Tacrolimus Dose Variability, CYP3A5 Genotype, and Acute Rejection in African American and European American Kidney Transplant Recipients.

S. Seibert,¹ D. Schladt,² B. Wu,³ W. Guan,³ C. Dorr,^2,7 D. Berglund,¹ R. Remmel,⁴ A. Matas,⁵ R. Mannon,⁶ A. Israni,^2,7 W. Oetting,¹ P. Jacobson,¹ For the DeKAF Genomics Investigators.

¹Dept of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota (UMN), Mpls, MN
²Chronic Disease Research Group, Minneapolis Medical Research Foundation, Mpls, MN
³Division of Biostatistics, School of Public Health, UMN, Mpls, MN
⁴Dept of Medicinal Chemistry, College of Pharmacy, UMN, Mpls, MN
⁵Division of Transplantation, Dept of Surgery, School of Medicine, UMN, Mpls, MN
⁶Dept of Nephrology, University of Alabama, Birmingham, AL
⁷Dept of Nephrology, Hennepin County Medical Center, School of Medicine, UMN, Mpls, MN

Meeting: 2017 American Transplant Congress

Abstract number: D65

Keywords: Gene polymorphism, Immunosuppression, Kidney transplantation, Rejection

Session Information

Session Name: Poster Session D: Kidney Immunosuppression: Novel Regimens and Drug Minimization

Session Type: Poster Session

Date: Tuesday, May 2, 2017

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Background: Poor immunosuppression with tacrolimus (TAC) after kidney transplantation contributes to the development of toxicity and loss of efficacy. We aimed to associate intra-patient TAC pharmacokinetic variability in adult African American (AA) and European American (EA) kidney transplant recipients with acute rejection (AR) and CYP3A5 loss of function (LOF) alleles.

Methods: Coefficients of variation of TAC trough concentrations (CVTT) and CV of TAC doses (CVTD) in the first 6 months after transplantation were tested for associations with AR and number of CYP3A5 LOF alleles (*3, *6, *7) in 246 AA and 1226 EA recipients separately.

Results: Mean CVTT was larger among AA recipients (AA: 30.17% vs EA: 25.18%, p<0.0001) while CVTD was larger among EA recipients (AA: 11.46% vs EA 16.60%, p<0.0001). AR occurred in 5.7% of AA and 6.8% of EA. CVTT was not associated with AR, but the recipients with the highest quartiles of CVTD (CV>19% AA; CV>24% EA) were at increased risk for AR in AA (hazard ratio (HR): 33.53, p=0.0001) and EA (HR: 1.81, p=0.012) in multivariable Cox proportional hazard models. In EA but not AA, an increasing number of CYP3A5 LOF alleles was associated with a lower CVTT and higher CVTD. In AA, each LOF allele was associated with an 84.5% reduction in risk of AR relative to those with no LOF alleles (HR 0.155, p=0.0015).

Conclusion: After adjusting for clinical factors, high variability of TAC doses in the first 6 months after transplant increases the risk for AR in AA and EA recipients. TAC dose variability is influenced by CYP3A5 genotype in EA recipients. CYP3A5 LOF alleles may be protective against AR in AA.

This work was supported by NIAID grants 5U19-AI070119 and 5U01-AI058013.

CITATION INFORMATION: Seibert S, Schladt D, Wu B, Guan W, Dorr C, Berglund D, Remmel R, Matas A, Mannon R, Israni A, Oetting W, Jacobson P, For the DeKAF Genomics Investigators Tacrolimus Dose Variability, CYP3A5 Genotype, and Acute Rejection in African American and European American Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Seibert S, Schladt D, Wu B, Guan W, Dorr C, Berglund D, Remmel R, Matas A, Mannon R, Israni A, Oetting W, Jacobson P. Tacrolimus Dose Variability, CYP3A5 Genotype, and Acute Rejection in African American and European American Kidney Transplant Recipients. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/tacrolimus-dose-variability-cyp3a5-genotype-and-acute-rejection-in-african-american-and-european-american-kidney-transplant-recipients/. Accessed November 22, 2024.

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