end-stage liver disease(MELD)score,graft source,wait time,perioperative course,postoperative complications,and survival rates.Continuous data were reported using the median and interquartile range.The Mann–Whitney U-test was used to compare the wait time between the living-related and deceased-donor groups.The chi-square or Fisher's exact test were used to compare the frequencies of between-group complications.Survival rates were calculated using the Kaplan–Meier method.RESULTS Ninety-four operated pediatric liver transplant patients were identified(54%were females).The median age at transplantation was 1.2(0.8-3.8)years.The median PELD and MELD scores were 20(13-26.8)and 19.5(15.8-26.3),respectively.Most grafts(81.9%)were obtained from living-related donors.The median wait time for the living donors was significantly shorter compared with the deceased donors at 1.6(0.3-3.1)mo vs 11.2(2.1-33.3)mo(P=0.01).Most patients were diagnosed with biliary atresia(74.5%),and infection was the most common complication within 30 d posttransplantation(14.9%).Without a desensitization protocol,9%of transplants were ABOincompatible.Eight hepatitis B core antibodies(anti-HBc)-negative recipients received positive anti-HBc grafts without different observed complications.The overall survival rate was 93.6%and 90.3%at 1 and 5 years,respectively.No graft loss during follow-up was noted among survivors.CONCLUSION A significant number of pediatric LT cases were reported in Thailand.Based on relatively comparable outcomes,ABO-incompatible and HBc antibody-positive grafts may be considered in an organ shortage situation.

Outcomes after liver transplantation in accordance with ABO compatibility: A systematic review and meta-analysis

AIM To evaluate the differences in outcomes between ABOincompatible(ABO-I) liver transplantation(LT) and ABO-compatible(ABO-C) LT.METHODS A systematic review and meta-analysis were performed by searching eligible articles published before November 28, 2016 on MEDLINE(Pub Med), EMBASE, and Cochrane databases. The primary endpoints were graft survival, patient survival, and ABO-I-related complications. RESULTS Twenty-one retrospective observational studies with a total of 8247 patients were included in this metaanalysis. Pooled results of patient survival for ABO-I LT were comparable to those for ABO-C LT. However, ABO-I LT showed a poorer graft survival than ABO-C LT(1-year: OR = 0.66, 95%CI: 0.57-0.76, P < 0.001; 3-year: OR = 0.74, 95% CI 0.64-0.85, P < 0.001; 5-yearr: OR =0.75, 95%CI: 0.66-0.86, P < 0.001). Furthermore, ABO-I LT was associated with more incidences of antibody-mediated rejection(OR = 74.21, 95%CI: 16.32-337.45, P < 0.001), chronic rejection(OR =2.28, 95%CI: 1.00-5.22, P = 0.05), cytomegalovirus infection(OR = 2.64, 95%CI: 1.63-4.29, P < 0.001), overall biliary complication(OR = 1.52, 95%CI: 1.01-2.28, P = 0.04), and hepatic artery complication(OR = 4.17, 95%CI: 2.26-7.67, P < 0.001) than ABO-C LT. In subgroup analyses, ABO-I LT and ABO-C LT showed a comparable graft survival in pediatric patients and those using rituximab, and ABO-I LT showed an increased acute cellular rejection in cases involving deceased donor grafts.CONCLUSION Although patient survival in ABO-I LT was comparable to that in ABO-C LT, ABO-I LT was inferior to ABO-C LT in graft survival and several complications. Graft survival of ABO-I LT could be comparable to that of ABO-C LT in pediatric patients and those using rituximab.