Evaluation of the Eurotransplant Senior Program. The Results of the First Year

Authors


Abstract

On 4 January 1999, the Eurotransplant Senior Program (ESP) was implemented within the Eurotransplant kidney allocation scheme.

Patients and Methods: Kidneys obtained from donors aged over 65 years of age (65 +) were allocated to a selected group of nonimmunized 65 + patients undergoing their first transplant. All transplants were performed locally to minimize cold-ischemic time. All transplants performed with kidneys from elderly donors that were allocated via ESP (ESP group) were compared to transplants performed with similar kidneys allocated via the standard renal allocation system (control group). Initial kidney function and 1-year graft outcome were assessed.

Results: In 1999, 227 ESP and 102 control transplants were performed. The duration of cold-ischemic time was 12 and 19 h for the ESP and control groups, respectively. No rejection episodes occurred in 60% and 67% of the ESP patients and controls, respectively, while a direct kidney function was observed in 59% of ESP and 49% of control patients. The 1-year graft survival rates, censoring for graft losses due to deaths in patients with functioning grafts, were 86% and 79%, respectively.

Conclusion: An old-for-old renal allocation algorithm can be successful provided that risk factors, such as cold-ischemic time, are reduced.

Abbreviations
ESP

Eurotransplant senior program

PNF

Permanent nonfunction

EI

ESP kidney transplant with initial function

ED

ESP kidney transplant with delayed graft function

EN

ESP kidney transplant with permanent nonfunction

CI

Control kidney transplant with initial function

CD

Control kidney transplant with delayed graft function

CN

Control kidney transplant with permanent nonfunction

MOF

Multi-organ failure

SAB

Subarachnoidal bleeding

CVA

Cerebrovascular accident

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Introduction

Although increased donor age is associated with reduced graft survival rates (1,2), changing trends in donor profiles in the context of a dramatic donor shortage have forced the transplant community to use organs from elderly donors (3–5). At the same time, an increase in the number of elderly patients on renal transplant waiting lists has heightened interest in the development of special allocation strategies for these patients.

Eurotransplant1 developed the Eurotransplant Senior Program (ESP), an allocation scheme based on the concept of matching between metabolic demand of the graft recipient and excretory capacity of the donor organ (6–8). The aims of ESP were twofold: to achieve a more efficient use of kidneys from donors aged over 65 years of age and to reduce the waiting time for elderly patients (9). Much has been written on the clinical implications of the use of donor kidneys from older donors, but little has been done to ensure a good outcome of these grafts. ESP is therefore the first tailor-made, old-for-old allocation program.

To evaluate ESP, a year-long study was implemented in January 1999. In the study, kidneys from elderly donors were to be allocated to elderly patients via the ESP allocation scheme. An allocation in which matching by age is the only driving factor is a challenge. Moreover, the use of organs from elderly donors is often accompanied by increased incidences of delayed loss of graft function and rejection (10). The only way to guarantee an acceptable degree of success, defined as graft viability, was therefore to impose strict rules on participating centers within the Eurotransplant region: to reduce ischemic damage, kidneys should not be shipped and, to reduce immunological risk, patients could not be immunized at the time of the match and only patients undergoing their first transplant were included.

Patients and Methods

As of 4 January 1999, kidneys obtained from donors aged 65 years or older could be allocated via ESP. Participation of the centers was on a strict voluntary basis. Centers were uniquely associated with ESP and all their eligible patients participated, except those for whom no informed consent was obtained. For these patients, kidneys were allocated via the usual allocation algorithm, the Eurotransplant Kidney Allocation System (ETKAS). In brief, ETKAS includes a mandatory exchange of zero HLA-A,-B,-DR renal allografts, and then patients are assigned points based on 5 allocation factors: number of HLA mismatches, chance of a good HLA-A, -B, -DR match (mismatch probability), waiting time, distance between donor and transplant program and national net kidney balance (11).

According to the ESP algorithm, kidneys from donors over 65 were assigned with priority to the registered ESP patients. In order to avoid any systematic bias in donor kidney quality, the acceptance of a donor organ for the ESP program was made at the time of patient registration and not during the allocation process. Inclusion criteria for ESP were: renal transplant candidates were aged 65 or older, had not undergone transplantation prior to the study, and had percentage panel reactive antibodies (PRA) of 5% or less. Centers were also required to keep the cold-ischemic time to a minimum by circumventing the HLA matching and by only transplanting kidneys into local recipients.

No strict rules for double kidney transplants were set out in the protocol, but centers were advised to transplant both kidneys when the donor creatinine clearance rate was below 70 mL/min.

All transplants performed in the Eurotransplant region, during the study period in which the kidney was obtained from a donor aged 65 years or older but was allocated through the normal allocation scheme, constituted the control group. Patients were not required to be over 65 years of age.

The efficiency of the ESP program in terms of usage of organs of reported 65 + aged donors is evaluated at 2 levels. First, the proportion of reported 65 + donors out of all kidney donors in centers that participated in the ESP program is compared to this same proportion in non-ESP centers. Then, transplanted/reported rates of organs from 65 + donors in ESP and non-ESP centers are compared. This latter rate is expressed as the proportion of kidney donors from whom at least one kidney was used for transplantation out of the total number of kidney donors reported.

The ESP allocation scheme was followed for 1 year, during which time all graft and patient outcomes were recorded. In order to perform a detailed study on early graft function, a special ESP questionnaire was sent out to the participating centers.

Categorical variables were evaluated with the 2-sided chi-square test, whereas a 2-sided Kruskal–Wallis test was used for continuous variables. Difference in graft and patient survival rates were assessed with the log-rank test. A p-value of less than 0.05 was considered significant. For data handling, SAS 6.12 was used, while statistical analysis was performed with SPSS 10.0.

Results

Forty-two of the 64 renal transplant centers in the Eurotransplant region took part in ESP. In 1999, in the region as a whole, 3096 cadaveric donor kidney transplants were performed, of which 389 were performed in patients aged 65 years or older. Of these, 227 patients received kidneys from elderly donors via the ESP route. While 162 patients aged 65 or older received a kidney via the normal kidney allocation scheme, 142 of these patients were transplanted with a kidney from a donor under 65 years of age; the other patients received an old-donor kidney and were eligible for the control group. In total, the control group comprised 102 patients who received elderly kidneys via the usual allocation procedure. Therefore, a total of 329 patients were included in the study (Table 1). Of these, a total of 33 patients were lost to follow-up (18 ESP and 15 controls), i.e. no questionnaire was returned to the ET office, which left 296 patients who were followed for the duration of the study. Median cold-ischemic times were significantly shorter for the ESP transplants compared to the control group, 12 h vs. 19 h, respectively (p = 0.03). As control kidney transplants were allocated via an HLA-driven system, the median number of HLA-A,-B,-DR mismatches is seen to be significantly lower compared to the age-matched kidney transplants in the ESP group, 2 vs. 4, respectively (p < 0.0001).

Table 1. : Descriptive statistics for ESP and control transplants
FactorESPControl
n = 227n = 102
  • *

    First transplants were living related renal transplants median (5th and 95th quantiles) values are given. eci, e causa ignota.

Age donor (years) 70 (65–76) 68 (65–76)
Retransplantation  2* 14
Double kidney transplant  6  7
Cold-ischemic time (h) 12 (5–23) 19 (8–30)
HLA mismatch gradient  4 (3–6)  2 (0–5)
% PRA
 0–5227 86
 6–84  0 15
 85 +  0  1
Donor:recipient gender match
 Male:male 67 33
 Male:female 32 20
 Female:male 71 34
 Female:female 57 15
Recipient age (years)
 16–50  0 27
 50–65  0 65
 65–70180  8
 70 + 47  2
Primary disease
 Glomerulonephritis 42 24
 IgA nephropathy  7  8
 Interstitial nephritis 21  7
 Tub. interstitial nephritis  4  2
 Drugs-induced nephropathy 13  3
 Cystic kidney disease 29 13
 Hereditary nephropathy  2  3
 Renal vascular disease  7  5
 DM type I  6  3
 DM type II  7  4
 Systemic disease  7  2
 Gout  2  0
 Kidney tumor  4  0
 Chronic kidney failure eci 76 28

Efficiency of the program

The centers participating in ESP reported 2 times more donors aged over 65 years compared to the non-ESP centers [175/1220 (14%) and 37/499 (7%), respectively] (Table 2). Our data furthermore show that the transplanted/reported ratio of organs from donors over the age of 65 is higher in ESP centers compared to non-ESP centers [152/175 (87%) and 29/37 (78%), respectively]. It should be remarked that 10 multiorgan donors were not part of the ESP-control study.

Table 2. : Number of reported and transplanted donors in ESP and non-ESP centers
 65 – year donors65 + year donors
 ReportedTransplantedReportedTransplanted
ESP centers1045995175152
Non-ESP centers 462424 37 29

Waiting list

The median waiting time before transplantation, that is the time between first dialysis and transplantation, for patients over the age of 65 decreased from 943 days in 1998 to 707 days in 1999. In contrast, for patients aged under 65 years at time of registration, the median waiting times remained at 850 days and 851 days for registrations before and after the introduction of ESP, respectively. While the renal waiting list for patients aged under 65 grew from 11 055 patients on 1 January 1999 to 11 428 on 1 January 2000, the number of elderly patients on the list decreased slightly from 905 to 872 patients. This represents a reduction from 7.7% to 7.1% in the proportion of elderly patients on the waiting list.

Age-matched transplants

The number of transplants performed with a kidney from a donor aged 65 or older has been steadily increasing, from 195 transplants in 1997, 285 transplants in 1998, to 345 transplants in 1999. The introduction of ESP in 1999 has, however, led to an increase in age-matched transplants performed with these elderly kidneys: 1997: 23, 1998: 36 and 1999: 237.

Initial renal function

A direct primary functioning kidney graft was obtained for 124 of the 209 ESP patients (59%) compared with 43 of 87 control patients (49%). Delayed graft function was seen in 68 (33%) and 32 (37%) of the ESP and control transplants, respectively, and kidneys suffered permanent nonfunctioning in 17 (8%) and 12 (14%) patients in each group, respectively (p = 0.2).

Functional classes

Based on the initial graft performance, the groups were further divided into the following subgroups: ESP or control kidney transplant with initial function (EI or CI), ESP or control kidney transplant with delayed graft function (ED or CD), and ESP or control kidney transplant with a permanent nonfunction (EN or CN) (Table 3). Six per cent (2/34) of the ESP transplants with a cold-ischemic time below 6 h suffered a permanent nonfunction, compared to 12% (12/104) of the ESP kidney transplants with a cold-ischemic time above 12 h (p = 0.5).

Table 3. : Demographics of patients grouped into six functional classes
FactorEIEDENCICDCN
n = 124n = 68n = 17n = 43n = 32n = 12
  1. Median (5th and 95th quantiles) values are given.

Age recipient (years)59 (34–67)67 (65–72)66 (65–72)69 (65–76)55 (35–68)59 (33–66)
Age donor (years)69 (65–76)70 (65–76)72(65–93)68 (65–73)68 (65–76)68 (65–76)
Cold-ischemic time (hours)
 < 624 8 2 4 3 4
 6–124028 3 7 2 1
 > 126032123227 7
HLA-A,-B,-DR mismatch grade
 0 0 0 011 4 0
 1 2 1 0 3 2 0
 2 4 3 0 8 7 7
 333 9 411 8 1
 44227 6 7 7 3
 53318 5 3 4 1
 61010 2 0 0 0

Basic information on administration of immunosuppressive drugs for these 6 groups is given in Table 4.

Table 4. : Administration of immunosuppressive drugs
Immunosuppressive regimesEIEDEN*CICDCN*
n = 124n = 68n = 16n = 43n = 32n = 11
  • *

    Missing information for 1 record.

Polyclonal induction3622 4 4 11
Monoclonal induction23 3 1 4 74
Steroids/MMF/CsA67341019195
Steroids/CsA 5 2 0 5 32
Steroids/CsA/Aza11 5 1 6 10
Steroids/FK506/Aza 2 3 1 2 10
Steroids/FK506 0 1 0 0 21
Steroids/MMF/FK50615 7 3 7 32
Steroids/MMF15 9 1 1 10
CsA/MMF 0 0 0 1 10
Steroids/CsA/MMF/FK506 1 3 0 1 00
Steroid/CsA/Rapamycine 1 1 0 1 10
Steroids/Rapamycine 0 0 0 0 01
Steroids/CsA 4 1 0 0 00
Steroids/Aza 2 1 0 0 00
Steroids/CsA/Aza/MMF 1 1 0 0 00

Post-transplant outcome

Graft survival rates for both study groups are shown in Figure 1. After 1 year, 79% and 73% of ESP and control grafts survived. When losses of grafts as a result of patient death were censored, survival rates in each group were 86% and 79%, respectively.

Figure 1.

Graft survival rates for ESP kidney transplants and control kidney transplants. Dashed line indicates the rates obtained while censoring for deaths with a functioning renal graft.

Post-transplant outcome stratified by functional classes

Table 5 summarizes the post-transplant outcome data for the subgroups EI, CI, ED and CD. It should be noted that there was no difference in the occurrence of rejection episodes between these groups (p = 0.5). The mean 1-, 3- and 6-month serum creatinine values were comparable between all four groups (p = 0.5). In this subset there was also no difference in 1-year post-transplant graft survival rate between the ESP and the control groups (Figure 2). There was, however, a significant association between graft survival at 1 year and initial functional status (initial graft function vs. delayed graft function) (p = 0.01).

Table 5. : Post-transplant outcome
End-pointEIEDCICD
n = 124n = 68n = 43n = 32
  1. Mean values (± s.d.).

  2. 95% Confidence intervals (CI).

No rejections78 (63%)41 (61%)31 (72%)22 (73%)
Creatinine (mg/dL)
 1 month1.7 ± 0.72.4 ± 0.92.1 ± 1.33.0 ± 1.6
 3 month1.9 ± 1.22.2 ± 0.72.2 ± 1.32.7 ± 1.2
 6 month1.9 ± 1.02.2 ± 0.92.1 ± 1.02.7 ± 0.6
1-year graft survival
(95% CI)
89% (83–95)80% (69–90)88% (78–98)72% (55–89)
1-year graft survival
(95% CI)
(censoring for death with functioning kidney)
95% (91–99)89% (81–97)92% (84–100)77% (61–94)
Figure 2.

Graft survival rates for ESP and control kidney transplants with an initial or delayed graft function.

Post-transplant mortality

Patient survival rates for ESP and control patients are shown in Figure 3. Survival at 1 year was 86% and 90% in the two groups, respectively.

Figure 3.

Patient survival rates for ESP and control kidney transplants.

The number of patients who died in the first year following transplant and the causes of death are summarized in Table 6. It should be stressed that 18 out of the 24 (75%) ESP deaths in the first year occurred in patients whose grafts still functioned. In the control group this proportion was 57% (four out of seven deaths).

Table 6. : Mortality during the first year following transplantation
 EI
n = 124
ED
n = 68
EN
n = 17
CI
n = 43
CD
n = 32
CN
n = 12
  1. Figures in parentheses are the numbers of deaths with a functioning kidney. SAB, subarachnoidal bleeding; CVA, cerebrovascular accident; MOF, multi-organ failure.

Number of deaths10114322
Number of deaths with a
unctioning kidney
10 80220
Patient's cause of death
 Sepsis 1 (1) 1111 (1) 
 Myocard. infarction 1 (1) 1 (1)  1 (1) 
 Cardiac arrest 1 (1) 2 (2)1  1
 Pulmonary infection 4 (4) 5 (4) 1 (1)  
 Mors in tabula     1
 Unknown 1 (1)  1 (1)  
 SAB  1    
 Endocarditis  1 (1)    
 Liver metastasis 1 (1)     
 CVA 1 (1)     
 Pulmonary embolism  1   
 MOF  1   

Figure 4 shows patient survival rates stratified by initial functional group. In both control and ESP patients the initial functional class was significantly associated with patient mortality (p = 0.0001).

Figure 4.

Patient survival rates for ESP and control kidney translants, stratified by initial functional clan.

Permanently nonfunctioning kidneys and contralateral kidneys

For each permanently nonfunctioning (PNF) kidney, the outcome for the contralateral kidney was also analyzed. Only one contralateral ESP kidney and two contralateral control kidneys also suffered PNF. In en-bloc transplants, PNF occurred twice with control kidneys and once with an ESP kidney. Delayed graft function was observed in seven of the contralateral ESP PNF kidneys and in two of the contralateral control PNF control kidneys. All other contralateral kidneys had good initial function.

Discussion

The idea of matching kidney-transplant donors and recipients on the basis of age has a long history and its rationale is very simple, namely that the functional capacity of a kidney should be greater than the physiological demand of the potential recipient (7–12). Nevertheless, prior to ESP, allocation of cadaveric renal grafts was never based solely on age-matching.

In this study, there was no difference in outcome parameters between patients who received transplants from elderly donors via ESP and those who received similar kidneys via the usual allocation procedure. and although the study was not set up as a randomized trial, these data suggest that the old-for-old allocation procedure was as effective as the usual system.

It should, however, be stressed that the trade-off between immunological and nonimmunological risk factors was well thought out (1). As HLA compatibility was disregarded in ESP, the program was restricted to nonimmunized recipients who were awaiting their first transplant. Also, a prerequisite of the study was to reduce the cold-ischemic time as much as possible to reduce the accumulation of risk factors, and hence maximize the outcome in these recipients. Although median cold-ischemic times were significantly lower in the ESP group compared to the control group (p = 0.03), still more than 50% of the ESP transplants experienced a cold-ischemic time of more than 12 h. The reason for this delay is that ESP transplants are considered as elective transplants, where the necessity to queue for the operating theater is an inevitable fact.

We hope that our data will help to change this attitude, as our patients seemed more likely to experience a primary nonfunction of their new allograft in case of a longer cold-ischemic time.

Contrary to other groups, we did not observe a lower incidence of rejection in the ESP group compared with the control group (13). It has been postulated that an aging immune system might cause this phenomenon, but, to consolidate this theory, more immunological parameters must be recorded and analyzed. We strongly believe that the excellent 1-year graft-survival rate of 86% in the ESP group was in fact due to the reduced cold-ischemic time. Nevertheless, it is interesting to consider the role of the association between risk of graft failure, donor age (increased immunogenicity), and recipient age (decreased immune responsiveness) in ESP (14,15).

With aging comes a progressive reduction in the glomerular filtration rate to about 50% of its maximum by the end of the sixth decade (16). Nephrotoxicity of calcineurin inhibitors can further compromise nephron mass and long-term function. Doubling the nephron mass by transplanting the kidneys en bloc might overcome these problems (17–21). The ESP allocation scheme therefore included the option of transplanting both kidneys to a single recipient in cases in which the donor creatinine clearance was below 70 mL/min. Standard biopsies to evaluate the percentage of glomerular sclerosis were not included in the protocol. This strategy probably needs further refinement as three of the en-bloc transplants suffered a PNF. A possible option could be to introduce a scoring system for marginal donors (22).

Renal transplantation should be considered as a treatment option for patients older than 65, although, in view of high mortality rates in this group, thorough screening for cardiovascular and infectious diseases and the provision of coronary artery bypass grafts or arterioplasty for at-risk patients and a tailored immunosuppressive therapy to control infections are mandatory (23,24).The availability of a comorbidity profile for all listed patients would certainly improve the assessment as well as the performance of the program.

Other groups have demonstrated a good outcome among patients who received kidneys from elderly donors, but, as our data clearly show, the occurrence of delayed graft function strongly predicts graft function at 1 year; hence the greatest care should be taken when expanding donor criteria (25–28).

Unquestionably, graft outcome with a younger donor kidney is better than for old-donor kidneys: in this 1999 cohort, the 1-month graft outcome for the 142 senior recipients who received a 65 + donor kidney was 93% (1). However, in view of the increased likelihood that an aged patient will die while waiting for an organ to become available (16–50-year-old patients: 2% mortality on the waiting list within 1 year, 65 +-year-old patients: 10% mortality, data not shown), the choice of obtaining an ESP transplant via this quicker but riskier route should be brought to the attention of elderly transplant candidates. In Eurotransplant centers, it is the responsibility of the treating transplant physicians to assist patients in making this choice and to ask for informed consent. At present, no detailed record of reasons for declining this ESP option is being kept at the central office.

In conclusion, it can be said that ESP has achieved its goals: an increased acceptance rate of older kidneys, reduced waiting time for elderly patients by almost 250 days, and the outcome of renal allografts allocated by the ESP scheme (age-match driven) did not differ from the outcome of grafts allocated in the usual way (HLA-match driven). Based on these results, the Eurotransplant Board decided to continue ESP and to incorporate the program into the regular allocation scheme as of January 2001.

Acknowledgments

The cooperation of all clinicians, transplant coordinators and medical administrators collaborating within the Eurotransplant International Foundation is gratefully acknowledged. Mr Erwin de Vries is thanked by the authors for his assistance in analyzing the data.

Footnotes

  • 1

    Eurotransplant is an organ exchange organization in which transplant centers, donor hospitals and tissue-typing centers in Austria, Belgium, Germany, Luxembourg, the Netherlands and Slovenia collaborate. ( http://www.eurotransplant.org)

Ancillary