Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation

Abstract

SummaryThe premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post-transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post-transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy.

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

“…This is in accordance with recently published data by Gaynor et al, 16 suggesting that trough levels <4 ng/mL should be avoided. This is in accordance with recently published data by Gaynor et al, 16 suggesting that trough levels <4 ng/mL should be avoided.…”

Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation

“…However, when we delineated mean TAC C 0 into different ranges, we found that patients with a mean TAC C 0 of 0 – 3.9 ng/ml and 4 – 5.9 ng/ml had a higher risk of T-cell mediated rejection compared to patients with a mean TAC C 0 of ≥ 8 mg/ml. This finding may be supported by other retrospective reports (32) as well as Gatault et al, as their control group achieved a TAC C 0 of 7.4 ng/ml with 3 episodes of T-cell mediated rejection at 12 months and the intervention group achieved a TAC C 0 of 5.6 ng/ml with 11 episodes of rejection (p=0.016) at 12 months.…”

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…[106] The lower exposure to Tac following standard dosing may be responsible for the higher acute rejection risk after kidney transplantation in recipients of African descent. [112] By contrast, CYP3A5 genotype appears not to be a risk factor for the poorer long-term kidney allograft survival observed in patients of African descent, despite its well-characterized influence on Tac dose requirement. [113] In addition to CYP3A5*3, the CYP3A5*6 and CYP3A5*7 variant alleles can also lead to the absence of functional CYP3A5 protein.…”