Risk Factors Predicting The Prognosis Of Abo-incompatible Liver Transplantation And Relationship To Biliary Duct Complications

Background: Liver transplantation is the only effective treatment for end-stage liver disease,but the gap between needs and donors is gradually widening,and the shortage of liver source causes many patients wait to die.Incorporating ABO-incompatible liver transplantation(ABO-i)into routine transplantation can effectively expand the liver source.In recent years,Japan and Korea has been widely performing ABO-i living donor liver transplantation(LDLT),showing that there is no significant difference for survival rate between ABO-i LDLT and ABO-compatible(ABO-c)LDLT.Liver donation in China mainly comes from the donation of cardiac death(DCD).There are few international studies on ABO-i DCD,and the international experience of immunosuppression for ABO-i cannot be used in China without adaptation.In recent years,Korean proposed that diffuse intrahepatic biliary strictures(DIHBS)is the only problem to that effect the prognosis of ABO-i.It seems to be the cornerstone of incorporating ABO-i into routine liver transplantation.However,little research has been done in China.This study,under the background of China,aims to explore the risk factors for the prognosis of ABO-i and the relationship with DIHBS,which will help to find strategies to improve the prognosis of ABO-i.Methods: This study is a retrospective cohort study,844 patients underwent liver transplantation at the First Affiliated Hospital of Zhejiang University School of Medicine from January 2015 to November 2019 were included.First,all patients were grouped to ABO-c(n=721)and ABO-i(n=123)and information compared,univariate analysis and multivariate Cox analysis were used to identify independent risk factors for graft survival.Second,all patients were grouped to in-hospital graft death(IHGD)(n=99)and in-hospital graft survival(IHGS)(n=745)and information compared,survival curve on ABO-c and ABO-i was plotted,multivariate Logistic analysis were used to identify independent risk factors for IHGS.Third,patients in IHGS were grouped to ABO-c(n=660)and ABO-i(n=85)and information compared,survival curve on ABO-c and ABO-i was plotted,univariate analysis and multivariate Cox analysis were used to identify independent risk factors for IHGS graft survival.Fourth,plot survival curve on ABO-c and ABO-i in IHGS with biliary complications removed.At last,patients in IHGS with ABO-i group to DIHBS(n=12)and DIHBS-free(n=73)and information compared,multivariate Logistic analysis were used to identify independent risk factors for DIHBS.Results: All 844 patients reveal that ABO-i has higher CHILD scores(P=0.035),higher MELD scores(P=0.002),more artificial liver support(ALS)(P=0.009),fewer immunity hepatitis diseases(IPS)(P=0.028),fewer cirrhosis(P=0.007),longer cold ischemia time(CIT)(P=0.001),more cytomegalovirus infections(CMV)(P<0.001),more in-hospital infections(IHI)(P=0.002),more IHGD(P<0.001),more biliary complications(BC)(P=0.013),more DIHBS(P<0.001).1-month,3-month,6-month,1-year,2-year,3-year graft survival(GS)of ABO-c and ABO-i are 93.2%-71.7%,89.2%-65.7%,86.5%-59.4%,81.3%-50.0%,73.8%-46.5%,69.2%-44.1%,GS of ABO-c is better than ABO-i(P<0.001).Independent risk factors for GS are ABO-i(HR = 2.612,95% CI: 1.949,3.501,P<0.001),ALS(HR=1.452,95% CI: 1.033,2.040,P=0.032),intraoperative blood loss(IBL)(HR=1.000,95% CI: 1.000,1.000,P=0.006),IHI(HR=2.923,95% CI: 2.157,3.961,P<0.001).All 844 patients reveal that IHGD has more ABO-i(P<0.001),more retransplantation(P=0.010),higher CHILD scores(P<0.001),higher MELD scores(P<0.001),more ALS(P<0.001),more drug-induced liver diseases(DILD)(P=0.007),less cirrhosis(P=0.004),longer operation time(P=0.017),more IBL(P=0.026),more ALS(P=0.010),more in-hospital hepatic thrombosis(IHHT)(P<0.001).Independent risk factors for IHGD are ABO-i(OR=4.689,95% CI: 2.826,7.782,P<0.001),retransplantation(OR=2.932,95% CI: 1.142,7.526,P=0.025),IBL(OR=1.000,95% CI: 1.000,1.000,P=0.039),IHI(OR=4.868,95%CI: 2.948,8.038,P<0.001).745 patients in IHGS reveal that ABO-i has more hepatitis C(P=0.03),longer WIT(P=0.011),more CMV(P<0.001),more BC(P<0.001),more anastomotic strictures(An S)(P=0.023),more DIHBS(P<0.001).3-month,6-month,1-year,2-year,3-year graft survival(GS)of ABO-c and ABO-i are 97.1%-95.9%,94.3%-87.1%,88.8%-73.2%,80.6%-68.2%,75.5%-64.7%,GS of ABO-c is better than ABO-i(P=0.005).Independent risk factors for GS are warm ischemia time(WIT)(HR=1.059,95% CI: 1.027,1.092,P<0.001),IHI(HR=2.692,95% CI: 1.638,4.424,P<0.001),An S(HR=1.719,95% CI: 1.058,2.793,P=0.029),DIHBS(HR=4.009,95% CI: 2.004,8.020,P<0.001).652 patients in IHGS without An S reveal that GS of ABO-c is no better than ABOi(Log-Rank test: P=0.214,Breslow test: P=0.148).728 patients in IHGS without DIHBS reveal that GS of ABO-c is no better than ABO-i(Log-Rank test: P=0.459,Breslow test: P=0.189).666 patients in IHGS without IHI reveal that GS of ABO-c is better than ABO-i(Log-Rank test: P=0.012,Breslow test: P=0.004).85 patients in IHGS with ABO-i reveal that there is no difference between DIHBS and DIHBS-free.GS of DIHBS-free is better than DIHBS(Log-Rank test: P<0.001,Breslow test: P<0.001).As for 12 patients in IHGS with ABO-i and DIHBS,the average follow-up time was 16.0±11.8(3.3-40.9 months),1 survives(8.3%),the average time to make diagnosis of DIHBS was 3.4±1.5 months(0.7-6.9 months).Conclusion: The analysis of 844 liver transplantation patients from our center since 2015,reveals that independent risk factors for all patients GS are ABO-i,ALS,IBL,IHI,independent risk factors for all patients IHGD are ABO-i,retransplantation,IBL,IHI,independent risk factors for 745 patients in HIGS GS are WIT,IHI,An S,DIHBS.In our center,perioperative period of ABO-i should be focused on since we have high IHGD,and IHI prevent is the most important thing to improve GS.For patients are ABO-i and IHGS,pay more attention to BC,especially DIHBS at least 6 months after transplantation.The incidence of DIHBS is 14.1%,however the incidence of graft death for those who got DIHBS is 91.6%.Rituximab breaks through the barriers of ABO-i,expands the liver source,helps save more patients with liver failure who wait for liver transplantation.Patients who are ABO-i,IHGS and DIHBS-free,have no difference GS compared to the those are ABO-c and IHGS.At present,there is high demand to solve IHGD,and explore preventive and therapeutic measures for DIHBS.