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

Abstract

De novo donor-specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)-based regimens are the most common among immunosuppressive approaches used in in clinical practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.32-4.79, P = .005) and by 12 months (OR 2.32, 95% CI 1.30-4.15, P = .004), and there was a graded increase in risk with lower mean TAC C . TAC time in the therapeutic range of <60% was associated with dnDSAs (OR 2.05, 95% CI 1.28-3.30, P = .003) and acute rejection (hazard ratio [HR] 4.18, 95% CI 2.31-7.58, P < .001) by 12 months and death-censored graft loss by 5 years (HR 3.12, 95% CI 1.53-6.37, P = .002). TAC minimization may come at a cost of higher rates of dnDSAs, and TAC time in therapeutic range may be a valuable strategy to stratify patients at increased risk of adverse outcomes.

Once‐daily vs twice‐daily tacrolimus for de novo living kidney transplantation patients including ABO/HLA compatible and incompatible: A randomized trial

“…Although it was not a significant difference, the TAC‐QD group had a considerably higher BPAR rate (HR: 1.87) and a relatively lower trough level in the early period than the TAC‐BID group (Figures and ). This is consistent with other studies that investigated optimal TAC exposure …”

“…This is consistent with other studies that investigated optimal TAC exposure. [26][27][28] TAC has a narrow therapeutic window, and its bioavailability varies between and within individuals. 29 Sapir-Pichhadze et al 30 found that variability in TAC trough levels is a risk factor for late KT failure.…”

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death

“…Consistent with our findings, lower tacrolimus exposure and time in the therapeutic range was found to increase the risk of de novo donor-specific antibodies in the first year of KTx 28. Our control group of animals receiving allografts procured under a non-DCD protocol with 4 hours of cold ischemia functioned well with minimal evidence of tissue injury.However, we found that the early renal function of the DCD allografts was significantly worse than that in the control group with only cold ischemia, suggesting the extended warm ischemia time led to more severe reperfusion injury in this large animal model.…”

“…Consistent with our findings, lower tacrolimus exposure and time in the therapeutic range was found to increase the risk of de novo donor-specific antibodies in the first year of KTx. 28 MHC-I and MHC-II determine the alloimmunogenicity of the grafts after transplantation; MHC-I is expressed in all nucleated cells, whereas the MHC-II is expressed only on antigen-presenting leukocytes, such as macrophage, dendritic cell, and B cells. 29,30 It has been reported that prolonged CIT was associated with higher rates of delayed grafts function (DGF) and AR, which may be related to increased immunogenicity due to IRI-induced alloantigen exposure;…”

Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

“…The desired clinical application of donor‐specific CAR‐Treg therapy would be as a treatment that enables diminished immunosuppression. However, a major risk of immunosuppression minimization is the development of donor‐specific anti‐HLA antibodies (DSAs) and antibody‐mediated rejection . The latter is one of the main causes of allograft loss and there is no effective treatment .…”