Genomic meta-analysis of growth factor and integrin pathways in chronic kidney transplant injury

Background: Chronic Allograft Nephropathy (CAN) is a clinical entity of progressive kidney transplant injury. The defining histology is tubular atrophy with interstitial fibrosis (IFTA). Using a meta-analysis of microarrays from 84 kidney transplant biopsies, we revealed growth factor and integrin adhesion molecule pathways differentially expressed and correlated with histological progression. A bioinformatics approach mining independent datasets leverages new and existing data to identify correlative changes in integrin and growth factor signaling pathways. Results: Analysis of CAN/IFTA Banff grades showed that hepatocyte growth factor (HGF), and epidermal growth factor (EGF) pathways are significantly differentially expressed in all classes of CAN/IFTA. MAPK-dependent pathways were also significant. However, the TGF beta pathways, albeit present, failed to differentiate CAN/IFTA progression. The integrin subunits beta 8, alpha v, alpha mu and beta 5 are differentially expressed, but beta 1, beta 6 and alpha 6 specifically correlate with progression of chronic injury. Results were validated using our published proteomic profiling of CAN/IFTA. Conclusions: CAN/IFTA with chronic kidney injury is characterized by expression of distinct growth factors and specific integrin adhesion molecules as well as their canonical signaling pathways. Drug target mapping suggests several novel candidates for the next generation of therapeutics to prevent or treat progressive transplant dysfunction with interstitial fibrosis.