The Importance of Using Serially Measured Tacrolimus Clearance Values, Especially During the Early Posttransplantation Period

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We read with interest the recent article by Egeland et al,1 in which they demonstrated a significantly higher hazard rate of first biopsy-proven acute rejection (BPAR) during the first 90 days after transplantation among patients having a higher tacrolimus (TAC) clearance, ie, daily TAC dose (mg) divided by TAC (12 hour) trough level (ng/mL), measured at 8 weeks after transplantation. Specifically, among 638 adults receiving (1) a kidney transplant at Oslo University Hospital between January 2009 and December 2013, and (2) TAC, mycophenolate mofetil, and corticosteroids as maintenance, 13.3% (85/638) developed a first BPAR (during the first 90 days after transplantation). Median time-to-first BPAR was 8 days after transplantation. Patients with a TAC clearance of more than 1.45 103 L at 8 weeks after transplantation, for example, representing 9.4% (60/638) of the cohort, had a significantly higher BPAR rate (P < 0.0001), which was maintained (either as a categorical or continuous variable, P < 0.001) after controlling for other significant baseline predictors in a Cox multivariable model.
We have 2 major concerns with their analysis and conclusions as reported. First, in viewing their Kaplan-Meier freedom-from-BPAR comparisons (Figures 1-3 in their paper), the unfavorable effect of higher TAC clearance seems to exist mainly during the first 10 to 14 days after transplantation; no unfavorable effect seemed to exist beyond that time. Apparently, no such time by covariate interaction effect was either reported or tested.
Second, in our opinion, the effect of TAC clearance should have been tested as a time-dependent covariate, with risk sets determined at each BPAR time point according to higher versus lower TAC clearance measurements at those times (or at least determined based on measurements made at times closer to the BPAR events, eg, at 7, 14, and 28 days after transplantation). Except for the patients who developed BPAR, in which TAC clearance measurements just before BPAR were used, the risk set at each BPAR time point for patients not developing BPAR was determined based on the TAC clearance measurement at 8 weeks after transplantation (as far as we could tell). An accurate assessment would compare at each BPAR time point (especially before 14 days after transplantation) patients with higher versus lower TAC clearance measurements at those time points, not at 8 weeks after transplantation. For patients not developing BPAR (86.7% of the cohort), our concern is that the authors’ approximation of TAC clearance at the early BPAR time points (ie, <14 days after transplantation) by the 8 week posttransplantation measurement may not be so accurate.
Several reports including 1 from our center2 have shown that if maintenance corticosteroids are used, then TAC clearance is significantly higher (ie, TAC bioavailability is significantly lower). In our report, use of maintenance corticosteroids at 1 month after transplantation (with an average daily dose of 10-15 mg) implied that the TAC dose (mg) needed to be 20% higher to achieve a comparable TAC trough level (to those not taking maintenance corticosteroids). In the study by Egeland et al,1 whereas the planned maintenance corticosteroid (prednisolone) dose at 8 weeks after transplantation was 10 mg for all patients, the starting dose was 20 mg in standard-risk patients (537/638) and, in fact, 80 mg in high-risk (101/638) patients. In addition, the intravenous dose of methylprednisolone given to standard-risk and high-risk patients on day 0 was 250 mg and 500 mg, respectively.
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