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Clinical Research
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Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development

Chris Wiebe, David N. Rush, Thomas E. Nevins, Patricia E. Birk, Tom Blydt-Hansen, Ian W. Gibson, Aviva Goldberg, Julie Ho, Martin Karpinski, Denise Pochinco, Atul Sharma, Leroy Storsley, Arthur J. Matas and Peter W. Nickerson
JASN November 2017, 28 (11) 3353-3362; DOI: https://doi.org/10.1681/ASN.2017030287
Chris Wiebe
Departments of *Medicine,
†Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada;
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David N. Rush
Departments of *Medicine,
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Thomas E. Nevins
Departments of ‡Pediatrics and
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Patricia E. Birk
§Pediatrics and Child Health,
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Tom Blydt-Hansen
‖Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
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Ian W. Gibson
†Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada;
¶Pathology, and
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Aviva Goldberg
§Pediatrics and Child Health,
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Julie Ho
Departments of *Medicine,
**Immunology, University of Manitoba, Winnipeg, Manitoba, Canada;
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Martin Karpinski
Departments of *Medicine,
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Denise Pochinco
†Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada;
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Atul Sharma
§Pediatrics and Child Health,
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Leroy Storsley
Departments of *Medicine,
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Arthur J. Matas
††Surgery, University of Minnesota, Minneapolis, Minnesota; and
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Peter W. Nickerson
Departments of *Medicine,
†Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada;
**Immunology, University of Manitoba, Winnipeg, Manitoba, Canada;
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Abstract

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient’s individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.

  • kidney transplantation
  • acute allograft rejection
  • donor specific antibody
  • Human leukocyte antigen
  • tacrolimus
  • allograft survival
  • Copyright © 2017 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 28 (11)
Journal of the American Society of Nephrology
Vol. 28, Issue 11
November 2017
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Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development
Chris Wiebe, David N. Rush, Thomas E. Nevins, Patricia E. Birk, Tom Blydt-Hansen, Ian W. Gibson, Aviva Goldberg, Julie Ho, Martin Karpinski, Denise Pochinco, Atul Sharma, Leroy Storsley, Arthur J. Matas, Peter W. Nickerson
JASN Nov 2017, 28 (11) 3353-3362; DOI: 10.1681/ASN.2017030287

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Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development
Chris Wiebe, David N. Rush, Thomas E. Nevins, Patricia E. Birk, Tom Blydt-Hansen, Ian W. Gibson, Aviva Goldberg, Julie Ho, Martin Karpinski, Denise Pochinco, Atul Sharma, Leroy Storsley, Arthur J. Matas, Peter W. Nickerson
JASN Nov 2017, 28 (11) 3353-3362; DOI: 10.1681/ASN.2017030287
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More in this TOC Section

  • Protocadherin 7–Associated Membranous Nephropathy
  • Advance Care Planning in Older Adults with CKD: Patient, Care Partner, and Clinician Perspectives
  • Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness
Show more Clinical Research

Cited By...

  • Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study
  • Molecular Mismatch--the Renaissance of HLA in Kidney Transplantation
  • Evaluation and Treatment of Acute Rejection in Kidney Allografts
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Keywords

  • kidney transplantation
  • acute allograft rejection
  • donor specific antibody
  • human leukocyte antigen
  • tacrolimus
  • allograft survival

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