Genetic polymorphism associated with high intra-patient variability in tacrolimus exposure and biopsy-proven nephrotoxicity of tacrolimus
Hyo Kee Keem1, Jaeseong Oh2, Sangil Min1, Chris Tae young Chung1, Hyejin Mo1, Hyunmin Ko1, Ahram Han1, Jongwon Ha1.
1Surgery, Seoul National University Hospital, Seoul, Korea; 2Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Korea
Introduction: Tacrolimus is known to have a narrow therapeutic window. The intra-patient variability (IPV) is defined as the fluctuation in tacrolimus concentration within an individual patient over a certain period of time. Although the high IPV of tacrolimus has been reported to be associated with long term inferior outcomes of renal transplantation, there are only a few studies which shows an association of tacrolimus IPV and renal toxicity. In addition, the influence of genetic polymorphism on the tacrolimus IPV remains still controversial.
Methods: A total of 101 patients who received the renal transplantation in Seoul national university hospital were prospectively enrolled in this study. The coefficient of variation (CV) which represents the ratio of the standard deviation (SD) to the mean, was used for the quantification of the IPV. We divided the cohorts into High IPV group and Low IPV group based on the several criteria using mean and subdivided SD of CV. Genetic analysis was conducted to determine which genes were associated with tacrolimus IPV.
Results: When we divided the cohorts as criteria of the mean + 0.25SD, there are more biopsy-proven tacrolimus nephrotoxicity in High IPV group than in Low IPV group (64.3% vs 35.7%, p = 0.012). Follow up periods was not different between two groups (3.34 ± 0.59 years and 3.23 ± 0.66 years, respectively, p = 0.514). There were no differences in mean tacrolimus concentration (6.82 ± 1.23 mg/dL vs 7.30 ± 1.05 mg/dL, p = 0.438) and time in therapeutic range (60.29 ± 27.26%, 51.65 ± 16.68%, p = 0.09) between groups. However, time above the therapeutic range was higher in High IPV group than in Low IPV group. (8.10 ± 16.34% vs 14.38 ± 11.51%, p=0.022) The genomic analysis showed that variant of ABCA1 (rs2274873), F5 (rs13306345) , ABCG2 (rs200170071, rs201108974, rs202008680) and NAT2(rs1799931) were related to tacrolimus IPV (p=0.005, p=0.006, p=0.004, p=0.007, p=0.003, p=0.005 , respectively).
Discussion: It is well known that graft and patient survival were associated with IPV in tacrolimus exposure. But association between IPV and biopsy-proven tacrolimus nephrotoxicity is first reported by our study. This result was due to High IPV group has more time above therapeutic range than Low IPV group. ABCA1 and ABCG2 were a member of the ABC protein subfamily which involve the ABCB1 already known as a tacrolimus transporter. Due to expression in the liver, the genetic variants of NAT2 have been associated with several drug metabolism and toxicity but not yet been identified in tacrolimus. Mutation of F5 encodes an essential cofactor of the blood coagulation cascade and has yet reported to be associated with tacrolimus pharmacokinetics.
Conclusion: The high IPV of tacrolimus concentration is associated with biopsy-proven nephrotoxicity in renal transplantation. The mutations of ABCA1, ABCG2, NAT2, and F5 genes affected the IPV of tacrolimus concentration. Further studies are required to validate for this results.
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