Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid
2011; Springer Science+Business Media; Volume: 24; Issue: 7 Linguagem: Inglês
10.1111/j.1432-2277.2011.01250.x
ISSN1432-2277
AutoresTadahiro Uemura, Eric Schaefer, Christopher S. Hollenbeak, Akhtar Khan, Zakiyah Kadry,
Tópico(s)Liver Diseases and Immunity
ResumoTransplant InternationalVolume 24, Issue 7 p. 640-650 ORIGINAL ARTICLEFree Access Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid Tadahiro Uemura, Tadahiro Uemura Division of Transplantation, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorEric Schaefer, Eric Schaefer Department of Public Health Sciences, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorChristopher S. Hollenbeak, Christopher S. Hollenbeak Department of Public Health Sciences, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA Division of Outcomes Research and Quality, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorAkhtar Khan, Akhtar Khan Division of Transplantation, Department of Surgery, Allegheny General Hospital, Pittsburgh, PA, USASearch for more papers by this authorZakiyah Kadry, Zakiyah Kadry Division of Transplantation, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this author Tadahiro Uemura, Tadahiro Uemura Division of Transplantation, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorEric Schaefer, Eric Schaefer Department of Public Health Sciences, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorChristopher S. Hollenbeak, Christopher S. Hollenbeak Department of Public Health Sciences, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA Division of Outcomes Research and Quality, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this authorAkhtar Khan, Akhtar Khan Division of Transplantation, Department of Surgery, Allegheny General Hospital, Pittsburgh, PA, USASearch for more papers by this authorZakiyah Kadry, Zakiyah Kadry Division of Transplantation, Department of Surgery, Penn State University, College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USASearch for more papers by this author First published: 23 March 2011 https://doi.org/10.1111/j.1432-2277.2011.01250.xCitations: 32 Tadahiro Uemura MD, PhD, Department of Surgery, H062, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. Tel.: +717 531 5921; fax: +717 531 5851; e-mail: tuemura@hmc.psu.eduZakiyah Kadry MD, Department of Surgery, H062, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. Tel.: +717 531 5921; fax: +717 531 5851; e-mail: zkadry@psu.edu Conflicts of Interest Declaration of no conflict of interest. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary In addition to standard corticosteroid induction, anti-thymocyte globulin (ATG) or daclizumab as induction immunosuppression has been reported for liver transplantation. However, the effects and long-term outcomes of antibody induction therapy are not well known, especially for hepatitis C (HCV). The United Network for Organ Sharing (UNOS) database was utilized to analyze 16 898 adult primary liver transplant patients who received ATG alone (n = 452), ATG and steroids (ATG + S) (n = 1758), daclizumab alone (n = 683), or steroid alone (n = 14 005), listed as induction immunosuppression. Graft and patient survival, and donor and recipient factors for survival were analyzed for HCV and all liver diseases. For patients with HCV, ATG + S had significantly inferior graft survival compared with daclizumab (P = 0.01) and steroids (P = 0.03). The Cox proportional hazards model also showed that ATG + S was a marginal risk factor for graft failure (P = 0.05). On the other hand, for patients with all the liver diseases, graft and patient survival were not significantly different between induction regimens. ATG induction appeared to be preferentially used in patients with renal dysfunction, with improvement in renal function after liver transplantation. Thus, ATG induction can be used for patients with renal dysfunction in non-HCV diseases. Daclizumab induction achieved satisfactory short-term and long-term outcomes of liver transplantation in all the liver diseases including HCV disease. Introduction Corticosteroid induction has traditionally been the standard immunosuppression treatment for liver transplantation for many years. Recently, however, induction therapy with antibodies has been increasingly used [1, 2]. Induction immunosuppression provides potential benefits through preservation of renal function, reduction in maintenance immunosuppression, and reduction in the number of acute rejection episodes [3-6]. However, issues with the use of antibody induction are an increased risk of over-immunosuppression, especially for hepatitis C patients. Thus, the use of induction therapy with antibodies in liver transplantation remains controversial. End stage of liver disease secondary to hepatitis C has become one of the leading indications for liver transplantation worldwide [7]. Recurrent hepatitis C is universal after liver transplantation, and it is associated with a significant reduction in graft and patient survival [8, 9]. The use of antibodies, such as OKT3 or anti-thymocyte globulin (ATG), for steroid resistant rejection has been shown to worsen hepatitis C recurrence [10-13]. Furthermore, it has been suggested that immunosuppressive induction therapy could increase the risk of aggressive hepatitis C recurrence [7, 14]. On the other hand, small single center analyses have shown that induction therapy with ATG can be safely given by delayed initiation of calcineurin inhibitor and decreased maintenance immunosuppressive therapy, thus reducing the risk of hepatitis C recurrence [15-17]. Thus, the impact of profound immunosuppressive effects from induction agents on liver transplantation for hepatitis C recipients is yet to be determined. The objective of this study was to analyze the effect and outcome of induction therapy (ATG and daclizumab) on liver transplantation in a population-based data set from the United Network for Organ Sharing (UNOS). Patients and methods This is a registry study based on data from the United Network for Organ Sharing/the Organ Procurement and Transplantation (UNOS/OPTN). Adult patients (≥18 years of age) who underwent liver transplantation after initiation of the Model for End-Stage Liver Disease (MELD) scoring system between 3/1/2002 and 12/31/2007 as reported to UNOS/OPTN were used in this analysis. Patients receiving multiple organ transplants and re-transplants were excluded. We first selected those patients who received ATG, daclizumab, or steroids listed as induction immunosuppression in the UNOS files. We then retained for analysis those patients who received ATG alone (n = 452), ATG in combination with steroids (ATG + S) (n = 1758), daclizumab alone (n = 683), or steroids alone (n = 14 005). Patients who received a combination of these induction agents were excluded: daclizumab and steroids (n = 743); and ATG and daclizumab (n = 32). HCV positive patients were those with a positive serologic test for hepatitis C. A total of 6612 patients were HCV positive: 207 received ATG, 786 received ATG + S, 251 received daclizumab alone, and 5386 received steroids alone. Patient survival was defined as the time from the date of primary transplant until the date of death. Patients alive at the last recorded follow-up were considered censored for patient survival. Graft survival was defined as the time from the date of primary transplant until the date of graft failure or death. A re-transplantation constituted graft failure. Patients alive and without a graft failure at the time of last follow-up were considered censored for graft survival. Both graft survival and patient survival were censored at 5 years as a result of limited follow-up after 5 years post-transplant in some groups. Demographics for recipients were age, gender, ethnicity, HCV status, the MELD score, status 1 assignment, medical condition pretransplant, history of transjugular intrahepatic portosystemic shunt (TIPS), spontaneous bacterial peritonitis, portal vein thrombosis, previous upper abdominal surgery, and the following at the time of transplant: total bilirubin, creatinine, international normalized ratio (INR), and albumin. Donor factors were status (living or deceased), age, gender, ethnicity, cold ischemia time and warm ischemia time. Recipient and donor factors were compared among the induction groups using chi-square tests for categorical variables and Kruskal–Wallis tests for continuous variables. In unadjusted analysis for patient and graft survival, the Kaplan–Meier method was used to estimate survival curves, and the log-rank test was used to test for differences among curves. The Cox proportional hazards model was used to evaluate patient mortality and graft loss among recipient and donor factors. Patients with a complete set of factors (complete cases) were used in the Cox models. For all the patients, there were 13 948 (83%) complete cases with 406 (90%) in the ATG group, 1409 (80%) in the ATG + S group, 564 (83%) in the daclizumab group, and 11 569 (83%) in the steroids group. For HCV patients, there were 5859 (89%) complete cases, with 198 (96%) in the ATG group, 641 (83%) in the ATG + S group, 220 (88%) in the daclizumab group, and 4800 (89%) in the steroids group. Renal and liver functions were analyzed in the first year after transplant using the set of patients who were alive and without a graft failure at their 1-year follow-up after primary transplant. Follow-up data at 6 months (±30 days) and 1 year (±60 days) post-transplant were used; follow-up data outside these ranges were excluded. Generalized linear models assuming a Gamma distribution were used to model mean renal and liver function levels over time, with the method of generalized estimating equations (GEE) used to account for correlation within the patients. Analysis was also conducted to assess overall survival and graft survival by induction and maintenance group combinations at 30 days postliver transplantation. Tacrolimus, mycophenolate mofetil (MMF) and steroid maintenance were predominantly used in the registry data. Therefore, four maintenance groups were of principal interest: tacrolimus, MMF and steroids; tacrolimus and MFF; tacrolimus and steroids; and tacrolimus alone. We compared survival end points between all pairs of induction and maintenance group combinations using unadjusted and adjusted Cox models. P-value was adjusted by Bonferonni correction because of the large number of comparisons. Patients alive (overall survival) and without a graft failure (graft survival) at a landmark of 30 days post-transplant were used for this analysis. The landmark is set as the patients may have started their third course of maintenance therapy (e.g. steroids) some days after transplant. For hepatitis C patients, the analysis for maintenance immunosuppression could not be performed because of small sample size. Results All recipients The characteristics of all recipients and donors are presented in Table 1. Approximately 30–40% of the patients were positive for HCV in all groups. The ATG group had a higher creatinine level at the time of liver transplantation (P < 0.001). Steroid induction was used more frequently in living donor liver transplantation (P < 0.001). Table 1. Demographics of all recipients and donors. ATG (n = 452) ATG + steroid (n = 1758) Daclizumab (n = 683) Steroid (n = 14 005) P-value Recipients Age (years) 52.0 ± 10.6 52.4 ± 10.1 52.1 ± 9.3 52.5 ± 10.1 0.42 Female (%) 33.6 31.8 31.8 33.2 0.59 Diagnosis (%) HCV 34.3 37.9 40.7 33.5 <0.001 HBV 3.5 1.8 2.5 3.8 Alcoholic 19.7 20.4 16.0 8.0 Cholestatic 7.5 9.2 7.0 9.2 Other 35.0 34.3 33.8 35.5 Race White 72.8 76.6 75.0 72.1 <0.001 Black 12.2 10.6 10.0 7.5 Hispanic 10.2 9.1 11.3 14.3 Asian 4.2 3.2 3.4 4.8 Other 0.6 0.5 0.4 1.3 MELD Score 21.8 ± 9.8 19.8 ± 9.8 18.9 ± 8.2 20.4 ± 9.7 <0.001 Bilirubin (mg/dl) 6.8 ± 9.6 6.7 ± 10.3 5.2 ± 7.0 7.4 ± 10.2 <0.001 Creatinine (mg/dl) 1.9 ± 1.6 1.6 ± 1.5 1.4 ± 1.2 1.5 ± 1.3 <0.001 INR 1.9 ± 1.2 1.7 ± 0.9 1.7 ± 0.9 1.8 ± 1.7 <0.001 Albumin (g/dl) 3.0 ± 0.7 2.9 ± 0.7 2.9 ± 0.6 2.9 ± 0.7 <0.001 Status 1 (%) 4.4 2.4 2.6 3.8 0.01 Pretransplant in ICU (%) 12.4 9.3 5.9 12.0 <0.001 History of SBP (%) 6.6 8.1 5.9 7.8 <0.001 History of TIPS 7.1 9.7 4.8 8.4 <0.001 Portal vein thrombus 3.8 4.5 2.5 4.0 <0.001 Donor Donor status (%) Deceased donor 96.9 96.3 97.7 93.7 <0.001 Living donor 3.1 3.7 2.3 6.3 Age (years) 40.4 ± 16.2 40.4 ± 16.3 40.7 ± 17.5 40.6 ± 17.1 0.99 Cause of death (%) Anoxia 13.9 17.3 12.9 12.7 <0.001 CVA 43.4 40.6 39.9 43.3 Trauma 39.3 38.2 44.7 41.4 CNS tumor 0.7 1.5 0.4 0.8 Other 2.7 2.4 2.1 1.8 Female (%) 43.6 42.9 41.9 40.1 0.06 Race White 69.0 75.1 65.2 69.7 <0.001 Black 14.2 15.2 16.8 12.5 Hispanic 12.8 7.1 15.8 14.0 Asian 2.2 1.9 1.5 2.4 Other 1.8 0.7 0.6 1.4 Cold ischemia time (h) 7.1 ± 4.8 7.2 ± 3.3 7.6 ± 2.9 7.4 ± 3.6 <0.001 Warm ischemia time (min) 37.7 ± 13.3 41.5 ± 20.6 43.7 ± 21.1 40.2 ± 19.1 <0.001 ATG, anti-thymocyte globulin; TIPS, transjugular intrahepatic portosystemic shunt; SBP, spontaneous bacterial peritonitis; MELD, model for end-stage liver disease; INR, international normalized ratio; CVA, cerebrovascular accident; CNS, central nervous system. Graft and patient survival Figure 1a shows graft survival in the unadjusted analysis. The ATG induction group had a graft survival of 85% at 1 year and 69% at 5 years compared to the ATG + S (84% and 67%, respectively), daclizumab (86% and 71%, respectively), and steroid groups (86% and 70%, respectively) (P = 0.26) (Fig. 1a). Patient survival also showed no significant difference in all groups (ATG: 1-year 88%, 5-year 72%, ATG + S: 1-year 87%, 5-year 71%, daclizumab: 1-year 89%, 5-year 75%, steroids: 1-year 89%, 5-year 73%) (P = 0.16). Table 2 presents the Cox proportional hazard models for patient mortality and graft loss that included donor and recipient factors. Hepatitis C, age of patient, African–American, creatinine ≥2 mg/dl, pretransplant ICU status, portal vein thrombosis, previous upper abdominal surgery, donor age, and Hispanic donors were significant risk factors for both graft survival and patient survival. There was no significant difference among the induction groups for patient mortality and graft loss (Table 2), although ATG + S versus steroids was close to significance for patient survival (HR = 1.12, P = 0.07) and graft survival (HR = 1.12, P = 0.05). Figure 1Open in figure viewerPowerPoint (a) Kaplan–Meier curves for graft survival (all subjects). (b) Mean creatinine levels in the first year post-transplant (all patients). Table 2. Cox proportional hazard model adjusting for donor and recipient factors in all patients. Variable Patient survival Graft survival HR 95% CI P-value HR 95% CI P-value Induction Anti-thymocyte globulin 1.12 (0.90–1.39) 0.32 1.11 (0.91–1.36) 0.29 Anti-thymocyte globulin + steroids 1.12 (0.99–1.27) 0.07 1.12 (1.00–1.26) 0.05 Daclizumab 1.01 (0.82–1.24) 0.94 1.02 (0.85–1.23) 0.82 Steroids (ref) (ref) Age 10-year increase 1.17 (1.12–1.22) <0.001 1.08 (1.04–1.12) <0.001 Gender Female 1.00 (0.92–1.09) 0.97 1.00 (0.92–1.08) 0.94 Male (ref) (ref) Race White (ref) (ref) Black 1.35 (1.19–1.53) <0.001 1.32 (1.17–1.48) <0.001 Hispanic 0.88 (0.78–0.99) 0.04 0.89 (0.80–1.00) 0.04 Asian 0.89 (0.74–1.08) 0.25 0.90 (0.76–1.08) 0.27 Other 1.44 (1.07–1.93) 0.02 1.37 (1.04–1.81) 0.03 HCV status Positive 1.38 (1.28–1.50) <0.001 1.35 (1.26–1.46) <0.001 Not positive/unknown (ref) (ref) Total bilirubin (mg/dl) ≥8 0.97 (0.86–1.09) 0.60 1.08 (0.96–1.20) 0.19 <8 (ref) (ref) Creatinine (mg/dl) ≥2 1.13 (1.01–1.28) 0.04 1.11 (0.99–1.24) 0.07 <2 (ref) (ref) INR ≥2 0.93 (0.83–1.04) 0.21 0.95 (0.85–1.05) 0.33 <2 (ref) (ref) Albumin (g/dl) ≥3 0.92 (0.85–0.99) 0.04 0.96 (0.89–1.03) 0.25 <3 (ref) (ref) MELD 30 1.32 (1.08–1.63) 0.01 1.18 (0.98–1.43) 0.08 UNOS status Status 1 0.92 (0.73–1.17) 0.50 1.00 (0.81–1.24) 0.99 Other (ref) (ref) Medical condition pretransplant ICU 1.53 (1.33–1.75) <0.001 1.41 (1.24–1.60) <0.001 Hospitalized 1.06 (0.94–1.19) 0.38 1.03 (0.92–1.15) 0.60 Not hospitalized (ref) (ref) TIPS Yes 1.06 (0.93–1.21) 0.40 1.00 (0.89–1.14) 0.96 No/unknown (ref) (ref) Portal vein thrombosis Yes 1.42 (1.20–1.69) <0.001 1.38 (1.17–1.62) <0.001 No/unknown (ref) (ref) Prev upper abdominal surgery Yes 1.15 (1.06–1.25) <0.001 1.14 (1.06–1.23) <0.001 No/unknown (ref) (ref) Donor status Deceased 1.05 (0.84–1.32) 0.65 0.80 (0.67–0.97) 0.02 Living (ref) (ref) Donor age 10-year increase 1.12 (1.10–1.15) <0.001 1.14 (1.12–1.17) <0.001 Donor sex Female 1.01 (0.94–1.10) 0.75 1.04 (0.97–1.12) 0.25 Male (ref) (ref) Donor race White (ref) (ref) Black 1.08 (0.96–1.21) 0.19 1.15 (1.04–1.28) 0.01 Hispanic 1.23 (1.10–1.37) <0.001 1.21 (1.09–1.34) <0.001 Asian 1.21 (0.96–1.53) 0.11 1.16 (0.93–1.45) 0.18 Other 1.12 (0.81–1.56) 0.49 1.05 (0.76–1.44) 0.78 Cold ischemia time (h) 12 1.17 (0.99–1.37) 0.06 1.29 (1.12–1.49) <0.001 INR, international normalized ratio; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt; UNOS, United Network for Organ Sharing. Renal function A total of 11 603 patients were identified for this analysis as per criteria described in the Patients and Methods section. A total of 11 600 patients (99%) had a creatinine value documented at the time of liver transplantation, 8805 patients (76%) had a creatinine value at 6 months, and 10 118 patients (87%) had a creatinine value at 1 year after liver transplantation. Figure 1b shows the creatinine level before and after liver transplantation among all groups. The ATG group had a significantly higher mean level of creatinine at 1.82 ± 0.10 mg/dl before transplant compared with the daclizumab group at 1.37 ± 0.06 mg/dl (P < 0.01) and the steroid induction group at 1.47 ± 0.01 mg/dl (P < 0.01), and showed a trend for significance compared with the ATG + S group at 1.62 ± 0.04 (P = 0.05). The ATG + S group had a significantly higher mean level than the daclizumab (P < 0.01) and steroids (P < 0.01) groups. However, the creatinine level in the ATG and ATG + S groups improved after liver transplant, and there were no significant differences at 6 and 12 months among the three groups (Fig. 1b). Maintenance immunosuppression We analyzed the effect of combination of maintenance immunosuppression with each induction on graft and patient survival. The tacrolimus, MMF, and corticosteroid groups encompassed 43.3% of patients; tacrolimus and MMF (12.0%); tacrolimus and corticosteroids (24.5%); tacrolimus alone (8.8%); and other maintenance immunosuppression (11.3%). There were no significant differences at the Bonferonni level for graft and patient survival in adjusted analysis for any combination of maintenance immunosuppression involving tacrolimus with ATG, ATG + S, daclizumab, or steroid induction. Hepatitis C recipients The characteristics of recipients with hepatitis C and donors are presented in Table 3. Table 3. Demographics of recipients with hepatitis C and donors. ATG (n = 207) ATG + steroids (n = 768) Daclizumab (n = 251) Steroid (n = 5386) P-value Recipients Age (years) 52.8 ± 6.8 52.4 ± 7.2 51.9 ± 6.6 53.0 ± 7.2 0.01 Female (%) 26.1 22.8 25.9 24.0 0.66 Race (%) White 73.9 72.9 71.3 69.0 <0.001 Black 12.1 14.5 11.6 8.4 Hispanic 10.1 10.3 13.5 17.8 Asian 3.4 1.8 3.2 3.4 Other 0.5 0.5 0.4 1.3 MELD Score 20.4 ± 9.5 19.0 ± 9.5 17.2 ± 7.8 19.6 ± 9.2 <0.001 Bilirubin (mg/dl) 5.6 ± 8.1 5.7 ± 8.8 4.4 ± 6.4 6.4 ± 9.5 <0.001 Creatinine (mg/dl) 1.7 ± 1.3 1.6 ± 1.6 1.3 ± 1.0 1.5 ± 1.2 <0.001 INR 1.9 ± 1.5 1.7 ± 0.7 1.6 ± 0.4 1.8 ± 0.9 <0.001 Albumin (g/dl) 3.0 ± 0.7 2.9 ± 0.7 2.9 ± 0.5 2.9 ± 0.6 0.04 Status 1 (%) 0.5 0.1 0 0.1 0.53 Pretransplant in ICU (%) 7.2 7.0 2.4 7.9 0.001 History of SBP (%) 7.9 8.1 6.7 9.1 0.22 History of TIPS 5.3 7.4 3.2 9.0 <0.001 Portal vein thrombus 2.9 3.3 3.2 4.3 0.02 Donors Donor status (%) Deceased 97.6 95.8 94.8 95.9 0.52 Living 2.4 4.2 5.2 4.1 Age (years) 41.3 ± 15.1 40.7 ± 15.7 40.5 ± 16.2 39.9 ± 16.1 0.22 Cause of death (%) Anoxia 15.3 15.0 11.8 13.1 0.03 CVA 46.5 41.5 40.3 42.6 Trauma 34.2 39.3 45.0 42.0 CNS tumor 0.5 1.4 0.4 0.7 Other 3.5 2.9 2.5 1.6 Female (%) 46.4 39.8 45.0 37.8 0.001 Race White 70.5 74.5 65.3 67.0 <0.001 Black 11.6 15.6 19.1 12.7 Hispanic 11.6 7.4 14.3 16.2 Asian 3.9 1.4 1.2 2.4 Other 2.5 1.1 0 1.7 Cold ischemia time (h) 7.3 ± 5.3 7.1 ± 3.2 7.6 ± 3.0 7.2 ± 3.4 0.02 Warm ischemia time (min) 35.8 ± 17.1 44.1 ± 22.1 43.2 ± 19.0 41.2 ± 19.0 <0.001 ATG, anti-thymocyte globulin; TIPS, transjugular intrahepatic portosystemic shunt; SBP, spontaneous bacterial peritonitis; MELD, Model for End-Stage Liver Disease; INR, international normalized ratio; CVA, cerebrovascular accident; CNS, central nervous system. Graft and patient survival in HCV recipients Figure 2a shows graft survival in unadjusted analysis. The ATG induction group had 84% graft survival at 1 year and 62% graft survival at 5 years, compared to the ATG + S (82% and 61%), daclizumab (90% and 73%), and steroid groups (85% and 66%), respectively (P = 0.03) (Fig. 2a). ATG + S had significantly worse graft survival compared with daclizumab (P = 0.01) and steroids (P = 0.03). ATG alone showed a trend for worse graft survival compared with daclizumab (P = 0.09) and steroids (P = 0.08). There was also a significant difference among the groups (P = 0.03) in the patient survival (ATG: 1-year 86%, 5-year 64%, ATG + S: 1-year 86%, 5-year 65%, daclizumab: 1-year 92%, 5-year 77%, steroids: 1-year 88%, 5-year 70%). ATG + S had significantly worse patient survival than daclizumab (P = 0.01) and steroids (P = 0.03), and ATG alone trended toward worse patient survival compared with daclizumab (P = 0.05) and steroids (P = 0.08). Table 4 presents Cox proportional hazard models for patient mortality and graft loss including donor and recipient factors for HCV patients. African–American patients, female recipients, creatinine ≥2 mg/dl, previous upper abdominal surgery, donor age, Hispanic donor, and Asian donor were significant risk factors for HCV for both graft loss and patient mortality. There was no significant difference among the induction groups for HCV patients in either model (Table 4). However, ATG + S versus steroids trended toward worse patient mortality (HR = 1.18, P = 0.05) and graft loss (HR = 1.15, P = 0.08). Figure 2Open in figure viewerPowerPoint (a) Kaplan–Meier curves of graft survival (HCV patients). (b) Mean creatinine levels in the first year post-transplant (HCV patients). Table 4. Cox proportional hazard model for donor and recipient factors in HCV patients. Variable Patient survival Graft survival HR 95% CI P-value HR 95% CI P-value Induction Anti-thymocyte globulin 1.17 (0.89–1.55) 0.27 1.09 (0.83–1.43) 0.53 Anti-thymocyte globulin + steroids 1.18 (1.00–1.39) 0.05 1.15 (0.98–1.35) 0.08 Daclizumab 0.85 (0.62–1.17) 0.32 0.80 (0.59–1.07) 0.14 Steroids (ref) (ref) Age 10-year increase 1.10 (1.02–1.19) 0.01 1.02 (0.95–1.09) 0.63 Gender Female 1.17 (1.03–1.33) 0.01 1.18 (1.05–1.33) 0.01 Male (ref) (ref) Race White (ref) (ref) Black 1.36 (1.15–1.61) <0.001 1.35 (1.15–1.58) <0.001 Hispanic 0.86 (0.74–1.01) 0.07 0.88 (0.76–1.03) 0.10 Asian 0.90 (0.66–1.23) 0.51 1.05 (0.79–1.39) 0.74 Other 0.96 (0.58–1.57) 0.86 0.99 (0.63–1.56) 0.96 Total bilirubin (mg/dl) ≥8 1.05 (0.87–1.27) 0.62 1.12 (0.94–1.34) 0.21 <8 (ref) (ref) Creatinine (mg/dl) ≥2 1.31 (1.09–1.57) 0.004 1.25 (1.05–1.48) 0.01 <2 (ref) (ref) INR ≥2 0.98 (0.83–1.17) 0.86 0.98 (0.84–1.16) 0.87 <2 (ref) (ref) Albumin (g/dl) ≥3 1.01 (0.91–1.13) 0.84 1.02 (0.92–1.13) 0.68 <3 (ref) (ref) MELD 30 1.16 (0.84–1.59) 0.36 1.09 (0.81–1.47) 0.56 Medical condition pretransplant ICU 1.24 (1.00–1.54) 0.05 1.12 (0.91–1.38) 0.27 Hospitalized 0.93 (0.78–1.11) 0.43 0.93 (0.79–1.10) 0.42 Not hospitalized (ref) (ref) TIPS Yes 0.98 (0.81–1.20) 0.88 0.91 (0.75–1.10) 0.34 No/unknown (ref) (ref) Portal vein thrombosis Yes 1.07 (0.81–1.42) 0.64 1.00 (0.76–1.31) 0.99 No/unknown (ref) (ref) Prev upper abdominal surgery Yes 1.14 (1.02–1.28) 0.03 1.13 (1.02–1.26) 0.02 No/unknown (ref) (ref) Donor status Deceased 1.24 (0.83–1.87) 0.30 0.79 (0.57–1.08) 0.14 Living (ref) (ref) Donor age 10-year increase 1.23 (1.18–1.27) <0.001 1.24 (1.20–1.28) <0.001 Donor sex Female 1.00 (0.90–1.12) 0.97 1.03 (0.93–1.14) 0.60 Male (ref) (ref) Donor race White (ref) (ref) Black 0.96 (0.81–1.14) 0.62 1.03 (0.88–1.20) 0.71 Hispanic 1.27 (1.08–1.48) 0.003 1.22 (1.06–1.42) 0.01 Asian 1.65 (1.24–2.20) <0.001 1.55 (1.18–2.05) 0.002 Other 1.10 (0.71–1.72) 0.66 1.00 (0.65–1.54) 0.99 Cold ischemia time (h) 12 0.99 (0.76–1.27) 0.91 1.22 (0.97–1.53) 0.08 INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; TIPS, transjugular intrahepatic portosystemic shunt. Renal function in HCV recipients A total of 4459 patients were identified for this analysis as per criteria described in the Patients and Methods section. A total of 4458 patients (99%) had a documented creatinine value at the time of liver transplantation, 3401 patients (76%) had a creatinine value at 6 months, and 3859 patients (87%) had a creatinine value at 1 year after liver transplantation. Figure 2b shows renal function in recipients with hepatitis C before and after liver transplant among all groups. The ATG group had a mean level of creatinine of 1.53 ± 0.09 mg/dl before transplant compared to ATG + S at 1.57 ± 0.07 mg/dl (P = 0.72), daclizumab at 1.29 ± 0.09 mg/dl (P = 0.06), and steroids at 1.44 ± 0.02 mg/dl (P = 0.31). ATG + S had a significantly higher mean level of creatinine at baseline compared with daclizumab (P = 0.01), and showed a trend for a higher creatinine level compared with steroid (P = 0.06). Creatinine in the ATG and ATG + S groups improved after liver transplant and there were no significant differences between the groups at 6 and 12 months (Fig. 2b). Total bilirubin in the first year in HCV recipients We compared mean total bilirubin at preliver transplant, 6 months, and 12 months after liver transplantation. A total of 4459 patients were identified for this analysis as per the criteria described in Patients and Methods. A total of 4452 patients (99%) had documented bilirubin value at the time of liver transplantation, 3391 patients (76%) had bilirubin value at 6 months, and 3874 patients (87%) had bilirubin value at 1 year after liver transplantation. The bilirubin levels were normalized after liver transplant in all groups, and there were no significant differences among the groups at 6 months or 1 year (Fig. 3). Figure 3Open in figure viewerPowerPoint Mean total bilirubin levels in the first year post-transplant (HCV patients). Discussion As the liver is considered to be an immunologically privileged organ, the use of antibody to prevent rejection has been perceived as unnecessary and could carry the risk of over-immunosuppression. On the other hand, antibody induction has some advantage over standard corticosteroid induction. Ramirez et al. reported that anti-IL2 induction achieved excellent graft and patient survival with a low incidence of acute rejection [1]. Furthermore, recent studies have shown that antibody induction (daclizumab or ATG) with delayed initiation of calcineurin inhibitors had significant benefits in preserving renal function after liver
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