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Keywords:

  • Elderly patients;
  • HLA-matching;
  • kidney transplantation;
  • marginal donors;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

Allocation of kidneys from donors older than 64 years to recipients older than 64 years was started in 1999 to improve use of older donor kidneys. Kidneys are allocated locally without HLA-matching to keep cold ischemia short.

We compared survival and rejection rates in elderly patients allocated in the old-for-old program (ESP) to patients aged 60 years and older based on HLA-matching, expected ischemia and waiting time (ETKAS).

The 69 ESP patients were older (67.9 ± 2.5 vs. 63.9 ± 2.9 years), had older donors (71.2 ± 3.9 vs. 44.6 ± 14.5 years) and more HLA-mismatches (4.2 ± 1.2 vs. 1.6 ± 1.7) than the 71 ETKAS patients, while ischemia was shorter (7.8 ± 3.4 vs. 14.2 ± 5.5 h). ESP and ETKAS had similar graft (1-year: 83.6% vs. 86.9%) and patient survival (85.2% vs. 89.5%). With the introduction of ESP, use of older recipients and donors rose from less than 2% to 16% and 11%, respectively. Incidence of acute rejections was significantly higher in the ESP group (1 year: 43.2% vs. 27.4%) and significantly correlated with the degree of HLA-matching.

Introduction of old-for-old allocation allows successful expansion of the donor and recipient pool without affecting patient and graft survival. HLA-matching should not be ignored, as the risk of acute rejection in elderly patients is substantial.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

The advantages of kidney transplantation are the same for young and old patients: Quality of life is better and patients are released from the tedium of dialysis. For patients aged 60–74 years, as for younger patients, survival after transplantation is significantly better than on the waiting list (1).

Still many clinicians are reluctant to perform kidney transplantations in elderly patients: Life expectancy of the elderly is limited, especially in ESRD patients. Donor organs are scarce and the demand for kidneys for younger patients already surpasses the supply.

Similar reservations apply to the use of kidney grafts from elderly donors: Older kidney grafts have, on average, shorter graft survivals, lower glomerular filtration rates and are more susceptible to ischemic damage (2,3).

The obvious solution might be to harvest older kidneys for particular use in older recipients – a setting in which long-term graft survival is not as important as in younger recipients (4). This form of donor and recipient age matching is ethically fair and physiologically logical.

While age matching alone is easy to achieve, an ideal allocation algorithm should insure the optimal combination of all factors that affect outcome. In this context it remains a matter of debate whether duration of cold ischemia, degree of HLA-matching or donor age is the predominant determinant for the outcome of transplantation in elderly recipients.

We report our single-center experience with two different allocation algorithms in recipients aged 60 years and older: Allocation across centers combining HLA-matching and expected cold ischemia time for renal allografts from donors younger than 65 years is compared with local allocation without HLA-matching for renal allografts from donors aged 65 years and older.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

Patients

We retrospectively analyzed all patients aged 60 years or older who received a first cadaveric renal allograft between January 1, 1997 and February 28, 2003 in our center. Patients were divided into two groups according to the algorithm used for graft allocation:

ETKAS (Eurotransplant Kidney Allocation System) group. Donor age less than 65 years. Mandatory exchange for zero-mismatched kidneys and allocation of all other kidneys based on a combination of the number of HLA-mismatches, chance of a good HLA-match (mismatch probability), waiting time, expected cold ischemia time (distance between donor and recipient center) and kidney exchange balance between participating countries (5).

ESP (Eurotransplant Senior Program) group. Donor and recipient age 65 years and greater. Local allocation based on waiting time only to keep cold ischemia to a minimum (6).

Immunosuppressive regimen

Since 1997 triple immunosuppression with antibody induction (Charité, Campus Virchow-Klinikum, Berlin, Germany) or without (Charité, Campus Mitte, Berlin, Germany) is the routine regimen for cadaveric kidney graft recipients in our center. Either cyclosporine microemulsion (Campus Mitte) with target trough levels of 150–200 ng/mL in the first 3 months and 80–120 ng/mL thereafter or tacrolimus (Campus Virchow-Klinikum) with target trough levels of 8–12 ng/mL in the first 3 months and 5–8 ng/mL thereafter is used. Mycophenolate mofetil is administered at a dose of 1 g b. i. d. per os (Campus Mitte). If gastrointestinal side-effects occur, the dose is reduced step by step until the side-effects are resolved. Initially 500 mg of methylprednisolone are administered intravenously for the first 3 days. Then the methylprednisolone dose is tapered to a maintenance dose of 4 mg daily after 90 days. As a result of participation in multicenter trials some patients have immunosuppressive regimens differing from this standard (Table 1).

Table 1.  Comparison of baseline patient characteristics. ESP group (local allocation without HLA-matching of kidneys from donors aged 65 years and greater) vs. ETKAS group (allocation with organ exchange between centers based on a combination of HLA-matching and expected cold ischemia time)
 ESPETKASp
  1. PRA = panel reactive antibodies, SD = standard deviation.

Patients [n]6971NS
Male recipient [%]59.459.2NS
Male donor [%]53.634.30.022
Diabetic nephropathy [%]11.62.80.044
Age at transplantation [years ± SD]67.9 ± 2.563.9 ± 2.9<0.001
Dialysis before transplant [years ± SD]4.7 ± 1.75.8 ± 3.10.024
Donor age [years ± SD]71.2 ± 3.944.6 ± 14.5<0.001
HLA-A-, -B- and -DR-mismatches [n ± SD]4.2 ± 1.21.6 ± 1.7<0.001
HLA-mismatches <3 [%]7.266.2<0.001
PRA at transplantation >3%[%]6.17.2NS
Cold ischemia time [h ± SD]7.8 ± 3.414.2 ± 5.5<0.001
Cold ischemia <12 h [%]87.933.8<0.001
Cold ischemia >24 h [%]02.8 
Antibody induction  NS
 Anti thymocyte globulin13 (19%)13 (18%) 
 Anti-IL2 antibodies36 (52%)30 (42%) 
Calcineurin inhibitor  NS
 Cyclosporine24 (35%)19 (27%) 
 Tacrolimus36 (52%)48 (68%) 
Mycophenolate53 (77%)21 (30%)NS
Rapamycin  NS
 Sirolimus6 (9%)6 (8%) 
 Everolimus 3 (4%) 
Methylprednisolone69 (100%)71 (100%)NS

Patient data and statistical analysis

In our center all patient data are stored in an electronic patient record system. Results from the laboratories, pathology and radiology departments as well as data on all hospitalizations are transferred online into the database. For this analysis all data on baseline characteristics, rejections, hospital admissions, delayed graft function (defined as dialysis in the first week after transplantation), graft loss and patient loss were retrieved from the patient record database. After discharge patients attend our outpatient clinics on a regular basis and are readmitted to our hospitals for any kind of complication during follow up.

Data of the ETKAS and ESP group were compared by a two-sided Chi-square test for categorical variables and by the Mann–Whitney U-test for continuous variables. Differences in graft and patient survival and incidence of acute rejections were assessed with the log-rank test. The contribution of the baseline characteristics (all variables listed in Table 1) to graft survival and incidence of acute rejections was analyzed in a Cox regression model. A p-value of less than 0.05 was considered significant. Statistical analysis was performed with SPSS 9.0.1 (SPSS Inc., Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

Since 1997, 140 first cadaveric kidney transplantations were performed in recipients aged 60 years and older in our center. In the ETKAS group 69 transplantations were performed, while 71 were performed in the ESP group. The ESP patients were significantly older, had older donors, and a higher number of HLA-mismatches, but considerably shorter cold ischemia times (Table 1). Average daily immunosuppression dosages did not differ between groups (cyclosporine ESP 243 ± 173 mg/day vs. ETKAS 239 ± 159 mg/day; tacrolimus ESP 5.8 ± 2.9 mg/day vs. ETKAS 6.5 ± 3.4 mg/day; mycophenolate ESP 1274 ± 524 mg/day vs. ETKAS 1408 ± 471 mg/day). The duration of follow up was shorter for the ESP group, as the ESP allocation was started later than ETKAS (18.1 ± 14.9 months vs. 26.4 ± 17.2 months; p = 0.003) while the median year of transplantation was 2001 for both groups. Follow up was current (defined as last contact less than 1 year before data extraction) for all patients but one.

Hospitalization

Patients from both groups spent the same time in hospital for transplantation [ESP median 29 days (range 13–96 days) and ETKAS median 28 days (range 14–90 days); difference not significant]. The ESP patients were readmitted to the hospital for significantly more days per year of follow up [median 9 days/year (range 0–194 days/year)] than the ETKAS patients [median 1 day/year (range 0–131 days/year)].

Graft and patient survival

In the ESP group the rate of delayed graft function was slightly lower than in the ETKAS group (27.5% vs. 35.2%; difference not significant). Graft survival was similar in both groups, with a 1-year graft survival of 83.6% in the ESP group and 86.9% in the ETKAS group (Figure 1; log-rank test not significant). Patient survival was 85.2% at 1 year in the ESP group and 89.5% in the ETKAS group (Figure 2; log-rank test not significant). Death with functioning graft was the most frequent cause of graft loss in both groups. In the Cox regression analysis none of the baseline characteristics was a significant predictor of graft survival.

image

Figure 1. Kidney graft survival. ESP group (local allocation without HLA-matching of kidneys from donors aged 65 years and greater) vs. ETKAS group (allocation with organ exchange between centers based on a combination of HLA-matching and expected cold ischemia time).

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image

Figure 2. Patient survival. ESP group (local allocation without HLA-matching of kidneys from donors aged 65 years and greater) vs. ETKAS group (allocation with organ exchange between centers based on a combination of HLA-matching and expected cold ischemia time).

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Acute rejections

Significantly more patients in the ESP group had an acute rejection (at 1 year 43.2% in the ESP group vs. 27.4% in the ETKAS group; p = 0.047; Figure 3). In the ESP group graft loss was significantly more frequent in the patients who experienced an acute rejection (33.3%) than in rejection-free patients (9.5%; p = 0.14). This association was not observed in the ETKAS patients (16.7% vs. 17%).

image

Figure 3. Incidence of first acute rejection. ESP group (local allocation without HLA-matching of kidneys from donors aged 65 years and greater) vs. ETKAS group (allocation with organ exchange between centers based on a combination of HLA-matching and expected cold ischemia time).

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Patients who had an acute rejection were hospitalized significantly longer for transplantation [median 36 days (range 14–90 days) vs. median 22 days (range 5–196 days); p = 0.001] and had to be readmitted to the hospital for significantly more days per year of follow up [median 16 days/year (range 0–194 days/year) vs. median 0 days/year (range 0–131 days/year); p = 0.001]. Renal function at 1 year (last creatinine value in the first year after transplantation) was slightly higher in patients who had an acute rejection (2.15 ± 1.36 mg/dL vs. 1.78 ± 1.16 mg/dL; not significant). This was observed in the ESP group (with AR 2.26 ± 1.16 mg/dL vs. 1.98 ± 0.97 mg/dL without AR) as well as in the ETKAS group (with AR 1.99 ± 1.64 mg/dL vs. 1.62 ± 1.29 mg/dL without AR). These differences were not significant in an anova, neither was the comparison between the ESP and ETKAS groups (2.09 ± 1.05 mg/dL vs. 1.72 ± 1.39 mg/dL).

The incidence of acute rejections was significantly higher in patients with a badly matched graft (three or more mismatches) compared with patients with a well-matched graft [less than three mismatches (Figure 4); p = 0.003]. Degree of HLA-matching was the sole significant predictor of acute rejection in the Cox regression analysis of all baseline characteristics [OR 3.85 (95% confidence interval: 1.71–8.68); p = 0.002].

image

Figure 5. Development of the share of donors and recipients aged 65 years and older at the Charité. Dedicated allocation of kidneys from older donors to older recipients was started in 1997.

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Changes in use of older donors and older recipients

Before the introduction of the ESP in our center only one recipient out of the 506 cadaveric kidney transplantations performed until then was older than 65 years and only 12 kidneys from donors older than 65 years had been used. Since the introduction of the ESP allocation algorithm, 16.0% of all recipients were 65 years and older and the share of donors aged 65 used in our center rose to 11.2% (Figure 5). From nine kidney transplantations in recipients aged 60 years and greater in our center in 1998 (the year before the start of ESP) the annual rate has risen to 42 in 2002. In our organ procurement region the number of used kidney grafts per year from donors aged 60 and greater has more than doubled from 32 in 1998 (the year before the ESP started) to 70 in 2002.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

Despite older recipients, older donors and inferior HLA-matching kidney graft survival in the ESP group was not significantly worse than in the ETKAS group. The implications of this finding are of course limited by the relatively small number of patients and the observational nature of this retrospective study.

The observed 1-year survival rates of 83.6% and 86.9%, respectively, for these two groups of elderly transplant recipients are in line with published data: The UNOS registry reports an unadjusted 1-year graft survival of 83.1% in recipients older than 60 years of age (7). Meier-Kriesche reports a 1-year survival of 81% from their single-center series of patients older than 60 years (8), and Palomar and Doyle report comparable figures for this age group with 78% and 86%, respectively (9). For patients of 65 years and greater with donors older than 65 years, Smits reports a 1-year graft survival of 79% (6). As in our experience, death with a functioning graft is the main cause of graft loss in these series. The unsatisfactory patient survival in our ESP and ETKAS groups of 85.2% and 89.5%, respectively, at 1 year is therefore no surprise. In the UNOS registry 1-year patient survival for recipients 65 years and older at 1 year is 88.0%, with a lower mortality rate in the subsequent years (3-year survival: 74.4%), as observed also in our population.

Isolated contemplation of these figures would make kidney transplantation hardly seem attractive for elderly patients. The benefit of transplantation for these patients becomes obvious only on the background of the convincing case-control studies published in the late nineties that demonstrate that the markedly worse survival on dialysis is in this age group (1,10,11). The expansion of the share of transplantations in older recipients that occurred at initiation of the dedicated ‘old for old’ organ allocation at our center can therefore be considered a success. In how far the new allocation algorithm on the one hand and the above-cited studies contributed to this expansion cannot be discerned, but the sharp rise in the first year of ESP allocation makes a major contribution most likely.

Contrary to expectations based on pathophysiological considerations we had to learn that elderly patients are very much capable of acute rejections. This was especially pronounced in the ESP group despite the even higher recipient age in this group. Several authors have supported the idea that elderly patients have a degree of immune incompetence and have a lower risk of acute rejection (12–14). This clearly is not the case in our patients with rates of acute rejection (AR) of 27.4% in the ETKAS group and 43.2% in the ESP group despite triple immunosuppression. As a result of the allocation ignoring HLA-compatibility the ESP group had significantly worse HLA-matching and Cox's regression analysis showed the degree of HLA-matching to be the sole factor influencing the risk of acute rejection in these patients. It is quite possible that the low power resulting from the small number of patients hampered the regression analysis and additional factors would have turned out to have a significant influence with higher patient numbers. It is quite possible that the observed rejection rates would be lower with more aggressive immunosuppression (e.g. quadruple therapy), but faced with an already high mortality a cautious approach was chosen in our center.

Other clinical studies with patients aged 60 and greater have reported similar rejection rates: Meier-Kriesche observed 15.6% AR in the first year under triple immunosuppression with MMF in a cohort with 2.1 ± 1.2 AB-mismatches and 1.4 ± 0.5 DR-mismatches (8). Palomar et al. reported an AR incidence of 26.8% with 1.2 ± 0.6 B-mismatches and 1.0 ± 0.6 DR-mismatches (15). With transplants matched as badly (4.4 mismatches) as in our ESP group, Voiculescu reported a similarly high AR rate of 52% for recipients older than 64 years (16).

While the effect of acute rejections on graft survival did not reach statistical significance in our population, patients with acute rejection required significantly longer hospitalization for transplantation and had to be readmitted for significantly more days. Again, with a higher number of patients the effect of AR on graft survival might have attained statistical significance. Thus AR is at least an important cause of morbidity in this age group, which is at the same time at an increased risk of over-immunosuppression (8). The immunosuppressive regimens were included in the multivariate analysis and did not turn out to have a significant effect in the multivariate analysis – which could of course also be because of a lack of power while there was at least enough power to find a significant effect for HLA-matching.

As our data clearly show the relation between the degree of HLA-matching and the risk of AR, we feel that achieving better HLA-matching might reduce the risk of AR also in this setting. That cold ischemia time showed no significant effect on the rates of delayed graft function and graft survival in our patients is most likely as a result of the fact that nearly all organs had rather short ischemia times, and should not be an argument to abandon short ischemia in favor of better HLA-matching. Better HLA-matching with the same ischemia times could be achieved if allocation remains restricted to local recipients, but with HLA-matching used instead of waiting time as the allocation criterion among the local recipients. This might be perceived as ‘unfair’ as waiting times would vary much more, but in the light of our experience it seems questionable whether an equal right to mediocre results is the best solution for elderly patients.

We conclude that the introduction of a dedicated allocation algorithm for older donors and recipients allows successful expansion of the donor and recipient pool without affecting patient and graft survival. As the risk of acute rejection in elderly recipients is still substantial and shows a strong relation to the number of HLA-mismatches, efforts to improve HLA-matching within the allocation algorithm are warranted.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References

No external funding was received for this analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Funding
  8. References
  • 1
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  • 2
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  • 3
    Wyner LM, McElroy JB, Hodge EE, Peidmonte M, Novick AC.Use of kidneys from older cadaver donors for renal transplantation. Urology 1993; 41: 107110.
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  • 8
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    Bonal J, Cleries M, Vela E. Transplantation versus haemodialysis in elderly patients. Renal Registry Committee. Nephrol Dial Transplant 1997; 12: 261264.
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    Ismail N, Hakim RM, Helderman JH. Renal replacement therapies in the elderly: Part II. Renal transplantation. Am J Kidney Dis 1994; 23: 115.
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    Bradley BA. Does the risk of acute rejection really decrease with increasing recipient age Transpl Int 2000; 13: S42S44.
  • 15
    Palomar R, Ruiz JC, Zubimendi JA et al. Acute rejection in the elderly recipient: influence of age in the outcome of kidney transplantation. Int Urol Nephrol 2002; 33: 145148.
  • 16
    Voiculescu A, Schlieper G, Hetzel GR et al. Kidney transplantation in the elderly: age-matching as compared to HLA-matching: a single center experience. Transplantation 2002; 73: 13561359.