Journal
CLINICAL TRANSPLANTATION
Volume 25, Issue 5, Pages 766-775Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1399-0012.2010.01365.x
Keywords
biomarkers; clinical trial; ischemia reperfusion injury; kidney transplant; selectins
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Funding
- Y's Therapeutics, Inc.
- Mary Beryl Patch Turnbull Scholar Program
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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 similar to 1 h 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 TNF alpha 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 TGF beta (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.
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