Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

Stephan R. Seibert, David P. Schladt, Baolin Wu, Weihua Guan, Casey Dorr, Rory P. Remmel, Arthur J. Matas, Roslyn B. Mannon, Ajay K. Israni, William S. Oetting, Pamala A. Jacobson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability. Methods: Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients’ number of CYP3A5 loss-of-function alleles was assessed. Results: Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001). Conclusion: CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes.

Original languageEnglish (US)
Article numbere13424
JournalClinical Transplantation
Volume32
Issue number12
DOIs
StatePublished - Dec 2018

Bibliographical note

Funding Information:
We acknowledge the contributions of our generous patients. We also acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers, and Danielle Berglund; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientists Marcia Brott and Amutha Muthusamy. This study was supported in part by NIH/NIAID grants 5U19‐AI070119 and 5U01‐AI058013. DeKAF Investigators: Arthur Matas, MD, Department of Surgery, University of Minnesota, Minneapolis, MN, Email: matas001@umn. edu; J. Michael Cecka, MD, UCLA Immunogenetics Center, Los Angeles, CA, Email: mcecka@ucla.edu; John Connett, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN, Email: john‐ c@biostat.umn.edu; Fernando G. Cosio, MD, Division of Nephrology, Mayo Clinic, Rochester, MN, Email: Cosio.Fernando@mayo.edu; Robert Gaston, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, Email: rgaston@uab.edu; Roslyn Mannon, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, Email: rmannon@uab.edu; Sita Gourishankar,MD, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada, Email: sitag@ual‐ berta.ca; Joseph P. Grande, MD, PhD, Mayo Clinic College of Medicine, Rochester, MN, Email: Grande.Joseph@mayo.edu; Lawrence Hunsicker, MD, Nephrology Division, Iowa City, IA, Email: lawrence‐ hunsicker@uiowa.edu; Bertram Kasiske, MD, Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN, Email: kasis001@ umn.edu; and David Rush, MD, Health Sciences Center, Winnipeg MB, Canada, Email: drush@exchange.hsc.mb.ca. Participating Centers: Participating transplant centers were University of Alberta, Edmonton, Canada; University of Manitoba, Winnipeg, Canada; University of Minnesota, Minneapolis, MN; Hennepin County Medical Center, Minneapolis, MN; Mayo Clinic, Rochester, MN; University of Iowa, Iowa City, IA; and University of Alabama, Birmingham, AL.

Funding Information:
Funding information This project was supported by grants (U19-AI070119 and U01-AI058013) from the National Institute of Allergy and Infectious Disease (AM, PJ, AI, WO) and by a Melendy Student Research Scholarship, University of Minnesota, College of Pharmacy (SS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or National Institute of Allergy and Infectious Disease. We acknowledge the contributions of our generous patients. We also acknowledge the dedication and hard work of our coordinators at each of the DeKAF Genomics clinical sites: University of Alberta, Nicoleta Bobocea, Tina Wong, Adrian Geambasu and Alyssa Sader; University of Manitoba, Myrna Ross and Kathy Peters; University of Minnesota, Mandi DeGrote, Monica Meyers, and Danielle Berglund; Hennepin County Medical Center, Lisa Berndt; Mayo Clinic, Tom DeLeeuw; University of Iowa, Wendy Wallace and Tammy Lowe; University of Alabama, Jacquelin Vaughn, Valencia Stephens and Tena Hilario. We also acknowledge the dedicated work of our research scientists Marcia Brott and Amutha Muthusamy. This study was supported in part by NIH/NIAID grants 5U19-AI070119 and 5U01-AI058013. DeKAF Investigators: Arthur Matas, MD, Department of Surgery, University of Minnesota, Minneapolis, MN, Email: matas001@umn.edu; J. Michael Cecka, MD, UCLA Immunogenetics Center, Los Angeles, CA, Email: mcecka@ucla.edu; John Connett, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN, Email: john-c@biostat.umn.edu; Fernando G. Cosio, MD, Division of Nephrology, Mayo Clinic, Rochester, MN, Email: Cosio.Fernando@mayo.edu; Robert Gaston, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, Email: rgaston@uab.edu; Roslyn Mannon, MD, Division of Nephrology, University of Alabama, Division of Nephrology, Birmingham, AL, Email: rmannon@uab.edu; Sita Gourishankar,MD, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada, Email: sitag@ualberta.ca; Joseph P. Grande, MD, PhD, Mayo Clinic College of Medicine, Rochester, MN, Email: Grande.Joseph@mayo.edu; Lawrence Hunsicker, MD, Nephrology Division, Iowa City, IA, Email: lawrencehunsicker@uiowa.edu; Bertram Kasiske, MD, Division of Nephrology, Hennepin County Medical Center, Minneapolis, MN, Email: kasis001@umn.edu; and David Rush, MD, Health Sciences Center, Winnipeg MB, Canada, Email: drush@exchange.hsc.mb.ca. Participating Centers: Participating transplant centers were University of Alberta, Edmonton, Canada; University of Manitoba, Winnipeg, Canada; University of Minnesota, Minneapolis, MN; Hennepin County Medical Center, Minneapolis, MN; Mayo Clinic, Rochester, MN; University of Iowa, Iowa City, IA; and University of Alabama, Birmingham, AL.

Funding Information:
This project was supported by grants (U19‐ AI070119 and U01‐AI058013) from the National Institute of Allergy and Infectious Disease (AM, PJ, AI, WO) and by a Melendy Student Research Scholarship, University of Minnesota, College of Pharmacy (SS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or National Institute of Allergy and Infectious Disease.

Publisher Copyright:
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords

  • acute rejection
  • graft failure
  • intra-patient variability
  • kidney transplant
  • tacrolimus

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