The association of pharmacokinetic variability of tacrolimus, interleukin gene polymorphisms and microrna expression with graft function in kidney transplant recipients

[K. S. Danković]

165 list.

Biografija autora: list. 164-165 Bibliografija: list. 140-163

Pharmacokinetics, Pharmacotherapy, Clinical Pharmacy

Objective: The main goal of this doctoral thesis was to investigate the association between the parameters of pharmacokinetic variability of tacrolimus (Tac), polymorphisms in interleukin (IL) genes and microRNA expression levels with graft function in the long-term period after kidney transplantation. Patients and Methods: The study included 115 kidney transplant recipients on Tac-based immunosuppression and 91 healthy controls. The thesis was conducted as a prospective study and a cross-sectional study. Tacrolimus daily dose and trough concentration in whole blood (C0) were recorded over a five-year post-transplantation period. The doseadjusted C0 (C0/D) and intraindividual pharmacokinetic variability (IPV) of Tac were calculated. Graft function was assessed using estimated glomerular filtration rate, while adverse outcomes in the long-term post-transplantation period were recorded (graft failure, chronic dysfunction and rejection, and doubling of serum creatinine concentration). Genetic polymorphisms -174G/C in the IL-6 gene, - 1082G/A, -819C/T, and -592C/A in the IL-10 gene, -607A/C and - 137G/C in the IL-18 gene were detected using appropriate PCR methods. Plasma concentrations of IL-6, IL-10, IL-18, and cystatin C were measured, as well as the urinary expression of miR-21-5p, miR- 142-3p, miR-155-5p, and miR-204-5p in patients and controls. Results: The findings of this study demonstrated that patients exhibiting both lower Tac C0/D and higher Tac IPV values had approximately a 3-fold increased risk of developing adverse outcomes during the five-year post-transplantation follow-up. Furthermore, gene polymorphisms IL-6 -174G/C, IL-10 -1082G/A, and IL-18 - 137G/C, the Tac metabolic phenotype determined based on Tac C0/D at the 3rd post-transplantation month, and the post-transplantation period were independent predictors of Tac C0/D from months 6 to 60. The study also showed a significant dysregulation of miR-204-5p in the urine of kidney transplant patients in the long-term period, demonstrating its correlation with Tac metabolic phenotype and graft function in the late post-transplantation period. Conclusion: The results of the doctoral dissertation may contribute to the improvement of post-transplantation outcomes, while also serving as a foundation for further research.

takrolimus, farmakokinetička varijabilnost, transplantacija bubrega, genski polimorfizam, interleukini, funkcija grafta, mikroRNK

tacrolimus, pharmacokinetic variability, kidney transplantation, gene polymorphism, interleukins, graft function, microRNA

615.015-616.61-089.843(43.3)

B740

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