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• W2007410147 abstract "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. ISCHEMIA/REPERFUSION Overall ischemia of an organ graft is the sum of a possible transient warm ischemic interval before or during actual removal from the donor, cold ischemia associated with preservation and storage, and that occurring during the period of revascularization to the recipient circulation. Physiologic and metabolic changes developing in tissues without circulation have been well described (see 7 for review). Because of the inhibition of membrane transport systems after the decrease of energy-rich phosphates, intracellular accumulation of ions and water causes cell swelling, particularly in the endothelium. The ensuing heterogeneity of capillary perfusion causes shunting of restored blood flow from areas of high to low pressure, with resultant compromise in microvascular flow (“no reflow”). Critical to the viability of the organ, reperfusion may also increase ischemic damage (“reflow paradox”) (8). This injury becomes manifest through rapid up-regulation and surface expression of adhesion molecules, particularly selectins, and activation of circulating host leukocytes and their binding to the vascular endothelium. It should be noted that in the original studies of cadaver renal allografts, the early presence of polymorphonuclear leukocytes (PMNs*) in glomerular capillaries was interpreted as heralding specific immunological injury; more likely, their presence may have represented ischemia/reperfusion injury in some cases (9). The adherent leukocytes, initially PMNs, release oxygen free radicals and inflammatory mediators, including platelet activating-like factors and leukotrienes (10). PMNs may also contribute to microvascular compromise by infiltrating the injured endothelial cells in such numbers as to obstruct small vessels. The important early contribution of this circulating cell population to the postischemic insult has been emphasized experimentally by reduction of its intensity in neutropenic animals (11). In addition, when leukocyte adhesion is prevented by the use of appropriate monoclonal antibodies, reperfusion injury is considerably blunted (12). After the initial events of rolling, slowing, and eventual adherence of the circulating cells to the endothelium, the adhesion molecule-cytokine cascade is amplified further; lymphocytes and macrophages infiltrate the graft substance and release various cytokines and other factors (7). One further consequence of these activation events is that allograft immunogenicity is increased by expression of MHC antigens, making cells potentially more prone to host immune attack (6). Some investigators have also suggested that neoantigens are produced and autoantibodies develop against the injured tissues (13). RELEVANCE TO CLINICAL TRANSPLANTATION Accruing clinical and experimental evidence suggests that an initial insult to organ allografts may influence both early and late functional survival. This injury may be either immunologic (acute rejection) or antigen independent (ischemia/reperfusion) (14). There seems to be a clear association between early (within 6 months of engraftment) acute rejections episodes and late graft loss from chronic rejection. In one representative series, for example, the 5-year cadaver graft survival was 65% among those individuals experiencing such an initial event and 86% (P<0.005) among those who did not (15). Whether delayed graft function (DGF), the principal manifestation of initial ischemia/reperfusion injury, alone affects ultimate graft behavior is under debate, particularly as the authors of many series have not controlled their studies for the presence or absence of rejection; in addition, most studies are retrospective, and some require that only grafts surviving >1 year be included (16, 17). However, many analyses show clear differences. In one such study, the 5-year functional survival rate of renal allografts that had early dysfunction was 69% vs. 79% among those that functioned immediately (15). In another, the 1-year graft survival was 84% vs. 61% in kidneys with satisfactory and unsatisfactory initial function, respectively (18). Although 2- and 5-year results were also decreased in affected kidneys, much of the affect of this early immune-independent event seems to occur in the first year. DGF is generally defined as a transient discrepancy between the functional capacity of the transplanted kidney and fulfillment of the physiological needs of the recipient, as manifested by oliguria, lack of decline in serum creatinine, or transient dialysis dependency. Such a condition is clinically vexing, producing difficulties for the patient and physician alike; these include uncertainty in assessing the coincident presence of acute immunological rejection, which necessitates increased use of diagnostic tests both invasive and noninvasive, prolonged hospitalization, higher costs, and delayed rehabilitation potential (19, 20). In addition, continuing dialysis after transplantation may produce its own set of problems; appropriate dosage of immunosuppressive agents may be difficult to gauge in anuric, oliguric, and uremic recipients. The use of potentially nephrotoxic immunosuppressive compounds may enhance ongoing tubular injury when full doses are continued or expose the recipient to an increased risk of rejection when the dosage is reduced. It is not unreasonable to accept the hypothesis that ischemia/reperfusion injury initiates an inflammatory response that provokes an increased level of acute host immunological reactivity (6). This would explain the apparent synergy between DGF and episodes of acute rejection; in combination, these two types of events lead to a less favorable graft outcome in an afflicted cohort of recipients than with either injury alone or where neither is experienced (2, 15-17). In one representative series, for example, the 5-year survival rate of cadaver grafts experiencing neither DGF nor acute rejection was 85%; that of grafts that have sustained both injuries was 60% (15); the results of grafts undergoing a single insult, regardless of type, were intermediate between the two. Several explanations have been offered for these observations (16): DGF increases the immunogenicity of the transplanted organ, making it more prone to host alloreactivity (21); and an acute rejection episode occurring in a nonfunctioning graft is difficult to diagnose and may be missed. However, it is possible that increased numbers of biopsies often performed in grafts with initial poor or absent function may show a higher rate of rejection than appreciated when a biopsy is not undertaken. The early injuries may also affect later events: initial acute rejection injury predisposes to chronic graft dysfunction (15); DGF may initiate a programmed process within the graft, which leads to chronic changes; the common denominator of both antigen-driven and antigen-independent early graft injuries may be the reduction of functioning renal mass, with the remaining hyperfiltering and hyperfunctioning nephrons deteriorating gradually over time (22). PRESCRIPTIVE MEASURES There are presently no consistently effective ways to prevent the changes of ischemia/reperfusion or to influence the development of subsequent DGF after renal transplantation. Future investigations will need to concentrate on inhibiting donor-related perturbations as they affect the peripheral organ to be transplanted or reducing cellular and molecular events in an “activated” kidney at the endothelial as well as the effector cell level using specific agents in the perfusate or administered to the recipient just before and/or shortly after engraftment. There is some current evidence, for instance, to suggest that an antilymphocyte function-associated antigen-1 (CD11a) monoclonal antibody and other antiadhesion molecule products may reduce the injury of ischemia/reperfusion, as reflected in a decreased incidence of dialysis-dependent DGF (12, 23). The extended significance of this unsolved problem of ischemia/reperfusion injury and its effects on ultimate graft fate are not only relevant to the present donor pool, but effective therapy for prevention and minimization of the insult could open avenues for donor utilization from sources not now considered seriously." @default.
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• W2007410147 title "EFFECTS OF INITIAL ISCHEMIA/REPERFUSION INJURY ON THE TRANSPLANTED KIDNEY1" @default.
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