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Impact of Tacrolimus Intraindividual Variability and CYP3A5 Genetic Polymorphism on Acute Rejection in Kidney Transplantation

Ro, Han MD, PhD*; Min, Sang-Il MD, PhD; Yang, Jaeseok MD, PhD†,‡; Moon, Kyung Chul MD, PhD§; Kim, Yon Su MD, PhD; Kim, Sang Joon MD, PhD; Ahn, Curie MD, PhD‡,¶,‖; Ha, Jongwon MD, PhD‡,‖

doi: 10.1097/FTD.0b013e3182731809
Original Article

Background: Wide variation in tacrolimus concentrations and low tacrolimus exposure have been reported to be associated with poor renal graft outcomes in non-Asians. The CYP3A5 polymorphism is a representative genetic factor that might affect this association, together with environmental factors. We investigated whether tacrolimus variability or the mean tacrolimus trough concentration can influence kidney allograft outcomes in Asians and whether the CYP3A5 polymorphism (rs776746) can affect this relationship.

Methods: Data from renal transplant patients between 2000 and 2010 were analyzed retrospectively. The tacrolimus intraindividual variability (IIV) and the mean tacrolimus trough concentration were calculated from the tacrolimus concentrations between 6 and 12 months after transplantation.

Results: A total of 249 renal transplant patients were enrolled. The patients with higher tacrolimus IIV had shorter rejection-free survival (P = 0.002). However, there was no difference in rejection-free survival between CYP3A5 expressers and nonexpressers. The tacrolimus IIV was not associated with the CYP3A5 polymorphism. High IIV of tacrolimus was an independent risk factor of biopsy-proven acute rejection after adjusting for mean tacrolimus concentration, HLA mismatch, induction therapy, donor type, and CYP3A5 polymorphism (hazard ratio 2.655, 95% confidence interval 1.394–5.056). Interestingly, the impact of tacrolimus IIV on acute rejection was significant in CYP3A5 expressers, whereas it was not in CYP3A5 nonexpressers.

Conclusions: The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.

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*Department of Internal Medicine, Gachon University Gil Medical Center, Incheon

Department of Surgery

Transplantation Research Institute, Seoul National University College of Medicine, Seoul

§Department of Pathology, Seoul National University Hospital, Seoul

Department of Internal Medicine, Seoul National University College of Medicine, Seoul

Transplantation Center, Seoul National University Hospital, Seoul, Korea.

Correspondence: Jaeseok Yang, MD, PhD, Transplantation Center, Seoul National University Hospital, 28, Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea (e-mail:

Supported by a grant from the Ministry of Knowledge Economy, Republic of Korea (project no. 10033838).

The authors declare no conflict of interest.

H. Ro and S.-I. Min equally contributed to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions this article on the journal's Web site (

Received March 12, 2012

Accepted September 06, 2012

© 2012 Lippincott Williams & Wilkins, Inc.