Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation

Yohan Park; Hanbi Lee; Sang Hun Eum; Eun Jeong Ko; Ji Won Min; Se-Hee Yoon; Won-Min Hwang; Sung-Ro Yun; Chul Woo Yang; Jieun Shin; Byung Ha Chung

doi:10.3389/fimmu.2022.1037566

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation

Front Immunol. 2022 Nov 16:13:1037566. doi: 10.3389/fimmu.2022.1037566. eCollection 2022.

Authors

Yohan Park^{1

2}, Hanbi Lee^{2

3}, Sang Hun Eum^{2

4}, Eun Jeong Ko^{2

3}, Ji Won Min^{2

5}, Se-Hee Yoon¹, Won-Min Hwang¹, Sung-Ro Yun¹, Chul Woo Yang^{2

3}, Jieun Shin⁶, Byung Ha Chung^{2

3}

Affiliations

¹ Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea.
² Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
³ Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
⁴ Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
⁵ Division of Nephrology, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
⁶ Department of Biomedical Informatics, College of Medicine, Konyang University, Nonsan, South Korea.

Abstract

Introduction: Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT.

Methods: In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared.

Results: The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup.

Discussion: High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Keywords: allograft; graft survival; metabolism; tacrolimus; transplant.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Humans
Kidney Transplantation* / adverse effects
Tacrolimus* / therapeutic use
Tissue Donors
Transplantation, Homologous

Substances

Tacrolimus