- Email: [email protected]
Effectiveness of Thymoglobulin Induction Therapy in Kidney Transplant From Deceased Donor With Mild to Moderate Acute Kidney Injury
Effectiveness of Thymoglobulin Induction Therapy in Kidney Transplant From Deceased Donor With Mild to Moderate Acute Kidney Injury Chang Hun Lee, Jun Gyo Gwon, and Cheol Woong Jung* Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Korea
ABSTRACT Background. The clinical benefit of rabbit antithymocyte globulin (Thymoglobulin) compared with basiliximab for induction therapy in kidney transplant (KT) resulting from acute kidney injury (AKI) donors remains controversial. In cases of severe AKI, the degree of kidney injury is too great to reveal influence of different induction therapies on clinical outcomes. We aimed to compare clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from deceased donors (DDs) with mild to moderate AKI. Methods. We retrospectively studied 147 patients who received KTs from DDs between 2009 and 2017 in our center; 91 patients received kidneys from AKI donors. The AKI severity was classified based on the Acute Kidney Injury Network (AKIN) staging, and patients with AKIN stage 3 (43 patients) were excluded. Clinical outcomes were compared according to the type of induction therapy. Results. Thymoglobulin and basiliximab induction groups showed no significant differences in demographic and baseline characteristics except donor age and follow-up period. The Thymoglobulin group had lower incidences of acute rejection and a trend toward a lower incidence of delayed graft function and better graft survival than the basiliximab group. There was no significant difference in BK infection rate; however, cytomegalovirus infection rate showed a trend toward a lower incidence in the basiliximab group. Conclusions. In cases of KT from AKIN stage 1 and 2 donors, Thymoglobulin showed better clinical outcomes than basiliximab, although it had a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI.
R
ABBIT antithymocyte globulin (Thymoglobulin; Genzyme, Cambridge, Mass, United States) was first approved in France in 1984 for the treatment of acute rejection in renal and heart transplant, acute graft-vs-host disease, and severe aplastic anemia, and in the United States, it has been indicated for the treatment of acute rejection episodes in kidney transplant (KT) recipients since 1998 [1,2]. A large number of transplantation centers use Thymoglobulin induction therapy in KTs from deceased donors (DDs) with acute kidney injury (AKI) to expect better graft outcomes. Basiliximab (Simulect; Novartis Pharma, East Hanover, NJ, United States), along with Thymoglobulin, is one of the most commonly used agents for induction therapy of KT. ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2611e2614 (2019)
In 2006, Brennan et al conducted a comparative study between Thymoglobulin and basiliximab induction therapy in high-risk patients with acute rejection and delayed graft function with KTs from DDs, and the use of Thymoglobulin showed a reduction in the incidence of acute rejection but
This study was supported by Korea University Grant. *Address correspondence to Cheol Woong Jung, MD, PhD, Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, 02841, Korea. Tel: þ82 2 920 5978; Fax: þ82 2 928 1631. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.061
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did not reveal a reduction in the incidence of delayed graft function [3]. They mentioned the possibility of factors that were too great to prevent delayed graft function. Therefore, we thought that excluding these factors would confirm more accurately the effect of Thymoglobulin. There are variety of causes that affect delayed graft function; however, in this study we focused on donor kidney function and defined it more simply based on Acute Kidney Injury Network (AKIN) criteria [4]. In this study, we aimed to compare the clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from DDs with mild to moderate AKI. METHODS Induction Therapy The total dose of about 4.0 to 5.0 mg/kg of body weight was used as an induction therapy in patients with Thymoglobulin. Induction therapy with Thymoglobulin was initiated intraoperatively prior to graft reperfusion and then on days 1, 2, and 4 postoperatively. The dose was decreased by 50% in patients with platelet counts of less than 80,000/mm3 or an absolute neutrophil count less than 3000/ mm3. If the platelet count was less than 50,000/mm3 or the absolute neutrophil count was less than 1500/mm3, then Thymoglobulin was withheld. Pretreatments with corticosteroids, acetaminophen, and an antihistamine were performed. In the basiliximab group, 20.0 mg of basiliximab (Simulect) was injected intravenously for the first time before graft reperfusion, followed by a second infusion on day 4. Neither premedication nor dose adjustments were performed.
LEE, GWON, AND JUNG and Fisher exact test, and continuous data were evaluated using the t test and Mann-Whitney test. Survival analysis was evaluated using Kaplan-Meier analysis and log-rank test. All analyses were 2-tailed, and a P value < .05 was considered statistically significant. Statistical analysis was performed using SPSS version 23.0 (IBM, Armonk, NY, United States).
RESULTS
The baseline and demographics of 2 groups were similar except donor age and follow-up period (Table 1). In the AKI patients, the mean ages of donors were significantly higher in the Thymoglobulin group (47.5 [SD, 10.3] years and 55.4 [SD, 12.8] years, respectively; P ¼ .03). The mean follow-up period was significantly longer in the basiliximab group (73.0 [SD, 6.1] months and 40.5 [SD, 7.4] months, respectively; P ¼ .003). There were significantly fewer patients with acute rejection in the Thymoglobulin group than in the basiliximab group (39.4% vs 0%; P ¼ .004) (Table 2). The incidence of delayed graft function was not significantly different but showed a trend toward a lower incidence in the Thymoglobulin group (15% vs 0%; P ¼ .17). Graft survival rates were 75.5% (basiliximab) vs 100% (Thymoglobulin) (P ¼ .11; Fig 1). Serum creatinine and creatinine clearance were not significantly different in all the observation periods in both AKI and non-AKI patients. The rate of cytomegalovirus infection was higher in the Thymoglobulin group, but there was no significant difference (18.2% vs 40.0%; P ¼ .15). The rate of BK infection was similar in both groups (9.1% vs 13.3%; P > .99).
Patients A total of 154 cases of DD KTs were performed between January 2009 and December 2017 in our center. Of these, 6 patients died within 1 month after surgery, and these patients were excluded because it was difficult to evaluate the function of the transplanted kidney. Simultaneous transplant with other organs was performed in 1 case, which was also excluded. A total of 147 patients were studied. We retrospectively analyzed 91 patients (61.9%) who received kidney allograft from AKI donors; 56 non-AKI patients were studied as a control group. The AKI severity was classified based on AKIN criteria, and among the 91 patients, patients with AKIN stage 3 (43 patients) were excluded.
DISCUSSION
The increasing number of candidates for transplant and relatively unchanged donor pool has led to the expansion of criteria for DD renal allograft acceptability, such as kidneys Table 1. Donor and Recipient Characteristics Patients
Basiliximab Group
Thymoglobulin Group
P Value
(n ¼ 33)
(n ¼ 15)
47.5 10.3 28 (84.8%) 23.0 3.0
55.4 12.8 12 (80.0%) 24.8 2.7
.026 1.000 .061
45.0 10.0 19 (57.6%) 22.8 3.0 32 (97.0%) 29 (87.9%) 285.1 235.9 3.63 1.26 73.0 6.1
50.1 9.1 8 (53.3%) 23.3 4.3 12 (80.0%) 9 (60.0%) 214.5 78.9 3.07 1.87 40.5 7.4
.094 1.000 .669 .084 .051 .131 .234 .003
Statistical Analysis
AKI (AKIN 1,2) Donor Age Gender (male) BMI Recipient Age Gender (male) BMI Hypertension DM CIT (min) HLA mismatch Follow-up period (month)
Categorical variables were summarized as numbers and percentages, and continuous variables were summarized as means with standard deviations. Categorical data were analyzed using c2 test
Values were presented as median (range) for age; mean SD for other continuous data; n (%) for categorical data. Abbreviations: AKI, Acute kidney injury; BMI, body mass index; CIT, Cold Ischemic time; DM, Diabetes mellitus; HLA, Human leukocyte antigen.
Efficacy End Points Based on medical records, we confirmed the occurrence and timing of biopsy-proven acute rejection, delayed graft function, graft loss, and death. All cases of acute rejection were confirmed by biopsy according to Banff criteria [5]. There are various definitions for delayed graft function; we defined it as requiring dialysis within 7 days of the transplant [6e9]. Serum creatinine and creatinine clearance rates were used to evaluate the allograft kidney function and were assessed at 1, 3, and 6 months and at 1, 3, and 5 years.
THYMOGLOBULIN INDUCTION IN TRANSPLANT
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Table 2. Clinical Outcomes Basiliximab group Thymoglobulin group AKI (AKIN 1,2)
(n ¼ 33)
(n ¼ 15)
P Value
Acute rejection† Antibody mediated T-cell mediated Delayed graft function† CMV infection† BK infection† Serum Creatinine (mg/dL)‡ Month 1 Month 3 Month 6 Year 1 Year 3 Year 5 Creatinine clearance (mL/min) Month 1 Month 3 Month 6 Year 1 Year 3 Year 5
13 (39.4%) 7 (21.2%) 10 (30.3%) 5 (15.2%) 6 (18.2%) 3 (9.1%)
0 (0%) 0 (0%) 0 (0%) 0 (0%) 6 (40.0%) 2 (13.3%)
.004 .082 .020 .167 .152 1.000
1.49 1.26 1.27 1.20 1.18 1.13
1.12 0.32 0.52 0.27 0.25 0.26
1.49 1.48 1.45 1.33 1.24 1.47
0.58 0.53 0.51 0.42 0.28 0.79
.998 .146 .270 .290 .546 .399
61.82 63.24 65.06 66.34 67.14 68.97
23.41 16.37 18.40 17.32 21.29 21.07
56.31 55.42 56.26 60.08 59.66 55.39
21.75 17.41 16.40 16.88 10.86 18.64
.444 .144 .123 .284 .383 .200
Values were presented as mean SD for other continuous data; n (%) for categorical data. † Chi-square or two-sided Fisher Exact Test. ‡ Log-rank test.
from donors with high serum creatinine levels, presumably due to AKI [10]. As the severity of donor AKI increases, the delayed graft function is increased and the choice of induction therapy to reduce it becomes more important [11]. Basiliximab and Thymoglobulin are the most commonly used agents for induction therapy of KT, and there have been many comparative studies on their efficacy and safety. There was no significant difference in efficacy between the 2 groups in the general randomized controlled trials, but Thymoglobulin was better in acute rejection in study of high-risk patients [12e16]. It is now common practice in the transplant community to select induction therapy on the basis of risk-benefit consideration. The choice of an induction agent remains debatable, but basiliximab may be preferred for low-risk patients while Thymoglobulin may be preferred for high-risk patients [17]. Heilman et al compared the post-transplant outcomes between the AKIN stage 3 and AKIN-1 and -2 groups and showed that delayed graft function was significantly higher in the AKIN stage 3 group (76% vs 54%; P ¼ .009) [18]. Even though Thymoglobulin is preferred in high-risk patients, the protective effect could not be sufficient for severely damaged kidneys prior to transplant. In fact, delayed graft function is directly influenced by the acute injury of the pretransplant kidney, and even Thymoglobulin will not easily overcome extreme kidney damage [19]. Since 2012, our center has preferred to use Thymoglobulin as an induction therapy for the immunologic high-risk
Fig 1. Kaplan-Meier survival analysis. (A) Graft survival rates, (B) Patient survival rates.
patients and the patients who have received a kidney from an AKI donor. Thus, the follow-up period was longer in the basiliximab group than in the Thymoglobulin group in this study. Because Thymoglobulin induction therapy was preferred in high-risk patients, the donor age was significantly higher in the Thymoglobulin group. Acute rejection was significantly lower in the Thymoglobulin group as in previous studies. Delayed graft function and graft survival rates were better in the Thymoglobulin group. The limitation of this study was that the study was retrospective and
2614
nonrandomized, and the number of patients in the Thymoglobulin group was too small to show statistical significance. There might be some selection bias because of the frequent use of Thymoglobulin induction for the specific patients group since 2012. CONCLUSION
Thymoglobulin showed better results in acute rejection, delayed graft function, and graft survival compared with basiliximab, in spite of a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI. REFERENCES [1] Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (Thymoglobulin). Drugs 2010;70: 691e732. [2] Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy 2006;26:1771e83. [3] Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. New Engl J Med 2006;355:1967e77. [4] Bagshaw SM, George C, Bellomo R. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1569e74. [5] Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cellemediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018;18:293e307. [6] Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant 2011;11:2279e96. [7] Akkina SK, Connaire JJ, Israni AK, Snyder JJ, Matas AJ, Kasiske BL. Similar outcomes with different rates of delayed graft
LEE, GWON, AND JUNG function may reflect center practice, not center performance. Am J Transplant 2009;9:1460e6. [8] Tapiawala SN, Tinckam KJ, Cardella CJ, et al. Delayed graft function and the risk for death with a functioning graft. J Am Soc Nephrol 2010;21:153e61. [9] Chang SH, Russ GR, Chadban SJ, Campbell SB, McDonald SP. Trends in kidney transplantation in Australia and New Zealand. Transplantation 2007;84:611e8. 1993e2004. [10] Kayler L, Garzon P, Magliocca J, et al. Outcomes and utilization of kidneys from deceased donors with acute kidney injury. Am J Transplant 2009;9:367e73. [11] Hall IE, Schröppel B, Doshi MD, et al. Associations of deceased donor kidney injury with kidney discard and function after transplantation. Am J Transplant 2015;15:1623e31. [12] Pilch NA, Taber DJ, Moussa O, et al. Prospective randomized controlled trial of rabbit antithymocyte globulin compared with IL-2 receptor antagonist induction therapy in kidney transplantation. Ann Surg 2014;259:888e93. [13] Liu Y, Zhou P, Han M, Xue C-B, Hu X-P, Li C. Basiliximab or antithymocyte globulin for induction therapy in kidney transplantation: a meta-analysis. Transplant Proc 2010;42:1667e70. [14] Ulrich F, Niedzwiecki S, Pascher A, et al. Long-term outcome of ATG vs. basiliximab induction. Eur J Clin Invest 2011;41:971e8. [15] Knight RJ, Kerman RH, Schoenberg L, et al. The selective use of basiliximab versus thymoglobulin in combination with sirolimus for cadaveric renal transplant recipients at low risk versus high risk for delayed graft function. Transplantation 2004;78:904e10. [16] Kyllönen LE, Eklund BH, Pesonen EJ, Salmela KT. Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety. Transplantation 2007;84:75e82. [17] Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transplant Int 2013;26:662e72. [18] Heilman R, Smith M, Kurian S, et al. Transplanting kidneys from deceased donors with severe acute kidney injury. Am J Transplant 2015;15:2143e51. [19] Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet 2004;364:1814e27.
ABSTRACT Background. The clinical benefit of rabbit antithymocyte globulin (Thymoglobulin) compared with basiliximab for induction therapy in kidney transplant (KT) resulting from acute kidney injury (AKI) donors remains controversial. In cases of severe AKI, the degree of kidney injury is too great to reveal influence of different induction therapies on clinical outcomes. We aimed to compare clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from deceased donors (DDs) with mild to moderate AKI. Methods. We retrospectively studied 147 patients who received KTs from DDs between 2009 and 2017 in our center; 91 patients received kidneys from AKI donors. The AKI severity was classified based on the Acute Kidney Injury Network (AKIN) staging, and patients with AKIN stage 3 (43 patients) were excluded. Clinical outcomes were compared according to the type of induction therapy. Results. Thymoglobulin and basiliximab induction groups showed no significant differences in demographic and baseline characteristics except donor age and follow-up period. The Thymoglobulin group had lower incidences of acute rejection and a trend toward a lower incidence of delayed graft function and better graft survival than the basiliximab group. There was no significant difference in BK infection rate; however, cytomegalovirus infection rate showed a trend toward a lower incidence in the basiliximab group. Conclusions. In cases of KT from AKIN stage 1 and 2 donors, Thymoglobulin showed better clinical outcomes than basiliximab, although it had a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI.
R
ABBIT antithymocyte globulin (Thymoglobulin; Genzyme, Cambridge, Mass, United States) was first approved in France in 1984 for the treatment of acute rejection in renal and heart transplant, acute graft-vs-host disease, and severe aplastic anemia, and in the United States, it has been indicated for the treatment of acute rejection episodes in kidney transplant (KT) recipients since 1998 [1,2]. A large number of transplantation centers use Thymoglobulin induction therapy in KTs from deceased donors (DDs) with acute kidney injury (AKI) to expect better graft outcomes. Basiliximab (Simulect; Novartis Pharma, East Hanover, NJ, United States), along with Thymoglobulin, is one of the most commonly used agents for induction therapy of KT. ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2611e2614 (2019)
In 2006, Brennan et al conducted a comparative study between Thymoglobulin and basiliximab induction therapy in high-risk patients with acute rejection and delayed graft function with KTs from DDs, and the use of Thymoglobulin showed a reduction in the incidence of acute rejection but
This study was supported by Korea University Grant. *Address correspondence to Cheol Woong Jung, MD, PhD, Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, 02841, Korea. Tel: þ82 2 920 5978; Fax: þ82 2 928 1631. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.061
2611
2612
did not reveal a reduction in the incidence of delayed graft function [3]. They mentioned the possibility of factors that were too great to prevent delayed graft function. Therefore, we thought that excluding these factors would confirm more accurately the effect of Thymoglobulin. There are variety of causes that affect delayed graft function; however, in this study we focused on donor kidney function and defined it more simply based on Acute Kidney Injury Network (AKIN) criteria [4]. In this study, we aimed to compare the clinical outcomes of Thymoglobulin and basiliximab induction therapy in KTs from DDs with mild to moderate AKI. METHODS Induction Therapy The total dose of about 4.0 to 5.0 mg/kg of body weight was used as an induction therapy in patients with Thymoglobulin. Induction therapy with Thymoglobulin was initiated intraoperatively prior to graft reperfusion and then on days 1, 2, and 4 postoperatively. The dose was decreased by 50% in patients with platelet counts of less than 80,000/mm3 or an absolute neutrophil count less than 3000/ mm3. If the platelet count was less than 50,000/mm3 or the absolute neutrophil count was less than 1500/mm3, then Thymoglobulin was withheld. Pretreatments with corticosteroids, acetaminophen, and an antihistamine were performed. In the basiliximab group, 20.0 mg of basiliximab (Simulect) was injected intravenously for the first time before graft reperfusion, followed by a second infusion on day 4. Neither premedication nor dose adjustments were performed.
LEE, GWON, AND JUNG and Fisher exact test, and continuous data were evaluated using the t test and Mann-Whitney test. Survival analysis was evaluated using Kaplan-Meier analysis and log-rank test. All analyses were 2-tailed, and a P value < .05 was considered statistically significant. Statistical analysis was performed using SPSS version 23.0 (IBM, Armonk, NY, United States).
RESULTS
The baseline and demographics of 2 groups were similar except donor age and follow-up period (Table 1). In the AKI patients, the mean ages of donors were significantly higher in the Thymoglobulin group (47.5 [SD, 10.3] years and 55.4 [SD, 12.8] years, respectively; P ¼ .03). The mean follow-up period was significantly longer in the basiliximab group (73.0 [SD, 6.1] months and 40.5 [SD, 7.4] months, respectively; P ¼ .003). There were significantly fewer patients with acute rejection in the Thymoglobulin group than in the basiliximab group (39.4% vs 0%; P ¼ .004) (Table 2). The incidence of delayed graft function was not significantly different but showed a trend toward a lower incidence in the Thymoglobulin group (15% vs 0%; P ¼ .17). Graft survival rates were 75.5% (basiliximab) vs 100% (Thymoglobulin) (P ¼ .11; Fig 1). Serum creatinine and creatinine clearance were not significantly different in all the observation periods in both AKI and non-AKI patients. The rate of cytomegalovirus infection was higher in the Thymoglobulin group, but there was no significant difference (18.2% vs 40.0%; P ¼ .15). The rate of BK infection was similar in both groups (9.1% vs 13.3%; P > .99).
Patients A total of 154 cases of DD KTs were performed between January 2009 and December 2017 in our center. Of these, 6 patients died within 1 month after surgery, and these patients were excluded because it was difficult to evaluate the function of the transplanted kidney. Simultaneous transplant with other organs was performed in 1 case, which was also excluded. A total of 147 patients were studied. We retrospectively analyzed 91 patients (61.9%) who received kidney allograft from AKI donors; 56 non-AKI patients were studied as a control group. The AKI severity was classified based on AKIN criteria, and among the 91 patients, patients with AKIN stage 3 (43 patients) were excluded.
DISCUSSION
The increasing number of candidates for transplant and relatively unchanged donor pool has led to the expansion of criteria for DD renal allograft acceptability, such as kidneys Table 1. Donor and Recipient Characteristics Patients
Basiliximab Group
Thymoglobulin Group
P Value
(n ¼ 33)
(n ¼ 15)
47.5 10.3 28 (84.8%) 23.0 3.0
55.4 12.8 12 (80.0%) 24.8 2.7
.026 1.000 .061
45.0 10.0 19 (57.6%) 22.8 3.0 32 (97.0%) 29 (87.9%) 285.1 235.9 3.63 1.26 73.0 6.1
50.1 9.1 8 (53.3%) 23.3 4.3 12 (80.0%) 9 (60.0%) 214.5 78.9 3.07 1.87 40.5 7.4
.094 1.000 .669 .084 .051 .131 .234 .003
Statistical Analysis
AKI (AKIN 1,2) Donor Age Gender (male) BMI Recipient Age Gender (male) BMI Hypertension DM CIT (min) HLA mismatch Follow-up period (month)
Categorical variables were summarized as numbers and percentages, and continuous variables were summarized as means with standard deviations. Categorical data were analyzed using c2 test
Values were presented as median (range) for age; mean SD for other continuous data; n (%) for categorical data. Abbreviations: AKI, Acute kidney injury; BMI, body mass index; CIT, Cold Ischemic time; DM, Diabetes mellitus; HLA, Human leukocyte antigen.
Efficacy End Points Based on medical records, we confirmed the occurrence and timing of biopsy-proven acute rejection, delayed graft function, graft loss, and death. All cases of acute rejection were confirmed by biopsy according to Banff criteria [5]. There are various definitions for delayed graft function; we defined it as requiring dialysis within 7 days of the transplant [6e9]. Serum creatinine and creatinine clearance rates were used to evaluate the allograft kidney function and were assessed at 1, 3, and 6 months and at 1, 3, and 5 years.
THYMOGLOBULIN INDUCTION IN TRANSPLANT
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Table 2. Clinical Outcomes Basiliximab group Thymoglobulin group AKI (AKIN 1,2)
(n ¼ 33)
(n ¼ 15)
P Value
Acute rejection† Antibody mediated T-cell mediated Delayed graft function† CMV infection† BK infection† Serum Creatinine (mg/dL)‡ Month 1 Month 3 Month 6 Year 1 Year 3 Year 5 Creatinine clearance (mL/min) Month 1 Month 3 Month 6 Year 1 Year 3 Year 5
13 (39.4%) 7 (21.2%) 10 (30.3%) 5 (15.2%) 6 (18.2%) 3 (9.1%)
0 (0%) 0 (0%) 0 (0%) 0 (0%) 6 (40.0%) 2 (13.3%)
.004 .082 .020 .167 .152 1.000
1.49 1.26 1.27 1.20 1.18 1.13
1.12 0.32 0.52 0.27 0.25 0.26
1.49 1.48 1.45 1.33 1.24 1.47
0.58 0.53 0.51 0.42 0.28 0.79
.998 .146 .270 .290 .546 .399
61.82 63.24 65.06 66.34 67.14 68.97
23.41 16.37 18.40 17.32 21.29 21.07
56.31 55.42 56.26 60.08 59.66 55.39
21.75 17.41 16.40 16.88 10.86 18.64
.444 .144 .123 .284 .383 .200
Values were presented as mean SD for other continuous data; n (%) for categorical data. † Chi-square or two-sided Fisher Exact Test. ‡ Log-rank test.
from donors with high serum creatinine levels, presumably due to AKI [10]. As the severity of donor AKI increases, the delayed graft function is increased and the choice of induction therapy to reduce it becomes more important [11]. Basiliximab and Thymoglobulin are the most commonly used agents for induction therapy of KT, and there have been many comparative studies on their efficacy and safety. There was no significant difference in efficacy between the 2 groups in the general randomized controlled trials, but Thymoglobulin was better in acute rejection in study of high-risk patients [12e16]. It is now common practice in the transplant community to select induction therapy on the basis of risk-benefit consideration. The choice of an induction agent remains debatable, but basiliximab may be preferred for low-risk patients while Thymoglobulin may be preferred for high-risk patients [17]. Heilman et al compared the post-transplant outcomes between the AKIN stage 3 and AKIN-1 and -2 groups and showed that delayed graft function was significantly higher in the AKIN stage 3 group (76% vs 54%; P ¼ .009) [18]. Even though Thymoglobulin is preferred in high-risk patients, the protective effect could not be sufficient for severely damaged kidneys prior to transplant. In fact, delayed graft function is directly influenced by the acute injury of the pretransplant kidney, and even Thymoglobulin will not easily overcome extreme kidney damage [19]. Since 2012, our center has preferred to use Thymoglobulin as an induction therapy for the immunologic high-risk
Fig 1. Kaplan-Meier survival analysis. (A) Graft survival rates, (B) Patient survival rates.
patients and the patients who have received a kidney from an AKI donor. Thus, the follow-up period was longer in the basiliximab group than in the Thymoglobulin group in this study. Because Thymoglobulin induction therapy was preferred in high-risk patients, the donor age was significantly higher in the Thymoglobulin group. Acute rejection was significantly lower in the Thymoglobulin group as in previous studies. Delayed graft function and graft survival rates were better in the Thymoglobulin group. The limitation of this study was that the study was retrospective and
2614
nonrandomized, and the number of patients in the Thymoglobulin group was too small to show statistical significance. There might be some selection bias because of the frequent use of Thymoglobulin induction for the specific patients group since 2012. CONCLUSION
Thymoglobulin showed better results in acute rejection, delayed graft function, and graft survival compared with basiliximab, in spite of a somewhat high rate of cytomegalovirus infection. It seems beneficial to use Thymoglobulin induction therapy in KTs from DDs with mild to moderate AKI. REFERENCES [1] Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (Thymoglobulin). Drugs 2010;70: 691e732. [2] Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy 2006;26:1771e83. [3] Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. New Engl J Med 2006;355:1967e77. [4] Bagshaw SM, George C, Bellomo R. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1569e74. [5] Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cellemediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018;18:293e307. [6] Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant 2011;11:2279e96. [7] Akkina SK, Connaire JJ, Israni AK, Snyder JJ, Matas AJ, Kasiske BL. Similar outcomes with different rates of delayed graft
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