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Keywords:

tacrolimus dose, pharmacokinetics, cyp3a4, cyp3a5, p-glycoprotein, abcb1, single nucleotide polymorphisms, renal transplantation, calcineurin inhibitor-associated nephrotoxicity, tacrolimus nephrotoxicity, single-nucleotide polymorphisms, kidney-transplant recipients, future-directions, acute rejection, mdr1 gene, cyclosporine, expression, toxicity, biopsies, Adult, Aged, Area Under Curve, Biopsy, Calcineurin, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Genotype, Humans, Immunosuppressive Agents, Kaplan-Meiers Estimate, Kidney Diseases, Kidney Transplantation, Male, Middle Aged, P-Glycoprotein, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Risk Factors, Tacrolimus, Treatment Outcome, Science & Technology, Life Sciences & Biomedicine, Medical Laboratory Technology, Pharmacology & Pharmacy, Toxicology, CYP3A4, CYP3A5, P-glycoprotein, ABCB1, SINGLE-NUCLEOTIDE POLYMORPHISMS, KIDNEY-TRANSPLANT RECIPIENTS, P-GLYCOPROTEIN, FUTURE-DIRECTIONS, ACUTE REJECTION, MDR1 GENE, CYCLOSPORINE, EXPRESSION, TOXICITY, BIOPSIES, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Calcineurin Inhibitors, Kaplan-Meier Estimate, 0301 Analytical Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

OBJECTIVES: Prolonged calcineurin inhibitor maintenance therapy in kidney allograft recipients is complicated by the development of chronic irreversible drug-induced nephrotoxicity (CNIT). METHODS: In 304 de novo renal graft recipients, the association among tacrolimus exposure indices (dose, C(0), AUC(0-12h)), CYP3A5, CYP3A4 and ABCB1 polymorphisms, clinical covariables and de novo arteriolar hyalinization as a histologic sign of CNIT was examined. RESULTS: Tacrolimus C(0) and AUC(0-12h) at 3 and 12 months posttransplantation did not differ between patients with and without CNIT. Patients who developed CNIT more often carried the CYP3A5*1 allele (32.4% versus 15.2%, P = 0.01). Twenty-five percent of recipients with tacrolimus dose requirements exceeding 0.2 mg/kg per day at 3 months posttransplantation developed CNIT, whereas 16.2% of patients with dose requirements between 0.10 and 0.20 mg/kg per day and 4.5% of patients who needed less than 0.10 mg/kg per day developed CNIT (P < 0.0001). These early differences in tacrolimus dose requirements between recipients with and without CNIT persisted during subsequent follow-up. In a Cox proportional hazards analysis, the CYP3A5*1 allele (hazard ratio: 2.38; 95% confidence interval: 1.15-4.92) or tacrolimus dose range (hazard ratio: 2.06; 95% confidence interval: 1.30-3.27) and continued corticosteroid therapy (hazard ratio: 4.75; 95% confidence interval: 1.13-19.98) were independently associated with CNIT. A Kaplan-Meier survival curve demonstrated a significant difference in CNIT-free survival (93.5% versus 81.8% versus 66.9%; log-rank test: P = 0.0006) between patients with, respectively, tacrolimus dose requirements less than 0.1, 0.1 or greater, less than 0.2, and 0.2 mg/kg per day or greater. More patients with CNIT sustained graft loss during follow-up (32.3% versus13.7%, P = 0.004). CONCLUSIONS: High early tacrolimus dose requirements, predominantly but not exclusively encountered in CYP3A5*1 expressers, are associated with the development of calcineurin inhibitor-related nephrotoxicity, especially in recipients who continue corticosteroid therapy.