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Introduction <p>Tacrolimus is a critical immunosuppressive agent in kidney transplantation, but its pharmacokinetic variability, especially intra-patient variability (IPV), can lead to suboptimal outcomes. Genetic polymorphisms in CYP3A5 and ABCC2 may influence tacrolimus metabolism and transport, affecting dosing requirements and IPV. However, their combined impact during the first year after kidney transplantation remains insufficiently characterized.</p> Aim <p>This study aimed to evaluate the influence of <i>CYP3A5*3 (rs776746)</i> and <i>ABCC2 (rs3740066, rs2273697)</i> polymorphisms on tacrolimus exposure, IPV (C0-IPV and C0/D-IPV), and short-term renal allograft function in kidney transplant recipients, with a focus on the first post-transplant year.</p> Method <p>A prospective cohort of 60 kidney transplant recipients was followed for one year. Tacrolimus trough concentrations (C0) were measured on postoperative Day 7, Day 14, Month 1, Month 3, Month 6, and Year 1. IPV was assessed using C0-IPV and dose-adjusted C0/D-IPV. Genotyping was performed using the SNaPshot platform. Multivariable regression models identified predictors of IPV and renal allograft function was evaluated by estimated glomerular filtration rate (eGFR) at Year 1.</p> Results <p><i>CYP3A5*3</i> expressers required significantly higher tacrolimus doses than non-expressers from Day 7 through Month 3 (<i>P</i> &lt; 0.05) and showed correspondingly lower C0/D values during this period (<i>P</i> &lt; 0.01). <i>ABCC2 rs3740066</i> was associated with C0/D at Month 6 (<i>P</i> = 0.037) and with the daily dose at Year 1 (<i>P</i> = 0.045). In the multivariable analysis, the <i>ABCC2 rs2273697</i> variant (β = 8.429, 95% CI: 1.301–15.557, <i>P</i> = 0.021) was independently associated with tacrolimus C0-IPV. No significant associations were observed between IPV (C0-IPV or C0/D-IPV) and eGFR at Year 1.</p> Conclusion <p><i>CYP3A5</i> genotyping remains valuable for optimizing initial tacrolimus dosing, while <i>ABCC2</i> polymorphisms, particularly <i>rs2273697</i>, contribute to tacrolimus C0-IPV during the first post-transplant year. Personalized dosing strategies using pharmacogenetic data could improve tacrolimus exposure stability. Larger studies with extended follow-up are needed to assess the long-term clinical implications of these findings.</p>

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ABCC2 rs2273697 is an independent determinant of tacrolimus intra-patient variability during the first year after kidney transplantation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Jia You,
  • Hongxia Liu,
  • Yunyun Yang,
  • JiaZhao Fu,
  • Mingxing Sui,
  • Wenyu Zhao,
  • Zhilong Yuan,
  • Tao Ma,
  • Zhuo Wang,
  • Xuebin Wang

摘要

Introduction

Tacrolimus is a critical immunosuppressive agent in kidney transplantation, but its pharmacokinetic variability, especially intra-patient variability (IPV), can lead to suboptimal outcomes. Genetic polymorphisms in CYP3A5 and ABCC2 may influence tacrolimus metabolism and transport, affecting dosing requirements and IPV. However, their combined impact during the first year after kidney transplantation remains insufficiently characterized.

Aim

This study aimed to evaluate the influence of CYP3A5*3 (rs776746) and ABCC2 (rs3740066, rs2273697) polymorphisms on tacrolimus exposure, IPV (C0-IPV and C0/D-IPV), and short-term renal allograft function in kidney transplant recipients, with a focus on the first post-transplant year.

Method

A prospective cohort of 60 kidney transplant recipients was followed for one year. Tacrolimus trough concentrations (C0) were measured on postoperative Day 7, Day 14, Month 1, Month 3, Month 6, and Year 1. IPV was assessed using C0-IPV and dose-adjusted C0/D-IPV. Genotyping was performed using the SNaPshot platform. Multivariable regression models identified predictors of IPV and renal allograft function was evaluated by estimated glomerular filtration rate (eGFR) at Year 1.

Results

CYP3A5*3 expressers required significantly higher tacrolimus doses than non-expressers from Day 7 through Month 3 (P < 0.05) and showed correspondingly lower C0/D values during this period (P < 0.01). ABCC2 rs3740066 was associated with C0/D at Month 6 (P = 0.037) and with the daily dose at Year 1 (P = 0.045). In the multivariable analysis, the ABCC2 rs2273697 variant (β = 8.429, 95% CI: 1.301–15.557, P = 0.021) was independently associated with tacrolimus C0-IPV. No significant associations were observed between IPV (C0-IPV or C0/D-IPV) and eGFR at Year 1.

Conclusion

CYP3A5 genotyping remains valuable for optimizing initial tacrolimus dosing, while ABCC2 polymorphisms, particularly rs2273697, contribute to tacrolimus C0-IPV during the first post-transplant year. Personalized dosing strategies using pharmacogenetic data could improve tacrolimus exposure stability. Larger studies with extended follow-up are needed to assess the long-term clinical implications of these findings.