We sincerely appreciate the letter from Professor Rui Shi regarding our publication [1]. We are grateful for the insightful comments and have addressed them in detail in the following discussion.

As this study was conducted in Korea, where hepatitis B infection has historically been the leading cause of liver transplantation (LT) until recently [2], the generalizability of our findings requires further validation in other regions. In recent years, the proportion of LT cases due to alcohol-associated liver disease has been increasing in Korea, alongside a rapid rise in the demand for LT in patients with metabolic dysfunction-associated steatotic liver disease in Europe and the United States [2,3]. Therefore, further investigation is warranted to assess the impact of intrapatient variability (IPV) in tacrolimus levels on the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD) following LT across different countries and time period. Despite this limitation, our study successfully identified the risk associated with IPV in tacrolimus levels, as well as the impact of tenofovir disoproxil fumarate (TDF) on CKD development in the LT setting [4]. Currently, limited data exist on the risk of TDF-induced CKD in LT patients, with only a recent study demonstrating a higher CKD risk associated with TDF compared to entecavir in this population [5]. Furthermore, our study simultaneously evaluated the risk of TDF alongside tacrolimus levels and their IPV in CKD development, allowing us to identify the significance of both factors. In Korea, TDF at a dose of 300 mg per day is a reimbursed treatment option for LT patients, whereas tenofovir alafenamide (TAF) is not covered by national insurance for this population [6]. Our findings provide valuable insights into the potential need for alternative antiviral therapies, including TAF, to mitigate CKD risk in LT patients.

Acute kidney injury (AKI) is a well-known risk factor for CKD development, underscoring the need for tailored management both before and after LT [7]. In our study, LT patients with AKI at the time of LT demonstrated a significantly higher rate of CKD development. As Professor Rui Shi noted, controlling AKI during the early post-LT period is also a crucial aspect of LT management [7,8]. Although our study consistently demonstrated the significance of IPV in tacrolimus levels on CKD development in both the normal kidney function and AKI groups at the time of LT, further investigation is needed to evaluate patient outcomes based on recovery from AKI during the early post-LT period and to assess the impact of IPV in these patients. Moreover, the retrospective design of our study inherently presents limitations, particularly in addressing unmeasured variables such as genetic polymorphisms in cytochrome P450 (CYP450) enzymes and concomitant medications. However, we aimed to mitigate this limitation by incorporating several potential risk factors for CKD development, including diabetes mellitus (DM), hypertension, and age, in our analysis of tacrolimus’s impact. Through detailed analyses, we consistently identified the significant impact of IPV in tacrolimus levels on CKD development, alongside the role of DM in CKD progression.

Our study also identified cut-off tacrolimus levels for reducing CKD risk in LT patients with normal kidney function at the time of LT and at 1-year post-LT. Given the increased potential risk of rejection at lower tacrolimus levels, it is crucial to maintain an appropriate balance to prevent both rejection and CKD development. In this regard, the combination of mammalian target of rapamycin inhibitors (mTORi) with a minimized tacrolimus dose offers a practical strategy to achieve lower tacrolimus levels while simultaneously reducing the risk of both rejection and CKD development. [8,9]. Indeed, similar to findings from randomized controlled trials, our previous study demonstrated improvements in renal function among LT patients following the use of mTORi [10,11]. Further studies focusing on LT patients receiving combination immunosuppressant therapy are warranted to optimize long-term outcomes.

Regarding the management of IPV, as Professor Rui Shi mentioned, it remains unclear whether minimizing IPV is clinically feasible for all patients. Tacrolimus is primarily metabolized by CYP450, and it has been shown that CYP3A51 expressors are fast metabolizers, while slow metabolizers predominantly express CYP3A53, leading to slower tacrolimus metabolism [12,13]. Given the significant impact of IPV on CKD development in LT patients observed in our study, further research is needed to identify factors influencing IPV, including genetic polymorphisms in CYP450. Based on our study, careful monitoring of tacrolimus levels and the implementation of meticulous management strategies—such as maintaining stable levels and avoiding excessive elevations or abrupt fluctuations—will be essential moving forward to minimize the risk of CKD and ESRD in LT patients.