Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

High Intrapatient Variability in Tacrolimus Exposure Is Not Associated With Immune-mediated Graft Injury After Liver Transplantation

van der Veer, Marlotte A.A.1; Nangrahary, Negina1; Hesselink, Dennis A.2,3; Erler, Nicole S.4,5; Metselaar, Herold J.3,5; van Gelder, Teun1,3; Darwish Murad, Sarwa MD, PhD3,5

doi: 10.1097/TP.0000000000002680
Original Clinical Science–Liver
Buy

Background. A high intrapatient variability (IPV) in tacrolimus exposure is associated with impaired long-term clinical outcome after kidney transplantation. It remains to be determined if this is equally detrimental for liver transplant recipients. The objective of this study was to investigate the association between IPV in tacrolimus exposure and immune-mediated graft injury after liver transplantation.

Methods. For 326 liver transplant recipients, transplanted between 2000 and 2015, tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 6 and 18 after liver transplantation and expressed as the coefficient of variation. Primary composite endpoint consisted of immune-mediated graft injury (chronic rejection, biopsy proven, and suspected late acute rejection) after month 6. Secondary outcomes were the association between tacrolimus IPV on (1) loss of renal function per year of follow-up and (2) cytomegalovirus viremia after month 6.

Results. Of the 326 included liver transplant recipients, 70 patients (21.5%) reached the primary endpoint. Median tacrolimus coefficient of variation was 28%. There was no significant difference in reaching the primary composite endpoint between the low- and high-IPV groups (P = 0.068). Model for End-Stage Liver Disease score pretransplantation and the number of acute rejections were identified as independent predictors for immune-mediated graft injury (P = 0.049 and 0.016). A higher IPV in combination with a low kidney function at baseline (estimated glomerular filtration rate < 40 mL/min) was associated with greater loss of renal function per year of follow-up (P = 0.007). Tacrolimus variability was not associated with late cytomegalovirus viremia.

Conclusions. High IPV in tacrolimus exposure beyond month 6 postliver transplantation was not associated with immune-mediated graft injury.

1 Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

2 Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

3 Rotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

4 Department of Biostatistics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

5 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Received 30 October 2018. Revision received 20 January 2019.

Accepted 8 February 2019.

D.A.H. has received lecture and consulting fees from Astellas Pharma, Chiesi Pharmaceutici SpA, and Hikma Pharma and grant support from Astellas Pharma and Chiesi Pharmaceutici SpA (paid to the Erasmus MC). T.v.G. has received lecture and consulting fees from Astellas Pharma, Chiesi Pharmaceutici SpA, and Roche Diagnostics and grant support from Astellas Pharma and Chiesi Pharmaceutici SpA (paid to the Erasmus MC).

M.v.d.V., N.N., D.H., H.M., T.v.G., and S.D.M. participated in research design. M.v.d.V. and N.N. participated in the performance of the research.

M.v.d.V., T.v.G., S.D.M., N.N., D.H., and H.M. participated in writing of article.

M.v.d.V. and N.E. participated in data analysis.

There was no funding for this study.

Correspondence: S. Darwish Murad, MD, PhD, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. (s.darwishmurad@erasmusmc.nl).

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.