Objectives: The impact of DGF on tacrolimus Cmin and dose requirements was evaluated in renal transplant recipients in the first postoperative week. The effects of the CYP3A5*3 A6986G polymorphism on initial mean tacrolimus Cmin and dose requirements in the presence and absence of DGF were assessed. This study also tested the hypothesis that if DGF influences early tacrolimus exposure, this would lead to a higher risk for NODAT (defined as the need for glucose-lowering medication for an uninterrupted period of ≥26 weeks).
Methods: This prospective, open-label, observational clinical cohort study enrolled renal allograft recipients aged ≥18 years. Tacrolimus was administered as an oral loading dose of 0.2 mg/kg/d and adjusted to achieve a target mean daily tacrolimus Cmin between 12 and 15 ng/mL. Cmin values and oral dose requirements in the first postoperative week were compared between patients with and without DGF. Patients were genotyped for the CYP3A4*1B -290A>G, CYP3A5*3 A6986G, ABCB1 Exon26 C3435T, ABCB1 Exon21 G2677T, and ABCB1 Exon21 G2677A single nucleotide polymorphisms. NODAT that occurred within the first 12 weeks after transplantation was confirmed using an oral glucose tolerance test.
Results: A total of 304 patients were enrolled (184 men, 120 women; mean [SD] age, 52.9 [14.1] years). Through day 3 after transplantation, mean (SD) 12-hour tacrolimus Cmin values were significantly higher in recipients experiencing DGF despite identical loading doses of 0.2 mg/kg. Mean tacrolimus dose requirements were significantly lower in patients with DGF during the first week. After recovery of DGF, mean tacrolimus dose requirements were not significantly different between recipients with and without DGF. In homozygous CYP3A5*3 carriers (n = 252), mean (SD) tacrolimus dose requirements remained significantly lower during DGF, while in CYP3A5*1 carriers with DGF (n = 52), lower mean dose requirements were observed only after postoperative day 4. The proportion of patients in whom NODAT developed was significantly greater in patients with DGF and tacrolimus Cmin >15 ng/mL on the first day after transplantation (27.2 % ) compared with recipients who remained free of DGF and had Cmin ≤15 ng/mL on day 1 (6.5 % ) (P = 0.016). On logistic regression analysis, greater recipient age (odds ratio [OR] = 1.044; 95 % CI, 1.009–1.080), higher tacrolimus Cmin on day 1 (OR = 1.048; 95 % CI, 1.017–1.080), and DGF (OR = 2.968; 95 % CI, 1.107–7.959) were associated with an increased risk for NODAT.
Conclusion: In this open-label, observational study, DGF was associated with higher initial mean tacrolimus Cmin values and lower daily dose requirements predominantly in CYP3A5 nonexpressers.