ABO-INCOMPATIBLE LIVER TRANSPLANTATION IN ACUTE AND
ACUTE-ON-CHRONIC LIVER FAILURE
RUNNING TITLE: ABO INCOMPATIBLE LIVER TRANSPLANTATION
Sezai Yilmaz1, Cemalettin Aydin1, Burak Isik1, Cuneyt Kayaalp1, Mehmet Yilmaz1,
Cengiz Ara1, Ramazan Kutlu2, Yasar Bayindir3, Veysel Ersan1
1Department
of General Surgery, Inonu University, School of Medicine, Malatya,
Turkey
2Department
3Department
of Radiology, Inonu University, School of Medicine, Malatya, Turkey
of Infectious Diseases and Clinical Microbiology, Inonu University, School
of Medicine, Malatya, Turkey
Corresponding Author:
Sezai Yilmaz, MD, Professor
Department of General Surgery,
Inonu University, School of Medicine,
Turgut Ozal Medical Center, 44315,
Malatya, Turkey
Tel: +904223410660 (ext.3707), Fax: +904223410229, E-mail: sezaiyilmaz@inonu.edu.tr
The authors consider the paper an Original Paper to be placed in liver section.
All authors declare that there is no conflict of interest or financial support.
Key
words:
ABO
incompatible,
acute,
acute-on-chronic,
liver
failure,
liver
transplantation
Abbreviations: ABO-Incompatible (ABO-I); liver transplantation (LTx); antibody
mediated rejection (AMR); living donor (LD); deceased donor (DD); plasmapheresis (PE);
ABSTRACT
Background/Aims: ABO-incompatible (ABO-I) liver transplantation (LTx) is an inevitable
problem in emergency conditions such as acute liver failure or acute-on-chronic liver failure when
deceased donor (DD) is not available or living donor (LD) selection is limited. This study
spesifically addressed the problem of emergency ABO-I LTx in critically ill adult patients having
acute liver failure or severely decompensated end stage liver disease.
Methodology: This series included 16 patients, of which 10 underwent ABO-I LD LTx and 6
patients underwent 7 ABO-I DD LTx. Two patients underwent ABO-compatible LD LT before
ABO-I DD LT, because of hepatic artery thrombosis. Multiple sessions of plasmapheresis were
used to reduce isoaglutinin titres to 1/16 or below before and after the transplantation. Splenectomy
was carried out after the graft reperfusion in the last 7 cases. In the first 9 patients splenic artery
ligation was performed. Data were prospectively collected and retrospectively analysed.
Results: The follow-up period ranged from 1 to 38 months. The mean follw-up period was
10.37 months. Median age of patients was 50 years (17-63 years). The MELD scores ranged from
17 to 30 (median 22.5). Median survival of patients was 9 months and mean survival was 19.5
months. Hospital mortality consisted of 3 patients (18.7 %). Two patients died due to small for size
graft syndrome and cerebrovascular bleeding respectively. Hepatic artery thrombosis developed in
3 patients. Two of them died at postoperative 4th and 9th months. Third patient is stil living with
hepatic necrosis problem.
Conclusion: ABO-I LTx remains an important and unavoidable therapeutic option in adult
patients with acute or acute-on-chronic liver failure awaiting an emergency procedure and in the
context of living donor liver transplantation. This option should be offered to all patients in cases of
immediate need for an allograft without the possibility to allocate a blood group compatible liver
graft.
INTRODUCTION
ABO-Incompatible (ABO-I) liver transplantation (LTx) is an inevitable problem in liver
transplantation (LTx) in the emergency conditions, because either deceased donor (DD) is not
available or living donor (LD) selection is limited. Refusing ABO-I LTx may lead to expeditious
death of the patient. Therefore, the use of grafts from ABO-I donors might be the only available
option.
Initial experiences have shown that while ABO-I living donor (LD) LTx can be performed
with relative safety in infants of <1 year-old, adult patients remained at considerable risk of early
mortality. In these cases, causes of death were infection secondary to antibody mediated rejection
(AMR) or over-immunosuppression, which usually presents as hepatic necrosis or intrahepatic
biliary complications (1).
ABO-I LTx has been most frequently performed for two indications: emergency
transplantations for acute liver failure or acute-on-chronic liver failure, when no ABO-compatible
donor is available (2).
This study spesifically addressed the problem of emergency LTx in critically ill adult patients
having acute liver failure or severely decompensated end stage liver disease.
PATIENTS AND METHODS
This series included sixteen patients, of which ten underwent ABO-I LD LTx and six patients
underwent seven ABO-I DD LTx. Two patients had undergone ABO-compatible LD LTx before
ABO-I DD LTx, because of hepatic artery thrombosis. Clinical characteristics of the patients,
donor-recipient blood group match, and outcomes are shown in Table 1.
The study was conducted under the institutional review board and all transplants were
performed at the University of Inonu at Malatya.
Multiple sessions of plasmapheresis (PE) were used to reduce isoaglutinin titers to 1:16 or
lower before and after the transplantation. A final preoperative PE was performed to each patient on
the day of the transplantation. In all patients, isoaglutinin titers were lowered below 1:16 by
maximum 2 PE sessions before transplantation. In the first 30 days after transplantation, rising titer
levels above threshold of 1:16 lead to repeated PE necessary. The mean of necessity of PE after
transplantation was 6.7 (range 4-9). Regarding PE technique, dual needle PE procedures were
performed using a cell separator (Com.Tec, Fresenius HemoCare GmbH, Bad Homburg, Germany),
single-stage channel filler and TPE disposable set (PL1, Fresenius Kabi AG, Bad Homburg,
Germany). Uniformly, vascular access was via a double lumen dialysis type catheter from internal
juguler vein, by an experienced radiologist, Ramazan Kutlu. The inlet flow rate was between 60 and
100 mL/min. The replacement fluids for plasma exchanges (fresh frozen plasma, 5% human
albumin, and normal saline) and their ratios were determined on the basis of the patient’s
coagulation parameters. Fresh frozen plasma used was always AB fresh frozen plasma that
presumably did not contain anti A and anti B antibodies.
Splenectomy was carried out after the graft reperfusion to suppress antibody production in the
last seven cases. No splenectomy was performed in the first nine patients. Instead, splenic artery
ligation was performed. Pneumococcal polysaccaride vaccine was given to all recipients.
No patient was given portal or intraarterial intrahepatic infusion therapy.
The standart immunosuppressive regimen consisted of induction therapy with IL-2 receptor
antagonist (Basiliximab, Simulect) antibodies directed against white blood cell epitopes.
Maintenance therapy consisted of corticosteroids and tacrolimus, and adjuvant immunosuppression
with mycophenolate mofetil. Therapy with steroids was initiated at surgery intraoperatively (500
mg methylprednisolone) and continued at 1.5 mg/kg body weight prednisolone tapered by 0.25
mg/kg was achieved. Tacrolimus was administered on the first postoperative day, starting with a
dose of 0.01 mg/ kg per day and increasing the daily dose by 1-2 mg according to renal function to
achieve a through plasma level of 15-20 ng/mL. Mycophenolate mofetil was started at a dose of 2
g/day.
Data were prospectively collected and retrospectively analysed. Survivals were analysed by
the Kaplan-Meier method.
RESULTS
Over the 9 year period, 550 LTxs were performed. Among them, 17 were ABO-I cases
performed in 16 patients (3%). They included 12 males and 4 females. The indications for
transplantations are shown in Table 1. All of the patients had either acute liver failure or acute-onchronic liver failure and had undergone LTx at an emergency conditions.
The follow-up period ranged from one to 38 months, and the mean follow-up period was
10.37 months. Median age of patients was 50 years (range 17 to 63 years). The blood type
combinations between recipients and donors are shown in Table 1. The MELD scores ranged from
17 to 30 (median 22.5). Strategies for the blood-type barrier consisted of PE, splenectomy (n: 7),
splenic artery ligation (n: 9). Rituximab was not used and local infusion therapy was not performed.
Clinical manifestations of AMR were hepatic necrosis and intrahepatic biliary complications.
Hepatic necrosis was diagnosed when levels of hepatic enzymes increased markedly on laboratory
studies and liver necrosis was observed on computed tomography (Figure 1), usually one week after
transplantation. Intrahepatic biliary complications were diagnosed when refractory cholangitis
developed and sclerosing change of the hepatic duct was observed on cholangiography (Figure 2).
Clinical AMR (n: 4; 25%) manifested as intrahepatic biliary complications in one patient (6.2%)
and hepatic necrosis in 3 patients (18.7%).
Totally 33 infection episodes were diagnosed in these 16 patients. Two of these episodes were
due to cytomegalovirus. The most common infectious complication in the remaining 31 episodes
was surgical site infection accounted for 12 (38.7%), and the other infections were 9 (29.0%)
pneumonia, 7 (22.6%) bloodstream infections, and 3 (9.7%) urinary tract infections. Pseudomonas
spp.(30.3%), Enterococcus spp. (21.2%), Acinetobacter spp. (12.1%), Escherichia coli (12.1%),
Klebsiella spp. (9.1%), Candida spp. (6.1%), Staphyloccus aureus (3.0%), Enterobacter spp.
(3.0%), and Stenotrophomonas maltophilia (3%) were isolated.
The cause of death was infection in 6 patients. Other two patients were lost due to small for
size graft syndrome and cerebrovascular bleeding. Three patients had hepatic artery thrombosis
after transplantation. Two of them died at postoperatively 4 and 9 months. Third patient is living
with hepatic necrosis problem in the posttransplant 33th month.
Median survival of patients was 9 months (range: 2.4-15.5) and mean survival was 19.5
months. Hospital mortality consisted of 3 patients (18.7 %). Mean survival of patients with ABO-I
LD LTx was 18.38 months compared to 10.33 months for those ABO-I DD LTx patients. Although
this result is not statistically significant, LD LTx in these patients seems more promising. Also the
results of O blood type recipients were worse than A and B blood types with mean life spans of 3.9,
22.5, and 18.5 months respectively.
DISCUSSION
In some experienced centers, the number of ABO-I cases has been increasing and currently
accounts for about 20% of total cases (1). Our center is the most ABO-I LTx performing center in
Turkey with only a ratio of 3%. This low ratio in our center with a large volume (175 cases in 2010)
may be due to availability of LDs for critically ill patients in emergency conditions because of
traditional causes. Therefore ABO-I donors are not needed. Furthermore local hepatic infusion
theraipes are not performed in our country. Basics and conventional tactics, like PE and
splenectomy, against AMR were applied to the patients those underwent ABO-I LTx.
There is no difference in transplantation outcomes between cases with identical blood types
and cases with compatible blood types. However, ABO-I cases show very poor results among adult
patients. The five-year survival rates were 59 %, 76 %, and 81 % in incompatible, compatible, and
identical, respectively (3). The 1-year survival rate increased to 88 % since 2006, comparable to
that for DD LTx (1).
The first report in ABO-I LD LTx was in the year 2000 by Todo et al (4). They published the
overall Japanese experience using ABO-I LD LTx for adult patients reporting about 20 % patient
survival at 2 years. Pretransplant ABO titer levels and older age were among other factors
associated with high morbidity and poor outcome in LD LTx. Our study focused on the
investigation of ABO-I LTx in only adults and in emergency conditions, like other centers (2,5,6).
Adult ABO-I LTx have been reported to be worse than children, with respect to patient and graft
survival (7). Encouraging survival rate in this study is important despite adult patients, emergency
conditions and LD LTx.
AMR is rarely observed clinically in liver transplantation. It usually manifests within 2 to 4
weeks after transplantation. In AMR, the preformed isoaglutinins bind to graft vasculature, resulting
in complement activation, migration of neutrophils, vessel damage, diffuse intravascular
thrombosis, and consequent activation of the fibrinolytic system with hemorrhagic necrosis of the
graft. In addition to AMR, a high incidence of hepatic artery thrombosis and biliary complications
can be found in patients receiving an ABO-I allograft. It has been suggested that this also may be
due to immunologic injury, since blood group antigens can also be found on bile duct epithelium
(8,9). The incidence of hepatic artery thrombosis is significantly higher in incompatible cases
compared with compatible and identical cases (7). Hepatic artery thrombosis developed in three
patients in our series. Clinical findings are not always related to antibody titer level, but hepatic
necrosis or intrahepatic biliary complications frequently corresponded with a hyperacute or acute
AMR phenomenon. Once hepatic necrosis developes, no patients survive (3). In some of our cases
we observed hepatic necrosis although antibody titres were kept below 1/16 and hepatic arteries
were patent.
In most clinical studies, two main strategies to reduce antibody-mediated complications have
been tested in combination. First, preformed isoaglutinins in the recipient are reduced before
transplantation by PE or immunoadsorption. Second, restoration of isoaglutinins by plasma cell is
suppressed by splenectomy, reinforced immunosuppression, or by specifically interfering with the
maturation or activation of B cells (10-16).
The role of PE in ABO-I LTx is the reduction of antibody titers such as anti-A or anti-B
antibodies. We carry out preoperatively PE as a general rule for ABO-I cases, and the recipients’s
antibody level against donor’s blood type is decreased to one sixteen of the baseline value before
LD LTx. Although PE decreased antibody titers significantly before LD LTx, antibody titers re-
elevated 3-7 days after transplantation occasionally. In these cases, it was not possible to maintain
low post-transplant antibody titers by methods other than PE. Recently, rituximab was introduced to
decrease the antibody. But rituximab is not effective for decreasing antibody titers after
transplantation.
Splenectomy decreases antibody titres but it also may lead to portal vein thrombosis.
Currently anti-CD20 monoclonal antibody (rituximab) may be used instead of splenectomy.
However there is no chance of rituximab prophylaxis in emergency conditions which usually
requires several administrations for several days before transplantation. Also the insurance system
in Turkey doesn’t provide the cost of rituximab with this indication yet.
We didn’t use portal vein or hepatic arterial infusion therapies. The reported incidence of
catheter-related complications such as portal vein thrombosis, hepatic artery thrombosis, bleeding,
sepsis, dislocation, embolism, superior mesenteric vein thrombosis is 16-37% (3). In addition in the
latest protocol of Kyushu group, local graft infusion was abandoned,, and rituximab, plasma
exchange, splenectomy and postoperative IVIG were employed (17).
ABO-I LTx remains an important and unavoidable therapeutic option in adult patients with
acute or acute-on-chronic liver failure awaiting an emergency procedure and in the context of living
donor liver transplantation. We report maintenance of acceptable patient survival in ABO-I LTx.
ABO-I LTx should be offered to all patients in cases of immediate need for an allograft without the
possibility to allocate a blood group compatible liver graft.
Acknowledgment: We thank Professor Saim Yologlu for his assistance in the statistical analysis of
the study.
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Table 1. Clinical characteristics of the patients, donor-recipient blood group match, and outcomes.
Case
Age
Diagnosis
MELD ABO Donorrecipient match
LD LTx /
DD LTx
Survival (months)
Cause of Death
1
47
Idiopathic subacute
fulminant failure
25
AO*
AB  O
DD LTx /
DD LTx
4
Dead
2
35
HBV
20
AB
LD LTx
38
Alive
3
53
Acute liver failure due
to drug
22
AO
LD LTx
9
Dead
Hepatic necrosis, AMR,
septic shock
4
59
Autoimmune hepatitis
25
AB
LD LTx
2
Dead
Pneumonia, ARDS
5
35
HBV
22
AB
LD LTx
33
Alive
6
63
Cryptogenic Cirrhosis
21
AO
LD LTx
4
Dead
Biliary complications,
septic shock
7
61
HBV + HCC
17
AO
LD LTx
ex
Hospital mortality
Small for size
8
57
HBV
24
AO
LD LTx
1
Dead
Pneumonia, septic shock
9
59
HBV + HCC
21
A  B **
DD LTx
17
Alive
10
55
HBV + HCC
17
AB  A
DD LTx
12
Alive
11
42
Acute liver failure due
to HBV
30
AO
DD LTx
ex
Hospital mortality
12
23
Cryptogenic Cirrhosis
20
BO
LD LTx
10
Alive
13
35
Hemochromatoziss
30
AO
LD LTx
1
Dead
Sepsis after second
transplantation, overimmunsuppression
Pneumonia, septic shock
CVE
14
17
HBV
30
BO
LD LTx
5
Alive
15
58
HBV
27
AB  O **
DD LTx
3
Alive
16
43
HBV
23
AB  A
LD LTx
25
Alive
(LD LTx: Living donor liver transplantation; DD LTx: Deceased donor liver transplantation; HBV: Hepatitis B virus; AMR: Antibody mediated rejection; ARDS: Adult respiratuar distress syndrome;
HCC: Hepatocellular carcinoma; CVE: Cerebrovascular event)
* Two ABO-I DD LTx were performed.
** ABO-I DD LTx was performed after ABO-compatible LD LTx.
Fig.1: Intrahepatic biliary complication.
Fig.2: Hepatic necrosis