1 Background and Rationale

1.1 Background

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The life expectancy of the population in general is increasing consistently, as is the age of the dialysis population. Consequently, donors and recipients are getting older, and renal transplantation has become a therapy that is not limited to the youngest segment of patients with terminal renal failure. Reluctance to use organs from elderly subjects has decreased with increasing discrepancy between the number of available donors and demand. Reluctance to put elderly patients on the waiting list still seems high, with a median age of patients on dialysis in Germany being 64 years but the median age of transplant patients being 49 years (http://www.quasi-niere.de). There are several likely reasons, including the fact that worse short-term and long-term outcomes have been reported for older recipients and as a result of the donor shortage younger patients are often given priority.

Despite expanding knowledge and experience with aging donors and recipients, numerous questions remain unanswered or controversial.

Amongst others, the main questions relate to:

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These questions will be addressed in the following sections, followed by a brief introduction to the Eurotransplant Senior Program and its analyses to date.

1.1.1 The effect of donor age on outcome after renal transplantation

Due to excessive waiting times of about 5 years or longer (source: http://www.quasiniere.de, ) and the increasing disparity between organ supply and demand, the use of kidneys from “marginal donors” or “expanded criteria donors” (ECDs) - with older age being one of the criteria - has become generally accepted and increasingly common (Metzger, et al., 2002). In the past decade, the proportion of deceased donors in the US older than 50 years of age has increased from 21% to over 30% with an increase in donors aged 65 and above from 4,2% in 1994 to 7,4% in 2004 (source: ). Eurotransplant data also show an increased usage of elderly donor kidneys in recent years with more than 14% of donors in 2003 being over 65 years old (Cohen 2004). In Germany ,this proportion is even higher at 20% (Figure 1; Source: DSO, ).

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Figure 1: Transplants in Germany by donor age (Source: DSO, )

Results documenting evidence of an inferior outcome of grafts from elderly donors were already published in 1974 (Darmady, 1974). In the early postoperative period, an increased rate of primary non-function and delayed graft function was reported, both of which are well-known risk factors for allograft survival in general (Cecka, et al., 1992;Sautner, et al., 1991). The impact on long-term outcome, however, was even more dramatic. In 1994, Alexander and co-workers reported the two-year transplant survival with regard to donor age in more than 30,000 transplantations performed between 1987 and 1991 (Alexander, et al., 1994) . When adjusted for various covariates (number of previous transplants, donor and recipient race, presence of diabetes mellitus, percentage of panel-reactive antibodies (PRA), cold ischemia time and HLA mismatch), the lowest risk for graft failure at one year was seen in kidneys obtained from donors aged 16-45 years. With each decade of increase in donor age, the relative risk rose by 15%-20%. The magnitude of this effect, however, increased exponentially with time, reaching an odds ratio for failure after two years of 3.25 with donors older than 70 years, compared with a group of 30-year-old donors. Terasaki reported a higher prevalence of delayed graft function, an increased need for postoperative dialysis, higher serum creatinine at discharge and higher acute rejection rates in recipients from older donor kidneys. The projected transplant half-life decreased from 10.2 years if the donor was 16-20 years old to 5 years for grafts retrieved from donors who were 60 years of age or older (Terasaki, et al., 1997). A particularly striking effect of donor age on long-term outcome was described by Gjertson in 1996 (Gjertson, 1996): in grafts surviving the first postoperative year, donor age accounted for 30% of the variability in outcome, the effect at one year was also significant, but at 4.1% much less striking. In an analysis by Nickerson et al., the adjusted odds ratio for an increase in serum creatinine of more than 20 μmol/L 6 to 24 months post-transplantation was 1.09 for every year increase in donor age (Nickerson, et al., 1998), and an analysis of the USRDS database published in 2005 confirmed that initial GFR at 6 months but also stability of GFR in the first year were significantly lower among recipients of donors > 55 years (Woo, et al., 2005).

Organs from elderly donors seem to be particularly susceptible to ischemia-reperfusion injury leading to increased rates of DGF. Ojo reported a 23% increase in DGF for every 6 hours of cold ischemia in transplant recipients of any age, consequently leading to higher risk of acute and chronic rejection (Ojo, et al., 1997). This effect seems to be even more pronounced with increasing donor age and has been found as an independent risk factor for chronic graft deterioration (Shoskes and Cecka, 1998;Tullius, et al., 2000).

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As a matter of concern, donor age has recently been shown to represent a significant risk factor for patient death with functioning graft(Meier-Kriesche, et al., 2002). The author speculates that the poor function of the aged graft could lead to hypertension and increased incidence of cardiovascular events.

Even with live donors some (Langle, et al., 1992;Matas, et al., 2000), but not all (Matas, et al., 1976), authors have argued that donor age determines long-term outcome.

In summary, donor age has been shown to have an impact on the incidence of DGF, graft function, graft survival and patient death with functioning graft and has thus turned out to be a powerful predictor of long-term outcomes after renal transplantation.

1.1.1.1 Age related changes in the graft

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Inferior outcomes in patients receiving an organ from an older donor might be related to changes in the donor organ as a result of the aging process. The biologic price of aging includes progressive deterioration of renal function and structure (Anderson and Brenner, 1986). Histopathological studies reveal a 20% to 25% loss of volume, particularly in cortex, fibrous intimal thickening of arteries, loss of glomeruli due to sclerosis with enlargement of the remaining glomeruli, patchy tubular atrophy and interstitial fibrosis in aging kidneys (Goyal, 1982). Kumar et al. performed pretransplant biopsies of kidneys from donors older than 55 years. Age-associated glomerulosclerosis was present in 85%, patchy interstitial fibrosis in 64%, thickening of the arteriolar wall and mesangium in 47%, chronic inflammatory cells in the interstitium in 29% and cystic changes in 6% of the kidneys (Kumar, et al., 1993). However, a clear correlation of age-associated changes in pre-transplant biopsies with postoperative function has not been shown, and association between function and donor age in individual cases is very weak. This is not completely surprising. The Baltimore Longitudinal Study of Aging showed that one-third of the participants did not evidence any change in glomerular filtration rate (GFR) over time (Lindeman, et al., 1985). Epstein concluded that the common denominator for the functional changes occurring with aging is more a diminution in the kidney’s ability to respond appropriately to the challenges of either deficits or excesses. These alterations attain clinical significance only when renal function is challenged by superposition of co-morbid conditions like hypertension or heart failure (Epstein, 1996;Fliser, et al., 1997;Fliser and Ritz, 1998). Not surprisingly therefore, the medical history of the donor provides information about the expected post transplant course independent of donor age. Kidneys from patients dying of cardiovascular events or stroke fail more often than do organs from donors dying of subarachnoidal haemorrhage (Troppmann, et al., 1991). Analyses of allografts from donors >55 years with a history of long-term arterial hypertension reported to UNOS showed decreased long-term function (Carter, et al., 2000). Ojo et al. report similar findings not only for pre-existing donor hypertension but also for diabetes, exerting only a modest, yet significant, negative effect on several transplant outcomes (Ojo, et al., 2000).

The postulate of an increased sensitivity of grafts from marginal donors towards additional injuries has nicely been illustrated by Tullius et al. (Tullius, et al., 2001) (Figure 2). 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 damage 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, acute rejection episodes, T cell activating processes, viral infections and drug toxicity may have a stronger impact on marginal grafts with the consequence of reduced long-term function.

Figure 2: The postulate of an increased sensitivity of grafts from marginal donors towards additional injuries (Tullius, et al., 2001)

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Ideally, what the transplant community would need is a measure for organ damage to predict the outcome of grafts from elderly donors. Creatinine clearance and biopsies have been tested for their predictive value; although creatinine clearance was determined as the optimal predictor of graft survival (Kerr, et al., 1999), others suggested a glomerulosclerosis index or the degree of fibrous intimal thickening at the time of implantation (Andres, et al., 2000)(Bosmans, et al., 2000). Singh et al. analyzed existing scoring systems and concluded that a donor CrCl of ≥70ml/min is a better discriminator than a donor CrCl of 90ml/min and comparable to the Nyberg variables (cold ischemia time, donor diabetes and hypertension; incremental donor age and cause of death) (Singh, et al., 2004).

1.1.2 The effect of recipient age on outcome after renal transplantation

In general, advanced recipient age is no longer a contraindication for renal transplantation. In the Eurotransplant area the number of renal recipients in the age category >65 years has more than doubled in the past ten years. The average number of recipients in the age group 60-65 increased by 37% from 1999 to 2003 as compared to the period from 1994-1998. In 2003, 10.8% of all transplantations reported to the Eurotransplant registry were performed in recipients older than 65 years (Cohen, et al., 2005). In the US Renal Data System, the percentage of renal transplant recipients ≥65 years of age also increased from 4.9% to 11.6% between 1994 and 2004 [Source:].

1.1.2.1 Mortality compared to patients on the waiting list

While older end stage renal disease (ESRD) patients on the waiting list have a 5 times greater likelihood of dying compared to patients less than 50 years (Smits, et al., 2002), transplantation has been shown to improve long term survival even in the higher age groups (Wolfe, et al., 1999).

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The long term mortality risk for transplant recipients was estimated to be 68 percent lower than that for patients on the waiting list. Figure 3 shows the relative risk of death among 23,275 kidney transplant recipients compared to patients on dialysis. The risk of death during the first 2 weeks after transplantation is 2.8 times higher than for patients on dialysis, and remains elevated until 106 days post-transplant. After this time, this risk was lower among transplant recipients with the likelihood of survival becoming equal at day 244. Analyses for the different age groups showed that an early benefit and the greatest difference in long-term survival was found among patients who were 20-39 years old with equal risk of death after 11 days, likelihood of survival being equal after 57 days and a projected increase in life expectancy of 17 years. Among the patients who were 60-74 years old, the cumulative survival rate improved after the first year, with a projected increased life span of five years and a decrease in the long term risk of death of 61 percent (Wolfe, et al., 1999) (Table 1).

Figure 3: Mortality RR for 23,275 First Cadaveric Transplant vs. 46,164 Waitlisted Dialysis Patients*(Wolfe, et al., 1999)

Table 1: Transplant vs. wait-listed dialysis patient survival for different age groups, 1991-1997(Wolfe, et al., 1999)

1.1.2.2 Graft survival

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Clearly, graft loss due to death is more common in the elderly, occurring at a rate of 1.1/100 patient years in recipients aged 18-49 and at 4.1/100 patient years in recipients older than 65 years (Meier-Kriesche, et al., 2000)

Contradictory results for death-censored graft survival have been published. In a study by Roodnat et al., the overall relative risk for allograft failure increased by only 1.44% for each year of recipient age (Roodnat, et al., 1999), even though patient survival decreased by 5% per year. Tesi et al. reported a five-year patient survival rate of 68.1% in elderly but 89.1% in younger recipients. Death-censored graft survival, on the contrary, was 11% better in the older group, so that crude graft survival was almost identical (Tesi, et al., 1994). In a large analysis by Gjertson one-year graft survival was 84.2% in recipients older than 65 years and 87.3 % in the age group 43-65 years. Uncensored five-year graft survival was 69.4% and 72.5%, respectively. These differences, although statistically significant, are quite small in absolute terms, and age accounted for only 2.1% of the variance in five year graft outcome (Gjertson, 1996).

Recent data, however, indicate that elderly recipients might be more prone to developing chronic allograft nephropathy and consequent graft loss. Using data from the USRDS, Meier Kriesche et al. demonstrated that eight-year death-censored graft survival is significantly decreased in the older age groups, being 67% for ages 18-49 vs. 62% for ages 50-64 and 51% for ages 65+. In multivariate analysis recipient age was a strong and independent risk factor for chronic allograft failure in Caucasians. These findings were reinforced by an analysis that was restricted to living donor transplants without rejection (Meier-Kriesche, et al., 2002). It has been argued that age-related factors, like increased concentrations of transforming growth factor beta or lipoproteins in the serum, might contribute to accelerated senescence of the graft (Meier-Kriesche, et al., 2002)(Janssen, et al., 1998)(Nakamura, et al., 1999)(see also 1.1.2.6.).

1.1.2.3 Immune response and rejection

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Conflicting data have been published regarding the impact of recipient age on the incidence of acute rejection. While Meier-Kriesche (see also Figure 5), Ismail, Hestin and Jassal report lower rejection rates according to the concept of a global deterioration of the aging immune system, other publications report a normal or even higher risk of acute rejection in the group of elderly kidney transplant recipients, e.g. De Fijter, Waiser, Schratzberger, Morris and Moreso (de Fijter, et al., 2001;Moreso, et al., 1999;Morris, et al., 1999;Schratzberger and Mayer, 2003;Waiser, et al., 2000). However, recent clinical trials with calcineurin inhibitor-free immunosuppressive regimens demonstrated a high incidence of acute rejection episodes in elderly recipients, particularly in the early post transplant period, leading to a conversion of immunosuppression in the majority of patients in this group (Kasiske, et al., 2000). The initial reports from the ESP also show higher than expected rates of acute rejection. The reduced incidence of acute rejection episodes may not apply, especially when grafts from older donors are allocated to elderly recipients. This will be further discussed in section 1.1.6.

1.1.2.4 Infectious complications in the elderly

Infections in the elderly occur more frequently and more severely, and have distinct features with respect to clinical presentation, laboratory results, microbial epidemiology, treatment, and infection control (Gavazzi and Krause, 2002). The reduced resistance to infection in the elderly is further compromised by immunosuppression, making this group particularly susceptible to opportunistic infections. In 2001 Meier-Kriesche showed that death related to infections during the first 24 months increased progressively whereas the incidence of acute rejection during the first 6 months decreases in transplant recipients with increasing age. In the highest age group the relative risk of death due to infection is increased by more than 6 times (Meier-Kriesche, et al., 2001) (Figure 5).

Figure 4: Incidence of infectious death during the first 24 months versus acute rejection in the first 6 months with increasing age (Meier-Kriesche, et al., 2001).

1.1.2.5 Other age related non-immunologic changes

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The incidence of most cancers also increases with age. There is concern that elderly transplant recipients on immunosuppression are particularly at risk for malignancies. Indeed, it has been reported that the mortality related to cancer in patients aged more than 65 years is 7.1 per 1000 patients compared with 2 per 1000 patients in patients aged less than 40-49 years (Meier-Kriesche, et al., 2001). Age related non-immunologic changes also include co-morbidities such as cardiovascular disease and hypertension but also lipid disorders and diabetes. Cardiovascular disease plays an increasing role with age (Kasiske, 2001) and pre-existing long-term hypertension of the recipient is considered a risk factor (Frei, et al., 1995). It has also been shown that increased concentrations of homocysteine, apolipoproteins, and altered insulin-like growth factors accelerate progression of arteriosclerosis in the elderly (Meier-Kriesche, et al., 2000).

1.1.2.6 Immunologic changes in the recipient

It is widely accepted that the immune system, and thus the immune response, become impaired with age (Wick and Grubeck-Loebenstein, 1997). The most relevant age-related immunologic modifications are related to T-cells, because they play a pivotal role in rejection and tolerance. Many studies have demonstrated the functional and phenotypic changes in T lymphocytes with age (less proliferation, shortening of telomeres, IL-2 secretion etc) theoretically leading to a cellular and humoral immunodeficiency in the elderly.Consequently, the incidence and severity of acute rejections in elderly recipients would be expected to be lower compared to younger recipients, providing an argument to support the concept of age-matching in renal transplantation.

However, there is some controversy on the decrease of total lymphocytes with aging vs. alteration of certain cell-subsets (Lehtonen, et al., 1990). Important changes in the immune system that may increase the incidence of chronic rejection include increased numbers of memory T cells, low CD4/CD8 ratio, T helpers 1 and 2 shift with increased pro inflammatory cytokines (tumour necrosis factor-α, interleukin [IL]-4, interferon-γ, transforming growth factor-β-1, and IL-6) (Meier-Kriesche, et al., 2000;Sandmand, et al., 2002), increased antigen-presenting cell activation (Castle, et al., 1999;Sidman, et al., 1987;Verbeke, et al., 2001), up-regulation of HLA-DR (Rea, et al., 1999), and production of anti-donor HLA antibodies (Paul, 1997;Smith, et al., 2000) supporting the findings of an increased rate of antibody mediated rejection (de Fijter, 2005;de Fijter, et al., 2001). IL-4 may play an important role in the development of transplant arteriosclerosis by stimulation of vascular smooth muscle cell proliferation (Bagley, et al., 2000).

1.1.3 Immunosuppressive therapy for the elderly

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As discussed above, elderly renal transplant recipients have both a higher incidence of patient death and allograft loss censored for death. Acute rejections are less frequent in older individuals; however this might not apply when grafts from older donors are allocated to elderly recipients and the consequence of a rejection, if it occurs, is negative for long-term graft survival. On the other hand, death by infection is exponentially increased in older versus younger renal transplant recipients. In general, the pharmacokinetics of the immunosuppressive agents are little affected by age, but the tolerance to these agents seems to decrease with increasing age.

Although there are some regimens recommended by single-centre studies, widely accepted immunosuppressive protocols specific to the elderly are not available.

Despite the fact that elderly transplant recipients appear to have a decreased risk of acute rejection, they have an independently increased risk of chronic allograft loss (Meier-Kriesche, et al., 2000). Part of this increased risk of chronic allograft nephropathy may be explained by an increased susceptibility to calcineurin inhibitor related nephrotoxicity. For this reason, protocols that avoid, minimize or delay the introduction of calcineurin inhibitor have been used for older recipients, and these suggest that minimization of these drugs is generally accompanied by improved renal function, especially when receiving a graft from an older donor (Arbogast, et al., 2005;Theodorakis, et al., 2000). A group from Munich reported long-term results of 89 patients on a CNI-free, MMF-based immunosuppressive protocol in elderly recipients of kidneys from elderly cadaver donors. They showed a cumulative 5-year patient and renal allograft survival of 87.69% and 69.81%, outcomes which are comparable with data from young recipients who have received allografts from young cadaver donors (Arbogast, et al., 2005).

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A recent analysis of more than 5,000 patients from the SRTR database indicated that in elderly renal transplant recipients, MMF is associated with lower early and late rejection rates as compared to Azathioprine and is associated with a significantly higher rate of patient survival 4 years post-transplantation (Meier-Kriesche, et al., 2004).

Induction therapies with antilymphocyte agents (antilymphocyteglobulin, antithymocyte globulin, and OKT3) do not seem appropriate for the elderly because they have been associated with a high incidence of infections and malignancies (Lundgren, et al., 1985). IL-2 receptor antibodies in the elderly seem promising but require further assessment (Pascual, et al., 2002). A retrospective data analysis on 183 kidney transplant recipients ≥60 years of age compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin [n = 29]; muromonab CD3 [n = 45]; IL-2 receptor antibody with [n = 40] and without (n = 69) corticosteroid maintenance. Patients with IL-2 receptor antibody induction had significantly lower rates of DGF and acute rejection, were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies and had much shorter hospital stays (Heifets, et al., 2004).

In summary, tailoring the immunosuppressive regime to take into account the altered immune response and increased risk of drug toxicity, infections, cardiovascular disease and changes associated with advanced age seems to be the best strategy to improve the survival and quality of life in the elderly transplant population.

1.1.4 The effect of age matching on outcome after renal transplantation

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The idea of age-matching has a long history and is based on the concept of “functional matching” between the decreasing metabolic demand of the recipient and with the reduced functional reserve of the elderly graft (Anderson and Brenner, 1986;Donnelly, et al., 1990;Gjertson, et al., 1997;Kuo, et al., 1996;Smits, et al., 1998), and is also based on the logical and fair principle that the shorter half-life of elderly organs meets the short life expectancy of elderly recipients. In addition, some believe that a corresponding age of donor and recipient may provide a better “immunologic matching” (Cecka and Terasaki, 1995;de Fijter, et al., 2001;Tesi, et al., 1994;Waiser, et al., 2000).

Analysis of clinical studies on the effects of age matching has shown conflicting data. In 1991, Donnelly et al. published their results of 141 consecutive first cadaveric transplants and noted that graft failure at two years was significantly greater when the donor was more than five years older than the recipient (Donnelly, et al., 1991). Subsequent studies were unable to replicate these findings, but the number of patients involved was quite low (Newstead and Dyer, 1992;Pirsch, et al., 1992).

Alexander et al. reported lower allograft survival of elderly kidneys when transplanted into elderly recipients, but the impact of donor age and recipient age on the risk of graft failure was independent. In 1995, Cecka and Teresaki repeated this analysis of the UNOS registry data and identified 1740 kidneys from donors over the age of 60 among 45922 cadaver transplants performed between October 1987 and March 1994. Actuarial graft survival (not censored for patient death) was significantly worse at one and especially at ten years in these kidneys, as compared to donors aged 19-30 years (70% vs. 84% at one year and 20% vs. 45% at ten years). Data censored for patient death, however, revealed the best survival of elderly kidneys in elderly recipients (one-year graft survival 78%, projected ten-year graft survival 43% as compared to 70% at one year and 22% projected ten-year graft survival in recipients aged 19 and 45 years). Moreover, at one year, serum creatinine tended to be lower in age matched elderly grafts. In another retrospective study analyzing various age allocations, the combination of a young recipient with an old donor provided a poor outcome (20.8% graft survival by 8 years), whereas old-to-old matches obtained the best long-term results (57.1% death-censored graft survival by 8 years) (Waiser, et al., 2000) (Figure 5).

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Figure 5: The influence of age-match on actual (death censored) graft survival (Kaplan-Meier plot with a log-rank test)(Waiser, et al., 2000)

YD, young donors (<55 years); OD, old donors (>55 years); YR, young recipients (<55 years); OR, old recipients (>55 years)

In contrast, other studies demonstrated no or only marginal beneficial effect of age matching (Kasiske and Snyder, 2002) or even reported a synergistic deleterious effect on renal allograft survival for the interaction of donor and recipient age (Meier-Kriesche, et al., 2002) (Figure 6).

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Figure 6: Death-censored graft survival beyond 6 months post-transplantation for different age matched groups (Meier-Kriesche, et al., 2002)

It is important to mention that these analyses were not intended to address issues of allocation or draw conclusions about age-matching programs that also have to take ethical and economic considerations into account.

1.1.5 Eurotransplant and the Eurotransplant Senior Program

The Eurotransplant International Foundation is responsible for the mediation and allocation of organ donation procedures in Austria, Belgium, Germany, Luxemburg, the Netherlands and Slovenia. In this international collaborative framework, the participants include all transplant hospitals, tissue-typing laboratories and hospitals where organ donations take place. The Eurotransplant region numbers well over 118 million inhabitants.

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The Eurotransplant Senior Program (ESP) is a natural response to the universal trend of extending donor criteria. The program obtains kidneys from donors older than 65 years and allocates them to a selected group of patients in the same age group with the aim of: (i) achieving a more efficient use of kidneys from elderly donors; and (ii) increasing the rate of transplantation in elderly patients. The rationale for the recipient age restriction is that a kidney graft that outlives the recipient is considered a success. If donor organs are physiologically slightly suboptimal, as is more likely with older donors, the graft has a greater chance of surviving an older than a younger recipient.

Thus, Eurotransplant developed the ESP, an allocation scheme based on the concept of matching between metabolic demand of the graft recipient and excretory capacity of the donor organ. The rationale for a donor and recipient age matching policy in which a kidney graft should outlive the recipient implied that HLA matching could be disregarded in assigning donor organs.

However, the use of organs from elderly donors is often accompanied by increased incidences of delayed graft function and rejection. To improve the chance of success, defined as graft viability, strict rules for participating centres within the Eurotransplant region were imposed: (i) to reduce ischemic damage, kidneys should be transplanted with the shortest possible cold ischemia time; and (ii) to reduce immunological risk, only non-immunized [i.e. panel-reactive antibody (PRA) <5%] first transplant recipients were included. The ESP allocation scheme furthermore included the option of transplanting both kidneys to a single recipient in cases in which the donor creatinine clearance was <70 ml/min.

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Tailor-made allocation schemes like ESP are designed by Eurotransplant and offered thereafter to the Eurotransplant community. Thus, treating physicians in individual centres have the responsibility to carry out the details of the programme and to obtain informed consent from their patients.

The idea of ESP was conceptualized by the Eurotransplant Kidney Advisory Committee in 1998 and finally approved by the Eurotransplant-Board as well as by the Ständige Kommission Transplantation der Bundesärztekammer. The program was implemented in January 1999. For the first two years (4 January 1999 to 4 January 2001), participation of the centres was on a voluntary basis. As of 4 January 2001, the ESP became part of the ETKAS (Smits, et al., 2002).

1.1.6 ESP analyses to date

Evaluations of the ESP program have been scarce to date and limited by short follow-up and/or the use of different or historical controls. Out of 8 reports, 2 have been published by ET comprising topline results of the entire ESP population, the remaining 6 are single centre analyses with 3* of them at least partially reporting results of the same patient population. The table below gives an overview of the publications to date, the number of ESP patients included in each analysis and the duration of follow-up.

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Table 2: Overview of published analyses of the ESP to date

Reference

Number of ESP patients

Years after start of ESP (mean FU)

Cohen et al 2005, Expanding the donor pool to increase renal transplantation (Cohen, et al., 2005).

876

3 years

Giessing et al 2004, Kidney donors and kidney transplantation in the elderly (Giessing, et al., 2004)*

68

5 year (23,3 mo)

Giessing et al 2004, "Old-for-old" cadaveric renal transplantation: surgical findings, perioperative complications and outcome (Giessing, et al., 2003)*

26

3 years

Fritsche at al.2003, Old-for-old kidney allocation allows successful expansion of the donor and recipient pool.(Fritsche, et al., 2003)*

69

4 years (18,1 mo)

Krüger at al 2002, Early experience with the ET Senior Program "Old For Old"; better to be number one?(Kruger, et al., 2002)

14

18 months (3 mo)

Smits at al. 2002, Evaluation of the Eurotransplant Senior Program. The results of the first year.(Smits, et al., 2002)

227

1 year

Schlieper at al 2001, Eurotransplant Senior Program 'old for old': results from 10 patients.(Schlieper, et al., 2001)

10

9 months (4 mo)

Beckurts at al. 2001, Single-center experience with the "Old for Old" program for renal transplantation.(Beckurts, et al., 2001)

20

24 mo (21 mo)

The results of the first year of the ESP program were published by Jaqueline Smits et al. in 2002. The analysis of 227 transplants demonstrated that 1-year graft survival rates censored for graft loss because of death were 86% compared with 79% when old grafts were allocated through the normal system Eurotransplant Kidney Allocation System (ETKAS) to recipients of any age. Median cold ischemia time was shorter in the ESP program (12 vs. 19 hours), while the number of HLA mismatches was significantly higher (4 vs. 2). Institution of ESP in participating centres doubled the number of organs harvested from donors older than 65 years, and the discard rate dropped from 22% to 13%. Median waiting time for recipients older than 65 years decreased within a year from 943 to 707 days, and the number of patients on the waiting list also decreased significantly from 905 to 872. There was no difference between the study groups with regard to initial transplant function or graft function at one year (censored and not-censored for patient death). It is interesting to note that the rejection rate observed in either group was quite high (38% in the ESP group and 30% in the Control group), even though 43% of the patients in the ESP program received mono- or polyclonal induction and 47% triple-immunosuppressive therapy (Smits, et al., 2002). This result, especially in the ESP age-matching group, was somewhat surprising as it was generally accepted that immune responsiveness steadily decreases as the age of the recipient increases. Cox regression analysis to determine if the higher HLA mismatch might have been the explanation was not performed.

The same significant increase in the incidence of acute rejections (1 year: 43,2% for ESP vs. 27,4% for Control) was found in the local 3-year analysis of 69 ESP patients by Fritsche. However, this could be explained by the increased HLA mismatch in this group (Fritsche, et al., 2003). The Control group consisted of 71 renal transplant recipients aged 60 years or older who received organs from any age donor via ETKAS

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Finally, a limited amount of results based on Eurotransplant data 3 years after starting the ESP were included in a recent publication by Cohen. Similar to the results after one year, the analysis of 876 transplants in the ESP demonstrated that 3-year graft survival rates censored for graft loss because of death were 70% compared with 71% in the control. No patient survival data are reported in this publication but the author concludes that the 3 year analysis shows no difference between patients who received grafts from elderly donors via ESP and those who received similar kidneys via the usual HLA-driven allocation procedure and suggests that, if care is taken to avoid the accumulation of additional risk factors such as long cold ischemic time and re-transplantation, an old-for-old allocation scheme can be operated successfully (Cohen, et al., 2005).

1.2 Rationale for performing this analysis

Preliminary evaluations of the program have shown that this program does not perceptibly harm the patients. However, as discussed above, available analyses of the program have limitations in terms of being single centre evaluations, a short follow-up, the use of different or historical controls as well as limited access to follow up data. Furthermore none of the existing analyses have performed any modelling/multivariate analyses looking for independent risk factors for long term outcomes. Information such as immunosuppressive regimens, biopsy proven rejection episodes, co-morbidities and hospitalizations are not part of the Eurotransplant database and thus have, if at all, only been part of the local evaluations.

All these factors combine to highlight the need to perform a more extensive ESP-5-year analysis on behalf of ETKAC. By collecting additional information on this unique cohort of prospectively age-matched elderly kidney transplant recipients over and above what is available in the Eurotransplant database and by looking at two different control groups, the results will serve as a base for further analyzing and improving the ESP allocation scheme. The number of ESP patients in this evaluation represents the biggest cohort of prospectively age-matched elderly renal transplant patients available for detailed analysis worldwide to date.


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