Normalization of Brain Death—Induced Injury to Rat Renal Allografts by Recombinant Soluble P-Selectin Glycoprotein Ligand

Abstract

Abstract. Donor brain death has been considered a significant risk factor for both early and late organ allograft dysfunction. This central injury not only evokes an upsurge of catecholamines with resultant peripheral tissue vasoconstriction and ischemia but also promotes release of hormones and inflammatory mediators that may also affect the organs directly. One of the resultant influences of these events is the rapid upregulation of the acute-phase adhesion molecules, the selectins. These initiate leukocyte adhesion to vascular endothelium and trigger subsequent cellular and molecular changes in the compromised tissues. An established F344 3 LEW rat model of chronic rejection was used to examine (1) whether the initial inflammatory events that develop within kidney allografts from brain-dead donors could be normalized using a recombinant soluble form of P-selectin glycoprotein ligand and (2) whether amelioration of these early changes would alter the inexorable progression of chronic allograft rejection. Untreated living donor controls experienced unrelenting chronic rejection over time. This complex process was accelerated in brain-dead donor kidneys. Treatment with P-selectin glycoprotein ligand prevented the early inflammatory changes in the transplanted organs and their subsequent (200 d) functional and morphologic manifestations, particularly when the soluble ligand was administered both to the donor before organ removal and to the recipient after engraftment. This strategy of using a naturally occurring selectin ligand to prevent donor-associated chronic graft dysfunction may be of special clinical interest in cadaver donor transplantation.The clinical findings that kidneys from living unrelated donors perform as well over the short and long term as those from living related sources and that grafts from both donor groups are invariably superior to those from cadavers have emphasized that antigen-independent events, which include increased donor age and intercurrent disease, the state of brain death, and the period of ischemia, influence the quality of solid organs after transplantation and are important risk factors for their eventual outcome (1,2). Brain death, a central catastrophe unique to the cadaver organ donor, produces profound physiologic and structural derangements in the peripheral tissues of experimental animals both before and after placement in the recipient (3,4). These include massive upregulation of major histocompatibility antigens, adhesion molecules, cytokines, and other acute-phase proteins. Ischemia with systemic vasoconstriction is an important facet of brain death, secondary to the initial burst of catecholamines released into the circulation (5). The early injury and the associated reperfusion after transplantation evoke nonspecific inflammatory changes in the affected organs. However, additional factors may contribute to the peripheral effects of brain injury. Important changes in the dynamics of a series of hormones have been identified (6,7). Because brain death may also influ...

Selectin Blockade Plus Therapy with Low-Dose Sirolimus and Cyclosporin A Prevent Brain Death-Induced Renal Allograft Dysfunction

“…rPSGL-Ig, a recombinant soluble form of PSGL-1, reacts with the selectins on the activated endothelium and prevents interaction with circulating leukocytes and platelets (26,32). As shown previously in grafted kidneys injured by I/R and by donor BD, the administration of rPSGL-Ig around the time of transplantation prevents many downstream inflammatory events (13,21). Others have noted similar effects (33).…”

“…Recombinant P-selectin glycoprotein ligand (rPSGL-Ig) can inhibit selectin activity developing in BD donor allografts and in kidneys injured by I/R, with attenuation of subsequent immune responses (13,(18)(19)(20)(21). In the current study, we analyzed the effects of selectin blockade with rPSGL-Ig, with or without maintenance immunosuppression with CsA and SRL, in a rat model of BD-induced renal allograft dysfunction.…”

UW is Superior Compared with HTK After Prolonged Preservation of Renal Grafts

“…Apart from functional biomarkers of injury, additional parameters associated with inflammation appear to be increased in grafts that were cold stored in HTK. P-selectin serves as an important mediator of leukocyte rolling and therefore its involvement in inflammation is expected [31][32][33][34][35]. Our finding that P-selectin expression and monocyte infiltration were significantly reduced in renal grafts that were stored in UW solution suggests causality, but still requires formal proof.…”

Early Events in Kidney Donation: Progression of Endothelial Activation, Oxidative Stress and Tubular Injury After Brain Death

“…Therapeutic role of administrating recombinant proteins targeted against P-Selectin have shown a marked improvement in graft outcome, blocking neutrophil and lymphocyte infiltration, and thus decreasing inflammatory response and ischemia-reperfusion injury (36)(37)(38)(39). Different therapeutic approaches were studied, administrating the P-Selectin blocker to the donor (after 6 h BD, kidneys perfused in situ, or after 3 h BD, intravenous injection) or to both donor and recipient (after 3 h BD intravenous injection to the donor and at the time of reperfusion in the recipient).…”