Optimal tacrolimus levels for reducing CKD risk and the impact of intrapatient variability on CKD and ESRD development following liver transplantation

Abstract

Background/aims: This study aimed to identify the risk factors for chronic kidney disease (CKD) and end-stage renal disease (ESRD) following liver transplantation (LT), with a specific focus on tacrolimus levels and intrapatient variability (IPV).

Methods: Among the 1,076 patients who underwent LT between 2000 and 2018, 952 were included in the analysis. The tacrolimus doses and levels were recorded every 3 months, and the IPV was calculated using the coefficient of variability. The cumulative incidence rates of CKD and ESRD were calculated based on baseline kidney function at the time of LT. The impact of tacrolimus levels and their IPV on the development of CKD and ESRD was evaluated, and the significant risk factors were identified.

Results: Within a median follow-up of 97.3 months, the 5-year cumulative incidence rates of CKD (0.58 vs. 0.24) and ESRD (0.07 vs. 0.01) were significantly higher in the acute kidney injury group than in the normal glomerular filtration rate (GFR) group. In the normal GFR group, the tacrolimus levels were identified as a risk factor for CKD, with a level of ≤4.5 ng/mL suggested as optimal for minimizing the risk of CKD. Furthermore, the IPV of tacrolimus levels and doses emerged as a significant risk factor for CKD development in both groups (p<0.05), with tenofovir disoproxil fumarate also being a risk factor in HBV-infected patients. The IPV of tacrolimus levels was also a significant factor in ESRD development (p<0.05).

Conclusion: This study elucidated the optimal tacrolimus trough level and highlighted the impact of IPV on the CKD and ESRD development post-LT.

Keywords: Chronic kidney disease; Diabetes mellitus; Liver transplantation; Tacrolimus; Tenofovir.

Figure 1.

(A, B) Cumulative incidence of CKD based on the baseline GFR at the time of LT. (C) Changes in the kidney function in CKD patients from the normal GFR group. (D, E) Changes in the distribution of kidney function according to the baseline GFR at LT time. CKD, chronic kidney disease; GFR, glomerular filtration rate; LT, liver transplantation.

Figure 2.

(A, B) Changes in the eGFR in ESRD patients and (C) cumulative incidence of ESRD according to the baseline GFR at the time of LT. eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; LT, liver transplantation; ESRD, end-stage renal disease.

Figure 3.

Changes in the risk of CKD development according to the tacrolimus level among patients with normal GFR at (A) the time of LT and (B) 1-year post-LT time. GFR, glomerular filtration rate; LT, liver transplantation; CKD, chronic kidney disease.

Figure 4.

Comparison in the serial changes of the tacrolimus level according to the development of (A, B) CKD and (C, D) ESRD. CKD, chronic kidney disease; ESRD, end-stage renal disease.

Figure 5.

Comparison of (A, B) total and (C, D) 3-year intrapatient variability between patients with and without CKD development during follow-up. (E, F) Comparison of total intrapatient variability between patients with ESRD, CKD without ESRD, and without CKD development during follow-up. CKD, chronic kidney disease; ESRD, end-stage renal disease; CV, coefficient of variants.