M-RNA Expression of Renal Transporters and Drug Metabolizing Enzymes Changes With Time Following Living and Deceased Donor Renal Transplantation.

Abstract

Introduction:A renal allograft undergoes cold ischemia(CI), warm-reperfusion injury, and calcineurin-inhibitor nephrotoxicity during its functional life-time. These abuses may alter the expression and activity of renal drug transporters(RDTs) and drug metabolizing enzymes(DMEs) which may inturn alter Transplant(Tx) medication disposition. Rodent data from our group suggests changes in mRNA expression of RDTs post-Tx. The objective of this study was to evaluate the effect of prolonged CI on longitudinal changes in RDTs and DMEs post-Tx in living donor(LD) and deceased donor(DD) renal-Tx recipients. Methods:GSE11166 microarray dataset (GPL570 Affymetrix-GeneChip) with baseline biopsies from 14DD and 14LD and 67 protocol renal biopsies obtained at 3, 6, 12 and 24months post-Tx was accessed through the NIH-Gene Expression Omnibus(GEO). Partek Genomic Suite® was used to analyze significant changes in mRNA expression of RDTs and DMEs deemed important for drug disposition by the FDA and EMA. Results:DD kidneys exhibited 1.5-5 fold decline in ABCB1, SLC22A1, CYP2B6, CYP3A4, and CYP3A7 and a 1.6-2.7 fold increase in SLCO4C1, SLC15A1, SLC22A1, CYP2C9 and UGT1A1 mRNA expression compared to LD.Table: No Caption available.ABCB4, SLC22A3, and CYP3A4 mRNA expression significantly and non-uniformly increased by 2 fold in DD kidney-Tx recipients, whereas ABCC4, SLC15A1, SLC22A5, SLCO4C1, CYP2C9 and UGT1A6 mRNA expression is significantly and non-uniformly decreased(ratio:0.32-0.54) in DD kidney-Tx recipients. Conclusion:Prolonged CI, Warm reperfusion injury, surgical stress associated with kidney-Tx and calcineurin-inhibitor nephrotoxicity significantly alters the mRNA expression of important RDTs and DMEs in DD transplant recipients compared to LD. GEO database combined with Partek Genomic Suite® is an invaluable tool to understand the changes in gene expression of target genes in publicly available NIH funded biosets.