Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics

Abstract

Most calcineurin inhibitor (CNI) based protocols reduce blood trough goals approximately 2–3 months post-transplant in clinically stable kidney transplant recipients. The CNI target trough level to prevent rejection, after reduction, is unknown. Using a multivariate Cox proportional hazards model we determined the association of time-varying tacrolimus (TAC) trough levels with acute rejection (AR) occurring in the first 6 months post-transplant, but specifically we assessed this association after 3 months. 1,930 patients received TAC based immunosuppression prior to AR in a prospective study. Of the 151 (7.8%) who developed AR, 47 developed AR after 3 months post-transplant. In an adjusted time varying multivariate model, each 1 ng/mL decrease in TAC trough levels was associated with a 7.2% increased risk of AR [HR=1.07, 95% CI (1.01, 1.14) P=0.03] in the first 6 months. There was an additional 23% increased risk of AR with each 1 ng/mL decrease in the TAC trough levels in months 3–6 [HR=1.23, 95% CI (1.06, 1.43) P=0.008]. In conclusion, lower TAC trough levels were significantly associated with increased risk of AR in the first 6 months post-transplant with additional risk of AR between months 3–6 post-transplant. The timing and practice of TAC dose reduction should be personalized based on the individual’s risk factors.

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation

“…They demonstrated in a multivariate analysis that low mean Tac exposure was independently associated with higher increase in biopsy‐proven chronicity scores [calculated as the sum of the four basic “chronic” Banff qualifiers (chronic glomerular damage, interstitial fibrosis, tubular atrophy, and vascular intimal thickening)] between 3 and 12 months after the transplantation. Recently, in the DeKAF study, a lower Tac exposure after month 3 was also associated with an increased risk of acute rejection . The association between the Tac IPV and poor kidney transplantation outcome was not significantly modified within four patients subgroups based on their mean Tac C 0 .…”

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

“…While our results do not match exactly with those reported by others, for example, Israni et al . reported a significant interaction effect of TAC level with time since transplant, and Richards et al . .…”

“…below the initial target TAC trough level of 8–11 ng/ml). Another recent study of 1930 patients found a significant association between lower TAC trough levels (on a continuous scale) and a significantly higher AR rate during the first 6 months post‐transplant in a Cox multivariable model, with an even stronger relationship found during 3–6 months vs. 0–3 months post‐transplant (i.e. interaction effect of TAC trough level with time post‐transplant).…”

Tacrolimus trough and dose intra‐patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

“…Tacrolimus has a narrow therapeutic window with high inter‐patient pharmacokinetic variability, requiring close monitoring of blood trough concentrations (initial goal 8‐12 ng/mL) and frequent early dose adjustments to reduce the risk of poor outcomes. Concentrations above the therapeutic range are associated with adverse effects such as nephrotoxicity, while sub‐therapeutic concentrations may increase the risk of acute rejection (AR) and graft failure (GF) . Many factors have been identified contributing to TAC inter‐patient pharmacokinetic variability such as drug‐drug interactions, drug‐food interactions, changes in hepatic metabolism, and nonadherence …”

“…Concentrations above the therapeutic range are associated with adverse effects such as nephrotoxicity, while sub-therapeutic concentrations may increase the risk of acute rejection (AR) and graft failure (GF). 1 Many factors have been identified contributing to TAC inter-patient pharmacokinetic variability such as drug-drug interactions, drug-food interactions, changes in hepatic metabolism, and nonadherence. 2 Genetic factors are also well-known to account for TAC pharmacokinetics differences between patients and several single-nucleotide polymorphisms (SNPs) have been associated with TAC troughs, including CYP3A5*3, CYP3A5*6, CYP3A5*7, CYP3A4*22, and possibly POR*28.…”