CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients.

PURPOSE: Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipients in the first-year post-transplant. METHODS: A total of 127 patients were included for genetic evaluation. Genomic DNA was isolated from peripheral blood and real-time PCR was used to analyze the main polymorphisms described for the genes CYP3A5 (rs776746; C > G) and PPARA (rs4823613; A > G and rs4253728; G > A). RESULTS: CYP3A5 expressors showed a lower Co/dose ratio than non-expressors, with the median values of this parameter <1.01 ng/mL/mg in the first group at all evaluated times. Additionally, PPARA variant homozygotes had a lower Co/D ratio than wild allele carriers in the 12-month post-transplant period, with a median value of 0.65 ng/mL/mg. In the CYP3A5 expressers, the presence of the variant homozygous genotype PPARA was associated with a lower value of Co/D compared with the other genotypic groups at month 12. CONCLUSION: In the population under study, polymorphisms on CYP3A5 and PPARA were identified as determining and independent factors associated with the reduction of Co/D of TAC. Thus, the genotyping of these genetic variants may be a useful tool for the individualized prescription of TAC in kidney transplant patients.

Effects of Combined Resistance Plus Aerobic Training on Body Composition, Muscle Strength, Aerobic Capacity, and Renal Function in Kidney Transplantation Subjects.

ABSTRACT: Lima, PS, de Campos, AS, de Faria Neto, O, Ferreira, TCA, Amorim, CEN, Stone, WJ, Prestes, J, Garcia, AMC, and Urtado, CB. Effects of combined resistance plus aerobic training on body composition, muscle strength, aerobic capacity, and renal function in kidney transplantation subjects. J Strength Cond Res 35(11): 3243-3250, 2021-Immunosuppression and a sedentary lifestyle may exacerbate complications such as early graft dysfunction and muscle loss, and reduce patient survival after kidney transplantation (KT). Therefore, the purpose of this study was to evaluate changes in body composition (BC), muscular strength, aerobic, and renal function in KT subjects submitted to combined resistance plus aerobic training. Twelve KT subjects were randomly assigned into groups: (G1) 12 weeks of combined training (3 males and 4 females, 54 ± 3 years); or (G2) nonexercise control (5 females, 43 ± 18 years). The subjects were evaluated for BC (dual-energy X-ray absorptiometry), estimated V̇o2peak, right-hand maximal grip strength (RHMGS) and left-hand maximal grip strength (LHMGS), and renal function. Post-training revealed that G1 reduced body fat percentage (p = 0.046), uric acid (Δ = -0.87; p = 0.023), urea (Δ = -9.43; p = 0.032), and creatinine (Δ = -0.15; p = 0.045), increased fat-free mass, estimated V̇o2peak, RHMGS, LHMGS (p < 0.05), and estimated glomerular filtration rate (eGFR) (Δ = 11.64; p = 0.017). G2 increased urea (Δ = 8.20; p = 0.017), creatinine (Δ = 0.37; p = 0.028), and decreased eGFR (Δ = -16.10; p = 0.038). After 12 weeks, urea (Δ = 24.94; p = 0.013), uric acid (Δ = 1.64; p = 0.044), and creatinine (Δ = 0.9; p = 0.011) were lower, whereas eGFR (Δ = 36.51; p = 0.009) was higher in G1. These data indicate that combined training instigates positive changes in BC, muscular strength, aerobic capacity, and renal function after KT.

Impact of POR*28 Variant on Tacrolimus Pharmacokinetics in Kidney Transplant Patients with Different CYP3A5 Genotypes.

BACKGROUND: The introduction of tacrolimus (TAC) to clinical practice was essential to the establishment of transplantation as a therapy for patients with chronic renal disease. However, the higher interindividual variation of TAC metabolism has been an important limiting factor for its clinical use. Although the relationship between CYP3A5 polymorphisms and TAC pharmacokinetics (PK) is well established, the effects of other genetic variants on TAC metabolism, such as POR*28, still remain uncertain. OBJECTIVE: The study aimed to evaluate the impact of POR variants on TAC PK in renal transplant patients with different CYP3A5 genotypes (expressers and non-expressers). METHODS: A total of 115 patients were included in this study. Genomic DNA was isolated from peripheral blood, and the real-time PCR technique was used to analyze the polymorphism POR rs1057868; C>T. RESULTS: During the initial post-transplant period, variant allele carriers (*1/*28 and *28/*28) showed a lower TAC dose requirement than POR wild homozygotes (*1/*1). Regarding the influence of the different polymorphisms of POR within the CYP3A5 expresser and non-expresser groups, no differences were observed in any of the PK parameters analyzed during 12 months after transplantation. CONCLUSION: In the studied population, the variant allelic POR*28 was significantly associated with lower TAC dose requirements and higher Co/D ratio in the first-month post-transplant. However, the effects of this polymorphism on the CYP3A5 enzyme activity were not observed.