Accelerated Rejection of Renal Allografts From Brain-Dead Donors

Transplantation has evolved as the treatment of choice for many patients with end-stage organ disease. Success has improved progressively, particularly in the short term. However, despite a functional survival rate of most grafts of more than 80% at 1 year, the ultimate goal of providing long-term treatment for an irreversible process has not been achieved; the rate of attrition over time has remained relatively stable throughout the entire experience. 1 Whereas early immune-mediated injury is considered to be primarily responsible for graft dysfunction and failure, the influence of nonimmunologic, antigen-independent events may have been underestimated; there appears to be a continuum between inflammatory changes secondary to an initial nonspecific insult and the onset of alloresponsiveness. This concept has been emphasized by recent pooled data from the United Network of Organ Sharing that show not only that survival rates of kidneys from living-unrelated and one haplotype matched living-related donors are similar, but also that organs from all living donors, regardless of differences in genetic relationship with a given recipient, demonstrate consistently superior results to those from cadavers. 2 Various risk factors that might explain this striking discrepancy include donor age and preexisting conditions such as hypertension or diabetes, the effects of initial ischemia/reperfusion injury, inadequate functioning nephron mass, and viral infections. An additional obvious difference between living and cadaver donor sources is the influence of brain death. Brain death is a profound central catastrophe uniquely relevant to the cadaver donor, the primary source of solid organs for transplantation. Such persons have suffered sudden, extensive, and irreversible central nervous system damage secondary to trauma, hemorrhage, or infarction. Both the initial and long-term function of engrafted cadaver organs may also depend on the cause of the injury as well as on donor demographics; results are worst when the organ is taken from an older donor who has died of an intracerebral hemorrhage or thrombotic stroke and best from a younger person who has died of acute head injury. 3 Besides age and other variables, the resultant physiologic and structural derangements that may occur during and after brain death and before organ removal and the actual engraftment procedure itself may be different between the two donor populations. In this regard, the use of young healthy living animals as donors in virtually all experimental studies of organ transplantation may not provide an accurate prototype for the study of clinical events involving cadavers. Brain death has been shown in several experimental models to perturb significantly the function and structure of somatic organs. 4,5 The objectives of the present study are to assess how a controlled and reproducible model of gradual-onset brain death alters renal graft survival after transplantation by influencing the process of acute host alloresponsiveness. The increased immunogenicity of kidneys from brain-dead donors secondary to rapid upregulation of histocompatibility antigens and proinflammatory mediators may explain in part the consistently inferior clinical results of organs from cadaver donors compared with those from living sources.