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TRANSPLANTATION OF ORGANS FROM MARGINAL DONORS1

2001; Wolters Kluwer; Volume: 72; Issue: 8 Linguagem: Inglês

10.1097/00007890-200110270-00001

1534-6080

Stefan G. Tullius, Hans‐Dieter Volk, Peter Neuhaus,

Liver Disease and Transplantation

The numberof patients awaiting organ transplantation has progressively increased during the last decade. Although the number of all registrants tripled during that time period only one-third of patients awaiting kidney or liver grafts and one-half of those hoping for heart grafts were transplanted in 1998. Thus, further progression of the discrepancy between suitable donors and potential recipients on waiting lists will have the consequence of an increasing use of organs from marginal donors. Clearly, organs that would have been thought unsuitable for transplantation not so long ago are currently used for transplantation. Although the engraftment of organs with reduced quality is associated with increasing rates of primary non- or delayed graft function a precise and broadly accepted definition of the term “marginal donor” is currently missing. Consequently, clinical trials based on different selection criteria are difficult to compare. Furthermore, organ-specific aspects reflected by divergent criteria for different organ systems seem to apply. Approaching a general accepted definition various risk factors influencing the quality of the graft will be analyzed, although scoring systems evaluating different risk factors will be suggested. Grafts with reduced quality may show an increased sensitivity toward additional damaging events as ischemia/reperfusion injury or acute rejection episodes. Interventions improving the condition of suboptimal grafts will be discussed. Finally, distinct recipient selection criteria may apply when using marginal grafts. Clinical trials matching grafts from old donors with old recipients are currently investigated. Age-adapted immunosuppressive regimens will be analyzed although an age- dependent immune response will be discussed. DONOR/RECIPIENT SELECTION OVER TIME An overall increase of organs transplanted has been observed from 1989–1995. However, numbers have not increase since 1996. During the same time period donor demographic characteristics changed. Although grafts harvested from donors aged 18–34 years have decreased, those from “elderly” donors in the age groups 50–64 and >65 years have increased. At the same time a remarkable increase in recipients age was observed (Fig. 1). Donor and recipient demographic data are representative for the situation in individual organ groups. During the same observation period causes of death changed reflecting increasing donor age: although death caused by accidents decreased an overproportional increase of cardiovascular related causes, intracranial hemorrhage, or stroke were observed (1). Recent clinical studies demonstrated the influence of cause of death on graft function in addition to time and treatment on the intensive care unit. Figure 1: Cadaveric donor and recipient characteristics adapted from the UNOS 1999 Annual Report are shown. Donor characteristics demonstrate an increase in the donor groups >50 years during the period from 1989–1998 although the amount of donors aged 18–34 years decreased. No significant differences were observed in the age groups 50 years) increased in the time period from 1989–1998 while the percentage of younger recipients (age group 18–34 years) decreased.Overall, those data illustrate the absence of clear rationales for age limits regarding donor and recipient selection. Rather an individual analysis of all risk factors for donor acceptance is currently in practice although precise diagnostic tools are debated. Both short- and long-term graft function are influenced by a variety of alloantigen-specific and -unspecific events. It can thus be hypothesized that the quality of the graft before organ retrieval may impact graft function. Donor criteria and additional unspecific inflammatory events may act in a synergistic or additive fashion. Additional alloantigen-specific factors as acute rejection and further T cell-stimulating processes after engraftment may result in reduced function of grafts from marginal donors (Fig. 2). Reduced functional capacity, an increase of immunogenecity or events related to senescence may influence alloantigen-specific events after organ engraftment. Figure 2: Postulate of an increased sensitivity of grafts from marginal donors towards additional injuries: Grafts from marginal donors may be particularly sensitive toward additional alloantigen-specific and -unspecific injuries before and after transplantation. The quality of the graft is influenced by various risk factors including donor age, previous diseases, and consequences of brain death. Further perioperative damages resulting from operative manipulations during the harvesting procedure and consequences of ischemia/reperfusion injury may damage grafts from marginal donors more than those from optimal donors. After transplantation alloantigen specific and unspecific changes as acute rejection episodes, T cell activating processes as viral infections and drug toxicity may have a stronger impact on marginal grafts with the consequence of reduced long-term function.Several clinical and experimental studies demonstrated the correlation of the quality of the graft with unspecifically damaging inflammatory events. It has been shown that delayed graft function associated with prolonged ischemia is related to increasing acute rejection rates and reduced long-term graft function (2). Although improved survival rates were demonstrated for renal transplantation from 1988 to 1996, donor age had increased over this time period suggesting that additional factors are influential for long-term graft success. Indeed, graft survival of organs from donors >50 years had increased during the last decade, however, the improvement remained far behind when compared to grafts from donors 50 years increased only by 36%. Interestingly, half-life expectancy increased particularly for grafts from living donors (112% for 1988–1995) after censoring for patients dying with functioning grafts. Graft quality determined by donor criteria in addition to perioperative inflammatory stimuli is clearly influencing graft outcome. Thus, an analysis of risk factors and their mechanisms seems necessary for a more precise definition of the term marginal donor. DONOR RISK FACTORS Donor age. Donor age has been shown in numerous clinical and experimental studies as a major risk factor for graft outcome, however, data are conflicting. Reduced short- and long-term graft survival was associated with increasing donor age (4,5). However, other reports observed similar 1- and 5-year graft function rates in recipients of renal allografts from younger ( 55 years) (6). In addition to age, race, and gender have been associated with reduced long-term graft survival explained previously by an inverse ratio of renal mass to work load resulting in glomerular hyperfiltration (7). However, as increasing numbers of organs are in need discard rates should be reduced with consistent organ quality. UNOS reported an increase of the discard rate from 5 to >7% between 1992–1997 for renal allografts although several reports described the successful use of organs from elderly donors. Although graft survival for cadaver kidneys was significantly better with younger grafts, 10-year death censored graft survival for patients receiving grafts from elderly living donors (>55 years/in absence of acute rejection) was >90%(8) suggesting the importance of a careful patient selection and the influence of additional unspecific inflammatory events as ischemia/reperfusion injury and brain death. Diagnostic tools seem necessary to predict the outcome of grafts from elderly donors. Creatinine clearance and biopsies were tested for their predictive value, although creatinine clearance was determined as the optimal predictor of graft survival (9) others suggested a glomerulosclerosis index or the degree of fibrous intimal thickening at the time of implantation (10,11). While the percentage of liver donors >50 years has increased from 2 to >17% from 1987 to 1992 according to UNOS data an adverse effect on 6-month graft survival was observed. However, graft failure rates in recipients of grafts from the oldest donor group in 1992 were comparable to those from young donors in 1987 (12). Similarly, liver grafts from marginal donors defined by a variety of risk factors including history of alcoholism, abnormal liver function test, cardiovascular diseases, or lengthy hypertension periods demonstrated comparable 1-year patient and graft survival with grafts from “good” donors. Interestingly, the refusal rate based on medical grounds was less in larger centers (13). Diagnostic criteria judging what is good or at least sufficient and what is not are still hard to find. Neither functional tests nor laboratory values seem predictive. However, liver grafts from elderly donors judged as of good quality by the harvesting surgeon demonstrated a similar outcome as those from younger donors (14). Age criteria have also been liberalized with cardiac, lung, and pancreas transplants. Although fatal acute graft failure was more prevalent, 5-year patient and graft survival rates in recipients of heart grafts were not significantly different comparing donors of the age groups 50 years (15). Others did not find differences in graft function and patient survival by 3 years when grafts from elderly donors (>40 years) were used, although an earlier development of coronary artery disease was observed (16). Hearts from donors ≥60 years have been engrafted successfully with satisfactory long-term results. However, it has been recommended not to accept grafts from elderly donors with signs of coronary insufficiency, compromised ventricle filling pressures or signs of segmental dysfunction (17). The development of pulmonary transplantation has been revisited recently including the utilization of so-called marginal grafts (18). Interestingly donor age has not been a risk factor per SE although the interaction between donor age (>55 years) and prolonged ischemia (>6 hr) predicted 1-year mortality (19). Pancreas grafts from elderly donors (>45 years) demonstrated similar graft survival although complication rates had not increased. Interestingly, organs sent by other teams were excluded from their study although the rapid “en bloc” harvesting technique had been used (20). Previous diseases, cause of death. Additional donor factors reducing the quality of the graft may include previous diseases with a systematic influence on the vascular system as arterial hypertension or diabetes mellitus. Analyzing the “kidneys that nobody wanted” 15 allografts were previously declined as a consequence of a history of arterial hypertension. When those grafts were finally used increased rates of primary non-function were observed although 1-year patient and graft survival rates were not different (21). Overall, the precise correlation of arterial hypertension and chronic graft deterioration remains unclear although already existing long-term hypertension of the recipient is considered a risk factor (22). Experimental studies demonstrated an acceleration of chronic graft rejection after systemic hypertension paralleled by increasing inflammatory markers. Analyses of cadaveric renal allografts from donors ≥55 years with a history of long-term arterial hypertension reported to UNOS demonstrated decreased long-term function with reduced creatinine clearance (23). Similar results have been reported from the CTS data base (24). Cause of death. With an increase of donor age the cause of death changed. Although the number of organ donors dying as a consequence of trauma injuries decreased, cardiovascular or cerebrovascular causes of death have increased (1). The development of transplant-vasculopathy may at least in part be conceptualized as a response to injury mode, thus demonstrating similarities to mechanisms involved in the development of conventional arteriosclerosis (25). Indeed, preexisting donor coronary disease has been associated with increased transplant-vasculopathy (16). Renal allograft function from donors with trauma injuries have significantly improved compared to those from donors dying of cardiac- or cerebrovascular complications (26). In an additional study, cause of donor death was shown to have a significant impact on long-term graft function in renal allografts (27). Similarly, using kidneys from non-heart-beating donors (NHBD) with cerebrovascular disease as the cause of death demonstrated reduced renal function (28). However, as a correlation of age and cause of death cannot be ignored their independent contribution on long-term graft function may be difficult to judge. Brain death. Organs of reduced quality determined by donor criteria and previous diseases may be additionally damaged by consequences of brain death. Those events in relation to transplantation have been receiving increased attention and have recently been reviewed (29). Experimental studies demonstrated increased acute and chronic rejection rates after brain death compared to living donor animals. Interestingly, grafts from brain dead donors demonstrated increased cellular infiltrates with increased proinflammatory cell markers when compared to living donors (30,31). Thus, particularly in grafts from marginal donors, brain death may represent an additional non-immune injury contributing to further perioperative and postoperative alloantigen-independent and -dependent events. THE RELATIONSHIP BETWEEN ORGAN QUALITY AND FURTHER SPECIFIC AND UNSPECIFIC DAMAGES The impact of unspecific damages on chronic graft dysfunction has been shown previously. Interestingly, mechanisms in models based on unspecific inflammatory damages did resemble changes occurring in chronic allograft models, albeit at later time intervals after transplantation. Thus, models of prolonged ischemia and those studying the consequences of brain death or reduction of functional kidney mass demonstrated characteristic morphological changes of chronic graft rejection associated with high numbers of infiltrating T cells and monocytes/macrophages with their products tumor growth factor (TGF-β), tumor necrosis factor (TNF-α), and interleukin- (IL) 6. The importance of those factors on the development of chronic graft deterioration including chronic fibrotic changes may also play a role in other chronic disorders (29–35). Experimental and clinical evidence demonstrates the correlation between organ quality determined by donor age, previous diseases including cause of death and additional peri- and postoperative alloantigen-dependent and -independent risk factors. It may thus be hypothesized that grafts from marginal donors are particularly sensitive to additional damages (Fig. 2). The increasing detrimental effects of prolonged ischemia with increasing age have been demonstrated in clinical and experimental studies. The impact of ischemia/reperfusion injury on both short and long-term grafts has been described in several experimental and clinical studies. Postulated mechanisms of ischemia/reperfusion injury have been reviewed elsewhere (36). Marginal grafts may be particularly sensitive towards prolonged ischemia. Several clinical studies demonstrated the correlation between delayed graft function, prolonged ischemia, and both acute and chronic rejection episodes. Delayed graft function associated with prolonged ischemia has been shown as an independent risk factor for chronic graft deterioration and was particularly detrimental in grafts from elderly donors (37). In clinical lung transplantation graft survival was reduced with increasing donor age and prolonged ischemia (19). Several clinical studies associated prolonged ischemia with delayed graft function and increased acute rejection episodes (2,38) although acute rejection episodes have been shown as one of the most influential risk factors for late graft dysfunction (39,40). In addition, increasing donor age has been associated with delayed graft function and vascular rejection in renal allografts (41) although heart grafts from older donors, particularly with prolonged ischemia, demonstrated reduced perioperative and long-term survival (42). We have observed an increased susceptibility of grafts from older donors to prolonged ischemia in a rat renal allograft model (43). Intensive care treatment seems to be of particular importance until the harvesting process is completed. Hemodynamic and electrolyte disturbances may reduce the quality of grafts from marginal donors further. Catecholamine application associated with reduced expression of adhesion molecules has been correlated with a superior long-term graft function (44). Recent experimental studies demonstrated reduced liver graft function after mechanical manipulations during organ harvesting. Further studies into the mechanisms demonstrated the involvement of Kupffer cell-dependent injuries associated with endothelial cell injury and microcirculatory disturbances. Interestingly, organ manipulation was particularly detrimental in a model of marginal grafts using fatty livers (45). Additional T cell-activating processes after engraftment may also play a role and may be of particular importance when dealing with suboptimal grafts. Viral infections have been associated with subsequent inflammation and vascular diseases. A relation between cytomegalovirus (CMV) infections and increasing rates of acute and chronic rejections has been demonstrated in experimental and clinical studies for various organ systems including renal allografts (46). Indeed, patients treated for CMV infections demonstrated reduced acute rejection rates while CMV-associated steroid-resistant rejection episodes improved with ganciclovir therapy (47). CMV infections have been shown to be associated with the expression of a variety of cytokines including interferon- (IFN) γ and IL-2. In addition, CMV infections correlated with an increased expression of MHC II antigens (48,49) as well as increased levels of IL-1β and several adhesion molecules. We could show in an experimental model that additional specific T cell stimuli simulated by secondary skin grafts after transplantation accelerated chronic graft rejection (Tullius SG, et al. Manuscript submitted for publication.). Although donor-specific skin grafts were more detrimental, additional third party skin placement also damaged the original kidney graft. Thus, experimental and clinical data imply that marginal grafts are particularly sensitive to additional damaging factors. Clinical and experimental studies determining the contribution of individual risk factors on the function of both optimal and suboptimal grafts seem crucial. Furthermore, to use as many organs as possible new avenues to improve the quality of marginal grafts need to be explored. IMPROVING THE QUALITY OF MARGINAL GRAFTS Manipulations of the organ mass have been receiving increased attention recently to extend the amount of donor organs and to improve the quality of grafts from suboptimal donors. Liver split-transplants and living related liver transplants are performed increasingly with good short and long-term results (50). Although the regenerative capacity of the liver is well recognized ratios of recipient weight to graft size 75 years or when a glomerulosclerosis rate of >15% was found in grafts from donors aged 60–74 years. This study demonstrated equivalent graft and patient survival rates compared to single grafts from donors <60 years or to grafts from donors aged 60–74 with a glomerulosclerosis rate of 60 years or those having a history of diabetes or arterial hypertension or clinical proteinuria (54). In a recently published study, a scoring system including degree of glomerulosclerosis, donor serum creatinine, and weight of both kidneys has been reported for the utilization of either single or double renal transplants (55). Long-term results were reported recently from the UNOS scientific registry with remarkable 3-year graft functioning rates of dual kidney transplants. On the basis of this study it was recommended to use grafts from donors >60 years with creatinine clearance levels 55 and >60 years, respectively. Although graft survival was significantly better in grafts from younger donors compared to those from elderly donors in the presence of one or more acute rejection episode, 10-year graft survival rates were comparable in the absence of acute rejection episodes (8). Treatment of unspecific inflammatory injuries. Donor-treatment may serve as an option to reduce unspecific inflammatory events. Steroides have been applied to donors in an uncontrolled study before, demonstrating increased mean arterial pressure eventually as a consequence of reduced cytokine levels and improved catecholamine sensitivity (57). Corticosteroides represent an important component in most of the current immunosuppressive regimes. However, only recent studies demonstrated molecular mechanisms nvolved that include the inhibition of NFκB, the most relevant transcription factor for acute injury and inflammatory processes (58). We observed improved graft survival after donor treatment with methylprednisolone in a rat renal allograft model using grafts from elderly donors with prolonged ischemia (59). Other donor-treatment strategies have been applied before in experimental models. Donor treatment with mycophenolate mofetil demonstrated protection against primary non-function and consequences of ischemia/reperfusion injury (60). In a clinical study improved liver graft function measured by reduced transaminases peaks has been shown after donor-treatment with prostaglandins (61). The induction of protective genes including heme-oxygenase-1 have gained recent interest. Heme-oxygenase-1 is the rate- limiting enzyme converting heme into biliverdin, carbon monoxide, and iron. The induction of heme-oxygenase-1 has been associated with the inhibition of inflammation and protection of the endothelium although the precise mechanisms remain elusive (62). Heme-oxygenase-1 induction has been shown to prolong the survival of heart grafts in mice while being associated with the absence of chronic graft rejection and long-term graft acceptance (63). Interestingly, pretreatment with cobalt protophorphyrin for the induction of Heme-oxygenase improved graft function in a rat steatotic liver isograft model although consequences of ischemia/reperfusion injury were reduced (64). In our own experimental study we observed a remarkable improvement of long-term graft function after a single donor-treatment for the induction of heme-oxygenase-1 both, in a model of “marginal” and “ideal” renal allografts with prolonged ischemia (64a). Additional approaches included modifications of organ perfusion. Adding anti-sense oligonucleotides directed against ICAM-1 to perfusion solutions ameliorated the consequences of ischemia/reperfusion injury and improved graft function in a rat renal isograft model (65). The anti-oxidative potential of N-acetylcystein (NAC) has been tested in experimental and clinical trials. Although improved liver function with reduced ischemia/reperfusion injury were observed in some studies other trials could not observe beneficial effects (66). Experimental models demonstrated improved sinusoidal perfusion and reduced cell adhesion after N-acetylcysteine application, however, NAC application had no beneficial effect in pig liver grafts from NHBD or in experimental renal transplantation model (67). In addition, new immunosuppressive drugs have been shown to have an impact on inflammatory damages. In an experimental study rapamycin and mycophenolic acid administered before and after mechanical arterial injury reduced arterial intimal thickening and allowed endothelial regrowth. When those drugs were given after the injury short-term beneficial effects were observed although long-term progressive lesions remained unchanged (68). Chronic graft deterioration was significantly reduced in experimental heart and renal allograft models when rapamycin and mycophenolat mofetil were administered (69). Further clinical investigations including donor-treatment regimens are warranted to prove their clinical value. FINDING THE RIGHT RECIPIENT AND TREATMENT FOR MARGINAL GRAFTS Donor/recipient matching. Although donor/recipient selection criteria based on HLA compatibility represent the standard for kidney allocation, the impact of HLA compatibility for heart or liver transplants remains debated. In addition, physiological matching for age, sex, and body weight are discussed and represent frequent clinical practice. For grafts from marginal donors transplantation to older recipients has been proposed. Although those selection criteria seem reasonable there are conflicting reports concerning age matching. Both acute and chronic rejections seem less common in older recipients although posttransplant morbidity has been mainly attributed to infections and an increased incidence for malignancies (70). In addition there is a greater loss of functioning grafts as a consequence of death. Some studies reported on improved patient and graft survival in renal transplants when grafts from young or old donors were transplanted into old recipients (≥55 years) although grafts from old donors demonstrated significantly reduced function in young recipients (71). Analyses of the UNOS data base described an improved function when kidney grafts from old donors (>60 years) were grafted into older recipients (>60 years) (72). Although grafts from elderly donors may be considered less immunogenic older recipients may demonstrate reduced immunological responses. However, increased recipient age has been shown as an independent risk factor for the development of chronic graft rejection (73). Interestingly, a single center study reported more acute rejection episodes in older recipients (≥65 years) compared to younger recipients with both groups matched for HLA-compatibility (74). Grafts from donors ≥60 years have been showing reduced graft survival rates in recipients ≥60 years compared to those from donors ≤60 years (75). Analyses for donor/recipient size demonstrated that matching for body surface area as a surrogate for nephron mass did not improve long-term results. Similarly matching for gender has been shown beneficial by some studies although others could not find improved renal allograft survival (6). Thus, although clinical data are not completely clear on the effects of matching for nonimmunological risk factors, transplantation of organs from older donors into elderly recipients seems justified. There is only little information available for an age-dependent alloresponse although it seems desirable to apply age- dependent immunosuppressive regimens when grafting organs from older donors into elderly recipients. Sparing nephrotoxic drugs and preferentially including immunosuppressive agents that have been shown to reduce unspecific inflammatory events may be advantageous. In a preliminary report low-immunological risk patients receiving renal allografts from suboptimal donors were treated with ATG, mycophenolate mofetil, and steroids. After a follow-up period of 6 months all grafts remained functioning although 30% of recipients had to be converted to cyclosporine A (76). In an additional preliminary study elderly recipients (63±5 years) receiving grafts from an elderly donor population (66±8 years) were treated with mycophenolate mofetil solely after an ATG induction therapy. One year graft survival rates were 92% although the incidence of acute rejection episodes and delayed graft function were reported as 20 and 29%, respectively; one graft was lost as a consequence of irreversible acute rejection while immunosuppression had to be converted to calcineurin inibitors in several patients (77). In our own preliminary clinical experience with the transplantation of renal allografts from donors ≥65 into recipients ≥65 years we observed a high incidence of acute rejection episodes requiring conversion to calcineurin inhibitors. Renal allografts from donors >60 years treated with tacrolimus- based immunosuppression demonstrated reduced 1- and 3-year patient and graft survival rates compared to kidney grafts from donors 80% at 1 year, rates not significantly different to kidneys from brain dead donors. Although those results are promising, long-term outcome may be reduced with increasing rates of delayed graft function. Grafts from NHBD dying of trauma functioned significantly better than those from NHBD dying of other causes (82-84). There are several additional clinical and experimental reports demonstrating promising results after the transplantation of liver, lung, and combined pancreas kidney grafts from NHBD (85-87). In addition, the potential collection of sufficient amounts of islets had been reported recently (88). Grafts from controlled NHBD, e.g., those with awaiting cardiac arrest demonstrated superior results as a consequence of reduced ischemic times (89). However, there have also been reports on successful transplantations utilizing grafts from NHBD who died outside the hospital (90). Viability tests and machine perfusion have been used successfully to improve the quality of grafts from NHBD, particularly for those with prolonged ischemia. Pulsatile machine perfusion offers the opportunity for quality assessment and may improve the function of grafts from NHBD (91-93). Furthermore, experimental studies have been showing a beneficial effect on the outcome of grafts from NHBD by adding pentoxifylline or l-arginine to perfusion solutions (94,95). Identifying the viability and reducing the consequences of ischemia/reperfusion injury seem of particular importance when using grafts from NHBD. Furthermore, grafts from NHBD may benefit from the absence of the consequences of brain death. Although grafts from NHBD may offer the opportunity to increase organ supply broad promotion of this approach should be discussed with care. Ethical issues related to the diagnosis of death, start of perfusion, and finally the impact of an increased incidence of delayed function on long-term graft outcome represent unsolved problems and require a cautious approach for the utilization of grafts from NHBD in order not to jeopardize well-functioning donor programs (96). THE ECONOMIC IMPACT OF USING MARGINAL GRAFTS The economic advantage of renal transplantation compared to dialysis has been demonstrated in various reports. With intensified costs for the first years a break even point has been calculated for renal transplantation when the graft is functioning for at least 2.5–4 years (97,98). However, costs may increase when using less than optimal grafts. Increased costs have been reported for organ retrieval from marginal donors defined by extreme age groups (55–75 or 60 years) or those receiving retransplants were used. The break even point increased from 4.4 to 13 years when grafts from marginal donors were grafted into high-risk recipients (98). The problem of increasing costs when using grafts from marginal donors has been summarized in a recent review article. Although facing additional costs, it has been suggested that suboptimal grafts need to be used when a reasonable chance of clinical success and improvement in quality of life can be expected. In addition, enforcing concepts to evaluate the quality of grafts from marginal donors and to improve their condition have been suggested (101). SUMMARY As the demand for transplantation will increase, further organs from suboptimal donors will be increasingly used in the future. The impact of the quality of the graft determined by a variety of risk factors including donor age, consequences of brain death, cause of death, and previous diseases has been shown in several experimental and clinical studies. An increased sensitivity of grafts from marginal donors toward unspecific inflammatory damages during organ harvesting and prolonged ischemia can be postulated. After engraftment alloantigen-specific events such as acute rejection episodes, consequences of drug toxicity and T cell activating processes as viral infections will damage those grafts further. All those events contribute to an increased functional deterioration of grafts from marginal donors compared to those from “ideal donors” (Fig. 2). After an analysis of the problem several questions remain open. Most importantly, a more precise and broadly accepted definition of the term marginal grafts is currently missing. Although the increasing demand for organs is requiring the utilization of suboptimal grafts, those grafts may only be used when a reasonable chance for clinical success including an improvement in quality of life can be expected. For renal allografts, scoring systems have been established in clinical trials to decide which organs should be accepted, rejected, or when dual transplants should be performed. Marginal grafts may be characterized by donor age, serum creatinine, cause of death, and creatinine clearance using the Cockgroft-Gault equation. An additional biopsy may deliver further information on the degree of sclerosis. Furthermore, anatomical variations, e.g., >1 renal artery need critical consideration in marginal kidney grafts. Donor age >65 years, creatinine clearance (Cockgroft-Gault) 1.5 mg/dl during a stable phase of the donor, degree of glomerulosclerosis >15% in addition to the cause of death and duration of ischemia may define marginal renal grafts. Various approaches to test liver graft function prior to engraftment have not been conclusive. The harvesting surgeon judging on the quality of the graft still seems to have the best predictive value. Analyzing donor and recipient risk factors donor age (>49 years), hospital stay of the donor >3 days, cold ischemic periods of >18 hr, and both moderate and severe fatty changes (30-60% and>60%) were significantly associated with primary graft dysfunction (102). Experimental and clinical data criteria as donor age (>55 years), cause of death, length of hospital stay of the donor, and previous diseases could also define marginal pancreas grafts. Similar criteria in addition to preexisting coronary artery disease on angiography or intracoronary ultrasound should be considered for the definition of marginal heart grafts. However, consensus agreements seem necessary to decide on general accepted definitions. The influence of a variety of risk factors and their correlation should be reflected in scoring systems defining the term marginal donor in individual organ groups. As grafts from marginal donors seem more sensitive toward additional damaging effects, concepts to improve the condition of suboptimal grafts need to be followed. Short ischemic periods seem of particular importance. Once grafts are defined as marginal, ischemic periods could be reduced to a minimum with a precise time schedule coordinating the harvesting procedure with the timing of transplantation. Although trials distributing renal grafts from donors >65 to recipients >65 years with the priority of minimized ischemic times have been started, other reports have demonstrated the impact of HLA matching even with prolonged ischemia (103). Dual kidney grafts have been performed successfully. However, additional surgical risks and prolonged ischemia in elderly patients with additional complications have to be considered. Using the rapid “en bloc” harvesting technique in marginal donors may reduce graft damage during the operative organ removal procedure. Improved graft function after donor treatment has been shown in several clinical and experimental studies. This treatment option may reduce the immunogenecity of the graft and reduce the sensitivity toward additional injuries associated with brain death, consequences of ischemia/reperfusion injury and alloantigen-specific influences after engraftment. Furthermore, modifications of the perfusion solutions and machine perfusion may predict graft quality and improve the quality of marginal grafts (104,105). Clinical and experimental trials are necessary to provide the marginal graft with an optimized age-adapted immunosuppression. However, there is only scarce information on age-associated immune responsiveness. Only a few age-adapted immunosuppressive regimens have been described. Although there are some reports available suggesting that immunoresponsiveness is decreasing with increasing age, individual donor and recipient differences may play a major role. Specific T cell reactivity tests or testing for individual gene expression in the future may be helpful to distinguish between those who need little and those who need a lot of immunosuppression (106). In summary, grafts from marginal donors need to be used with an increasing demand for transplantation. A general accepted definition scoring the degree and correlation of risk factors needs to be established to decide that organs should be accepted or refused. Various opportunities for the improvement of organ quality including donor-treatment, modifications of organ perfusion and donor-recipient matching have to be exploited further based on broadly accepted, organ-specific definitions. Age-adapted immunosuppressive regimes after an analysis of age-dependent immunological responses need to be studied further. Acknowledgments. The authors thank Prof. Bruno Watschinger and Dr. Johann Pratschke for their helpful comments and review of the manuscript.