ABO-Incompatible Adult Living Donor Liver Transplantation...

Review ArticleABO-Incompatible Adult Living Donor Liver Transplantation inthe Era of Rituximab: A Systematic Review and Meta-Analysis

Dipesh Kumar Yadav ,1 Yong Fei Hua,1,2 Xueli Bai,1 Jianying Lou,3 Risheng Que,1

Shunling Gao,1 Yun Zhang,3 Ji Wang,1 Qinfen Xie,4 Muhammad Ibrahim Alhadi Edoo,1

Vikram Kumar Chutturghoon,1 and Tingbo Liang 1

1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine,Hangzhou, 310003 Zhejiang, China2Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Medical School ofNingbo University, Ningbo, 315041 Zhejiang, China3Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine,88 Jiefang Road, Hangzhou, 310009 Zhejiang, China4Department of Hepatobiliary Surgery, Shulan (Hangzhou) Hospital, Hangzhou, 310000 Zhejiang, China

Correspondence should be addressed to Tingbo Liang; [email protected]

Received 17 February 2019; Accepted 7 May 2019; Published 11 June 2019

Academic Editor: Cataldo Doria

Copyright © 2019 Dipesh Kumar Yadav et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Aim. The primary aim of this study is to compare the short- and long-term outcomes between ABO-incompatible (ABOi) adultliving donor liver transplantation (ALDLT) with rituximab prophylaxis and ABO-compatible (ABOc) ALDLT. Background. Thestrategy of ABOi liver transplantation (LT) was originated initially to increase the donor pool and to enable liver transplantationin emergency conditions. However, ABOi ALDLT remains a controversial approach in comparison to ABOc ALDLT. Methods.PubMed, Embase, and the Cochrane Library study search were accomplished to recognize studies comparing ABOi and ABOcALDLT. Meta-analyses were conducted based on the evaluation of heterogeneity using a fixed-effect model and a random-effectmodel to assess the short- and long-term outcomes following ABOi ALDLT with rituximab prophylaxis. Results. Nine studiescomprising a total of 3,922 patients (ABOi = 671 and ABOc = 3,251) were identified. There was no significant difference betweenABOi and ABOc groups for 1-year, 3-year, and 5-year OS and graft survival, respectively. Moreover, 1-year and 3-year OS andDFS were similar between both groups for HCC patients. However, ABOi ALDLT had higher incidences of CMV infection,AMR, overall biliary complications, and biliary stricture than ABOc ALDLT and had other comparable postoperativecomplications. Conclusion. Our meta-analysis included studies comparing ABOi and ABOc ALDLT after the introduction ofrituximab in a desensitization protocol for ABOi ALDLT. The results of ABOi ALDLT were comparable with those of ABOcALDLT. However, biliary complications, CMV infection, and AMR remain a concern in the era of rituximab.

1. Introduction

Liver transplantation (LT) has now become an ideal treat-ment option for patients with liver cancer and end-stage liverdiseases [1, 2]; however, its use is restricted due to a limiteddonor pool [3, 4]. In past decades, different attempts andbreakthroughs have been made to increase the donor pool[5]. One of them is living donor liver transplantation(LDLT); this applies both for urgent and elective LT [5, 6].

Moreover, in the shortage of ABO-compatible (ABOc)donors and to increase the donor pool, ABO-incompatible(ABOi) LT remains the only option for many with a rapidlyworsening liver function or for one who remains on a longwaiting list [7, 8]. The liver is considered as an immune-privileged organ since it has a low incidence of humoralrejection unlike the kidney and the heart [9, 10]. Taking thisinto consideration, different innovative B cell desensitizationprotocols, such as the use of total plasma exchange (TPE),

HindawiGastroenterology Research and PracticeVolume 2019, Article ID 8589402, 16 pageshttps://doi.org/10.1155/2019/8589402

http://orcid.org/0000-0002-3068-6483

http://orcid.org/0000-0003-0143-3353

https://creativecommons.org/licenses/by/4.0/

https://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1155/2019/8589402

double-filtration plasmapheresis, local graft infusion therapy(LGIT), splenectomy, rituximab, mycophenolate mofetil(MMF), and intravenous immunoglobulin G (IVIG), havebeen used to breach the blood group barrier leading to signif-icant advancements in the outcome of ABOi [11, 12]. Thus,ABOi is no longer contemplated as a contraindication for LT.

ABOi LDLT pediatric patients are considered safe andwith acceptable results probably because of their immatureimmune system [11, 13, 14]. However, the safety of ABOiadult LDLT (ALDLT) is debatable among the transplantcommunity due to different risks associated to it, especiallyearlier graft loss, acute cellular rejection (ACR), antibody-mediated rejection (AMR), and vascular and biliary compli-cations, compared to those associated to ABOc ALDLT[15–17]. Likewise, hepatocellular carcinoma (HCC) recur-rence after ABOc ALDLT remains another major concerndue to the patient’s immunosuppressed state [18]. An effec-tive desensitization protocol for ABOi ALDLT is verydemanding. The introduction of rituximab, an anti-CD20monoclonal antibody, to the desensitization protocol hasbrought about a significant reduction in the incidence ofAMR and has improved the outcome of ABOi ALDLT [12,19, 20]. Rituximab acts on the CD20 antigen present on Bcells, thus reducing the production of B cells which aremainly responsible for acute rejection and AMR [21, 22].Monteiro et al. [23] were the first to report the case of ritux-imab use in ABOi LT in 2003. Since then, there have beenseveral studies that have reported on rituximab prophylaxisin ABOi ALDLT [22, 24–31].

To our knowledge, no systematic evaluations have beenperformed to determine the effectiveness and safety of therituximab regimen in ABOi ALDLT. This study is aimed atcomparing the short- and long-term outcomes betweenABOi ALDLT with rituximab prophylaxis and ABOcALDLT. Additionally, this meta-analysis also intended toassess the long-term outcomes of HCC patients followingABOi ALDLT with rituximab prophylaxis compared to thoseof HCC patients following ABOc ALDLT.

2. Methods

2.1. Search Strategy. Qualified studies for this systematicreview and meta-analyses were selected following the earliersettled convention with the PubMed/MEDLINE, Embase,and Cochrane Library databases by two authors (DY andYFH), using a combination of the following Medical SubjectHeadings (MeSH) and non-MeSH terms: liver transplan-tation, ABO-incompatible liver transplantation, ABO-compatible liver transplantation, hepatocellular carcinoma,tumor recurrence, primary liver carcinoma, and HCC. Addi-tionally, the pertinent bibliography lists of articles were takeninto consideration to distinguish other important studies.After preliminary screening, duplicate articles, abstracts, orunpublished studies were ruled out. The Preferred ReportingItems for Systematic Reviews and Meta-Analysis (PRISMA)guidelines were used to perform this meta-analysis [32].

2.2. Study Selection. We considered both retrospective andprospective studies eligible for this meta-analysis with respect

to the outcomes. Additionally, considering the outcome goalsand ensuring the quality of this meta-analysis, we only con-sidered fully published studies and excluded studies withonly abstracts. Additionally, we designed the following pre-defined eligibility criteria for the selection of studies with atleast one outcome of interest.

2.2.1. Inclusion Criteria

(1) The study should have a definition of ABOi ALDLTand ABOc ALDLT. ABOi ALDLT includes the fol-lowing donor-to-recipient combinations: A to B andO; B to A and O; and AB to A, B, and O. Other com-binations are regarded as ABOc, including the ABO-identical blood group

(2) The study should contain ALDLT and should com-pare short- and long-term results between ABOiALDLT and ABOc ALDLT

(3) The study should have sufficient data to conduct ameta-analysis

(4) Adult participants (>16 years of age).

2.2.2. Exclusion Criteria

(1) A study without human subjects

(2) A study with pediatric patients and deceased donorliver transplant

(3) A study containing advanced disease stage or extra-hepatic metastases

(4) A study with no comparison between ABOi ALDLTand ABOc ALDLT

(5) A study with a multiorgan transplant

(6) A study with older patients above 70 years

(7) A study with duplicate data from the same institution

(8) Publications such as review articles, editorials, casereports, conferences, and letters

2.3. Data Extraction. All data were extracted according to thestudy selection criteria and were abstracted in a systematizeddata abstraction form using Microsoft Excel 2007 (MicrosoftCorp.). The extracted data included the first author, studycharacteristics (publication year, country, and study design),participant characteristics (average age of the recipients,sample size of ABOi and ABOc ALDLT, pretransplantMELD score, disease characteristics, pretransplant AFP levelfor HCC patients, number and size of tumors for HCCpatients, pretransplant therapies, hospital stay, and the dura-tion of follow-up), and outcomes (biliary complications,infectious complications, vascular complications, acute cellu-lar rejection, antibody-mediated rejection (AMR), graft sur-vival, overall survival (OS), and disease-free survival (DFS)for HCC patients). Moreover, in case of insufficient data,investigators were approached to collect more relevant

2 Gastroenterology Research and Practice

results. Conflicts in data extraction were resolved by discus-sion or consensus with a 3rd reviewer.

2.4. Quality Assessment. The quality of included studieswas evaluated with the Newcastle-Ottawa scale (NOS)[33]. The scale comprises 3 assessment factors: (1) assess-ment of a selection of the study groups; (2) comparabilityof the 2 groups; and (3) outcome assessment. The NOSranges from 0 to 9. Studies with scores of 7 points andabove were considered to be of high quality, those with4-6 points were considered to be of moderate quality,and those with less than 4 points were considered to beof lower quality (Supplementary Table 1).

2.5. Statistical Analysis. All results are accounted for as in theoriginal articles and were double-checked. A meta-analysiswas carried out with RevMan Version 5.3 (Review Manager,Copenhagen: The Nordic Cochrane Center, The CochraneCollaboration, 2014). Outcomes are calculated as pooled

odds ratios (ORs) and standard mean difference (SMD) withcorresponding 95% confidence intervals (CIs). Fixed-effector random-effect models were utilized to compute summaryestimates based on the evaluation of heterogeneity. Overalleffects were evaluated by utilizing the Z-test, and heterogene-ity was tested by using Cochran’s χ2 test. The I2 statistic wasutilized to evaluate heterogeneity, which was characterizedas low, moderate, or high withI2esteemed at >25%, >50%,and >75%, respectively [34]. Two-sided P values less than0.05 were considered significant.

3. Results

3.1. Study Search and Included Studies. The database scansrecognized 1,430 references for assessment (Figure 1), and191 full-text articles were assessed for eligibility. Further-more, 182 articles were excluded (articles that did not meetthe inclusion criteria (n = 163) and those with insufficientdata (n = 19)). The remaining 9 retrospective studies between

Records identified through databasesearching

(n = 1,413)

Additional records identifiedthrough other sources

(n = 17)

Records screened (n = 1,430)

Records screened(n = 850)

Records removeda�er abstract review:

review, case report, meta-analysis and others (n = 659)

Full-text articles assessedfor eligibility

(n = 191)

Full-text articles excluded(n = 182)

Not meeting inclusioncriteria (n = 163)

No available data (n = 19)

Studies included in meta-analysis(n = 9)

Records a�er duplicates andirrelevant studies were removed

(n = 580)

Iden

tifica

tion

Scre

enin

gEl

igib

ility

Incl

uded

Figure 1: Preferred reporting items for systematic review and meta-analysis study flow diagram for literature search.

3Gastroenterology Research and Practice

2015 and 2018 were eligible according to the inclusion cri-teria and were included in this meta-analysis, with a totalof 3,922 patients (ABOi = 671 and ABOc = 3,251) (Table 1)[22, 24–31]. Although we identified 9 studies for inclusionin the analysis, two of the studies (study nos. 1 and 2) [25, 26]identified were from the same institutions in Korea as thoseof study nos. 3 and 4 [27, 28]. These two studies were onlyidentified to calculate the outcome of interest for ABOiALDLT in HCC patients and were not used for other calcu-lations in this meta-analysis.

4. Meta-Analysis

4.1. Primary Outcome

4.1.1. Patients’ Preoperative and Perioperative Outcomes.Meta-analyses of preoperative and perioperative outcomesare shown in Figure 2. To assess the outcome measurementof the MELD score, a total of 2,764 patients were incorpo-rated in 7 studies [22, 24, 27–31]. Theχ2test (P < 0 00001andI2 = 91%) and meta-analysis using a random-effectmodel revealed that there was no significant difference inthe MELD score between the ABOi and ABOc groups(SMD: -1.31, 95% CI: -2.83 to 0.21, P = 0 09, Figure 2(a)).

After classifying the data according to ischemia type,i.e., warm ischemia and cold ischemia, a meta-analysisusing a random-effect model revealed that there was no sig-nificant difference in warm ischemia time (SMD: 1.14, 95%CI: -2.61 to 4.89, P = 0 55, Figure 2(b)) [22, 27, 28, 31]between the ABOi and ABOc groups. However, a meta-analysis using a fixed-effect model revealed that cold ische-mia time was significantly shorter in the ABOi group thanin the ABOc group (SMD: -3.23, 95% CI: -4.62 to -1.84,P < 0 00001, Figure 2(c)) [22, 27, 28, 31].

4.1.2. Postoperative Short-Term Outcomes. Meta-analyses ofpostoperative short-term outcomes, i.e., infectious complica-tions, vascular complications, hospital stay, and biliary com-plications, are shown in Figure 3.

(1) Infectious Complications. Under subgroup analysis, over-all infections, bacterial infections, fungal infections, and cyto-megalovirus (CMV) infections were taken underconsideration for meta-analysis.

A meta-analysis using a fixed-effect model revealedthat there was no significant difference between the ABOiand ABOc groups for overall infections (OR: 1.25, 95% CI:0.50 to 3.12, P = 0 63, Figure 3(a)) [24, 29], bacterial infec-tions (OR: 0.69, 95% CI: 0.42 to 1.15, P = 0 16, Figure 3(b))[27, 28, 31], and fungal infections (OR: 0.65, 95% CI: 0.31to 1.34, P = 0 24, Figure 3(c)) [27, 28], respectively. However,a meta-analysis using a fixed-effect model revealed that CMVinfection was significantly higher in the ABOi group than inthe ABOc group (OR: 1.85, 95% CI: 1.13 to 3.03, P = 0 01,Figure 3(d)) [22, 27, 28, 31].

(2) Vascular Complications. Under subgroup analysis,hepatic artery stenosis, portal vein stenosis, and bleeding

were taken under consideration for meta-analysis. A meta-analysis using a fixed-effect model revealed that there wasno significant difference between the ABOi and ABOcgroups for hepatic artery stenosis (OR: 2.86, 95% CI:0.93 to 8.76, P = 0 07, Figure 3(e)) [22, 27, 29, 31], portalvein stenosis (OR: 1.19, 95% CI: 0.30 to 4.65, P = 0 80,Figure 3(f)) [27, 29, 31], and bleeding (OR: 0.88, 95% CI:0.49 to 1.59, P = 0 67, Figure 3(g)) [22, 27, 29], respectively.

(3) Biliary Complications. After classifying data according tobiliary complication types, i.e., overall biliary complications,biliary leakage, and biliary stricture, a meta-analysis revealedthat there was no significant difference between the ABOiand ABOc groups for biliary leakage (OR: 1.13, 95% CI:0.54 to 2.36, P = 0 75, Figure 3(h)) [22, 28, 29]. However,overall biliary complications (OR: 1.47, 95% CI: 1.07 to2.03, P = 0 02, Figure 3(i)) [24, 27, 28] and biliary stricture(OR: 1.49, 95% CI: 1.14 to 1.96, P = 0 004, Figure 3(j)) [22,27–31] were significantly higher in the ABOi group than inthe ABOc group.

(4) Hospital Stay. To assess the outcome measurement ofhospital stay, a total of 842 patients were incorporated in5 studies [22, 24, 28, 29, 31]. Theχ2test (P = 0 12andI2 = 45%) and meta-analysis using a fixed-effect modelrevealed that hospital stay was significantly longer in theABOi group than in the ABOc group (SMD: 3.39, 95%CI: 2.14 to 4.64, P < 0 00001, Figure 3(k)).

4.1.3. Postoperative Long-Term Outcomes. Meta-analyses ofpostoperative long-term outcomes, i.e., graft rejection, over-all survival (OS), and graft survival, are shown in Figure 4.

(1) Graft Rejection. After classifying data according to graftrejection types, i.e., antibody-mediated rejection (AMR)and acute cellular rejection (ACR), a meta-analysis using arandom-effect model revealed that AMR was significantlyhigher in the ABOi group than in the ABOc group (OR:21.58, 95% CI: 2.45 to 190.07.13, P = 0 006, Figure 4(a))[22, 24, 27–31]. However, a meta-analysis using a fixed-effect model revealed that there was no significant differ-ence in ACR between the ABOi and ABOc groups (OR:0.98, 95% CI: 0.67 to 1.43, P = 0 90, Figure 4(b)) [22, 24,27–31].

(2) Overall Survival (OS). To assess the outcome measure-ment of overall survival, data were classified according to 1-year, 3-year, and 5-year OS, respectively. A meta-analysisrevealed that there was no significant difference between theABOi and ABOc groups for 1-year (OR: 0.88, 95% CI: 0.59to 1.30, P = 0 51, Figure 4(c)) [22, 24, 27, 28, 30], 3-year(OR: 1.02, 95% CI: 0.73 to 1.43, P = 0 91, Figure 4(d))[22, 24, 27, 28, 30], and 5-year ( OR: 1.00, 95% CI: 0.68to 1.47, P = 0 13, Figure 4(e)) [24, 27, 30] OS, respectively.

(3) Graft Survival. To assess the outcome measurement ofgraft survival, data were classified according to 1-year, 3-year,and 5-year graft survival, respectively. A meta-analysisrevealed that there was no significant difference between


Table1:Stud

ycharacteristicsinclud

edin

meta-analysis.

Stud

yID

Stud

yLT type

Cou

ntry

and

institute

Stud

yperiod

Stud

ytype

Arm

sNo.of

pts.

Disease

characteristics

Follo

w-up

DZprotocol

Immun

osup

pressant

Nos.

1Kim

JMetal.

(2018)

[25]

Adu

ltLD

LT

SouthKorea,

Samsung

MedicalCenter

2010

to2015

Retrospective

ABOi

59

HCC

28±19

mon

ths

Rituxim

ab+

TPE

Indu

ction:

basilixim

ab+PGE1+

gabexatemesilate+

methylpredn

isolon

e.Maintenance:

corticosteroids+

tacrolim

us+MMF

9

ABOc

181

31±1

9mon

ths

2Yoonetal.

(2018)

[26]

Adu

ltLD

LT

SouthKorea,

AsanMedical

Center

2008

to2015

Retrospective

ABOi

165

HCC

48mon

ths

Rituxim

ab+

TPE+LG

IT

Maintenance:

corticosteroids+

tacrolim

us+MMF

9

ABOc

753

48.7mon

ths

3Song

WGetal.

(2016)

[27]

Adu

ltLD

LT

SouthKorea,

AsanMedical

Center

2008

to2013

Retrospective

ABOi

235

HBV,H

CV,

ALF

,cirrhosis,

andACLF

34±13

3mon

ths

Rituxim

ab+

TPE+LG

IT±

splenectom

y±cyclop

hosphamide

Maintenance:

corticosteroids+

tacrolim

us+MMF+

basilixim

ab

8

ABOc

1301

34±13

3mon

ths

4Kim

JMet.al

(2016)

[28]

Adu

ltLD

LT

SouthKorea,

Samsung

MedicalCenter

2010

to2013

Retrospective

ABOi

47

HBV,H

CV,

ALF

,HCC,

alcoho

lic,

cirrho

sis,and

ACLF

25±11

5mon

ths

Rituxim

ab+

TPE±L

GIT

Maintenance:

corticosteroids+

tacrolim

us+MMF+

basilixim

ab

7

ABOc

9423

±75

mon

ths

5Kim

JDetal.

(2016)

[29]

Adu

ltLD

LT

SouthKorea,

Catho

licUniversityof

Daegu

2011

to2014

Retrospective

ABOi

25HBV,H

CV,

ALF

,HCC,

andACLF

226±

172m

onths

Rituxim

ab+TPE+

LGIT+MMF

Maintenance:

corticosteroids+

tacrolim

us+MMF

7

ABOc

7522

6±17

2mon

ths

6Kim

SHetal.

(2018)

[22]

Adu

ltLD

LT

SouthKorea,

National

CancerCenter

2014

and

2016

Retrospective

ABOi

43HBV,H

CV,

ALF

,HCC,

cirrho

sis,

andACLF

209±

79m

onths

Rituxim

ab+IV

IG

Indu

ction:

basilixim

abMaintenance:

corticosteroids+

tacrolim

us+MMF

7

ABOc

8621

±56m

onths

7LeeCFetal.

(2015)

[30]

Adu

ltLD

LT

Taiwan,C

hang-

Gun

gMem

orial

Hospital

2006

to2013

Retrospective

ABOi

46HBV,H

CV,

ALF

,HCC,

alcoho

lic,

cirrho

sis,PBC,

andACLF

>5years

Rituxim

ab±T

PE

Maintenance:

corticosteroids+

tacrolim

us+MMF

8

ABOc

340

>5years


Table1:Con

tinu

ed.

Stud

yID

Stud

yLT type

Cou

ntry

and

institute

Stud

yperiod

Stud

ytype

Arm

sNo.of

pts.

Disease

characteristics

Follo

w-up

DZprotocol

Immun

osup

pressant

Nos.

8Ikegam

iTetal.

(2016)

[31]

Adu

ltLD

LT

Japan,

Kyushu

University

Hospital

1997

to2013

Retrospective

ABOi

19ALF

,cho

lestatic

disease,and

cirrho

sis

51±

21y

ears

Rituxim

ab+

TPE+LG

IT+

splenectom

y±IV

IG

Maintenance:

corticosteroids+

tacrolim

us+MMF

8

ABOc

389

51±

21y

ears

9ChaeMSetal.

(2018)

[24]

Adu

ltLD

LT

SouthKorea,

St.M

ary’s

Hospital

2009

to2016

Retrospective

ABOi

32HBV,H

CV,

ALF

,alcoh

olic,

autoim

mun

e,andcryptogenic

33±

102

years

Rituxim

ab+

TPE+LG

IT

Indu

ction:

basilixim

abMaintenance:

corticosteroids+

tacrolim

us+MMF

9

ABOc

3233±

102

years

ABOc—

ABO

compatible;ABOi—

ABO

incompatible;LG

IT—localgraftinfusion

therapy;

MMF—

mycop

heno

late

mofetil;

PGE1—

prostaglandinE1;

IVIG

—intravenou

sim

mun

oglobu

lin;TPE—totalplasma

exchange;N

OS—

New

castle-O

ttaw

aqu

alityassessmentscale;HBV—hepatitisBvirus;HCV—hepatitisCvirus;ACLF

—acute-on

-chron

icliver

failu

re;A

LC—acuteliver

failu

re;P

BC—prim

arybiliary

cirrho

sis;

DZprotocol—desensitizationprotocol.


the ABOi and ABOc groups for 1-year (OR: 0.93, 95% CI:0.60 to 1.46, P = 0 76, Figure 4(f)) [27, 30, 31], 3-year (OR:0.84, 95% CI: 0.57 to 1.25, P = 0 39, Figure 4(g)) [27, 30],and 5-year (OR: 0.96, 95% CI: 0.66 to 1.39, P = 0 83,Figure 4(h)) [27, 30, 31] graft survival, respectively.

4.1.4. Outcome for ABOi ALDLT for Patients with HCC.Meta-analyses of the outcome for ABOi ALDLT for patientswith HCC are shown in Supplementary Figure 1. To assessthe outcome measurement of ABOi ALDLT for patientswith HCC, a total of 1,158 patients were incorporated in 2studies [25, 26]. A meta-analysis using a fixed-effect modelrevealed that there was no significant difference inpreoperative AFP level (SMD: -5.96, 95% CI: -238.26 to226.34, P = 0 96, Supplementary Figure 1(a)) between theABOi and ABOc groups for patients with HCC. However,the preoperative MELD score was significantly lower in theABOi group than in the ABOc group for patients with

HCC (SMD: -1.13, 95% CI: -1.88 to -0.38, P = 0 003,Supplementary Figure 1(b)).

A meta-analysis of pretransplant tumor characteristicsfound that the maximum tumor diameter was significantlysmaller in ABOi LDLT than in ABOc ALDLT (SMD: -0.30,95% CI: -0.56 to -0.03, P = 0 03, Supplementary Figure 1(c)).However, the number of tumors was not significantlydifferent among both groups (SMD: -0.22, 95% CI: -1.15 to1.58, P = 0 76, Supplementary Figure 1(d)). There were nouseful data for the meta-analysis of tumor size > 3 cm ortumor nodules more than 3.

To assess the outcome measurement of overall survival(OS) for HCC patients, data was classified according to 1-year and 3-year OS, respectively. There were no useful datato calculate 5-year OS. A meta-analysis revealed that therewas no significant difference between the ABOi and ABOcgroups for 1-year (OR: 1.31, 95% CI: 0.67 to 2.56, P = 0 43,Supplementary Figure 1(e)) and 3-year (OR: 1.17, 95% CI:

Study or subgroup

Chae MS (2018)Ikegami T (2016)Kim JD (2016)Kim JM (2016)Kim SH (2018)Lee FC (2015)Song WG (2016)

Total (95% CI)Heterogeneity: Tau2 = 3.33; Chi2 = 67.14, df = 6 (P < 0.00001); I2 = 91%Test for overall effect: Z = 1.69 (P = 0.09)

15.4% 1.00 (−0.50, 2.50)−2.20 (−4.78, 0.38)−0.80 (−4.59, 2.99)−2.00 (−4.45, 0.45)−0.00 (−0.68, 0.68)

−1.00 (−1.67, −0.33)−4.20 (−5.07, −3.33)

−1.31 (−2.83, 0.21)

−20 −10 0Favours (ABOi) Favours (ABOc)

10 20

11.9%8.5%

12.3%17.4%17.5%17.0%

100.0%

32389759486

3401301

2317

3.127.39.96.51.51.59.5

1117.217.6121115

16.9

321925474346

235

447

35.57.8

7.252

2.255.5

1215

16.8101114

12.7

ABOiMeanMean SD SD

ABOcTotal Total Weight Mean difference

IV, random, 95% CIMean difference

IV, Random, 95% CI

(a) MELD score

Ikegami T (2016)Kim JM (2016)Kim SH (2018)Song WG (2016)

Study or subgroup ABOiMeanMean

393017

50.8

389 22.4% −2.00 (−6.25, 2.25)1.00 (−3.32, 5.32)

−1.00 (−1.77, −0.23)6.90 (3.29, 10.51)

1.14 (−2.61, 4.89)

−20 −10

Favours (ABOi) Favours (ABOc)

0 10 20

22.2%31.0%24.3%

100.0%

9486

1301

1870

1312.52.8343.2

412918

43.9

194743

235

344

912.251.6221.5

SD SDABOc

Total Total Weight Mean differenceIV, random, 95% CI

Mean differenceIV, random, 95% CI

Total (95% CI)Heterogeneity: Tau2 = 11.65; Chi2 = 18.50, df = 3 (P < 0.0003); I2 = 84%Test for overall effect: Z = 0.60 (P = 0.55)

(b) Warm ischemia

Study or subgroup ABOiMeanMean

85767180

0.4% −7.00 (−29.75, 15.75)−3.00 (−28.42, 22.42)

−3.00 (−4.43, 1.57)−7.10 (−13.21, −0.99)

−3.23 (−4.62, −1.84)

0.3%94.2%5.2%

100.0%

3899486

1301

1870

5724.332.3387.1

927974

87.1

194743

235

344

4987.25

4.530.2

SD SDABOc

Total Total Weight Mean differenceIV, fixed, 95% CI

Mean differenceIV, fixed, 95% CI

Ikegami T (2016)Kim JM (2016)Kim SH (2018)Song WG (2016)

Total (95% CI)Heterogeneity: Chi2 = 1.75, df = 3 (P = 0.63); I2 = 0%Test for overall effect: Z = 4.55 (P < 0.00001)

Favours (ABOi) Favours (ABOc)−20 −10 0 10 20

(c) Cold ischemia

Figure 2: Forest plot of patients’ preoperative and perioperative outcomes: (a) MELD score, (b) warm ischemia, and (c) cold ischemia.


Study or subgroup

Chae MS (2018) 33.8% 1.00 (0.19, 5.37)0.38 (0.46, 4.08)66.2%

3275

1.25 (0.50, 3.12)

0.01Favours (ABOi) Favours (ABOc)

0.1 1 10 100

100.0%107

314

17

3225

57

36

9

Kim JD (2016)

Total events

ABOi ABOcEvents Total Events Total Weight Odds ratio

M-H, fixed, 95% CIOdds ratio

M-H, fixed, 95% CI

Total (95% CI)

Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 = 0%Test for overall effect: Z = 0.48 (P = 0.63)

(a) Overall infections

Total eventsTotal (95% CI)


ABOi

Ikegami T (2016)Kim JM (2016)Song WG (2016)

23 143301 1784

38994

1301

473561

1947

235

1139

ABOcEvents Total Events TotalStudy or subgroup Weight Odds ratio


M-H, fixed, 95% CI0.40 (0.05, 3.10)0.64 (0.30, 1.38)0.81 (0.50, 1.65)

0.69 (0.42, 1.15)100.0%

10.6%43.3%46.1%

0.01Favours (ABOi) Favours (ABOc)

0.1 1 10 100

(b) Bacterial infections



Study or subgroup

Kim JM (2016)Song WG (2016)

ABOcABOiEvents Total Events Total Weight Odds ratio


M-H, fixed, 95% CI

0.65 (0.31, 1.34)

0.73 (0.26, 2.10)0.58 (0.21, 1.56)

100.0%

55.0%45.0%

10 49282 1395

64

47235

1930

941301

Favours (ABOi)

0.01 0.1 1 10 100

Favours (ABOc)

(c) Fungal infections



Study or subgroup

Kim JM (2016)Kim SH (2018)

Ikegami T (2016)

Song WG (2016)



M-H, fixed, 95% CI

1.85 (1.13, 3.03)

1.28 (0.36, 4.53)1.18 (0.45, 3.06)1.85 (0.73, 4.69)3.75 (1.48, 9.50)

100.0%

17.5%

17.5%

33.8%31.3%

3

10

840

235

344

19

4347

13

18761

89

1471

1301

1870

389

8694

Favours (ABOi) Favours (ABOc)0.01 0.1 1 10 100

(d) Cytomegalovirus (CMV) infection



Study or subgroup

Kim JM (2016)Kim SH (2018)

Ikegami T (2016)

Song WG (2016)



M-H, fixed, 95% CI


2210

235432519

4

5 12

116

1301

322 1851

8675

389

41.2%21.6%16.3%21.0%

2.86 (0.93, 8.76)

2.78 (0.51, 15.28)4.15 (0.37, 47.06)3.08 (0.19, 51.20)1.51 (0.08, 27.83)

100.0%

(e) Hepatic artery stenosis

Figure 3: Continued.




Study or subgroup

Kim JD (2016)Ikegami T (2016)

Song WG (2016)



M-H, fixed, 95% CI


34.0%48.8%17.2%

1301

1765 100.0%279

75389

437

2352519

1

142

01 3.03 (0.35, 25.97)

0.41 (0.02, 8.14)1.39 (0.15, 12.45)

1.19 (0.30, 4.65)

(f) Portal vein stenosis



Study or subgroup

Kim JD (2016)Kim SH (2018)Song WG (2016)

ABOiEvents Total

ABOcEvents Total Weight Odds ratio


M-H, fixed, 95% CI


1112

2354325

59

14 74

213

1301

303 1462

8675

70.3%5.3%

24.4%

0.88 (0.49, 1.59)

1.03 (0.53, 2.00)1.00 (0.09, 11.35)0.41 (0.09, 1.98)

100.0%

(g) Bleeding



Study or subgroup

Kim JD (2016)Kim JM (2016)Kim SH (2018)



M-H, fixed, 95% CI


552

434725

7

12 23

124

86

115 255

9475

31.5%54.5%14.0%

1.13 (0.54, 2.36)

1.48 (0.44, 4.99)0.81 (0.27, 2.46)1.54 (0.27, 8.98)

100.0%

(h) Biliary leak



Study or subgroup

Chae MS (2018)Kim JM (2016)Song WG (2016)



M-H, fixed, 95% CI


469

12

2354732

156

67 190

2113

1301

314 1427

9432

66.4%19.6%14.0%

1.47 (1.07, 2.03)

1.79 (1.24, 2.57)0.82 (0.34, 1.97)0.88 (0.32, 2.40)

100.0%

(i) Overall biliary complications



Study or subgroup

Ikegami T (2016)

Kim JM (2016)

Song WG (2016)



M-H, fixed, 95% CI


46

5

3

235

47

19

156

90 379

16

78

1301

418 2285

94

389

47.8%

11.9%

7.6%

1.49 (1.14, 1.96)

1.79 (1.24, 2.57)

0.58 (0.20, 1.70)Kim SH (2018) 13 46 24 86 14.9% 1.02 (0.46, 2.26)Lee FC (2015) 23 46 101 340 15.0% 2.37 (1.27, 4.41)

Kim JD (2016) 0 25 4 75 2.8% 0.31 (0.02, 5.99)0.75 (0.21, 2.63)

100.0%

(j) Biliary stricture



0.76 to 1.80, P = 0 48, Supplementary Figure 1(f)) OS,respectively. Furthermore, there were no data available tocalculate OS stratified according to the Milan criteria.

To assess the outcome measurement of disease-free sur-vival (DFS), data were classified according to 1-year and 3-year DFS, respectively. There were no useful data to calculate5-year DFS. A meta-analysis revealed that there was no sig-nificant difference between the ABOi and ABOc groups for1-year (OR: 1.26, 95% CI: 0.76 to 2.09, P = 0 37, Supplemen-tary Figure 1(g)) and 3-year (OR: 1.08, 95% CI: 0.74 to 1.59,P = 0 68, Supplementary Figure 1(h)) DFS, respectively.Furthermore, classifying data according to the Milancriteria, a meta-analysis revealed that there was nosignificant difference between ABOi and ABOc groupsfor 1-year (OR: 0.55, 95% CI: 0.27 to 1.10, P = 0 09,Supplementary Figure 1(i)) and 3-year (OR: 0.22, 95% CI:0.01 to 3.50, P = 0 28, Supplementary Figure 1(j)) DFSbeyond the Milan criteria. There were no useful data tocalculate 5-year DFS beyond the Milan criteria. Moreover,there were also no useful data to calculate DFS within theMilan criteria.

5. Discussion

In spite of the colossal prospect of growing the donor poolthrough ABOi LDLT, the safety of ABOi ALDLT is debatableamong the transplant community due to poor results in therecipients such as earlier graft loss, acute cellular rejection(ACR), antibody-mediated rejection (AMR), vascular com-plications, and biliary complications when compared tothose of ABOc ALDLT [15–17]. The utilization of ABOi liv-ing donor is an alluring answer for growing the liver donorpool, and different novel procedures for the desensitizationof ABO incompatibility have yielded promising outcomes[11, 12]. However, earlier studies such as those not usingrituximab in the desensitization protocol followed by ABOiLDLT showed inferior graft survival and patient survivalcompared to those of ABOc LDLT [15]. Nonetheless, theintroduction of rituximab to the desensitization protocolhas brought about significant improvements in the outcomesof ABOi LDLT [12, 19, 20].

ABOi LDLT in pediatric patients is considered safe andwith acceptable results, probably because of their immature

immune system [11, 13, 14]. Egawa et al. found that the5-year patient survival rate was significantly higher ininfants than in adults (85% vs. 52%) [17]. Similarly, sev-eral other studies found poor outcomes of ABOi LDLTin adults [15, 16]. Thus, ABOi LDLT in adults seems to becontroversial to many.

An effective desensitization protocol is the Achilles’ heelof ABOi ALDLT. However, the standard desensitization pro-tocol for ABOi ALDLT is yet to be implemented. Most of thecenters use their own desensitization protocol with or with-out rituximab [15]. Thus, in the scenario of conflicting resultsfrom different studies, the most important attention regard-ing ABOi ALDLT is graft survival, posttransplant complica-tions, and patient survival rate following ABOi ALDLT. Astandard desensitization protocol should be designed by tak-ing both the benefits and risks into consideration. Before theera of rituximab, the high incidence of early graft loss due toAMR was the major concern of ABOi LT [12, 35, 36]. How-ever, the incidence of AMR decreased from 23.5% to 6.2%after the introduction of rituximab, as reported by a multi-center study from Japan [12].

To date, few systematic reviews and meta-analyses havebeen conducted comprehensively to analyze the short-termand long-term outcomes of ABOi and ABOc LT. However,an earlier meta-analysis was reported that was not specificto ABOi ALDLT after the introduction of rituximab in thedesensitization protocol. Our meta-analysis includes ninerelatively high-quality studies conducted between 2015 and2018, all containing ALDLT using rituximab in the desensiti-zation process for ABOi ALDLT, with a total of 3,858patients (ABOi = 639 and ABOc = 3,219); thus, we believe itis the first study of its type.

In our meta-analysis, there was no significant differ-ence between the ABOi and ABOc ALDLT groups in termsof 1-, 3-, and 5-year graft survival and overall survival. Asreported by Egawa et al. [12], the significant reduction inthe incidence of AMR after the introduction of rituximabmight be the cause of the improvement in graft survival ofABOi ALDLT. Moreover, the largest single-center study bySong et al. [27] also reported similar outcomes in theirstudy. Currently, there are no definitive answers as towhy the overall survival of ABOi group did not differ fromthe ABOc group. Previously, some studies stated that the

Study or subgroup

Chae MS (2018)Ikegami T (2016)Kim JD (2016)Kim JM (2016)Kim SH (2018)

Total (95% CI)Heterogeneity: Chi2 = 7.29, df = 4 (P = 0.12); I2 = 45%Test for overall effect: Z = 5.33 (P < 0.00001)

86.1% 3.50 (2.16, 4.84)−8.00 (−18.85, 2.85)

6.20 (1.05, 11.35)6.00 (−2.41, 14.41)−0.30 (−6.18, 5.58)

3.39 (2.14, 4.64)

−20 −10 0Favours (ABOi) Favours (ABOc)

10 20

1.3%5.9%2.2%4.5%

100.0%

32389759486

676

2.1233

11.320.1617.3

2244

24.929

19.6

3219254743

166

3.2523

11.425.7515.4

25.536

31.135

19.3

MeanABOi

SDABOc

Mean SD Total Total Weight Mean differenceIV, fixed, 95% CI

Mean differenceIV, fixed, 95% CI

(k) Hospital stay

Figure 3: Forest plot of postoperative short-term outcomes: (a) overall infections, (b) bacterial infections, (c) fungal infections, (d)Cytomegalovirus (CMV) infection, (e) hepatic artery stenosis, (f) portal vein stenosis, (g) bleeding, (h) biliary leak, (i) overall biliarycomplications, (j) biliary stricture, and (k) hospital stay.


Chae MS (2018)Ikegami T (2016)Kim JD (2016)Kim JM (2016)Kim SH (2018)Lee FC (2015)Song WG (2016)

Study or subgroup ABOcABOiEvents Total Events Total Weight Odds ratio

M-H, random, 95% CIOdds ratio

M-H, random, 95% CI

Total (95% CI)Total eventsHeterogeneity: Tau2 = 4.12; Chi2 = 12.42, df = 4 (P < 0.01); I2 = 68%Test for overall effect: Z = 2.77 (P = 0.006)

21.58 (2.45, 190.07)

0.001 0.1 1Favours (ABOi) Favours (ABOc)

10 1000

1720

02

22

2354643

2547

1932

0

25 2

00

00

02

130134086

7594

38932

19.9%

447 2317 100.0%

18.8%

18.8%

18.7%23.7%

208.48 (12.49, 3479.38)38.26 (1.81, 809.78)

Not estimable

Not estimable10.38 (0.49, 220.79)

111.29 (5.15, 2406.68)1.00 (0.13, 7.57)

(a) Antibody-mediated rejection (AMR)

Study or subgroup ABOc Odds ratio Odds ratioABOiTotalEvents Events Total Weight M-H, fixed, 95% CI M-H, fixed, 95% CI

Chae MS (2018)Ikegami T (2016)Kim JD (2016)Kim JM (2016)Kim SH (2018)Lee FC (2015)Song (2016)


Total (95% CI)Total events

540602

19

6.3%7.9%1.4%

18.4%1.9%0.2%

63.9%

1.30 (0.31, 5.35)1.57 (0.49, 4.75)

0.97 (0.04, 24.67)0.66 (0.24, 1.81)

0.66 (0.03, 16.42)38.26 (1.81, 809.78)

0.85 (0.51, 1.41)

32389759486

3401301

4581

1710

122

36 203

321925474346

235

100.0% 0.98 (0.67, 1.43)

Favours (ABOi)

0.01 0.1 1 10 100

Favours (ABOc)

2317447

(b) Acute cellular rejection (ACR)


Chae MS (2018)Kim JM (2016)Kim SH (2018)Lee FC (2015)Song (2016)



17423738

226

22.2%11.5%15.4%22.5%28.5%

0.38 (0.13, 1.09)1.23 (0.41, 3.72)0.15 (0.03, 0.76)1.12 (0.50, 2.52)1.32 (0.65, 2.69)

329486

3401301

248284

2751236

360 1701

32474346

235

100.0% 0.88 (0.59, 1.30)

Favours (ABOi)

0.01 0.1 1 10 100

Favours (ABOc)

1853403

(c) 1 yr overall survival


Chae MS (2018)Kim JM (2016)Kim SH (2018)Lee FC (2015)Song (2016)



12403535

217

12.1%10.9%13.6%21.7%41.7%

0.88 (0.32, 2.40)1.54 (0.60, 3.96)0.71 (0.27, 1.89)1.04 (0.51, 2.15)1.01 (0.60, 1.71)

329486

3401301

137474

2561200

339 1617

32474346

235

100.0% 1.02 (0.73, 1.43)

Favours (ABOi)

0.01 0.1 1 10 100

Favours (ABOc)

1853403

(d) 3 yr overall survival



higher MELD score was the risk factor for patient survivalafter LT [17, 20, 27]. However, when we looked for aMELD score between the ABOi and ABOc groups, ourmeta-analysis did not find any significant difference betweenboth groups.

The incidences of postoperative complications were com-parable between both groups. However, ABOi ALDLT hadhigher incidences of CMV infection, AMR, overall biliarycomplications, and biliary stricture than adult ABOc ALDLT.

The possible cause of the higher incidence of CMV might bebecause of the immunocompromised state due to rituximab.Rituximab suppresses different stages of B cell differentiationleading to a rapid decrease in the peripheral B cell populationwithin 48-72 hours, but which can last for several months[27,37, 38]. Furthermore, repeated dosing of rituximab inducesprolonged hypogammaglobulinemia which has a high riskfor serious infectious complications [27, 38]. Likewise, inour meta-analysis two [27, 31] out of four studies reporting

Study or subgroupABOc Odds ratio Odds ratioABOi

Events Total Events TotalWeight

M-H, fixed, 95% CI M-H, fixed, 95% CI

Chae MS (2018)Lee FC (2015)Song WG (2016)



0.47 (0.14, 1.61)1.01 (0.51, 2.01)1.14 (0.68, 1.91)

14.7%31.6%53.8%

32340

1301

9243

1189

3246

235

1.00 (0.68, 1.47)

0.01 0.1Favours (ABOi) Favours (ABOc)

1 10 100

100.0%1673313

533

217

1441255

(e) 5 yr overall survival




Ikegami (2016)Lee FC (2015)Song WG (2016)



2.35 (0.31, 18.06)1.12 (0.50, 2.52)0.75 (0.43, 1.33)

4.3%29.4%66.3%

389340

1301

344275

1233

1946

235

0.93 (0.60, 1.46)

0.01 0.1


1 10 100

100.0%2030300

1838

219

1852275

(f) 1 yr graft survival

Study or subgroup ABOc Odds ratio Odds ratioABOiEvents Total Events Total Weight M-H, fixed, 95% CI M-H, fixed, 95% CI

Lee FC (2015)Song WG (2016)



1.04 (0.51, 2.15)0.76 (0.48, 1.22)

28.1%71.9%

3401301

2561197

46235

0.84 (0.57, 1.25)

0.01 0.1


1 10 100

100.0%1641281

35211

1453246

(g) 3 yr graft survival




Ikegami T (2016)Lee FC (2015)Song WG (2016)



2.10 (0.47, 9.27)1.01 (0.51, 2.01)0.84 (0.53, 1.34)

5.4%29.0%65.6%

389340

1301

312243

1189

1946

235

0.96 (0.66, 1.39)

0.01 0.1


1 10 100

100.0%2030300

1733

211

1742261

(h) 5 yr graft survival

Figure 4: Forest plot of postoperative long-term outcomes: (a) antibody-mediated rejection (AMR), (b) acute cellular rejection (ACR), (c) 1yr overall survival, (d) 3 yr overall survival, (e) 5 yr overall survival, (f) 1 yr graft survival, (g) 3 yr graft survival, and (h) 5 yr graft survival.


on CMV infection have used splenectomy in their desensiti-zation protocol. Studies have shown that splenectomy isassociated with a higher rate of serious infectious complica-tions including CMV infection in LDLT [39]. Thus, arepeated dose of rituximab and inclusion of splenectomy inthe desensitization protocol should be considered carefully.However, rituximab has additionally supplanted the need ofsplenectomy to prevent a posttransplant rebound increaseof isohemagglutinins (IHs) [27, 40].

Despite the fact that after the introduction of rituximabto the desensitization protocol, the incidence of hepaticnecrosis caused by AMR has disappeared, diffuse intrahepa-tic biliary stricture (DIHBS), which is a modest type ofAMR, still remains to be the concern in ABOi ALDLT[19,27]. Moreover, in the study by Song et al., DIHBS wasreported to be solely in patients undergoing ABOi ALDLT[27]. The adequate reduction of B cells and the eliminationof serum IH titers are important steps concerning the pre-vention of AMR[30]. In instances of AMR, IHs initiate theimmune response by binding to the graft vessels leading tothe activation of the complement system and inflammation,which may further lead to hepatic artery thrombosis andnecrosis of the liver [36, 41]. Since ABO antigens are presenton the bile duct epithelium, the activation of the immuneresponse contributes to the increased incidence of uncom-promising and continuous intrahepatic bile duct injury withABOi LT [41]. As discussed earlier, rituximab, being an anti-CD20 monoclonal antibody, can suppress the activated B cellpopulation in circulation through antibody-dependent cell-mediated cytotoxicity, direct antigen antibody reaction, andcomplement-dependent cytotoxicity; however, it is unableto suppress stem cells and plasma cells [42, 43]. Interestingly,plasma B cells only get triggered after they encounter allo-grafts after LT [30]. Moreover, it has also been reported thatsome B cells may rescue themselves preoperatively at thetime of rituximab treatment and later can get activated afterLT that produces antibodies [30]. Although rituximab maythoroughly control AMR over ABO barriers, it does not per-form as such on the ground, so that it cannot annihilateplasma cells that are present on the epithelium of the bileducts, thus leading to DIHBS and biliary stricture [31, 43].This explains why ABOi ALDLT has a higher incidence ofAMR, overall biliary complications, and biliary stricture.However, our meta-analysis showed that the ABOi grouphad a significantly shorter cold ischemia time than the ABOcgroup; the reason might be due to the concern of transplantsurgeons to reduce the incidence of the ischemic type of bil-iary stricture. Nevertheless, this has not shown to improvethe incidence of biliary stricture or overall biliary complica-tions in the ABOi ALDLT group. Previously, some of thestudies have outlined that the rise in posttransplant donor-specific antibody (DSA) titers is significantly associated withthe incidence of AMR; therefore, an association of DSAshould also be taken into consideration as the cause ofAMR [44–46]. In our understanding, the most importantkey to avoid AMR in ABOi ALDLT is the inhibition of newlyproduced antibodies. TPE is a standard procedure todecrease DSA titers, yet the titer required to avoid AMR isnot well characterized [47]. Furthermore, the dosing and

timing of rituximab is also a concern regarding AMR [12,27]. Egawa et al. [12] reported that consistent single dosesof rituximab (500 mg/m2 or 375 mg/m2) had a lower fre-quency of AMR than a single low dose (300 mg/m2). In thecontext of comparison between TPE and rituximab, Kozakiet al. [48] found that rituximab was not sufficient for decreas-ing antibody titers after ABOi LDLT, and TPE remains to bea mainstay of treatment for such patients. On the other hand,Kim et al. [22] concluded that desensitization using rituxi-mab and IVIG without TEP for ABOi LDLT was safe andeffective in achieving sufficient desensitization with compa-rable outcomes.

Furthermore, a few case reports and series have beendivulged in regard to the utilization of plasma cell depletingagents, such as bortezomib, in the treatment and preventionof AMR related with the anti-HLA antibody [49, 50]. Borte-zomib specifically prompts apoptosis among plasma cells,further diminishing isoagglutinin production [51]. However,further study is needed to prove the efficacy and safety of bor-tezomib combined with rituximab in the desensitization pro-tocol for ABOi ALDLT.

Moreover, our review of studies suggested that there wasno significant difference between the ABOi and ABOc groupsfor 1-year and 3-year OS and DFS for patients with HCC fol-lowing ABOi ALDLT. However, the MELD score and themaximum tumor diameter were significantly lower in ABOiALDLT for patients with HCC, probably because of the care-ful patient selection for ABOi ALDLT. Both the studiesreporting on the recurrence of HCC for ABOi ALDLTrevealed that rituximab does not increase the risk of HCCrecurrence [25, 26]. Nevertheless, it has been found that over-exposure to tacrolimus and basiliximab during the first yearafter LT increases the risk of HCC recurrence [52, 53].

Despite the high quality of the papers incorporated intothis meta-analysis, there are various shortcomings concern-ing this meta-analysis. Firstly, there is a potential publicationbias, because studies are less likely to outline negative find-ings. It could also be affected by the limited resources to iden-tify unpublished trials. Secondly, only English-languagestudies were incorporated. Thus, the quality of outcomeswas compromised to some extent, which is a typical reasonfor publication bias. Additionally, we could not identifytwo-arm studies comparing ABOi and ABOc ALDLT beforethe era of rituximab except for a few case reports or a one-arm study; this would have been of great importance if thecomparative results before and after the era of rituximabwere established. Moreover, the studies included in thismeta-analysis have used different desensitization protocolsand immunotherapies after LT; thus, it was difficult toharmonize these different protocols to the results of themeta-analysis. However, this meta-analysis is still of greatsignificance for comparing different outcomes betweenABOi and ABOc ALDLT in the era of rituximab andmay prove beneficial for the clinicians in choosing theappropriate strategy (Figure 5).

Our meta-analysis included the largest number of studiescomparing ABOi and ABOc ALDLT and all those usingrituximab prophylaxis for ABOi ALDLT. ABOi ALDLTshowed comparable results with that of ABOc ALDLT.


However, CMV infection, biliary stricture, and AMR remainthe major concerns in the era of rituximab. Nevertheless, aclinical trial is required for the comparisons of patient out-comes with/without rituximab, dosing, and timing ofrituximab in a large cohort; anyhow, it would be hard towithdraw rituximab prophylaxis when the current out-comes are so much promising in the era of rituximab. Thus,we suggest the need for an effective and standardized desen-sitization protocol in addition to rituximab in the future.

Abbreviations

ABOc: ABO compatibleABOi: ABO incompatibleACR: Acute cellular rejectionALDLT: Adult living donor liver transplantationAMR: Antibody-mediated rejectionCMV: CytomegalovirusACR: Acute cellular rejectionHBV: Hepatitis B virusHCC: Hepatocellular carcinomaHCV: Hepatitis C virusIHs: IsohemagglutininsLDLT: Living donor liver transplantationLT: Liver transplantationMELD: Model for end-stage liver diseaseAFP: alpha-FetoproteinTPE: Total plasma exchangeIVIG: Intravenous immunoglobulin GDFS: Disease-free survivalOS: Overall survival.

Disclosure

This manuscript was presented as a poster in the 2nd Inter-national Advanced Liver and Pancreas Surgery Symposium,Seoul, Korea.

Conflicts of Interest

The authors declare no competing interests.

Acknowledgments

This work was supported by grants from the 973 program(No. 2014CB542101), the National Natural Science Founda-tion of China (No. 81472212), the Key Program of MedicalScientific Research Foundation of Zhejiang Province, China(No. WKJ-ZJ-1410), the Key Program of Administration ofTraditional Chinese Medicine of Zhejiang Province, China(No. 2014ZZ00), and the Zhejiang Provincial Program forthe Cultivation of High-level Innovative Health Talents.

Supplementary Materials

Supplementary Table 1 Newcastle-Ottawa quality assessmentscale. Supplementary Figure 1: forest plot of HCC patients.(a) AFP level, (b) MELD score for HCC patients, (c) maxi-mum tumor diameter, (d) number of tumors, (e) 1-year over-all survival for HCC patients, (f) 3-year overall survival forHCC patients, (g) 1-year disease-free survival, (h) 3-yeardisease-free survival, (i) 1-year disease-free survival beyondMilan criteria, and (j) 3-year disease-free survival beyondMilan criteria. (Supplementary Materials)

ALDLT (no splenectomy)

Basiliximab 20 mg as induction agent

Tacrolimus concentration of 8-12 ng/ml during the first month & 5-8 ng/ml therea�er

No local infusion

MMF 1-1.5 g/day

Plasma exchange until isoagglutinin titer ≤1:16

Rituximab 375 mg/m2 body surface area

Isoagglutinin titer ≤1:16 Posttransplant days

+21 days−7 daysIn between −21 and −14 days

Pretransplant days

Basiliximab 20 mg on day 4

Plasma exchange if isoagglutinin titer >1:32

If AMR-bortezomib (1.3 mg/m2 IV) weekly for four doses

Corticosteroids tapered over 3 months

Figure 5: Suggested simplified desensitization protocol for ABO incompatible adult living donor liver transplantation. ALDLT—adult livingdonor liver transplantation; MMF—mycophenolate mofetil; AMR—antibody-mediated rejection.


http://downloads.hindawi.com/journals/grp/2019/8589402.f1.doc

References

[1] J. Bruix, M. Sherman, and American Association for the Studyof Liver Diseases, “Management of hepatocellular carcinoma:an update,” Hepatology, vol. 53, no. 3, pp. 1020–1022, 2011.

[2] A. Forner, J. M. Llovet, and J. Bruix, “Hepatocellular carci-noma,” The Lancet, vol. 379, no. 9822, pp. 1245–1255, 2012.

[3] P. G. Northup, N. M. Intagliata, N. L. Shah, S. J. Pelletier, C. L.Berg, and C. K. Argo, “Excess mortality on the liver transplantwaiting list: unintended policy consequences and Model forEnd-Stage Liver Disease (MELD) inflation,” Hepatology,vol. 61, no. 1, pp. 285–291, 2015.

[4] H. Yeh, E. Smoot, D. A. Schoenfeld, and J. F. Markmann,“Geographic inequity in access to livers for transplantation,”Transplantation, vol. 91, no. 4, pp. 479–486, 2011.

[5] G. Sapisochin and J. Bruix, “Liver transplantation for hepato-cellular carcinoma: outcomes and novel surgical approaches,”Nature reviews Gastroenterology & Hepatology, vol. 14, no. 4,pp. 203–217, 2017.

[6] R.A.Fisher, “Livingdonor liver transplantation: eliminating thewait for death in end-stage liver disease?,” Nature reviews Gas-troenterology &Hepatology, vol. 14, no. 6, pp. 373–382, 2017.

[7] M. Stegall, “ABO-incompatible liver transplant: is it justifi-able?,” Liver Transplantation, vol. 9, no. 1, p. 31, 2003.

[8] D. W. Hanto, A. H. Fecteau, M. H. Alonso, J. F. Valente, andJ. F. Whiting, “ABO-incompatible liver transplantation withno immunological graft losses using total plasma exchange,splenectomy, and quadruple immunosuppression: evidencefor accommodation,” Liver Transplantation, vol. 9, no. 1,pp. 22–30, 2003.

[9] R. Watson, T. Kozlowski, V. Nickeleit et al., “Isolated donorspecific alloantibody-mediated rejection after ABO compatibleliver transplantation,” American Journal of Transplantation,vol. 6, no. 12, pp. 3022–3029, 2006.

[10] R. B. Colvin, “C4d in liver allografts: a sign of antibody-mediated rejection?,” American Journal of Transplantation,vol. 6, no. 3, pp. 447-448, 2006.

[11] S. Rummler, A. Bauschke, E. Bärthel et al., “Current techniquesfor AB0-incompatible living donor liver transplantation,”World Journal of Transplantation, vol. 6, no. 3, pp. 548–555,2016.

[12] H. Egawa, S. Teramukai, H. Haga et al., “Impact of rituxi-mab desensitization on blood-type-incompatible adult livingdonor liver transplantation: a Japanese multicenter study,”American Journal of Transplantation, vol. 14, no. 1,pp. 102–114, 2014.

[13] T. Yandza, T. Lambert, F. Alvarez et al., “Outcome of ABO-incompatible liver transplantation in children with no specificalloantibodies at the time of transplantation,” Transplantation,vol. 58, no. 1, pp. 46–50, 1994.

[14] T. H. Renard and W. S. Andrews, “An approach to ABO-incompatible liver transplantation in children,” Transplanta-tion, vol. 53, no. 1, pp. 116–120, 1992.

[15] E. C. Lee, S. H. Kim, and S.-J. Park, “Outcomes after livertransplantation in accordance with ABO compatibility: a sys-tematic review and meta-analysis,”World Journal of Gastroen-terology, vol. 23, no. 35, pp. 6516–6533, 2017.

[16] J. Wu, S. Ye, X. Xu, H. Xie, L. Zhou, and S. Zheng, “Recipientoutcomes after ABO-incompatible liver transplantation: a sys-tematic review and meta-analysis,” PLOS ONE, vol. 6, no. 1,article e16521, 2011.

[17] H. Egawa, S. Teramukai, H. Haga, M. Tanabe, M. Fukushima,and M. Shimazu, “Present status of ABO-incompatible livingdonor liver transplantation in Japan,” Hepatology, vol. 47,no. 1, pp. 143–152, 2008.

[18] S. Miyagi, N. Kawagishi, S. Sekiguchi et al., “The relation-ship between recurrences and immunosuppression on livingdonor liver transplantation for hepatocellular carcinoma,”Transplantation Proceedings, vol. 44, no. 3, pp. 797–801,2012.

[19] G. W. Song, S. G. Lee, S. Hwang et al., “Biliary stricture is theonly concern in ABO-incompatible adult living donor livertransplantation in the rituximab era,” Journal of Hepatology,vol. 61, no. 3, pp. 575–582, 2014.

[20] J. M. Kim, C. H. D. Kwon, J.-W. Joh et al., “ABO-incompatibleliving donor liver transplantation is suitable in patients with-out ABO-matched donor,” Journal of Hepatology, vol. 59,no. 6, pp. 1215–1222, 2013.

[21] H. Egawa, K. Ohmori, H. Haga et al., “B-cell surface markeranalysis for improvement of rituximab prophylaxis in ABO-incompatible adult living donor liver transplantation,” LiverTransplantation, vol. 13, no. 4, pp. 579–588, 2007.

[22] S. H. Kim, E. C. Lee, J. R. Shim, and S. J. Park, “A simplifiedprotocol using rituximab and immunoglobulin for ABO-incompatible low-titre living donor liver transplantation,”Liver International, vol. 38, no. 5, pp. 932–939, 2018.

[23] I. Monteiro, L. M. McLoughlin, A. Fisher, A. N. de la Torre,and B. Koneru, “Rituximab with plasmapheresis and splenec-tomy in ABO-incompatible liver transplantation,” Transplan-tation, vol. 76, no. 11, pp. 1648-1649, 2003.

[24] M. S. Chae, N. Lee, H. J. Choi et al., “Comparison of livergraft regeneration between ABO-compatible and ABO-incompatible living donor liver transplantation: a propensityscore matching analysis,” Annals of Transplantation, vol. 23,pp. 507–519, 2018.

[25] J. M. Kim, C. H. D. Kwon, J. W. Joh et al., “ABO-incompatibleliving donor liver transplantation with rituximab and totalplasma exchange does not increase hepatocellular carcinomarecurrence,” Transplantation, vol. 102, no. 10, pp. 1695–1701, 2018.

[26] Y. I. Yoon, G. W. Song, S. G. Lee et al., “Outcome of ABO-incompatible adult living-donor liver transplantation forpatients with hepatocellular carcinoma,” Journal of Hepatol-ogy, vol. 68, no. 6, pp. 1153–1162, 2018.

[27] G.‐. W. Song, S.‐. G. Lee, S. Hwang et al., “ABO-incompatibleadult living donor liver transplantation under the desensitiza-tion protocol with rituximab,” American Journal of Transplan-tation, vol. 16, no. 1, pp. 157–170, 2016.

[28] J. M. Kim, C. H. D. Kwon, J.-W. Joh et al., “Case-matchedcomparison of ABO-incompatible and ABO-compatible livingdonor liver transplantation,” British Journal of Surgery,vol. 103, no. 3, pp. 276–283, 2016.

[29] J. D. Kim, D. L. Choi, S. G. Kim, and A. J. Lee, “Single-centerexperience of ABO-incompatible living-donor liver transplan-tation with a new simplified intravenous immunoglobulin pro-tocol: a propensity score-matching analysis,” TransplantationProceedings, vol. 48, no. 4, pp. 1134–1138, 2016.

[30] C. F. Lee, C. H. Cheng, Y. C. Wang et al., “Adult living donorliver transplantation across ABO-incompatibility,” Medicine,vol. 94, no. 42, article e1796, 2015.

[31] T. Ikegami, T. Yoshizumi, Y. Soejima, H. Uchiyama,K. Shirabe, and Y. Maehara, “Feasible usage of ABO


incompatible grafts in living donor liver transplantation,”Hepatobiliary Surgery and Nutrition, vol. 5, no. 2, pp. 91–97,2016.

[32] D. Moher, A. Liberati, J. Tetzlaff, D. G. Altman, and thePRISMA Group, “Preferred reporting items for systematicreviews and meta-analyses: the PRISMA statement,” Annalsof Internal Medicine, vol. 151, no. 4, pp. 264–269, 2009.

[33] C. K.-L. Lo, D. Mertz, and M. Loeb, “Newcastle-Ottawa Scale:comparing reviewers’ to authors’ assessments,” BMC MedicalResearch Methodology, vol. 14, no. 1, p. 45, 2014.

[34] J. P. Higgins, S. G. Thompson, J. J. Deeks, and D. G. Altman,“Measuring inconsistency in meta-analyses,” BMJ, vol. 327,no. 7414, pp. 557–560, 2003.

[35] J. Gugenheim, D. Samuel, H. Bismuth, and M. Reynes, “Livertransplantation across ABO blood group barriers,” The Lancet,vol. 336, no. 8714, pp. 519–523, 1990.

[36] A. J. Demetris, R. Jaffe, A. Tzakis et al.et al., “Antibody-medi-ated rejection of human orthotopic liver allografts: a study ofliver transplantation across ABO blood group barriers,” TheAmerican Journal of Pathology, vol. 132, no. 3, pp. 489–502,1988.

[37] D. Toki, H. Ishida, S. Horita, K. Setoguchi, Y. Yamaguchi, andK. Tanabe, “Impact of low-dose rituximab on splenic B cells inABO-incompatible renal transplant recipients,” Transplant,vol. 22, no. 4, pp. 447–454, 2009.

[38] H. Genberg, A. Hansson, A. Wernerson, L. Wennberg, andG. Tyden, “Pharmacodynamics of rituximab in kidney allo-transplantation,” American Journal of Transplantation, vol. 6,no. 10, pp. 2418–2428, 2006.

[39] A. Badawy, Y. Hamaguchi, S. Satoru, T. Kaido, H. Okajima,and S. Uemoto, “Evaluation of safety of concomitant splenec-tomy in living donor liver transplantation: a retrospectivestudy,” Transplant International, vol. 30, no. 9, pp. 914–923,2017.

[40] S. D. Lee, S. H. Kim, S. Y. Kong, Y. K. Kim, S. A. Lee, and S. J.Park, “ABO-incompatible living donor liver transplantationwithout graft local infusion and splenectomy,” HPB, vol. 16,no. 9, pp. 807–813, 2014.

[41] L. Sanchez-Urdazpal, K. P. Batts, G. J. Gores et al., “Increasedbile duct complications in liver transplantation across theABO barrier,” Annals of Surgery, vol. 218, no. 2, pp. 152–158,1993.

[42] P. Boross and J. H. Leusen, “Mechanisms of action of CD20antibodies,” American Journal of Cancer Research, vol. 2,no. 6, pp. 676–690, 2012.

[43] G. J. Weiner, “Rituximab: mechanism of action,” Seminars inHematology, vol. 47, no. 2, pp. 115–123, 2010.

[44] M. Kasahara, T. Kiuchi, K. Takakura et al., “Postoperativeflow cytometry crossmatch in living donor liver transplanta-tion: clinical significance of humoral immunity in acuterejection,” Transplantation, vol. 67, no. 4, pp. 568–575,1999.

[45] L. J. Wozniak, M. J. Hickey, R. S. Venick et al., “Donor-specificHLA antibodies are associated with late allograft dysfunctionafter pediatric liver transplantation,” Transplantation, vol. 99,no. 7, pp. 1416–1422, 2015.

[46] J. G. O’Leary, H. Kaneku, B. M. Susskind et al., “High meanfluorescence intensity donor-specific anti-HLA antibodiesassociated with chronic rejection postliver transplant,” Ameri-can Journal of Transplantation, vol. 11, no. 9, pp. 1868–1876,2011.

[47] M. Honda, Y. Sugawara, M. Kadohisa et al., “Long-termoutcomes of ABO-incompatible pediatric living donor livertransplantation,” Transplantation, vol. 102, no. 10, pp. 1702–1709, 2018.

[48] K. Kozaki, H. Egawa, M. Ueda et al., “The role of apheresistherapy for ABO incompatible living donor liver transplanta-tion: the Kyoto University experience,” Therapeutic Apheresisand Dialysis, vol. 10, no. 5, pp. 441–448, 2006.

[49] S. M. Flechner, R. Fatica, M. Askar et al., “The role of pro-teasome inhibition with bortezomib in the treatment ofantibody-mediated rejection after kidney-only or kidney-combined organ transplantation,” Transplantation, vol. 90,no. 12, pp. 1486–1492, 2010.

[50] F. Paterno, M. Shiller, G. Tillery et al., “Bortezomib for out-comes of ABO-incompatible pediatric living donor liver trans-plantation,” American Journal of Transplantation, vol. 12,no. 9, pp. 2526–2531, 2012.

[51] D. K. Perry, J. M. Burns, H. S. Pollinger et al., “Proteasomeinhibition causes apoptosis of normal human plasma cells pre-venting alloantibody production,” American Journal of Trans-plantation, vol. 9, no. 1, pp. 201–209, 2009.

[52] J. R. Parfitt, P. Marotta, M. AlGhamdi et al., “Recurrent hepa-tocellular carcinoma after transplantation: use of a pathologi-cal score on explanted livers to predict recurrence,” LiverTransplantation, vol. 13, no. 4, pp. 543–551, 2007.

[53] J.-Y. Lee, Y. H. Kim, N.-J. Yi et al., “Impact of immunosup-pressant therapy on early recurrence of hepatocellular carci-noma after liver transplantation,” Clinical and MolecularHepatology, vol. 20, no. 2, pp. 192–203, 2014.


Stem Cells International

Hindawiwww.hindawi.com Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawiwww.hindawi.com

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwww.hindawi.com Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwww.hindawi.com

Submit your manuscripts atwww.hindawi.com

https://www.hindawi.com/journals/sci/

https://www.hindawi.com/journals/mi/

https://www.hindawi.com/journals/ije/

https://www.hindawi.com/journals/dm/

https://www.hindawi.com/journals/bmri/

https://www.hindawi.com/journals/jo/

https://www.hindawi.com/journals/omcl/

https://www.hindawi.com/journals/ppar/

https://www.hindawi.com/journals/tswj/

https://www.hindawi.com/journals/jir/

https://www.hindawi.com/journals/jobe/

https://www.hindawi.com/journals/cmmm/

https://www.hindawi.com/journals/bn/

https://www.hindawi.com/journals/joph/

https://www.hindawi.com/journals/jdr/

https://www.hindawi.com/journals/art/

https://www.hindawi.com/journals/grp/

https://www.hindawi.com/journals/pd/

https://www.hindawi.com/journals/ecam/

https://www.hindawi.com/

https://www.hindawi.com/

ABO-Incompatible Adult Living Donor Liver Transplantation...

Documents

Transcript of ABO-Incompatible Adult Living Donor Liver Transplantation...