Intrapatient variability of tacrolimus trough level may be not the cause, but an indirect parameter of comorbidities: Editorial on “Optimal tacrolimus levels for reducing CKD risk and the impact of intrapatient variability on CKD and ESRD development following liver transplantation”

Article information

Clin Mol Hepatol. 2025;31(2):589-591

Publication date (electronic) : 2025 January 24

doi : https://doi.org/10.3350/cmh.2025.0076

Jongman Kim

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Corresponding author : Jongman Kim Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-1719, Fax: +82-2-3410-0040, E-mail: yjongman21@gmail.com

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

Received 2025 January 20; Accepted 2025 January 23.

The development of chronic kidney disease (CKD) or end-stage renal disease (ESRD) in liver transplant recipients is a major challenge [1-3]. Tacrolimus is a major immunosuppressant after liver transplantation [4,5]. If it is overused, it increases the risk of renal dysfunction, hypertension, diabetes, and de novo malignancy. If it is underused, it can cause acute rejection and graft failure [1,6]. Therefore, maintaining an appropriate drug dose and trough level balance is crucial in patient management after liver transplantation (LT) [7]. This study’s examination of tacrolimus levels and intrapatient variability (IPV) in tacrolimus trough level is timely and therapeutically pertinent, given that CKD impacts up to 45% of LT patients and substantially elevates mortality risk [8]. This work addresses a significant gap in the care of liver transplant patients by defining appropriate tacrolimus thresholds and demonstrating the influence of IPV on long-term kidney outcomes. Investigating the link between tacrolimus concentration and clinical disorders is a challenging endeavor.

This study utilizes a substantial cohort of 952 liver transplant patients with a median follow-up duration of 97.3 months [8]. The authors rigorously assess the long-term effects of tacrolimus levels and IPV on the progression of CKD and ESRD following LT, utilizing kidney function trends, risk factor analysis, and sophisticated statistical methodologies, such as time-dependent competing risk models, to enhance the robustness of the results. The current study offers practical recommendations for transplant-related physicians and transplant surgeons, including keeping tacrolimus levels below 4.0 ng/mL beyond the first year post-transplantation and treating IPV to mitigate the chances of CKD and ESRD. This research also underscores the effects of tenofovir disoproxil fumarate in patients infected with hepatitis B virus (HBV), providing customized management approaches for this high-risk population.

The development of CKD post-transplantation is affected by pre-transplant renal function; however, multiple factors interact in a complex manner [1]. This study identifies disparities in baseline features across the comparison groups, including an elevated incidence of CKD (59.5%) and ESRD (10%) in the acute kidney injury group relative to the normal glomerular filtration rate group. The difficulties of attributing the onset of CKD and ESRD post-transplantation to tacrolimus trough levels and IPV are evident, considering the definitive state of kidney function before and after transplantation. Elevated IPV may arise from multiple sources. IPV is influenced by poor medication adherence and the presence or lack of cytochrome 3A5 expression [5]. In addition, various complications including biliary complications, infections, HBV recurrence, hepatocellular carcinoma recurrence, and de novo malignancy necessitate ongoing adjustments in tacrolimus dosage, which can perpetuate liver graft and renal injury, potentially culminating in CKD and ESRD [7,9,10]. In the present study, patients did not undergo tacrolimus monotherapy exclusively. A multitude of patients received combination therapy using mammalian target of rapamycin inhibitors or mycophenolate mofetil. It is necessary to examine the impact of this combination of medications on renal function. Additionally, research on the impact of tacrolimus IPV should be carried out using homogeneous data devoid of exceptional events to yield unequivocal evidence.

Lee et al.’s study significantly enhances our understanding of CKD and ESRD hazards post-transplantation by identifying optimal tacrolimus dosages and emphasizing the significance of IPV [8]. These findings provide insight that will inform clinical guidelines; however, further research is necessary to mitigate the limitations and confirm the results in various contexts.