PMID- 36466843 OWN - NLM STAT- MEDLINE DCOM- 20221206 LR - 20221206 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation. PG - 1037566 LID - 10.3389/fimmu.2022.1037566 [doi] LID - 1037566 AB - 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. CI - Copyright (c) 2022 Park, Lee, Eum, Ko, Min, Yoon, Hwang, Yun, Yang, Shin and Chung. FAU - Park, Yohan AU - Park Y AD - Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea. AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Lee, Hanbi AU - Lee H AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Eum, Sang Hun AU - Eum SH AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Ko, Eun Jeong AU - Ko EJ AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Min, Ji Won AU - Min JW AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Yoon, Se-Hee AU - Yoon SH AD - Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea. FAU - Hwang, Won-Min AU - Hwang WM AD - Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea. FAU - Yun, Sung-Ro AU - Yun SR AD - Division of Nephrology, Department of Internal Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, South Korea. FAU - Yang, Chul Woo AU - Yang CW AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Shin, Jieun AU - Shin J AD - Department of Biomedical Informatics, College of Medicine, Konyang University, Nonsan, South Korea. FAU - Chung, Byung Ha AU - Chung BH AD - Transplantation Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. AD - Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221116 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - WM0HAQ4WNM (Tacrolimus) SB - IM MH - Humans MH - *Tacrolimus/therapeutic use MH - *Kidney Transplantation/adverse effects MH - Transplantation, Homologous MH - Tissue Donors MH - Allografts PMC - PMC9709474 OTO - NOTNLM OT - allograft OT - graft survival OT - metabolism OT - tacrolimus OT - transplant COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/12/06 06:00 MHDA- 2022/12/07 06:00 PMCR- 2022/01/01 CRDT- 2022/12/05 04:12 PHST- 2022/09/06 00:00 [received] PHST- 2022/11/02 00:00 [accepted] PHST- 2022/12/05 04:12 [entrez] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.1037566 [doi] PST - epublish SO - Front Immunol. 2022 Nov 16;13:1037566. doi: 10.3389/fimmu.2022.1037566. eCollection 2022.