Basiliximab is superior to low dose rabbit anti-thymocyte globulin in pediatric kidney transplant recipients: The younger, the better

To the Editor: To reduce the risk of acute rejection (AR) after renal transplantation, immunosuppressive induction therapy has been commonly used in the perioperative period. At present, rabbit anti-thymocyte globulin (rATG) and basiliximab are the two main induction agents used for kidney transplantation. In adult kidney transplantation, the incidence of AR with rATG induction is generally lower than that with basiliximab.[1] Children have different immune systems than adults do. In pediatric kidney transplantation, which induction therapy is more effective in preventing early AR is an important clinical question worth answering. Because there are few reports in this field and differences in the immune systems of children at different ages, we have now conducted a total and age-stratified analysis of Chinese multicenter cohort data to compare the AR rates and other outcomes between rATG and basiliximab induction therapy groups in pediatric deceased-donor kidney transplantation. A total of five hospitals, including The First Affiliated Hospital of Zhejiang University, Changhai Hospital affiliated to Naval Military Medical University, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, The First Affiliated Hospital of Sun Yat-sen University and The First Affiliated Hospital of Zhengzhou University, participated in this retrospective multicenter cohort study, all of which are major transplant centers for pediatric kidney transplantation in China. The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (No. TJ-IRB20230872) and registered in ClinicalTrial.gov (NCT06087003). The clinical and research activities being reported are consistent with the principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” The inclusion criteria were as follows: (1) recipient age ≤18 years old at the time of kidney transplantation; (2) renal grafts came from deceased donors; (3) recipient received either rATG or basiliximab induction therapy; (4) transplantation occurred between January 1, 2013, and June 30, 2022. Recipients of multiorgan transplants, recipients with pretransplant panel reactive antibodies (PRA) >10% and recipients who received no induction or combined induction or induction other than rATG and basiliximab were excluded from the study. Follow-up ended on June 30, 2023. Outcomes of interest were delayed graft function (DGF), AR (including total AR during the period of follow-up, AR within 3 months, AR within 6 months, and AR within 12 months after transplantation), the occurrence of cytomegalovirus (CMV) viremia, the development of pneumonia as well as urinary tract infection requiring hospitalization, graft loss, and patient death. The dosing schedule for basiliximab was as follows: two doses of 10 mg basiliximab were given intravenously to children <35 kg body weight; two doses of 20 mg were given to children ≥35 kg, with the first dose given during the transplant surgery and the second on post-transplant day 4. Induction with rATG was started intraoperatively at a dose of 0.5–1.0 mg/kg and was then given once a day at the same dosage for 2–4 days. The cumulative dose for rATG in this study was 2.5 ± 1.5 mg/kg. Baseline characteristics are described using the mean (standard deviation [SD]) or median (IQR) for continuous variables and frequencies and percentages for categorical variables. The group comparison was made using t-tests or Wilcoxon rank-sum tests for continuous variables, and Pearson χ2 tests for categorical variables. Associations between induction therapy and AR as well as other outcomes were assessed using logistic regression and Cox regression. To balance the confounding effects of the baseline characteristics on induction therapy and AR, logistic regression and Cox regression methods with propensity score and inverse probability weighting were also used [Supplementary Methods, https://links.lww.com/CM9/C204]. Results were expressed as odds ratio (OR), 95% confidence interval (CI) from the logistic regression, hazard ratio (HR), and 95% CI from the Cox regression. Two-sided P-values <0.05 were considered statistically significant. All statistical analyses were conducted using Stata 15.0 (Stata-Corp LP, College Station, TX, USA) and R 4.3.1 (Lucent Technologies, Murray Hill, NJ, USA). A total of 958 patients were included in the study (395 patients in the basiliximab group and 563 patients in the rATG group) [Supplementary Figure 1, https://links.lww.com/CM9/C204]. The median follow-up time was 26.0 months in the basiliximab group and 30.9 months in the rATG group. A comparison and detailed description of baseline characteristics are shown in Supplementary Table 1 and Supplementary Results, https://links.lww.com/CM9/C204. The total AR incidence during the follow-up period was statistically lower in the basiliximab group than in the rATG group (12.9% vs. 15.8%). Multivariable logistic regression based on multiple imputed data showed that basiliximab induction therapy reduced the overall risk of AR to a greater extent than did rATG induction, with an adjusted OR of 0.61 (95% CI: 0.40–0.93, P = 0.022). Regression models based on complete data and propensity scores also showed similar differences (OR = 0.55 and 0.54, P = 0.006). Furthermore, all three regression models indicated a significant reduction in the risk of early AR within 3 months post-transplantation after basiliximab induction as compared to rATG induction (adjusted OR: 0.49–0.54, P <0.05). The regression models based on complete data and propensity scores showed that basiliximab induction therapy reduced the incidence of AR within 6 months after transplantation as compared to rATG induction (adjusted OR: 0.58 and 0.59, P <0.05). We then divided the patients into three age-related subgroups: ≤3 years old, 4–12 years old, and 13–18 years old. Risk coefficient analysis of the correlation between basiliximab and AR was performed for each subgroup. The advantage of basiliximab in preventing AR as compared to the rATG group was associated overall with recipient age. Regardless of the AR subgroup, basiliximab had a significant advantage over rATG in reducing AR risk for recipients ≤3 years of age (P <0.05). Basiliximab also had a superior protective effect over rATG on total AR in children aged 4–12 years, but did not present a more protective effect on AR in children aged 13–18 years [Figure 1A]. Furthermore, when age were added to the regression model, it was found that, as compared to rATG induction, basiliximab induction significantly reduced the risk of total AR and AR within 3 months in recipients aged 0–11 years. In addition, basiliximab induction showed a superior protective effect over rATG on AR within 6 months and AR within 12 months in recipients aged 0–9 years [Figure 1B].Figure 1: AR risk coefficient analysis based on recipient age. (A) Logistic regression based on age groups. Risk coefficient analysis for each subgroup showed that the advantage of basiliximab in preventing AR, compared to the rATG group, was overall associated with recipient age. (B) The effect of induction therapy on AR at each year of age. The red horizontal line represents the null line, indicating an OR=1 for the induction agent and AR. The red vertical line represents the OR value for AR corresponding to the recipient age. Below this age, the risk of AR with basiliximab was lower than with rATG, while above this age, there was no difference in the risk of AR between basiliximab and rATG. Basiliximab induction significantly reduced the risk of total AR and AR within 3 months in recipients aged 0–11 years. It also showed a superior protective effect over rATG on AR within 6 months and AR within 12 months in recipients aged 0–9 years. *P <0.05. AR: Acute rejection; OR: Odds ratio; rATG: Rabbit anti-thymocyte globulin; y: Year.There were no statistically significant differences in the incidence of DGF, CMV viremia, or urinary tract infection between the two groups. However, the incidence of pneumonia in the basiliximab group (9.1%, 36/395) was significantly lower than that in the rATG group (14.0%, 79/563), with an adjusted OR of 0.46 (95% CI: 0.26–0.81, P = 0.008). In addition, the graft loss rates in the basiliximab group and the rATG group were 8.1% (32/395) and 10.0% (56/563), respectively, and the patient mortality rates in the two groups were 1.0% (4/395) and 1.4% (8/563), respectively, with no statistically significant difference [Supplementary Table 2, https://links.lww.com/CM9/C204]. Our study clarified the advantages of basiliximab induction therapy for reducing AR risk in younger pediatric recipients, which differ from previous reports and perceptions. In a recent report, Riad et al[2] compared the outcomes of 4576 pediatric renal transplant recipients. They found that induction therapy with rATG and basiliximab were comparable in terms of the incidence of AR. The reasons why our results differ from the above may include: (1) the different age composition of the pediatric recipients (≤12 years of age: 56.2% in our study vs. 40.7% in their study); (2) the different cumulative dose of rATG; (3) the transplantation time of the included patients was different: our study was relatively recent (2013–2022), whereas theirs started earlier and took place over a longer period (2000–2018), perhaps contributing to differences in maintenance immunosuppression protocols and drug usage. In addition, a recent report that included 227 pediatric kidney transplant recipients found that induction therapy with a single dose of rATG (3 mg/kg) was associated with higher efficacy for preventing AR compared to basiliximab.[3] Usage of a single high dose of rATG, as well as the older mean age of pediatric recipients (>12 years), may have caused their results to be inconsistent with our findings. It is important to note that the rATG doses were relatively lower in our study. In China, the cumulative dose of rATG used in both adult and pediatric recipients is generally lower than the standard dose (>4.5 mg/kg) used in the United States because of patient tolerance issues and concerns about post-transplant infection. Therefore, it cannot be ruled out that this difference may have contributed to the decreased rATG-induced effect in our study. However, two recent studies in the United States have reported that low-dose rATG is non-inferior to higher or standard dose in low-risk pediatric kidney transplant recipients.[4,5] In addition, despite the small rATG dosage in our study, the incidence of AR at 12 months was 11%, even lower than the rate reported based on US Scientific Registry of Transplant Recipients (SRTR) data (15.7%).[2] Therefore, the advantages of basiliximab induction therapy found in our study should be clinically significant. In conclusion, we have demonstrated that basiliximab induction therapy has advantages over low-dose rATG in pediatric kidney transplant recipients with low immunological risk. In particular, we have shown that the effect of basiliximab induction on AR after pediatric kidney transplantation is significantly associated with recipient age. For pediatric recipients younger than 11 years of age, the use of basiliximab may be better. This study provides an important reference for guiding the rational selection of induction therapy drugs for pediatric kidney transplantation. Acknowledgments We thank Dr. Deborah McClellan for editorial assistance. Funding The study was supported by the Clinical Research Flagship Project of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. 2019CR108). Conflicts of interest None.