One of the clear principles resulting from the experience in clinical transplantation is that organs from living-related donors are functionally superior, both in the short and long term, to those from cadaver sources. This credo, which has persisted regardless of progressive improvements in overall results, has been explained primarily by genetic relationships between the donor and the host. The results of kidney allografts from living-related donors and those from cadavers matched at six HLA antigens with their recipients, for instance, are considerably better than those from mismatched cadaver organs (1). Compelling recent evidence suggests, however, that nonimmunological factors may also be important in explaining this difference (2). Indeed, it has become clear, based on the analysis of thousands of renal transplant recipients in North America, that the survival rates of kidneys from living unrelated donors are virtually identical to those of one haplotype-matched living-related sources and consistently greater than those of mismatched cadaver transplants (3). Because the essential dissimilarity between kidneys obtained from a cadaver and those from a living-unrelated source is physiologic and not genetic, attention to the effects of initial injury to the organ as it relates to subsequent graft survival seems worthwhile to design future interventions to effect physiological improvement.

Because of an ever-increasing demand for organs by those with end-stage renal disease, pressures to expand criteria for donor acceptance have mounted. Kidneys from “marginal” or “high-risk” cadaver donors (a term not well defined but including the elderly and those with hypertension or arteriosclerosis) are being used increasingly, despite being associated with relatively unsatisfactory early and late graft survival (4). Cardiovascular instability during brain death, putative circulating factors from the injured brain that may alter cell function and dynamics in peripheral organs, as well as injuries secondary to organ removal and storage may influence graft outcome negatively (5). In addition, the insult from ischemia/reperfusion surrounding engraftment may trigger alloresponsiveness in the host, making it potentially more prone to rejection (6), as well as compromising or destroying numbers of functioning nephron units. The increasing consideration toward using organs from non-heart beating cadaver donors may amplify this initial injury. We now examine why ischemia/reperfusion injury is a serious and clinically relevant issue in long-term graft survival.