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The Risk Factors to Predict Acute Rejection in Liver Transplantation
The Risk Factors to Predict Acute Rejection in Liver Transplantation Y.-C. Wang, T.-J. Wu, T.-H. Wu, C.-F. Lee, H.-S. Chou, K.-M. Chan, and W.-C. Lee ABSTRACT Purpose. The aim of this study was to evaluate risk factors for an acute cellular rejection episode (ARE) among adult liver transplant (OLT) patients. Materials and methods. We retrospectively reviewed 110 consecutive patients who underwent OLT between May 2007 and December 2010. The diagnosis of ARE was based upon clinical and biochemical data; liver biopsy was only performed when clinical presentation was equivocal. We recorded donor and recipient characteristics, perioperative immune status, and postoperative laboratory data. Forty patients (36.4%) who suffered a clinical rejection episode and received pulsed or recycled steroid therapy (R group), were compared with 70 (63.6%) free of rejection (N group). Results. The mean age of R recipients was 46.61 ⫾ 9.97 years, which was younger than the N group (51.86 ⫾ 8.37, P ⫽ .005). R group patients displayed a lower pre-OLT creatinine (P ⫽ .016) and higher alanine aminotransferase (P ⫽ .048). Cox regression model showed recipient age to be the only significant factor to predict ARE (odds ratio ⫽ 1.071, P ⫽ .003). The cutpoint of age was 46 years by receiver operating characteristic analysis. Patients younger than 46 years showed higher initial CD8⫹ T-cell counts (P ⫽ .038). Conclusion. Recipient age was significantly associated with ARE; younger patients showed higher CD8⫹ lymphocyte counts than older patients. More aggressive immunosuppression should be considered for younger recipients to prevent ARE. CUTE ALLOGRAFT REJECTION is still common after liver transplantation (OLT) despite welldeveloped immunosuppressive agents. The incidence of acute allograft rejection under current immunosuppressive regimens ranges from 20% to 40%.1 The majority of acute cellular rejection episodes (ARE) occur within 4 weeks; however, late reactions can happen 6 months after OLT. Acute cellular rejection produces allograft damage that relates to allograft survival. Therefore, identification of risk factors for ARE may provide important information to adjust immunosuppression to improve long-term graft survival and minimize adverse effects of immunosuppressive agents. The basic mechanisms of acute cellular rejection rely on activation of recipient T cells by either donor or recipient antigen-presenting cells.2 Several clinical factors have been cited to relate to the incidence of acute rejection: recipient age, renal functional impairment, high aspartate aminotransferase (AST) levels in donors, few HLA-DR matches, long cold ischemia times and older donors.3 In this study,
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0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2012.01.041 526
we analyzed the risk factors for ARE among adult OLT patients. PATIENTS AND METHODS From May 2007 to December 2010, we enrolled 110 OLT patients in this study. They were divided into two groups: ARE and no ARE. We compared their demographic features, including recipient age, gender, Model for End-stage Liver Disease score, indications for transplantation, and category of chronic hepatitis as well as preoperative hematologic indices (leukocyte, hemoglobin, platelet, monocyte, lymphocyte, CD4 and CD8 lymphocyte ratio) and biochemical results (blood urea nitrogen, creatinine, AST, alanine From the Chang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung University Medical School, Taoyuan, Taiwan. Address reprint requests to Wei-Chen Lee, Chang-Gung Transplantation Institute, Chang-Gung Memorial Hospital, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan. E-mail: weichen@cgmh. org.tw © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 526 –528 (2012)
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aminotransferase, bilirubin, and albumin). The data were analyzed employing SPSS software (version 13) to evaluate Pearson 2 and Student t tests for significance.
RESULTS
Among 110 patients, 40 (36.4%) displayed an ARE within 3 months after transplantation. Patients with ARE were younger than those without ARE: 43.01 ⫾ 14.44 versus 51.86 ⫾ 8.37 years old, (P ⫽ .001). Donor age did not show significance. Regarding pretransplant laboratory data, ARE patients displayed lower levels of creatinine (0.85 ⫾ 0.65 vs 1.26 ⫾ 1.11 mg/dL, P ⫽ .016) and higher values of ALT (76.2 ⫾ 80.4 vs 50.5 ⫾ 54.2 IU/L, P ⫽ .048), compared with those free of ARE. Pretransplant differentiate lymphocyte counts were not significantly associated with ARE. Upon multivariate analysis using logistic regression, recipient age was the only independent predictor of acute cellular rejection (odds ratio ⫽ 1.071 [1.022–1.121], P ⫽ .003; Table 1). By receiver operating characteristic curve analysis, the cutpoint was 46 years distinguishing subjects with versus without ARE (Fig 1). The incidence of ARE was higher among patients younger than or equal to 46 years old (63.2% vs 22.2%, P ⬍ .001). If the patients were divided into two groups based upon younger or older than 46 years old, the absolute CD8⫹ lymphocyte counts were significantly higher among the former cohort before OLT, postOLT week 1, and post-OLT week 4: 185.61 ⫾ 232.05 versus 93.41 ⫾ 86.55/L (P ⫽ .029), 161.31 ⫾ 165.35 versus 136.55 ⫾ 144.29/L (P ⫽ .046), and 148.52 ⫾ 154.56 versus 61.05 ⫾ 42.74/L (P ⫽ .019), respectively. DISCUSSION
An ARE is not uncommon after OLT; the incidence ranges from 20% to 40%. In our study, recipient age was the only
Fig 1. Analysis of optimal recipient age cut-point to predict acute rejection. ROC, receiver operating characteristic.
independent factor contributing to acute cellular rejection. Bradley reported that the risk of an ARE decreased exponentially with increased age.4 In pediatric OLT, about half of the patients experience at least one ARE.5 Thus, the dosage of immunosuppressants should be increased to prevent ARE among young recipients. In Conversely, immunosuppressant dosages should be minimized among old recipients to avoid overimmunosuppression. According to the findings in this study, CD8⫹ T-cell counts closely related to age. Thymic involution and decreasing number of CD8⫹ T cells with increased age could be associated with a
Table 1. Demographic Characteristic and Clinical Features of Recipients Rejection (n ⫽ 40)
Recipient age (mean ⫾ SD) Recipient gender Male Female MELD (mean ⫾ SD) Viral hepatitis HBV carrier HCV carrier Both HBV and HCV No HBV or HCV Creatinine (mg/dL) T-bilirubin (mg/dL) AST (IU/L) ALT (IU/L) CD4⫹ lymphocyte percentage (%) CD8⫹ lymphocyte percentage (%) Ascites (mL) (mean ⫾ SD) Blood loss (mL) (mean ⫾ SD)
No Rejection (n ⫽ 70)
43.01 ⫾ 14.44
51.86 ⫾ 8.37
28 12 18.08 ⫾ 8.48
53 17 19.24 ⫾ 10.52
19 (47.5%) 9 (22.5%) 1 (2.5%) 11 (27.5%) 0.851 ⫾ 0.65 9.74 ⫾ 14.54 101.48 ⫾ 96.92 76.2 ⫾ 80.37 27.63 ⫾ 11.56 12.49 ⫾ 8.52 1538 ⫾ 2936 2218 ⫾ 26108
37 (52.9%) 19 (27.1%) 1 (1.4%) 13 (18.6%) 1.26 ⫾ 1.11 7.88 ⫾ 11.46 99.16 ⫾ 203.96 50.54 ⫾ 54.17 25.18 ⫾ 13.88 11.90 ⫾ 7.24 2916 ⫾ 4547 3250.8 ⫾ 39398
Univariate Analysis P Value
Multivariate Analysis P Value
.001 .513
.003 — — — — — — — — — .095 — — .067 — — — .238
.550 .694
.016 .461 .946 .048 .369 .716 .058 .146
SD, standard deviation; MELD, Model for End-stage Liver Disease; HBV, hepatitis B virus; HCV, hepatitis C virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
528
reduced incidence of AREs in older recipients. The relation of CD8⫹ T-cell counts to AREs has not been well defined. Kubota et al reported significantly higher CD8 T-cell infiltration into the liver parenchyma, biliary endothelium, and portal tracts in patient with ARE.6 This finding implied that CD8⫹ T-cell counts might be a guide to adjust immunosuppressant dosages. In conclusion, prediction of the possibility of an ARE might lead to different immunosuppressive regimens after transplantation. Immunosuppression should be minimized in older patients with low CD8⫹ T-cell counts to minimize adverse effects of immunosuppressive agents. REFERENCES 1. Gonzalez MG, Madrazo CP, Rodriguez AB, et al: An open, randomized, multicenter clinical trial of oral tacrolimus in liver
WANG, WU, WU ET AL allograft transplantation: a comparison of dual vs. triple drug therapy. Liver Transpl 11:515, 2005 2. Sanchez-Fueyo A, Strom TB: Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology 140:51, 2011 3. Wiesner RH, Demetris AJ, Belle SH, et al: Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 28:638, 1998 4. Bradley BA: Rejection and recipient age. Transpl Immunol 10:125, 2002 5. Zetterman RK, Belle SH, Hoofnagle JH, et al: Age and liver transplantation: a report of the Liver Transplantation Database. Transplantation 66:500, 1998 6. Kubota N, Sugitani M, Takano S, et al: Correlation between acute rejection severity and CD8-positive T cells in living related liver transplantation. Transpl Immunol 16:60, 2006
A
0041-1345/12/$–see front matter doi:10.1016/j.transproceed.2012.01.041 526
we analyzed the risk factors for ARE among adult OLT patients. PATIENTS AND METHODS From May 2007 to December 2010, we enrolled 110 OLT patients in this study. They were divided into two groups: ARE and no ARE. We compared their demographic features, including recipient age, gender, Model for End-stage Liver Disease score, indications for transplantation, and category of chronic hepatitis as well as preoperative hematologic indices (leukocyte, hemoglobin, platelet, monocyte, lymphocyte, CD4 and CD8 lymphocyte ratio) and biochemical results (blood urea nitrogen, creatinine, AST, alanine From the Chang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung University Medical School, Taoyuan, Taiwan. Address reprint requests to Wei-Chen Lee, Chang-Gung Transplantation Institute, Chang-Gung Memorial Hospital, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan. E-mail: weichen@cgmh. org.tw © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 526 –528 (2012)
RISK FACTORS FOR ACUTE REJECTION
527
aminotransferase, bilirubin, and albumin). The data were analyzed employing SPSS software (version 13) to evaluate Pearson 2 and Student t tests for significance.
RESULTS
Among 110 patients, 40 (36.4%) displayed an ARE within 3 months after transplantation. Patients with ARE were younger than those without ARE: 43.01 ⫾ 14.44 versus 51.86 ⫾ 8.37 years old, (P ⫽ .001). Donor age did not show significance. Regarding pretransplant laboratory data, ARE patients displayed lower levels of creatinine (0.85 ⫾ 0.65 vs 1.26 ⫾ 1.11 mg/dL, P ⫽ .016) and higher values of ALT (76.2 ⫾ 80.4 vs 50.5 ⫾ 54.2 IU/L, P ⫽ .048), compared with those free of ARE. Pretransplant differentiate lymphocyte counts were not significantly associated with ARE. Upon multivariate analysis using logistic regression, recipient age was the only independent predictor of acute cellular rejection (odds ratio ⫽ 1.071 [1.022–1.121], P ⫽ .003; Table 1). By receiver operating characteristic curve analysis, the cutpoint was 46 years distinguishing subjects with versus without ARE (Fig 1). The incidence of ARE was higher among patients younger than or equal to 46 years old (63.2% vs 22.2%, P ⬍ .001). If the patients were divided into two groups based upon younger or older than 46 years old, the absolute CD8⫹ lymphocyte counts were significantly higher among the former cohort before OLT, postOLT week 1, and post-OLT week 4: 185.61 ⫾ 232.05 versus 93.41 ⫾ 86.55/L (P ⫽ .029), 161.31 ⫾ 165.35 versus 136.55 ⫾ 144.29/L (P ⫽ .046), and 148.52 ⫾ 154.56 versus 61.05 ⫾ 42.74/L (P ⫽ .019), respectively. DISCUSSION
An ARE is not uncommon after OLT; the incidence ranges from 20% to 40%. In our study, recipient age was the only
Fig 1. Analysis of optimal recipient age cut-point to predict acute rejection. ROC, receiver operating characteristic.
independent factor contributing to acute cellular rejection. Bradley reported that the risk of an ARE decreased exponentially with increased age.4 In pediatric OLT, about half of the patients experience at least one ARE.5 Thus, the dosage of immunosuppressants should be increased to prevent ARE among young recipients. In Conversely, immunosuppressant dosages should be minimized among old recipients to avoid overimmunosuppression. According to the findings in this study, CD8⫹ T-cell counts closely related to age. Thymic involution and decreasing number of CD8⫹ T cells with increased age could be associated with a
Table 1. Demographic Characteristic and Clinical Features of Recipients Rejection (n ⫽ 40)
Recipient age (mean ⫾ SD) Recipient gender Male Female MELD (mean ⫾ SD) Viral hepatitis HBV carrier HCV carrier Both HBV and HCV No HBV or HCV Creatinine (mg/dL) T-bilirubin (mg/dL) AST (IU/L) ALT (IU/L) CD4⫹ lymphocyte percentage (%) CD8⫹ lymphocyte percentage (%) Ascites (mL) (mean ⫾ SD) Blood loss (mL) (mean ⫾ SD)
No Rejection (n ⫽ 70)
43.01 ⫾ 14.44
51.86 ⫾ 8.37
28 12 18.08 ⫾ 8.48
53 17 19.24 ⫾ 10.52
19 (47.5%) 9 (22.5%) 1 (2.5%) 11 (27.5%) 0.851 ⫾ 0.65 9.74 ⫾ 14.54 101.48 ⫾ 96.92 76.2 ⫾ 80.37 27.63 ⫾ 11.56 12.49 ⫾ 8.52 1538 ⫾ 2936 2218 ⫾ 26108
37 (52.9%) 19 (27.1%) 1 (1.4%) 13 (18.6%) 1.26 ⫾ 1.11 7.88 ⫾ 11.46 99.16 ⫾ 203.96 50.54 ⫾ 54.17 25.18 ⫾ 13.88 11.90 ⫾ 7.24 2916 ⫾ 4547 3250.8 ⫾ 39398
Univariate Analysis P Value
Multivariate Analysis P Value
.001 .513
.003 — — — — — — — — — .095 — — .067 — — — .238
.550 .694
.016 .461 .946 .048 .369 .716 .058 .146
SD, standard deviation; MELD, Model for End-stage Liver Disease; HBV, hepatitis B virus; HCV, hepatitis C virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
528
reduced incidence of AREs in older recipients. The relation of CD8⫹ T-cell counts to AREs has not been well defined. Kubota et al reported significantly higher CD8 T-cell infiltration into the liver parenchyma, biliary endothelium, and portal tracts in patient with ARE.6 This finding implied that CD8⫹ T-cell counts might be a guide to adjust immunosuppressant dosages. In conclusion, prediction of the possibility of an ARE might lead to different immunosuppressive regimens after transplantation. Immunosuppression should be minimized in older patients with low CD8⫹ T-cell counts to minimize adverse effects of immunosuppressive agents. REFERENCES 1. Gonzalez MG, Madrazo CP, Rodriguez AB, et al: An open, randomized, multicenter clinical trial of oral tacrolimus in liver
WANG, WU, WU ET AL allograft transplantation: a comparison of dual vs. triple drug therapy. Liver Transpl 11:515, 2005 2. Sanchez-Fueyo A, Strom TB: Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology 140:51, 2011 3. Wiesner RH, Demetris AJ, Belle SH, et al: Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 28:638, 1998 4. Bradley BA: Rejection and recipient age. Transpl Immunol 10:125, 2002 5. Zetterman RK, Belle SH, Hoofnagle JH, et al: Age and liver transplantation: a report of the Liver Transplantation Database. Transplantation 66:500, 1998 6. Kubota N, Sugitani M, Takano S, et al: Correlation between acute rejection severity and CD8-positive T cells in living related liver transplantation. Transpl Immunol 16:60, 2006