Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts.
BACKGROUND
Molecular biomarkers validated previously in animal models are increasingly being studied in conjunction with traditional clinical endpoints in therapeutic trials.


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.
Lowe Family Genomics Core, Johns Hopkins University, Baltimore, MD, USA.
Chris
C
Cheadle
Tonya
T
Watkins
Eva
E
Ehrlich
Kathleen
K
Barnes
A Osama
AO
Gaber
Stefan
S
Hemmerich
Hamid
H
Rabb
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D002102:Cadaver; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D016030:Kidney Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D019007:P-Selectin / Q000037:antagonists & inhibitors; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015424:Reperfusion; D015427:Reperfusion Injury / Q000175:diagnosis* / Q000235:genetics / Q000517:prevention & control*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D015415:Biomarkers; D016207:Cytokines; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins