Utilization rates of organs from elderly donors have shown the highest proportional increase during the last decade. Clinical reports support the concept of transplanting older organs. However, the engraftment of such organs has been linked to accelerated immune responses based on ageing changes per se and a proinflammatory environment subsequent to compromised injury and repair mechanism. We analyzed the clinical consequences of transplanting older donor organs and present mechanistic aspects correlating age, injury repair and effects on host immunoresponsiveness.
To meet the increasing demand, organs from older donors are used for transplantation with increasing frequency. In the absence of a generally applicable definition of age, we analyzed outcomes based on the currently existing definitions for expanded criteria donors (ECD) in the United States and those defining the European Senior Program (ESP). As organs from older donors are mostly used in renal transplantation, our analysis will focus on the consequences of transplanting this cohort of kidneys.
Ageing is linked to organ-intrinsic changes potentially affecting immunogenicity and functional attrition rates. Injuries inevitable associated with transplantation such as brain death (BD) and prolonged cold or warm ischemia (in organs procured after cardiac arrest) may result in injury-specific and age-dependent repair mechanisms that affect organ quality and the host immune response.
Understanding aspects of organ age, injury, repair and immune responsiveness have far-reaching translational aspects and may pave the way to improved organ quality, reduced immunogenicity and adapted immunosuppression.
Defining Donor Age
In the United States, ECD are defined by age (>60 years) or age (50–60 years) plus additional risk factors (stroke as the cause of death, history of arterial hypertension and final serum creatinine > 1.5 mg/dL). This definition is based on an arbitrary cutoff with a 70% higher risk of graft failure in ECD compared to non-ECD donor kidneys (1). More detailed donor risk profiles have been developed recently for renal transplants with the goal to reduce the overlap between ECD and non-ECD donors in predicting transplant outcome (2). Transplanting ECD kidneys is associated with reduced morbidity and mortality in subgroups of patients, particularly older recipients, diabetics and those with longer waiting times (3,4). Although the utilization rate of ECD kidneys has increased by more than 40% during the last decade (5) current listing practices vary greatly and have been largely inconsistent with published recommendations for their allocation (6).
In Europe, organs from elderly donors (≥65 years) have been allocated predominantly to older recipients (≥65 years). Recipients of older organs in the so-called ESP have a low-immunological risk (panel reactive antibody <5%) and this allocation system does not take HLA-matching into account. Allocation in the ESP aims to reduce organ injury by allocating organs in a limited geographical area, thus keeping ischemic times brief. Organ availability doubled with this allocation algorithm and waiting times for elderly recipients were reduced. Graft survival was not significantly different when older organs were transplanted into older recipients. However, outcomes of older organs were inferior when compared to the allocation of overall available kidneys (7).
In a recent, large-volume and risk-adjusted analysis of the United Network for Organ Sharing (UNOS) database, we observed rates of acute rejection increasing in parallel with every decade of increasing donor age. An increased incidence of acute rejection has also been reported by others when older organs are being transplanted (8). In a combinatorial analysis of donor and recipient age, acute rejections occurred most frequently when older organs were transplanted into younger recipients. This effect was blunted when older grafts were allocated to older recipients, reflecting a reduced potency of the immune response with increasing recipient age (9,10). An analysis of the renal transplant population listed with UNOS in the previous decade (1988–1998) linked an increased risk of graft failure to organ age (>55 years) but was unable to detect an advantage of transplanting older organs into older recipients (11). The ESP, which disregards HLA-matching, associated the engraftment of older organs with more frequent acute rejection rates (7).
Donor age has also been linked to increased rates of Chronic Allograft Nephropathy (CAN, Refs. 12,13). It is important to note, however, that features of CAN such as interstitial fibrosis/tubular atrophy (IFTA) and glomerulosclerosis are also observed as a consequence of physiological aging processes (14). Delayed graft function (DGF) is more frequent after transplantation of older organs and may be reflective of donor age-specific injury and repair processes. Risk prediction models have, at the same time, associated DGF with increased acute rejection and graft failure rates (12,15,16). Graft survival may be influenced by aging processes per se and/or by compromised repair processes following unspecific injuries. In general, graft survival has been inferior when older organs were transplanted; however, this association has been less prominent in more recent studies. Also of note, pathogenesis-based transcript sets obtained short-term after transplantation were comparable in organs from deceased and living donors in the absence of DGF, suggesting a complex interference of age, injury and transplant outcome (15,17–20).
Donor Age and Injury Pattern
Organs from donors procured after cardiac arrest (DCD) have experienced a several-fold (>700%) utilization rate in the United States during the last decade (21). Such organs undergo a prolonged warm ischemia interval but are not exposed to the inflammatory consequences linked to BD. Although the incidence of DGF in kidneys of DCD has exceeded 90% in some clinical studies, kidneys from DCD have, in general, graft survival rates comparable to those of BD donors (22,23). Of relevance, aging seems to affect injury and repair mechanisms in kidneys from DCD in a more sensitive way and inferior outcomes of DCD organs from donors >50 years have been reported (24). Moreover, effects of prolonged cold ischemia and HLA incompatibility were more detrimental in organs from DCD (23).
Those clinical data suggest that the initial injury, either as a consequence of prolonged warm ischemia as in organs from DCD, or as a result of cold ischemia and BD experience different and age-dependent injury and repair programs.
Aging in Renal Versus Nonrenal Transplants
Biological aging is associated with a functional decline of almost all organ systems, although organ-specific aging differences seem relevant (25). The liver, for instance, preserves its function relatively well and has an excellent capacity to regenerate. Although, morphological changes are observed in the aging liver, mechanisms and clinical consequences associated with those structural changes remain unclear.
The kidney, in contrast, has an age-related 10% loss of functional mass per decade in most studies (26,27). Of note, additional risk factors such as hypertension, diabetes, arteriosclerosis and dyslipidemia may play a role in renal aging as not all healthy individuals show comparable functional deterioration (28). Structurally, a loss of functioning glomeruli and an augmenting glomerulosclerosis is observed and reflected by an attrition of glomerular filtration rates (0.4–1.02 mL/min per year; Ref. 29).
The changes of aging in other organ systems and their relevance to injury, repair and consequences after transplantation have been less well studied.
Mechanistic Aspects of Organ Age-Dependent Injury and Repair
Clinical and experimental data suggest that organ age is linked to compromised repair processes. Ischemia-reperfusion injury (IRI) entails various pathophysiological events that include microcirculatory disorders, endothelial cell activation, expression of proinflammatory cytokines and adhesion molecules and the loss of endothelial integrity. All these can result in inflammation and edema (30).
There is evidence supporting an age-related susceptibility to IRI. In general, limited antioxidant defense potential, reduced regenerative capacities and compromised mitochondrial abilities are observed in a variety of tissues with increasing age (31). Age-related impairment of the cytochrome C binding site in mitochondria of cardiomyocytes, for example, has been linked to impaired oxidative function and reduced tolerance to ischemic injury (32). The mitigation of the mitochondrial function results in a depletion of intracellular energy contents with a more pronounced IRI in the elderly (33). Impaired microcirculation in the early phase of reperfusion may play an additional role (34).
Heat shock protein-70 (HSP-70), a molecular chaperone involved in transmitochondrial protein transport is an important cytoprotectant. Liver ischemia experiments have shown that HSP-70 is dramatically reduced in elderly mice; ischemic preconditioning failed to communicate protective effects in older livers and hearts (35).
Telomere shortening is a critical component of aging. Physiologically, telomeres protect the integrity of chromosomes. Once telomere length has reached a critical threshold, cells lose the capacity to replicate, become senescent and undergo apoptosis. Moreover, the division of cells is paralleled by a progressive attrition of cell divisions commonly referred to as the “Hayflick limit”.
Senescent cells are characterized by a greater heterogeneity, accumulation of lipofuscin granules and a lack of response to mitogenic stimuli. Those cells show a growth arrest, an altered balance of apoptosis/proliferation, dysfunction of growth factors and the secretion of proinflammatory cytokines. Stress-induced premature senescence linked to oxidative stress, DNA damage or mitochondrial damage may further augment biological senescence processes (36). Telomere dysfunction has been identified as the driver of senescent and apoptotic depletion affecting stem-cell reserves and tissue degeneration. Moreover, reactivation of telomerase in experimental systems was able to reverse tissue degeneration (37–39).
Those studies are suggestive that cellular senescence, albeit only partly understood at this time, impacts the susceptibility of old organs to injury and reduces repair capacity. These and other factors may influence transplant outcome (36,40–42; Figure 1)
Organ Age and Immunoresponsiveness
The compromised capacity of the aging organ to repair may play an important role in accelerating an immune response. In general, it is believed that nonspecific injuries induce a proinflammatory milieu which, in turn, may activate innate and adaptive immune responses.
The recruitment of recipient's dendritic cells (DC) into the graft activating recipient's T cells via the indirect pathway represents an important link between injury and immune response. DC activation, increased apoptosis and antigen presentation by parenchymal cells may play a role in augmenting the immune response when transplanting older organs: When T cells have been cocultured with old antigen-presenting cells, an increased proliferation has been observed, suggesting an enhanced antigen presenting capacity of old DCs (13,43). Inconsistencies, however, of the phenotypic evaluation of DCs has led to varying results in regard to the capacity of aging DCs to mount an immune response (40,44,45). It has also been recently shown that IRI enhances the immunogenicity of DCs via toll-like receptor 4 and nuclear factor-kappa B activation (46), a link requiring further exploration.
Cell death via apoptosis is a physiological part of the aging process and older grafts contain more apoptotic cells. Abnormal apoptotic cells constitute a significant source of local inflammation and have previously been linked to autoimmune diseases and persistent inflammation (47). Phagocytosis and clearance of apoptotic cells inhibit a panel of proinflammatory cytokine production (48). Previous in vitro studies demonstrated a compromised phagocytic function of older DCs suggesting that the observed increased immunogenicity of old organ grafts could also be linked to an impaired phagocytosis of apoptotic cells (49).
As a consequences of impaired capacitates to repair, old parenchymal cells express more MHC molecules. Proinflammatory cytokines detected after IRI in aging organs may, furthermore, augment innate and adaptive immune responses when transplanting older organs (Figure 1; 50,51).
The ever-increasing need for organs and the discrepancy between supply and demand will undoubtedly demand the utilization of organs from older donors (52). To optimize the utilization and allocation of older organs, it will be critical to understand age and injury-specific repair mechanisms. Moreover, it will become increasingly important to explore mechanisms linking organ age, repair and injury to the recipient's immune response. The overall augmented inflammatory milieu in older organs, age-dependent aspects of antigen presentation and recognition, mechanisms of senescence and the cascade of age, injury-specific repair mechanisms linked to innate and adaptive immune responses represent some of the future studies of interest. Understanding mechanisms of organ age and transplant outcome may allow defining novel targets for the improvement of organ quality, ways to manipulate immunogenicity and finally provide a conceptual framework of age-specific aspects in preservation, immunosuppression and organ allocation.
Future research on the effects of age and transplantation has the potential of answering other general questions. The correlation of donor age and environment appears fascinating and models in which older graft will be transplanted into a young recipient may well be suited to explore the potential of “reprogramming” senescence.
The authors wish to thank N. L. Tilney, MD, for carefully reading the manuscript.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.