*Purpose: African American patients generally have a rapid metabolism and thus require higher doses of tacrolimus after kidney transplantation. Ketoconazole inhibits tacrolimus metabolism and can be used to reduce the dosage and financial cost of the latter. The long-term safety of this practice has not been reported.

*Methods: African American kidney transplant patients were identified from the Tulane University Hospital transplant database between 2006 and 2010. Among them, ketoconazole was given to 127 patients (Group 1) while 82 patients did not receive ketoconazole (Group 2). All received triple maintenance therapy of tacrolimus, mycophenolate, and steroid. Protocol biopsy was performed in all patients to confirm acute rejection.

*Results: There was no significant difference in patient demographics between the two groups. Both groups achieved similar trough levels while Group 1 required significantly lower doses of tacrolimus. The 5-year incidence of acute rejection was significantly higher in Group 1 than in Group 2 (38.6% vs 20.7%, p = 0.01). Kaplan-Meier analysis of 5-year graft survival (69.3% vs 75.6%, p = 0.3) and patient survival (85% vs 87.8%, p = 0.6) showed no statistical difference between the groups. Multivariable analysis showed that the addition of ketoconazole was an independent risk factor for acute rejection (HR 3.13, 95% CI 1.28-7.60; p = 0.012), while a higher tacrolimus dose in the 2^nd month of transplant was protective (HR 0.79, 95% CI 0.64-0.91; p = 0.036).

*Conclusions: Combination therapy of ketoconazole and tacrolimus significantly increases the risk of acute rejection in African Americans after kidney transplantation. The higher incidence of acute rejection may be related to the lowered dose of tacrolimus from ketoconazole co-administration. Further study is needed to define the pharmacokinetic curve of tacrolimus when co-administered with ketoconazole so that proper tacrolimus trough levels can be determined for clinical practice.

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