Clinical outcomes of standard vs. delayed initiation of immediate-release tacrolimus following donation after circulatory death in kidney transplantation in China: Results from a randomized controlled trial

To the Editor: Globally and in China, there are shortages of available organs and long transplantation waitlists. Donation after cardiac (or circulatory) death (DCD) and donation after brain death are extensively studied methods of organ donation from deceased donors and have emerged as a potential way of enlarging the donor pool.[1] DCD has historically been associated with worse clinical outcomes after transplant although advances in immunosuppressive therapies, anti-human leukocyte antigen antibody detection, and transplantation techniques have improved outcomes.[1] A major concern for DCD kidney transplantation is a high incidence of delayed graft function (DGF).[1] DGF has been associated with many factors including age, sex, and race of the donor or recipient, cold and warm ischemia times, and calcineurin inhibitor (CNI) at discharge.[2] CNIs are known for their potential effect on kidneys due to arteriolar vasoconstriction, which induces acute tubular dysfunction.[3] Consequently, the use of CNIs in DCD kidney transplant recipients is considered a clinical challenge given the potential risks associated with DGF.[4,5] Strategies such as the delayed initiation of tacrolimus after transplant have been explored to compensate for this effect.[3] Here, we explored the efficacy and safety of alternative immunosuppressive regimens: delayed initiation of immediate-release tacrolimus (IR-TAC; Prograf®, Astellas Pharma China, Inc.) vs. standard initiation of IR-TAC regimen on graft function after receiving a DCD kidney transplant. This was a phase IV, prospective, randomized, controlled, multicenter, open-label clinical study (registered in ClinicalTrials.gov, NCT03644485) conducted in adult patients with end stage renal disease suitable for primary DCD kidney transplantation. Patients were enrolled across 15 centers in China from October 21, 2018, to July 15, 2022. The full list of inclusion and exclusion criteria is included in Supplementary Materials, https://links.lww.com/CM9/C333. Eligible patients were randomized 1:1 into two groups. In both groups, patients received twice-daily IR-TAC together with induction therapy for one month [Supplementary Figure 1, https://links.lww.com/CM9/C333] followed by conversion to once-daily prolonged-release tacrolimus (PR-TAC) for five months. In the standard IR-TAC group, the twice-daily IR-TAC was administered within 24 h of kidney transplantation. In the delayed IR-TAC group, the twice-daily IR-TAC was administered beyond 48 h but within 120 h after kidney transplantation. The study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines and applicable national laws and regulations. Independent Ethics Committee approval of the study protocol was obtained prior to study initiation. Written informed consent was obtained from patients prior to study participation. The primary endpoint was the incidence of DGF within the first week after transplantation. DGF was defined as a dialysis requirement during the first seven days after transplant in this study. The key secondary endpoints included the incidence of acute rejection (AR; including biopsy-proven and clinically suspected AR), renal function measured by estimated glomerular filtration rate (eGFR; derived using the abbreviated Modification of Diet in Renal Disease formula) at one month and six months after transplantation, patient and graft survival six months after transplantation, and the incidence, severity, causality of treatment-emergent adverse events (TEAEs) and 6-months serious adverse events (SAEs) throughout the study period. The efficacy analysis was performed on the full analysis set (FAS), which included all randomized patients who received at least one dose of the study drug and had at least one efficacy data value after treatment. The primary objective was assessed by a non-inferiority analysis. A statistically significant test was made at the alpha = 0.05 level without adjustments for multiplicity. The safety analysis was conducted using the safety analysis set (SAF), which included all randomized patients who received at least one dose of the study drug. Patients were allocated to the groups according to the treatment received. The graft survival and patient survival rates for the FAS and 95% confidence interval (CI) were estimated using the Kaplan–Meier method and Greenwood formula. The P-values reported for biopsy-proven AR were based on Fisher’s exact test and for clinically suspected AR on a chi-squared test. The sample size was calculated using Power Analysis and Sample Size Version 11 software (NCSS, Kaysville, USA). SAS® Version 9.4 (SAS Institute, Cary, USA) was used to process, summarize, and analyze data. Of the 315 patients who signed the informed consent form during the study, 31 patients were screen failures, and the remaining 284 patients were randomized. The FAS comprised 278 patients (delayed IR-TAC group: 140, standard IR-TAC group: 138). The SAF comprised 278 patients (delayed IR-TAC group: 137, standard IR-TAC group: 141). Overall, for FAS, the mean age of recipients was 42.2 years; 73.7% (205) were males, and 97.5% (271) were Han. The baseline demographics and characteristics were similar in both groups [Supplementary Table 1, https://links.lww.com/CM9/C333]. As per the inclusion criteria, 93.9% and 6.1% of donor kidneys were Maastricht Class III and Class IV, respectively. Other donor characteristics are presented in Supplementary Table 1, https://links.lww.com/CM9/C333. Overall, the mean tacrolimus daily dose was 5.42 mg. The mean tacrolimus daily dose was similar in both groups (delayed IR-TAC group: 5.38 mg, standard IR-TAC group: 5.46 mg). During the study period, the mean tacrolimus blood trough concentration was above 6 ng/mL [Supplementary Figure 2, https://links.lww.com/CM9/C333]. The delayed IR-TAC group had slightly higher blood concentration early after the transplant compared with the standard IR-TAC group. After conversion to PR-TAC at day 30, trough levels remained generally similar between both groups throughout the study. The incidence of DGF within the first week after transplantation was 23.9% (95% CI: 17.1–31.9%) in the standard IR-TAC group compared with 20.0% (95% CI: 13.7–27.6%) in the delayed IR-TAC group [Figure 1A]. The difference in incidence between the two groups was −3.9% (−13.6, 5.8%). As the upper limit of the CIs was less than 15% these results demonstrate that delayed IR-TAC was non-inferior to standard IR-TAC. The incidence of clinically suspected AR six months after transplantation was 5.7% [95% CI: 2.5–10.9%] in the delayed IR-TAC group and 2.9% [95% CI: 0.8–7.3%] in the standard IR-TAC group [Figure 1B]. The incidence of biopsy-proven AR over the same period was the same in both groups (1.4% [95% CI: 0.2–5.1%]) [Figure 1C]. Overall, the incidences of AR were similar between both groups. There was an increase in eGFR after transplantation and after conversion to PR-TAC at day 30, eGFR remained stable throughout the study in both groups [Supplementary Figure 3, https://links.lww.com/CM9/C333]. Patient survival rates six months after transplantation were 98.6% in the standard IR-TAC group compared with 100% in the delayed IR-TAC group [Supplementary Table 2, https://links.lww.com/CM9/C333]. There were two deaths in the standard IR-TAC group. One patient died on day 33 due to serious TEAEs of myocardial infarction and epilepsy and the death was considered unrelated to the study drug, and one patient died during the follow-up period on day 246 due to septic shock. Graft survival (death with a functioning graft was treated as graft failure) was 99.3% in the standard IR-TAC group compared with 100% in the delayed IR-TAC group [Supplementary Table 3, https://links.lww.com/CM9/C333]. There was one graft failure (0.7%) and two deaths with a functioning graft (1.4%) in the standard IR-TAC group. Overall, 35.5% and 35.8% of patients reported drug-related TEAEs in the standard IR-TAC group and the delayed IR-TAC group, respectively [Supplementary Table 4, https://links.lww.com/CM9/C333]. The most common drug-related TEAEs were hyperlipidemia (4.3%), hyperglycemia (3.6%), urinary tract infection (3.2%), pneumonia (2.9%), hyperkalemia (2.5%), diabetes mellitus (2.5%), hepatic function abnormal (2.2%), and blood creatinine increased (2.2%). Overall, the TEAEs related to the study drug were balanced between both groups.Figure 1: Incidence of DGF within the first week after transplantation (A) and incidence of clinically suspected (B) and biopsy-proven (C) AR (FAS). *The first week after transplantation was calculated from the end date of transplantation. †Wald asymptotic confidence limits for the difference in the incidence of DGF (incidence in the delayed IR-TAC group – incidence in standard IR-TAC group) is presented, if the upper limit of the 95% CI was less than 15%, it could be concluded that the efficacy was non-inferior between groups. ‡ P-value calculated via chi-squared test. § P-value calculated via Fisher’s exact test. AR: Acute rejection; CI: Confidence interval; DGF: Delayed graft function; FAS: Full analysis set; IR-TAC: Immediate-release tacrolimus.Our prospective study aimed to explore the clinical impact of the timing of initiation for IR-TAC, given together with induction therapy, followed by conversion to PR-TAC in DCD kidney transplantation recipients in China. This study found that the incidence of DGF was similar in kidney transplant recipients receiving either delayed or standard initiation of IR-TAC with similar tolerability profiles. These results suggest that the delayed initiation of IR-TAC, together with induction treatment followed by PR-TAC, could be a viable immunosuppressive regimen for DCD kidney transplantation recipients. Importantly, these findings expand the array of treatment options available to treating physicians, allowing them the opportunity to individualize their treatment approach. The incidence of AR was comparable between groups. The renal function remained generally stable after transplantation in both groups and after conversion to PR-TAC at day 30, with a significant difference between groups at day 180. Our study had some limitations. This was an open-label study with only a short 6-month follow-up. Furthermore, a control group of patients who did not convert to PR-TAC was not included. Our study was a prospective, randomized, controlled, multicenter study to assess different initiation timings of IR-TAC, combined with induction treatment followed by conversion to PR-TAC, in DCD kidney transplant recipients from China. The incidence of DGF within the first week after DCD kidney transplantation was similar between groups. The safety profile was consistent with other tacrolimus studies and generally comparable between both groups. The delayed initiation of IR-TAC, together with induction therapy followed by conversion to PR-TAC, is a potential alternative immunosuppressive regimen that provides treating physicians with adaptable options for tailoring patient care. Prior publication A summary of this study was submitted to and accepted by the 21st Biennial Congress of the European Society for Organ Transplantation (ESOT) as an abstract and for a brief poster presentation in Athens, Greece, on September 17–20, 2023. Acknowledgments The authors would like to thank all centers participating in this study. The authors thank Shilpa Khobragade, PhD, and Pedro de Campos Silva, PhD, from Lumanity Scientific Inc. for providing medical writing support/editorial support. Conflicts of interest This study and its resultant publications were initiated, funded, and reviewed by Astellas Pharma China, Inc. Medical writing and editorial support was funded by Astellas Pharma China, Inc. All authors report non-financial support from Astellas during the conduct of the study. LZ had an unpaid role as Secretary-General for the Society of Transplant Technology, China Medicinal Biotechnology Association. ZS, JX, JC, CW, WS, MG, WX, and ZC have nothing to disclose. JW and RH are employees of Astellas China. MB is an employee of Astellas Pharma Europe. MS is an employee of Astellas Pharma Singapore Pte Ltd.