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 of Radiology, Inonu University, School of Medicine, Malatya, Turkey
3Department 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-on- chronic 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.
(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.
Case Ag
e
Diagnosis MELD ABO Donor- recipient 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 Sepsis after second transplantation, over- immunsuppression
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 Pneumonia, septic shock
12 23 Cryptogenic Cirrhosis 20 B O LD LTx 10 Alive
13 35 Hemochromatoziss 30 A O LD LTx 1 Dead 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
Fig.1: Intrahepatic biliary complication.
Fig.2: Hepatic necrosis
