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Beneficial Effects of Recombinant Soluble P-Selectin Glycoprotein Ligand (rPSGL-Ig) on Donor Brain-Death–Related Early Changes and Late Outcome after Kidney Transplantation

Ana Maria Waaga

Joana E. Kist-van Holthe

Igor A. Laskowski

Susanne M. Lenhard

Gray D. Shaw

Wayne W. Hancock

Nicholas L. Tilney

Systemic changes occurring after donor brain death (BD) may intensify early inflammatory processes in peripheral organs and accelerate acute allograft rejection after transplantation. Selectins are responsible for initial binding of circulating inflammatory cells to activated vascular endothelium. By competitive binding, a recombinant soluble selectin ligand (rPSGL-Ig) has been shown to inhibit their activity and to block the subsequent inflammatory cascade. In this study, the authors investigated both early and late effects of rPSGL-Ig in a chronic rejection rat renal allograft model. Six hours after induction of BD, kidneys from F344 donors were grafted into Lewis recipients. Kidneys from living donors (group 1) and normotensive BD-donors (group 2) served as controls. rPSGL-Ig was given intravenously (50 µg) to the donor animal 3 h after BD. A 2nd dose was given to the host after transplantation (n = 8, group 3). All recipients were treated with low-dose cyclosporin A (1.5 mg/kg, 10 d). Urinary protein levels (24-h urine) were measured serially, followed by histological analysis of the kidneys 200 days after transplantation. The mRNA transcription of representative inflammatory molecules was examined in untreated and treated BD donors before transplantation (6 h after BD) and after 200 days. Proteinuria in animals in groups 1 and 2, but not in group 3, increased progressively after approximately 12 weeks. Histologically, grafts from sPSGL-Ig treated animals showed only minor changes at 200 days, whereas the changes of chronic rejection had developed in untreated controls. Cytokine and chemokine activity, both early and late, was up-regulated in control kidneys, but not in those from the treated group. These data suggest that administration of rPSGL-Ig inhibits early inflammatory processes associated with donor BD. In turn, resultant chronic allograft dysfunction is prevented. These findings may be of particular clinical interest.

Key Words: brain death (BD) • recombinant soluble P-selectin glycoprotein ligand (rPSGL-Ig) • kidney transplantation (KTx)

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