CYP3A5 Expressor Genotype of the Transplanted Kidney Increases the Risk of Preterm Graft Loss and Acute Rejection.

INTRODUCTION: Tacrolimus is metabolized mainly in the liver by the CYP3A enzyme family, with a particularly well-documented role of CYP3A5. CYP3A5 is also expressed in the renal tissue and is present in the transplanted kidney. To date, the association between donor CYP3A5 polymorphisms and transplant outcome remains poorly understood. The aim of this study was to assess the effect of donor CYP3A5 expression on early and long-term transplant outcomes. METHODS: A retrospective cohort study including 207 patients who received kidney grafts from 110 deceased donors was conducted at a single Central European Center. Tissue samples from all donors were studied for CYP3A5 single-nucleotide polymorphism (rs776746). Death-censored graft loss within 5-year follow-up, acute rejection occurrence, and kidney function, measured using serum creatinine and MDRD eGFR, were compared between groups of patients with allografts from rs776746 carriers (CYP3A5 expressors) and noncarriers (CYP3A5 nonexpressors). RESULTS: Recipients who received kidneys from CYP3A5 expressors (n = 24) were at significantly higher risk of death-censored graft loss within 5-year follow-up (adjusted HR, 95% CI: 6.82, 2.01-23.12; p = 0.002) and acute rejection within the 1st posttransplant year (adjusted OR, 95% CI: 4.62, 1.67-12.77; p = 0.003) than those who did not (n = 183). The median time to loss of function was 1.93 [IQR; 0.77-3.19] years. CONCLUSIONS: Donor CYP3A5 expressor status is associated with worse renal graft survival and a higher risk of acute rejection. Determination of donor CYP3A5 genotype is a potentially useful tool that may improve kidney transplant outcomes.

Donor CYP3A5 Expression Decreases Renal Transplantation Outcomes in White Renal Transplant Recipients.

BACKGROUND After renal transplantation, immunosuppressants should be administered to prevent organ rejection and prolong graft survival. One of them is tacrolimus, which is metabolized by the CYP3A enzyme family. The variability of the CYP3A5 gene in renal transplant recipients has been previously studied for its correlation with acute rejection and allogeneic kidney function. CYP3A5 enzyme is also present in the renal tissue, and its relevance has not yet been extensively investigated. This study aimed to evaluate the effect of donor and recipient CYP3A5 expression status on early and long-term transplant outcomes. MATERIAL AND METHODS Single-nucleotide polymorphism in CYP3A5 (rs776746) was analyzed in 95 kidney transplant recipients and their grafts. The effect of donor and recipient genotypes on the primary endpoint, which was the loss of the renal graft over 5-year follow-up, was assessed. The secondary endpoints were biopsy-proven acute rejection, proteinuria, delayed graft function, and renal function. RESULTS Patients who received a CYP3A5*1 allele-carrying kidney (n=16) were at greater risk of graft loss (adjusted hazard ratio, 95% CI: 10.61, 2.28-49.42, P=.003) than those with the CYP3A5*3/*3 genotype (n=79). Renal CYP3A5 expression was also a predictor of acute rejection between the 2nd and 12th post-transplant months (adjusted odds ratio, 95% CI: 4.36; 1.08-17.6, P=.038) and proteinuria at different time intervals. No effect of the recipient CYP3A5 genotype was observed. CONCLUSIONS The donor CYP3A5 genotype is associated with inferior transplantation outcomes. Local renal tacrolimus metabolism is a potential target for improving long-term transplantation outcomes.

Renal Cyp3a5-Expressing Genotype Decreases Tacrolimus-to-Dose Ratio in Small Cohort of Renal Transplant Recipients-Preliminary Report.

BACKGROUND: Previous reports have established that patient CYP3A5 allelic variability may be the most important genetic contributor to interindividual variation in tacrolimus exposure in renal transplant recipients. However, CYP3A5 protein is expressed in the allogenic kidney. The aim of this study was to investigate the role of the renal CYP3A5 genotype in tacrolimus concentration-to-dose ratio within 3 years posttransplant. METHODS: A retrospective cohort study of 90 renal transplant recipients and their donors evaluated the effect of the CYP3A5 single-nucleotide polymorphism (rs776746) on tacrolimus exposure. The area under the curve for tacrolimus concentration-to-dose ratio within 3-year follow-up was calculated and compared in kidneys carrying at least 1 CYP3A5*1 allele and those carrying the CYP3A5*3/*3 genotype. RESULTS: A significant effect of CYP3A5 expression on tacrolimus exposure was observed in both donors (mean ± SD: 23.8 ± 7.9 vs 32.6 ± 7.4 ng/mL/mg, respectively; P < .001) and recipients (mean ± SD: 27.1 ± 8.0 vs 32.2 ± 7.9 ng/mL/mg, respectively; P = .034) and was lower when CYP3A5 enzyme occurred. Thus, new groups were formed: the group in which at least 1 of the pairs, donor or recipient, had a CYP3A5 expressing allele (n = 23) had lower exposure to tacrolimus compared with nonexpressors (n = 67; mean ± SD: 26.2 ± 7.6 vs 33.2 ± 7.4 ng/mL/mg, respectively; P < .001). CONCLUSION: Intrarenal metabolism of tacrolimus may affect both local and systemic drug exposure. Nonexpressors receiving kidneys with the CYP3A5*1 allele may benefit from higher tacrolimus doses to hasten achievement of target drug concentrations.

Suppressor Properties of Human CD8(+)CD28(-) T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA.

Human CD8(+)CD28(-) T suppressor cells were previously shown to be involved in the control of the immune response to transplanted allografts. It seems essential to examine how immunosuppressive drugs influence these cells. However, the CD8(+)CD28(-) population contains both suppressor (Ts) and cytotoxic (Tc) T cells, and the phenotype of the Ts subpopulation has not been identified explicitly. It is proposed that the transcription factor FOXP3 may be helpful in distinguishing the Ts and Tc subpopulations. The aim of this study was to evaluate the influence of the immunosuppressive drugs cyclosporine A (CsA) and rapamycin (RAPA) on the level, suppressor properties, and phenotype of human CD8(+)CD28(-) T cells in vitro. The model used was the mixed leukocyte reaction performed with peripheral blood mononuclear cells from healthy volunteers. It was observed that CD8(+)CD28(-) T cells from cultures with CsA or RAPA had similar suppressor properties to cells from control cultures, although the drugs influenced the expression of FOXP3. CsA and RAPA did not interfere with the suppressor properties of human CD8(+)CD28(-) T cells in vitro, although they affected the expression of the FOXP3 molecule.

Susceptibility to ovarian endometriosis in Polish population is not associated with HLA-DRB1 alleles.

BACKGROUND: Endometriosis is associated with inflammatory autoimmune reactions; however, aetiopathogenesis of the disease is still poorly understood. While autoimmune disorders are often associated with particular HLA alleles, the possible involvement of HLA in the aetiopathogenesis of endometriosis is still a subject of controversy. The aim of the study was to examine the distribution of HLA-DRB1 alleles in women with endometriosis. To ensure homogeneity of the studied group, only women with ovarian endometrial cysts were included. METHODS: The study included 65 Polish patients of Caucasian origin in whom ovarian endometriosis had been confirmed by laparoscopic and histopathological examinations. HLA-DRB1 alleles were typed using a reverse slot blot method. A frequency of particular HLA-DRB1 alleles in patients was compared with that of a control group of 700 unrelated ethnically matched individuals as well as 193 age-matched women without endometriosis. RESULTS: No statistically significant differences were found in the distribution of HLA-DRB1 alleles in patients with ovarian endometriosis as compared with control populations. CONCLUSIONS: The results of the present study show that ovarian endometriosis is not associated with particular HLA-DRB1 allele(s). This may suggest that aetiology of this form of endometriosis may be not primarily associated with class II HLA-mediated autoimmune reactions.