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

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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 1 2018

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Cytochrome P-450 CYP3A
Graft Rejection
Tacrolimus
African Americans
Genotype
Kidney
Alleles
Transplants
Genomics
Kidney Transplantation
Immunosuppression
Transplant Recipients

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Cite this

@article{000db2eb913049e6b6494d8e76ea7e52,
title = "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",
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.",
keywords = "acute rejection, graft failure, intra-patient variability, kidney transplant, tacrolimus",
author = "Seibert, {Stephan R.} and Schladt, {David P.} and Baolin Wu and Weihua Guan and Casey Dorr and Remmel, {Rory P} and Matas, {Arthur J} and Mannon, {Roslyn B.} and Israni, {Ajay K.} and Oetting, {William S} and Jacobson, {Pamala A}",
year = "2018",
month = "12",
day = "1",
doi = "10.1111/ctr.13424",
language = "English (US)",
volume = "32",
journal = "Clinical Transplantation",
issn = "0902-0063",
publisher = "Wiley-Blackwell",
number = "12",

}

TY - JOUR

T1 - Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype

T2 - Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

AU - Seibert, Stephan R.

AU - Schladt, David P.

AU - Wu, Baolin

AU - Guan, Weihua

AU - Dorr, Casey

AU - Remmel, Rory P

AU - Matas, Arthur J

AU - Mannon, Roslyn B.

AU - Israni, Ajay K.

AU - Oetting, William S

AU - Jacobson, Pamala A

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - acute rejection

KW - graft failure

KW - intra-patient variability

KW - kidney transplant

KW - tacrolimus

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U2 - 10.1111/ctr.13424

DO - 10.1111/ctr.13424

M3 - Article

C2 - 30318646

AN - SCOPUS:85055740404

VL - 32

JO - Clinical Transplantation

JF - Clinical Transplantation

SN - 0902-0063

IS - 12

M1 - e13424

ER -