Influence of Tacrolimus Metabolism Rate on Kidney Graft Survival

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Abstract

Introduction

For clinical routine, a low ratio between tacrolimus trough level and daily tacrolimus dosage (metabolism rate) was suggested as a useful parameter for identification of patients with an increased risk of inferior kidney function after transplantation. Using the data from the Collaborative Transplant Study (CTS) we evaluated the clinical usefulness of the metabolism rate and analyzed whether it identifies all patients with an increased risk of graft loss due to low tacrolimus exposure.

Materials and Methods

More than 10,000 adult patients who received a deceased donor kidney transplant between 2000 and 2015 and who had a functioning graft >1 years and known tacrolimus dosage and trough level at year 1 were analyzed by the Kaplan-Meier-Method for graft survival during the post-transplant years 2–5. The findings were confirmed by multivariate Cox-regression analysis.

Results

Analysis of graft survival demonstrated that a tacrolimus trough level of <5 ng/ml at 1 year post-transplant was significantly associated with inferior graft survival during post-transplant years 2 to 5. An inferior outcome was also observed in patients with a high daily tacrolimus dosage of ≥0.12 mg/day/kg. Considering these cut-offs, particularly poor graft survival was found in the group of patients with the lowest metabolism rate (low trough level despite a high dose; hazard rate (HR) 2.95, P<0.001) (Figure 1). The univariate analysis of the metabolism rate revealed that a value of 50 mg*day/ml is a suitable cut-off for poor graft survival. However, even in patients with a poor metabolism rate of <50, a sufficient trough level resulted in good graft survival (Figure 2a). Conversely, patients with a good metabolism rate of ≥50 showed inferior graft survival if the trough level was <5 ng/ml (Figure 2b).

Discussion

Because both the trough level as well as the dosage were known for all patients, an unintended under- or overdosing of tacrolimus could be excluded. Patients with a very low tacrolimus metabolism rate had a high risk of graft loss; however, they made up only 1.5% of the study population. Patients with a below-average metabolism rate can either have a low trough level and normal dosage (15% of all patients) or a medium trough level and high dosage (13%). Only the first of these two groups showed a significantly worse graft survival (HR=1.39, P<0.001). Importantly, the risk of graft failure increased by more than 50% in patients with a good renal function (creatinine of <130 μmol/L, no rejection treatment) if the 5 ng/ml trough level was not achieved (HR=1.52, P=0.006).

Conclusion

The CTS data indicate that regardless of the tacrolimus metabolism rate, good results are obtained only with a tacrolimus trough level of ≥5 ng/ml.

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