ObjectiveTo improve the quality of organs from brain-dead donors by assessing the influence of alternative strategies on the early behavior of kidneys after transplantation into unmodified hosts. Summary Background DataKidneys transplanted from living donors perform consistently better than those from cadaver sources. The authors have recently shown that donor brain death produces inflammatory changes in peripheral organs within hours, amplifies coincident ischemia-reperfusion injury, and accelerates acute and chronic rejection. Normalization of the graft by donor hormone treatment has hitherto been unsuccessful. MethodsA standardized rat model of brain death was used. Experimental groups included recipients of allogeneic grafts from living and brain-dead donors (F3443 LEW). Donors were treated immediately after induction of brain death either with intravenous steroids, which block inflammatory cytokine release, or a soluble P-selectin glycoprotein ligand (sPSGL), which blocks initial selectin-mediated cellular adhesion. Kidney grafts were examined serially up to 10 days by morphology, immmunohistology, and reverse transcriptase-polymerase chain reaction. ResultsOverall survival of ummodified recipients of kidneys from brain-dead donors was significantly reduced versus living donors. Animals with organs from brain-dead donors that had received steroids or sPSGL survived significantly longer than those from untreated brain-dead donors. The intensity of ischemia-reperfusion injury and of acute rejection was reduced. Cellular infiltration and transcription of mRNA of representative proinflammatory mediators were diminished. ConclusionsTreatment of organ donors at the time of brain death markedly improves organ quality after kidney transplantation, upgrading it to that from a living donor.The catastrophic central injury of brain death (BD) has been shown to perturb significantly the function and structure of somatic organs in situ by rapid upregulation of inflammatory mediators and other acute phase proteins.

We describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

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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...