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

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.