Does Lymphocyte Cross-Matching Predict Acute Rejection and Graft Survival in Liver Transplantation? D.J. Joo, M.K. Ju, K.H. Huh, M.S. Kim, G.H. Choi, J.S. Choi, K.O. Jeon, and S.I. Kim ABSTRACT Introduction. The role of lymphocyte cross-matches (LCM) remains controversial in the liver transplant field. The aim of this study was to correlate the risk for acute rejection episodes and graft survival in liver transplantation with pretransplant LCM results. Patients and Methods. We enrolled 184 adult liver transplantation patients, excluding pediatric and second grafts. The 129 living donor and 55 deceased donor liver transplantations were divided into 2 groups: LCM (⫹); (n ⫽ 20) and LCM (⫺); (n ⫽ 164). Results. There were no differences in the demographic features, such as gender and recipient age, original disease, Model for End-Stage Liver Disease score, donor type, number of human leukocyte antigen mismatches, and cold ischemia times. There were no hyperacute rejection episodes in the LCM (⫹) group. Also, posttransplant complications such as acute rejection episode, biliary complication, or hepatic artery thrombosis were not different. Acute rejection episodes occurred in 5.0% of the LCM (⫹) group and 15.2% of the LCM (⫺) group (P ⫽ .317). Bile duct complications after transplantation arose in 20.0% of the LCM (⫹) group and in 32.9% of the LCM (⫺) group (P ⫽ .312). The 2 groups showed no difference in graft survival rate analyzed by the Kaplan–Meier method according to LCM results. Conclusion. Pretransplant LCM results were not associated with overall graft survival or acute rejection episodes in this study. ECAUSE the liver is well known for its immune tolerance, transplantations have been performed on patients who are positive by lymphocyte cross-matching (LCM). Nevertheless, LCM and human leukocyte antigen (HLA) mismatch issues are still controversial.1– 4 Donorspecific antibodies (DSA) can induce antibody-mediated rejection (AMR) after organ transplantation, which remains a serious problem field.1,2 We focused on the predictive value of pretransplant LCM status to affect acute rejection episodes and graft survival after liver transplantation.
PATIENTS AND METHODS We enrolled 184 adult patients who underwent liver transplantation between June 2006 and September 2010, excluding pediatric recipients and second grafts. There were 129 living donor and 55 deceased donor transplantations. A positive LCM result was defined to involve T and B lymphocyte antigen presentation, by complement-dependent cytotoxicity (CDC). We divided the patients into 2 groups, LCM (⫹) and LCM (⫺) groups. Panel reactive antibody (PRA) was screened by the 0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2012.01.071 418
enzyme-linked immunosorbent assay (ELISA) method with Lambda Cell Tray lymphocytotoxicity assays (One Lambda Inc., Calif). Medical records were retrospectively reviewed for each patient’s clinical and immunologic characteristics, acute rejection episodes, and graft survival. The main immunosuppressive agent was tacrolimus. Induction therapy with the interleukin-2 receptor antibody (basiliximab) was used except for cases of identical HLA matching. An antimetabo-
From the Department of Surgery (D.J.J., M.K.J., K.H.H., M.S.K., G.H.C., J.S.C., S.I.K.) and The Research Institute for Transplantation (D.J.J., M.K.J., K.H.H., M.S.K., G.H.C., J.S.C., K.O.J., S.I.K.), Yonsei University College of Medicine, Seoul, Korea. Supported by the 2010 –2011 research grant of the Research Institute for Transplantation, Yonsei University College of Medicine. Address reprint requests to Myoung Soo Kim, MD, Department of Surgery, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea. E-mail: [email protected]
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 418 – 420 (2012)
MEANING OF LYMPHOCYTE CROSS-MATCHING lite was prescribed depending on the patient’s condition or side effects after transplantation. Continuous variables are presented as mean values ⫾ standard deviations or medians with ranges for analysis by 2-tailed Student t-test. Categorical variables presented as proportions are analyzed by 2. P ⬍ .05 was considered significant.
The mean follow-up was 23.1 ⫾ 17.0 months after transplantation. The mean age of the 184 enrolled patients was 51.0 ⫾ 9.2 years. There were 141 male and 43 female recipients. Living donor liver transplantations were performed in 129 and deceased donor liver transplantations in 55 patients. Liver transplantation indications were B-viral cirrhosis (n ⫽ 52; 28.3%), C-viral cirrhosis (n ⫽ 2; 1.1%), alcoholic cirrhosis (n ⫽ 17; 9.2%), autoimmune cirrhosis (n ⫽ 3; 1.6%), primary biliary cirrhosis (n ⫽ 1; 0.5%), metabolic liver disease (n ⫽ 3; 1.6%), acute liver failure (n ⫽ 11; 6.0%), and hepatocellular carcinomas (n ⫽ 95; 51.6%). Among 184 liver recipients, 20 patients (10.9%) including 9 males and 11 females showed a positive LCM result pretransplantation. Table 1 presents the clinical characteristics and transplant outcomes of the 2 groups. There were no differences between the groups except for the PRA: Class I and class II antibodies (Ab) in the LCM (⫹) were higher than those in the LCM (⫺) group. Class I PRA were 55.4 ⫾ 40.3% and 8.2 ⫾ 20.0% in the LCM (⫹) and LCM (⫺) groups, respectively; class II PRA, 30.6 ⫾ 35.4% and 3.0 ⫾ 12.2%, respectively. Gender, age, Model for EndStage Liver Disease score, original disease, HLA mismatch, cold ischemia time, donor type, ABO blood type, and antimetabolite administration were not different between the groups (Table 1). There were no hyperacute rejection episodes in the LCM (⫹) group. Also, there were no differences in the prescribed antimetabolite immunosuppressive agents. Posttransplant complications of acute rejection episodes, biliary problems, and hepatic artery thrombosis occurred without distinction between the 2 groups. Twenty-five (15.2%) LCM (⫹) group patients experienced an acute rejection episode, but only 1 (5.0%) case among the LCM (⫺) group (P ⫽ .317). Biliary complications such as biliary stenosis or leakage occurred in 54 (32.9%) patients in the LCM (⫺) and 4 (20.0%) patients of the LCM (⫹) group (P ⫽ .312). Hepatic artery thrombosis occurred in 3 (1.8%) LCM (⫺) and 1 (5.0%) LCM (⫹) group (P ⫽ .441). Graft survival rates among the 2 groups were not different (Fig 1). The 1-year survival rate of the LCM (⫺) group was 91.7% and that of the LCM (⫹) group was 88.2%. Thereafter, there was no mortality cases in the LCM (⫹) group during the follow-up period. All 4 LCM (⫹) mortality cases were early deaths within 6 months after transplantation. The causes of 2 of the cases were primary nonfunction, and 1 was biliary necrosis owing to hepatic artery thrombosis. The remaining mortality case resulted from
419 Table 1. Clinical Characteristics and Outcomes of the Groups Characteristics
Gender (male vs female) Age (y) MELD Original disease Cirrhosis (viral, alcoholic, or autoimmune) Biliary cirrhosis Acute liver failure Malignancy Others PRA (%) Class I Class II HLA mismatching Cold ischemic time (h) Donor type (living vs deceased) ABO type (identical vs compatible) Complications Acute rejection Biliary complication Hepatic artery thrombosis Immune suppression Antimetabolite administration
LCM (⫺) (n ⫽ 164)
LCM (⫹) (n ⫽ 20)
132:32 51.0 ⫾ 9.3 17.1 ⫾ 10.5
9:11 50.9 ⫾ 8.7 16.3 ⫾ 6.7
.610 .959 .735 .254
1 (0.6%) 11 (6.7%) 87 (53.0%) 2 (1.2%)
0 (0.0%) 0 (0.0%) 8 (40.0%) 1 (5.0%)
8.2 ⫾ 20.0 3.0 ⫾ 12.2 3.2 ⫾ 1.6 5.3 ⫾ 6.5 116:48
55.4 ⫾ 40.3 30.6 ⫾ 35.4 3.8 ⫾ 1.1 5.9 ⫾ 3.3 13:7
⬍.0001 .003 .103 .769 .610
25 (15.2%) 54 (32.9%) 3 (1.8%)
1 (5.0%) 4 (20.0%) 1 (5.0%)
.317 .312 .441
Abbreviations: HLA, human leukocyte antigen; LCM, lymphocyte crossmatch; MELD, Model for End-Stage Liver Disease; PRA, panel reactive antibody.
fulminant hepatic failure owing to de novo B-viral infection after transplantation. DISCUSSION
The liver is a unique organ in its interactions with the host immune system.5 Bettens et al6 reported nested polymerase chain reactions of donor-specific HLA-DR alleles to show that all liver recipients display microchimerism within the first 3 months after transplantation.6 However, in accordance with prior studies, microchimerism did not correlate with freedom from rejection or the ability to tolerate staged immunosuppressive drug withdrawal.7,8 Thus, the mechanism for immune tolerance of liver grafts is unclear; it is more complex than simply induction of anergy to transferred donor cells. There is still some controversy as to the role of DSAs in liver transplantation.5 Lymphocytotoxic cross-matching detects antidonor lymphocytotoxic antibodies.9 A positive T-cell cross-matching has been reported to be closely related to acute rejection episodes and that before transplantation, a predictor of an early, refractory acute rejection episode.10 Also, HLA antigens are known to be more widely expressed than ABO antigens; an immunologic challenge can occur in LCMpositive settings. Japanese groups have reported a poorer survival rates for LCM-positive than for ABO incompatible
JOO, JU, HUH ET AL
events have been reported to be related to antibodymediated rejection,13 there was no definite evidence of antibody-mediated rejection to be related to positive LCM in the current study. In conclusion, pretransplant LCM results cannot predict acute rejection episodes or poor graft survival after liver transplantation. Thus, positive LCM results and high PRA are not barriers to liver transplantation.
Graft survival rate according to the LCM results.
groups.1 However, a Finnish group reported no difference between LCM-positive and -negative groups.11 In the current study, we did not observe any effect of pretransplant LCM on overall acute rejection episodes or graft survival rates. These results implied that there was little risk associated with preformed DSA among liver transplant recipients. In the current study, we only checked pretransplant LCM results; however, a recent report suggested that recipients with an unknown preoperative cross-match who develop early cholestasis of unclear etiology should be cross-matched or tested for the presence of DSAs to evaluate AMR.12 High PRA is possibly related to the existence of preformed DSA. The current study also showed a higher PRA percentage among the positive LCM than the negative group. Intravascular thrombotic events can arise from circulating DSAs in antibody-mediated rejection after organ transplantation.13 Biliary complications or hepatic artery thrombosis is related to immunologic reactions in cases of acute rejection. In terms of the posttransplant complications, we could not find any differences between the 2 groups. Because posttransplant complications or graft survival may relate not only to immunologic but also to multifactorial issues, a multivariate analysis is necessary for proper evaluation. However, the small number of patients in the current study was a limitation for a multivariate analysis factors. Although early graft dysfunction or thrombotic
1. Hori T, Uemoto S, Takada Y, et al: Does a positive lymphocyte cross-match contraindicate living-donor liver transplantation? Surgery 147:840, 2010 2. Leffell MS, Zachary AA: The role of the histocompatibility laboratory in desensitization for transplantation. Curr Opin Organ Transplant 14:398, 2009 3. Balan V, Ruppert K, Demetris AJ, et al: Long-term outcome of human leukocyte antigen mismatching in liver transplantation: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Hepatology 48: 878, 2008 4. Kasahara M, Kiuchi T, Uryuhara K, et al: Role of HLA compatibility in pediatric living-related liver transplantation. Transplantation 74:1175, 2002 5. Rosen HR: Transplantation immunology: what the clinician needs to know for immunotherapy. Gastroenterology 134:1789, 2008 6. Bettens F, Tiercy JM, Campanile N, et al: Microchimerism after liver transplantation: absence of rejection without abrogation of anti-donor cytotoxic T-lymphocyte-mediated alloreactivity. Liver Transpl 11:290, 2005 7. Hisanaga M, Hundrieser J, Boker K, et al: Development, stability, and clinical correlations of allogeneic microchimerism after solid organ transplantation. Transplantation 61:40, 1996 8. Devlin J, Doherty D, Thomson L, et al: Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 27:926, 1998 9. Takakura K, Kiuchi T, Kasahara M, et al: Clinical implications of flow cytometry crossmatch with T or B cells in living donor liver transplantation. Clin Transplant 15:309, 2001 10. Sugawara Y, Makuuchi M, Kaneko J, et al: Positive T lymphocytotoxic cross-match in living donor liver transplantation. Liver Transpl 9:1062, 2003 11. Matinlauri IH, Hockerstedt KA, Isoniemi HM: Equal overall rejection rate in pre-transplant flow-cytometric cross-match negative and positive adult recipients in liver transplantation. Clin Transplant 19:626, 2005 12. Kozlowski T, Rubinas T, Nickeleit V, et al: Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 17:357, 2011 13. Della-Guardia B, Almeida MD, Meira-Filho SP, et al: Antibody-mediated rejection: hyperacute rejection reality in liver transplantation? A case report. Transplant Proc 40:870, 2008