Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation

BACKGROUND:CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. OBJECTIVE:The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. PARTICIPANTS AND METHODS:The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. RESULTS:No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). CONCLUSION:Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.Ronga Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C.Sallustio, Andrew A. Somogy

No major effect of innate immune genetics on acute kidney rejection in the first 2 weeks post-transplantation

Background: Innate immunity contributes to acute rejection after kidney transplantation. Genetic polymorphisms affecting innate immunity may therefore influence patients' risk of rejection. IL2 -330T > G, IL10 -1082G > A, -819C > T, and -592C > A, and TNF -308G > A are not associated with acute rejection incidence in Caucasian kidney transplant recipients receiving a calcineurin inhibitor, ciclosporin or tacrolimus (TAC). However, other important innate immune genetic polymorphisms have not yet been extensively studied in recipients and donors. In addition, innate immunogenetics have not been investigated in kidney transplant cohorts receiving only TAC as the calcineurin inhibitor. Objective: To investigate the effect of recipient and donor CASP1, CRP, IL1B, IL2, IL6, IL6R, IL10, MYD88, TGFB, TLR2, TLR4, and TNF genetics on acute kidney rejection in the first 2 weeks post-transplant in TAC-treated kidney transplant recipients. Methods: This study included 154 kidney transplant recipients and 81 donors successfully genotyped for 17 polymorphisms in these genes. All recipients were under triple immunosuppressant therapy of TAC, mycophenolate mofetil, and prednisolone. Recipient and donor genotype differences in acute rejection incidence within the first 2 weeks post-transplantation were assessed by logistic regression, adjusting for induction therapy, human leukocyte antigen mismatches, kidney transplant number, living donor, and peak panel-reactive antibody scores. Results: A trend (Cochran-Armitage P = 0.031) of increasing acute rejection incidence was observed from recipient IL6 -6331 T/T (18%) to T/C (25%) to C/C (46%) genotype [C/C versus T/T odds ratio (95% confidence interval) = 6.6 (1.7 to 25.8) (point-wise P = 0.017)]. However, no genotype differences were significant after Bonferroni correction for multiple comparisons. Conclusions: This study did not detect any statistically significant effects of recipient or donor innate immune genetics on acute rejection incidence in the first 2 weeks post-transplantation. However, the sample size was small, and future larger studies or meta-analyses are required to demonstrate conclusively if innate immune genetics such as IL6 influence the risk of acute rejection after kidney transplantation.Rong Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C. Sallustio, and Andrew A. Somogy

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

First published: 01 March 2021AIM: Long-term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intra-renal exposure. METHODS: This study investigated the relationship between trough blood (C0Blood ) and allograft (CGraft ) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function and time post-transplant. C0Blood and CGraft were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes. RESULTS: C0Blood ranged from 2.6-52.3 ng/mL and CGraft from 33-828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C0Blood compared to non-expressors, whilst delayed graft function was associated with higher C0Blood . Linear regression showed that the significant predictors of CGraft were C0Blood (point-wise P = 7x10-10 ), dose (P = 0.004) and an interaction between C0Blood and acute tacrolimus nephrotoxicity (P = 0.0002), with an adjusted r2 = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between CGraft and acute nephrotoxicity depended on one very high CGraft (828 pg/mg tissue). CONCLUSIONS: Recipient and donor CYP3A5 and ABCB1 3435C>T genotypes are not determinants of allograft tacrolimus exposure in kidney transplant recipients. However, tacrolimus dose and C0Blood were significant predictors of CGraft , and the relationship between C0Blood and CGraft appeared to differ in the presence or absence of acute nephrotoxicity.Benedetta C. Sallustio, Benjamin D. Noll, Rong Hu, Daniel T. Barratt, Jonathan Tuke ... at al

Macro‐ and Micromorphology of Subsurface Carbon in Riparian Zone Soils

Soil organic matter (SOM) contains fractions that range from very active to passive, relative to microbial-driven ecosystem processes and functions. A classification system is needed that can test the hypothesis that SOM can be separated by morphology into functionally meaningful fractions. The objectives of this study were to use macro- and micromorphological techniques to classify the various C forms present in saturated (or seasonally saturated) subsurface horizons of hydric riparian soils, and to increase our understanding of their genesis. Nine soils formed in outwash or alluvium, located in Rhode Island riparian wetlands, were described and sampled up to depths of over 3 m. The majority of these soils had seasonally high water table levels at or above the soil surface. Thirty-four thin sections were constructed from undisturbed samples collected from subsurface horizons for micromorphological investigation. Six C forms (roots, fragmental organic matter [FOM], lenses, infillings, masses, and horizon C) and five root-decomposition classes were identified. All C forms were more abundant in the subsurface of alluvial soils than in the subsurface of outwash soils. Masses and roots were the most abundant C form identified. Most masses have likely formed from dispersion of C associated with decomposed roots. Alluvial deposition has resulted in considerable C in subsurface riparian zone soils in the form of buried A and O horizons, lenses, and FOM. Illuvial-horizon C was found primarily in sandy horizons having outwash parent materials. Carbon dating suggested that many of these C forms persist for thousands of years in the riparian subsurface. The variety of C forms that exist in riparian zone subsoils suggests that understanding C morphology, and how these forms are related, may prove useful for developing functionally different morphologic classes of soil C. © Soil Science Society of America

Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy

10.1093/annonc/mdm599Annals of Oncology195915-91