The study by Lee et al., published in Clin Mol Hepatol, provides valuable insights into the long-term risks of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in liver transplant (LT) recipients, with a particular focus on the role of tacrolimus levels and intrapatient variability (IPV) [1]. The findings are timely given the increasing incidence of CKD and ESRD in LT patients, and the study’s rigorous longitudinal design adds to our understanding of immunosuppressive management after LT. However, despite its merits, several limitations warrant further discussion to clarify the broader applicability and implications of these findings.

The cohort consists primarily of patients from a single tertiary hospital in South Korea, which may limit the extrapolation of the results to other geographic regions, particularly areas with different patient demographics or healthcare systems. For example, patients from regions with high rates of hepatitis B virus infection treated with antiviral therapies such as tenofovir disoproxil fumarate (TDF) may have different outcomes compared to populations with a higher prevalence of hepatitis C or alcohol-related liver disease. In addition, the study distinguishes between LT patients with normal glomerular filtration rate and those with acute kidney injury (AKI) at the time of transplantation. While this stratification is important, the analysis of the long-term effects of AKI is confounded by the lack of detailed evaluation of the severity and reversibility of AKI at baseline. It is unclear whether patients who recovered from AKI during the early post-LT period experienced different renal outcomes compared to those with persistent renal dysfunction.

Second, the study identifies tacrolimus IPV as a significant risk factor for CKD and ESRD, but the clinical interpretation of IPV remains complex. While variations in tacrolimus levels are associated with worse outcomes, the underlying mechanisms for this relationship are not fully understood. Tacrolimus metabolism is influenced by numerous factors, including genetic polymorphisms in cytochrome P450 enzymes [2], concomitant medications, and comorbidities such as diabetes mellitus (DM) [3]. The study does not address whether IPV is primarily driven by pharmacokinetic factors (e.g., variability in drug absorption or metabolism) or external clinical factors (e.g., abrupt dose adjustments due to rejection or infection). As a result, it remains unclear whether minimizing IPV is clinically feasible or whether other factors, such as optimizing tacrolimus dosing strategies or incorporating alternative immunosuppressants, could reduce the risk of CKD.

Third, although the study provides valuable data on the long-term development of CKD and ESRD after LT, the median follow-up of approximately 8 years may not be sufficient to fully capture the cumulative effects of tacrolimus on renal function. Long-term renal outcomes may be influenced by other evolving factors, such as the progressive development of fibrosis, infection, or the development of malignancy [4]. Furthermore, while the study shows an association between tacrolimus levels and renal dysfunction, it does not establish causality. The observed association between high tacrolimus levels and CKD could be influenced by confounding variables, such as pre-existing comorbidities, which were not fully adjusted for in the analysis. A randomized controlled trial would be needed to definitively determine whether tacrolimus IPV directly contributes to CKD progression or whether other unmeasured factors play a more important role.

Fourth, the identification of TDF as a risk factor for CKD in HBV-infected LT patients is another important contribution of the study. However, the retrospective nature of the analysis limits the ability to draw definitive conclusions about the mechanistic role of TDF. While the association between TDF and renal dysfunction is well established in non-LT populations, the specific effects of TDF in LT recipients may differ due to immunosuppressive therapy and other factors unique to this patient population. In addition, the study does not account for the possibility of dose-dependent effects of TDF or the long-term effects of antiviral resistance on renal function, both of which could influence renal outcomes. Further studies with prospective designs and detailed analyses of TDF dosage and duration of use would provide clearer evidence of its role in post-LT renal dysfunction.

Finally, the study also highlights the role of several clinical factors in the development of CKD, including DM and tacrolimus dosage adjustments. However, unmeasured confounders such as patient medication adherence, comorbid conditions, and variations in post-LT care (e.g., infection management and renal protection strategies) may influence the observed associations. Reliance on medical records for data collection introduces potential biases in the measurement of clinical outcomes, and variations in clinical practice between hospitals may affect the generalizability of the results. For example, the use of alternative immunosuppressive regimens, such as mammalian target of rapamycin inhibitors, may not have been adequately considered in the analysis, despite their growing role in minimizing the risk of CKD after LT.