Development of de novo donor-specific antibodies (dnDSA) is the first step in the evolution of antibody-mediated rejection, which constitutes the leading cause of death-censored graft loss. Tacrolimus (TAC) is one of the most commonly used medications for maintenance immunosuppression. Over the past decade, TAC minimization strategies have been employed to mitigate toxicity, however it is unknown whether this practice increases the risk for dnDSA. The purpose of this study was to identify a lower threshold of mean TAC trough levels associated with increased risk of dnDSA.

From 2007 to 2013, consecutive kidney transplant recipients who were initiated and maintained on TAC as part of their maintenance triple immunosuppression regimen in the first year of transplant were prospectively screened for dnDSA at months 1, 6, 12, and when clinically indicated. TAC troughs measured 2 weeks to 12 months or until dnDSA development were used for analysis and levels exceeding 20 ng/ml were individually evaluated by chart review. Logistic regression was used to calculate odds ratios, which were adjusted for HLA mismatches, age, gender, ethnicity, donor type, induction therapy, and delayed graft function.

There were 562 patients included in the analysis with 134 (23.8%) patients who developed dnDSA by 12 months. 53 (9.4%) and 71 (12.6%) patients had a mean TAC trough of <7 ng/ml at 6 months and 12 months, respectively. A mean TAC trough <7 ng/ml within the first 6 months post-transplant was associated with dnDSA by 6 months (OR 2.25, 95% CI 1.39-3.65, p=0.001) and a mean trough level <7 ng/ml within 12 months was associated with dnDSA by 12 months (OR 1.88, 95% CI 1.23-2.88, p=0.004). There was a graded increase in risk of dnDSA by 6 months with lower mean TAC troughs (<6 ng/ml: OR 2.58, 95% CI 1.48-4.48, p<0.001; <5 ng/ml: OR 3.14, 95% CI 1.47-6.71, p=0.003; <4 ng/ml: 3.76, 95% CI 1.16-12.23, p=0.028; <3 ng/ml: 5.24, 95% CI 1.17-23.51, p=0.031) and this trend was consistent for dnDSA by 12 months.

Our results are the first to show progressively lower TAC trough levels associate with increasing risk of dnDSA development. Caution should be used when dosing TAC troughs below 7.0 ng/ml within the first year of kidney transplantation.

CITATION INFORMATION: Davis S, Gralla J, Klem P, Wiseman A, Cooper J. Lower Mean Tacrolimus Troughs Increase Risk of De Novo Donor-Specific Antibodies in the First Year of Kidney Transplant. Am J Transplant. 2017;17 (suppl 3).

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