o:3286 Povezanost farmakokinetičke varijabilnosti takrolimusa, genskih polimorfizama interleukina i ekspresije mikrornk sa funkcijom grafta kod pacijenata sa transplantiranim bubregom The association of pharmacokinetic variability of tacrolimus, interleukin gene polymorphisms and microrna expression with graft function in kidney transplant recipients : doctoral dissertation sr Objective: The main goal of this doctoral thesis was to investigatethe association between the parameters of pharmacokinetic variabilityof tacrolimus (Tac), polymorphisms in interleukin (IL) genes andmicroRNA expression levels with graft function in the long-termperiod after kidney transplantation. Patients and Methods: The studyincluded 115 kidney transplant recipients on Tac-basedimmunosuppression and 91 healthy controls. The thesis wasconducted 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 doseadjustedC0 (C0/D) and intraindividual pharmacokinetic variability(IPV) of Tac were calculated. Graft function was assessed usingestimated glomerular filtration rate, while adverse outcomes in thelong-term post-transplantation period were recorded (graft failure,chronic dysfunction and rejection, and doubling of serum creatinineconcentration). 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 PCRmethods. Plasma concentrations of IL-6, IL-10, IL-18, and cystatin Cwere 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 patientsexhibiting both lower Tac C0/D and higher Tac IPV values hadapproximately a 3-fold increased risk of developing adverse outcomesduring 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/Dat the 3rd post-transplantation month, and the post-transplantationperiod were independent predictors of Tac C0/D from months 6 to 60.The study also showed a significant dysregulation of miR-204-5p inthe urine of kidney transplant patients in the long-term period,demonstrating its correlation with Tac metabolic phenotype and graftfunction in the late post-transplantation period. Conclusion: Theresults of the doctoral dissertation may contribute to the improvementof post-transplantation outcomes, while also serving as a foundationfor further research. Biografija autora: list. 164-165Bibliografija: list. 140-163 Datum odbrane: 25.12.2025 Pharmacokinetics, Pharmacotherapy, Clinical Pharmacy 91552100 191004937 91552101 8837 2026-05-14T13:58:41.053Z 45 no 46 Katarina, Danković 106909961 2025 63 mentor Nikola Z., 1984- Stefanović 24110439 2025 63 član komisije Branka, 1962- Mitić 6592615 2025 63 član komisije Marija, 1977- Vukelić-Nikolić 27243111 2025 63 član komisije Radmila, 1961- Veličković-Radovanović 13900135 2025 63 član komisije Marijana, 1972- Ćurčić 12835431 2025 165 list. 3464894 http://phaidrani.ni.ac.rs/o:3286 no yes 12 2026-05-14T13:58:41.320Z 70 takrolimus, farmakokinetička varijabilnost, transplantacija bubrega,genski polimorfizam, interleukini, funkcija grafta, mikroRNK tacrolimus, pharmacokinetic variability, kidney transplantation, genepolymorphism, interleukins, graft function, microRNA 615.015-616.61-089.843(43.3) B740 1738 18A05 18A0530 2025