Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts

Introduction: Molecular biomarkers validated previously in animal models are increasingly being studied in conjunction with traditional clinical endpoints in therapeutic trials. Patient and Methods: We hypothesized that human kidneys would exhibit a brisk, gene-specific inflammatory response during ischemia reperfusion injury (IRI), which would be modified by anti-adhesive therapy. Forty deceased-donor kidneys were biopsied prior to implantation and ∼1h after reperfusion during an intervention trial with the selectin antagonist YSPSL (recombinant P-selectin glycoprotein ligand Ig). Ten inflammatory genes were measured by RT-PCR and normalized to three housekeeping genes. Results: Pre-implantation kidney biopsies were already significantly inflamed relative to healthy tissue, with transcripts encoding IL-6, IL-8, and CD25>10-fold elevated. After reperfusion, IL-6 and IL-8 increased additional 60- and 120-fold (p<0.05), while already elevated CD25-levels remained stable. Furthermore, transcripts encoding MCP-1, E-selectin, and TNFα were also induced significantly upon reperfusion (p<0.0005). Systemic treatment of the recipient with YSPSL pre-reperfusion, with or without pre-implantation YSPSL flush of the donor organ, attenuated the post-reperfusion increase in MCP-1 and TGFβ (p<0.05), E-selectin and hemoxygenase 1 transcripts (p<0.1). Conclusions: Our data in humans demonstrate a robust increase in inflammatory gene transcript levels during kidney transplantation IRI and reduction thereof by inhibition of leukocyte adhesion.