Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.
OBJECTIVE
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.
Department of Nephrology and Renal Transplantation, University Hospitals of Leuven, Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
Dirk R J
DR
Kuypers
Maarten
M
Naesens
Hylke
H
de Jonge
Evelyne
E
Lerut
Kristin
K
Verbeke
Yves
Y
Vanrenterghem
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001706:Biopsy; D065095:Calcineurin Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007674:Kidney Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus