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

Authors


  • The clinical trial underlying this report was registered on http://www.ClinicalTrials.gov under the identifier NCT00298168.

  • This study was funded by Y’s Therapeutics, Inc.

  • Conflict of interest: SH was a salaried employee of Y's Therapeutics, Inc. No other conflicts of interest.

Corresponding author: Stefan Hemmerich PhD, RAC, Y’s Therapeutics, 1539 Granger Way, Redwood City, CA 94061, USA.
Tel.: +1 510 717 2768; fax: +1 510 548 1310;
e-mail: stefan.hemmerich@yahoo.com

Abstract

Cheadle C, Watkins T, Ehrlich E, Barnes K, Gaber AO, Hemmerich S, Rabb H. Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts.
Clin Transplant 2011: 25: 766–775. © 2010 John Wiley & Sons A/S.

Abstract:  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 ∼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 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.

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