We sincerely appreciate Professor Kim’s interest in our study and his thoughtful comments in the editorial [1]. As Professor Kim mentioned, chronic kidney disease (CKD) develops in up to 45% of patients following liver transplantation (LT), significantly impacting patient survival [2-4]. Similarly, in our study, approximately 36% (n=341) of the 952 included patients developed CKD during a median follow-up of 97.3 months [5]. Given the impact of CKD on increased mortality in LT patients, identifying risk factors for CKD and end-stage renal disease (ESRD), as assessed in our study, remains a critical issue in LT management.

As Professor Kim commented, multiple factors contribute to the development of CKD after LT in a complex manner. In this context, identifying the optimal trough level of tacrolimus—a cornerstone immunosuppressant for LT patients— to reduce CKD risk, alongside other potential risk factors, is one of the key highlights of our study. Through detailed analysis, we demonstrated that a tacrolimus level of ≤4.5 ng/mL is optimal for reducing CKD risk in patients with normal kidney function at the time of LT, while a level of ≤4.0 ng/mL is optimal beyond the first year post-transplantation [6]. Moreover, we identified tenofovir disoproxil fumarate as an additional risk factor for CKD development in patients with hepatitis B virus infection, underscoring the need to consider alternative antiviral options, such as tenofovir alafenamide [6,7], to mitigate CKD risk in this high-risk population.

Meanwhile, although we attempted to assess potential risk factors for CKD in our analyses, unmeasured variables—such as the use of potentially nephrotoxic drugs and various complications—may have influenced CKD development [8,9]. In particular, regarding IPV in tacrolimus levels, we agree with Professor Kim’s comments that IPV can be affected by multiple factors, including genetic polymorphisms in cytochrome P450, poor compliance, and various complications [3,10]. Although our study found no significant differences in the rate of rejection or critical infections between patients with higher and lower IPV in tacrolimus levels [6], other unmeasured complications—such as biliary complications, hepatocellular carcinoma recurrence, and de novo malignancy—may have influenced IPV [1]. Moreover, with the increasing use of mammalian target of rapamycin inhibitors in combination with lower tacrolimus doses in LT patients, evaluating the impact of combination therapy on IPV in tacrolimus levels and subsequent CKD development is warranted in future studies. To further elucidate the role of IPV in tacrolimus levels—a novel finding of our study—on CKD and ESRD development, additional research is needed to enhance our understanding of its clinical implications.

In conclusion, our findings provide clinical recommendations and perspectives on tacrolimus levels and their IPV in relation to CKD development. We determined that maintaining tacrolimus levels ≤4.5 ng/mL is optimal for reducing CKD risk in patients with normal kidney function at the time of LT, while keeping tacrolimus levels ≤4.0 ng/mL beyond the first year post-LT is ideal. Moreover, we highlight the impact of IPV in tacrolimus levels on CKD and ESRD development, emphasizing the importance of minimizing steep fluctuations in tacrolimus levels in LT patients. To further validate these findings and enhance their clinical implications, additional studies are warranted.