The number of patients requiring treatment for end-stage renal disease (ESRD) has increased dramatically over the past decades (1). Much of this increase is attributable to a disproportionate increase in older ESRD patients. Although the incidence of ESRD in the age group of 65 to 74 yr was 640 per million population in the United States in 1988, the rate of new patients on renal replacement therapy reached 1384 per million population in 2000. An even more pronounced increase was observed in patients ≥75 yr, with incident rates of 512 and 1588 per million population in 1988 and in 1997, respectively (1,2). In 2000, more than 51% of incident hemodialysis (HD) patients in the United States were ≥65 yr old.
Among the treatments that are available for ESRD—HD, peritoneal dialysis, and kidney transplantation—the latter is the most desirable because it has been found to be associated with greater longevity, better quality of life, and economic benefits resulting from a successful transplantation for the patient (3), and to be more cost-effective compared with HD or peritoneal dialysis (4). However, the disparity between the numbers of potential transplant recipients and available organs has progressively widened over the last 15 yr (5–7).
There has been concern that providing elderly ESRD patients with scarce donor kidneys may not be a worthwhile investment because of limitations on the useful life of the donor organ imposed by the inherently higher mortality risk in older patients (7). However, little is known about long-term patient and graft survival of elderly patients, especially after having undergone a uniform and thorough examination for comorbidities before being added to the wait list (8). Most of the previous studies lack adequate control for other factors that influence these outcomes. Although survival of elderly patients with ESRD is limited by higher age per se, patient survival is additionally influenced by several comorbid conditions (9–11). Graft loss in the elderly patient population is mainly related to patient’s death, primarily caused by cardiovascular disease, infection, and malignancy (11–14). Thus, careful assessment and control for such factors is of cardinal importance when studying outcomes of kidney transplantation in elderly patients or when drawing comparisons to younger age groups.
Thorough screening procedures have been put into place to select appropriate patients to be wait-listed for kidney transplantation. Applying such algorithms appears to be particularly important in elderly patients. At our institution, patients are screened for cardiovascular, gastrointestinal, pulmonary, infectious, and malignant comorbidities before being placed on the wait list. According to clinical practice guidelines (15–18), only patients free from significant comorbidities or after resolution of comorbidity-related issues are put on the wait list.
The data regarding the influence of comorbid conditions on patient and graft survival are conflicting. To better understand the importance of the combined effect of age and several comorbidities in elderly transplant recipients with respect to long-term patient and graft survival, we conducted the present retrospective study. It was our aim to specifically compare the outcomes of patients ≥65 yr of age at transplantation with their younger peers.
Materials and Methods
We included all patients who had been wait-listed and received a kidney transplant at the transplant center of the Vienna General Hospital and who were ≥50 yr on date of transplantation. As part of the wait-listing process, all patients had to undergo a standardized workup of all major organ systems. Results from the workup process were reported and documented on a standardized form. For all patients, we extracted a large number of baseline characteristics from these forms and notes from medical charts at admission for kidney transplantation: age, gender, date of transplantation, time on renal replacement therapy, time on wait list, whether it was the first kidney transplant received, and identity of the referring dialysis unit. We assessed several comorbidities: hypertension, diabetes, coronary artery disease (CAD; all patients underwent routine coronary angiography), cerebrovascular disease, peripheral artery vascular disease, congestive heart failure, valvular disease or previous valve repair surgery, atrial fibrillation, any malignancy, chronic obstructive pulmonary disease, tuberculosis, and gastrointestinal comorbidity such as peptic and duodenal ulcers, diverticulosis, diverticulitis, gastritis, or past gastrointestinal surgery (Table 1). We also categorized the underlying renal disease with the system adopted by the European Renal Association-European Dialysis and Transplant Association (19). From height and weight, each patient’s body mass index was calculated as the weight in kilograms divided by the square of height in meters. From laboratory tests, we registered hepatitis B, hepatitis C and CMV status, and the highest/latest titer of panel-reactive antibodies. Other covariates pertained to donor characteristics, or the transplant procedure: donor age, donor gender, donor CMV status, living related/unrelated or cadaveric donor, cold ischemia time, and number and types of HLA mismatch. Information on induction and immunosuppressive therapy was also collected.
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Table 1: Baseline characteristics by age group (n = 627)
From the date of transplantation, patients were followed up for the following outcomes: presence and type of surgical complication associated with the transplantation procedure, presence of primary nonfunction, delayed graft function (defined as the need for HD post transplant for >7 d), serum creatinine at discharge, length of hospital stay, date of irreversible loss of transplant function defined as the reinstitution of chronic dialysis, date and cause of patient death, and the last date when patients were seen.
Patients were grouped into three categories by age at time of transplantation: 50 to 59 yr, 60 to 64 yr, or ≥65 yr. Because it was our aim to specifically study the oldest age group, all analyses used this category as the referent group. We then compared the baseline characteristics among these groups by simple linear regression for continuous variables, and simple logistic regression for categorical variables. Primary outcomes analyses focused on patient survival, graft survival, and graft survival censored for patient death. We used Kaplan-Meier curves to display the time course of each event of interest. We then used univariate and multivariate Cox proportional-hazard models to test for the independent effects of the available covariates on the outcomes. All patients were censored at 5 yr after transplantation, because the data became sparse beyond that follow-up range. We forced two dummy covariates indicating the two younger age categories into all multivariate models. With model parsimony in mind, we selected the other model covariates by an automated backward elimination process at P > 0.15. Observing the rule that not more than one covariate per ten events be used in multivariate models, we then used a manual elimination process to select out variables with the highest P values step by step. However, all independently significant covariates at the P < 0.05 level were included in the final multivariate models. We examined the validity of the proportional-hazard assumption by testing for significance of covariate-time interaction terms. All analyses were conducted by SAS version 8.2 statistical analysis software (SAS Institute, Cary, NC). This study was approved by the local institutional review board.
Results
Of the 1250 patients having received a kidney transplant at our institution between January 1, 1993, and December 31, 2000, 627 patients were ≥50 yr of age at transplantation and so constituted our study cohort: 335 patients (53.4%) were between 50 and 59 yr old at time of transplantation (group 1), 141 patients (22.5%) were between 60 and 64 yr old (group 2), and 151 patients (24.1%) were ≥65 yr (group 3; median = 68.4 yr; interquartile range: 66.4 to 70.9; maximum = 78.6). The median follow-up for the three age groups were 1179 d, 1170 d, and 899 d, respectively. Only 6 patients were lost to follow-up, all in the youngest age group. Table 1 shows important covariate information for each age group. Several baseline covariates differed significantly by age group: older patients tended to have less hypertension, but more coronary artery disease and peripheral artery disease. Older patients were also less likely to have had a previous kidney transplant, or to have had high panel-reactive antibody titers, but they were more likely to have mismatches on the HLA-DR locus. Donor age was also higher in recipients ≥65 yr compared with the other age groups. The likelihood of induction therapy with antithymocyte globulin appeared to increase with age, and the oldest age group was less likely to receive cyclosporine A or azathioprine as part of the immunosuppressant regimen (Table 1).
Short-Term Outcomes of Kidney Transplantation
Among the three age groups, the rates of undesired short-term outcomes were very similar (Table 2). Primary nonfunction was observed in 6.6%, 5.8%, and 7.3% of patients (P = 0.87), and among the remaining patients, delayed graft function was found in 23.2%, 23.9%, and 22.3% (P = 0.96) of 50 to 59, 60 to 64, and ≥65 yr olds, respectively. The corresponding in-hospital mortality rates were 4.2%, 3.5%, and 3.3%, respectively (P = 0.67). The median length of the initial hospital stay was 28 d for patients between 50 and 59 yr, 26 d for transplant recipients 60 to 64 yr, and 27 d for those ≥65 yr (P = 0.79). Among those patients discharged with a functioning transplant, serum creatinine at discharge was 1.57 mg/dl (±0.59), 1.48 mg/dl (±0.49), and 1.48 mg/dl (±0.48) for the 50 to 59, 60 to 64, and ≥65 yr groups, respectively.
Table 2: Short-term outcomes after kidney transplantation
Determinants of 5-Yr Patient Survival
During the 5-yr observation period, we observed 126 deaths (20.1%) in this cohort: 55 (16.4%) in the group aged 50 to 59; 34 (24.1%) in the group aged 60 to 64; and 37 (24.5%) in the group aged ≥65 yr at time of transplantation (P = 0.048). The Kaplan-Meier curves depicting cumulative survival by age group indicate superior unadjusted survival for patients in the 50 to 59 yr age group compared with the patients ≥65 yr at transplantation (Figure 1). From the univariate Cox proportional-hazard model of 5-yr patient survival, we find that patients in the 50 to 59 age group had a 39% reduced mortality rate compared with the group of ≥65-yr-old transplant recipients (hazard ratio [HR] = 0.61; 95% confidence interval [CI], 0.40 to 0.93; Table 3). Unadjusted mortality of patients between 60 to 64 yr at transplantation did not differ from those in the oldest group (HR = 0.91; 95% CI, 0.57 to 1.46). Inclusion of other important predictors of death did not change these associations materially: being between 50 to 59 yr old at transplantation yielded a 34% lower risk of mortality compared with age ≥65. However, after multivariate adjustment, this effect was no longer significant (HR = 0.66; 95% CI, 0.43 to 1.03; Table 3). The adjusted mortality between the two older age groups (60 to 64 versus ≥65 yr) remained comparable (HR = 1.07; 95% CI, 0.66 to 1.74). Other covariates selected into the final multivariate model are also shown in Table 3: increasing donor age (HR = 1.02 per year; 95% CI, 1.01 to 1.03), BMI greater than 28kg/m2 (HR = 1.47; 95% CI, 0.99 to 2.18), presence of CAD (HR = 1.65; 95% CI, 1.13 to 2.40), presence of gastrointestinal comorbidity (HR = 1.73; 95% CI, 1.17 to 2.57), cardiomyopathy (HR = 2.33; 95% CI, 1.12 to 4.85), and cold ischemia time greater than 22 h (HR = 1.43; 95% CI, 0.98 to 2.08) were all independently associated with greater mortality risk in these patients.
Figure 1.:
Kaplan-Meier plot of cumulative 5-yr patient survival.
Table 3: Determinants of patient death (Cox proportional hazards models)
Determinants of 5-Yr Graft Survival
The combined end point of death or graft failure was observed in 155 patients over the 5-yr observation period. Kaplan-Meier curves for this outcome by age group are shown in Figure 2. The three curves are virtually superimposed, at least for the first 3 yr of follow-up. Univariate proportional-hazard analyses revealed that there was no significant difference in graft survival among the three age groups. Compared with the oldest group of transplant recipients (≥65 yr), the relative risks of graft failure were 1.08 (95% CI, 0.70 to 1.67) for those aged 60 to 64, and 0.88 (95% CI, 0.60 to 1.28) for those between 50 and 59 yr at time of transplantation (Table 4). After multivariate adjustment, these results were found to be robust. Compared with kidney graft recipients ≥65 yr at time of transplantation, the hazard ratios were 1.28 (95% CI, 0.82 to 2.02), and 1.02 (95% CI, 0.68 to 1.53) for the 60 to 64 and the 50 to 59 yr old patients, respectively (Table 4). Also associated with the combined end point of graft loss or patient mortality were increasing donor age (HR = 1.02 per year; 95% CI, 1.01 to 1.03), recipient BMI greater than 28 kg/m2 (HR = 1.70; 95% CI, 1.21 to 2.40), presence of coronary artery disease (HR = 1.47; 95% CI, 1.04 to 2.07), peripheral artery disease (HR = 1.32; 95% CI, 0.95 to 2.13), presence of any gastrointestinal comorbid condition (HR = 1.58; 95% CI, 1.11 to 2.26), previous heart valve surgery (HR = 1.70; 95% CI, 0.93 to 3.11), and mismatch on HLA locus A (HR = 1.33 per mismatch; 95% CI = 1.04 to 1.70). Having a living donor (HR = 0.12; 95% CI, 0.02 to 0.85) and recipient cytomegalovirus positivity (HR = 0.73; 95% CI, 0.51 to 1.05) were associated with improved graft survival (Table 4).
Figure 2.:
Kaplan-Meier plot of cumulative 5-yr graft survival.
Table 4: Determinants of graft loss or patient death (Cox proportional hazards models)
Determinants of 5-Yr Transplant Survival: Death-Censored Analysis
These analyses evaluated graft failure as the only outcome of interest and censored patients at death, loss to follow-up, and at 5 yr posttransplantation. Both univariate and multivariate analyses showed a nonsignificant trend toward an inverse relationship between graft failure and higher age: older patients were less likely to experience the event of graft failure, but the confidence intervals covered the null value in all univariate and multivariate models (results not shown).
Discussion
In our study of 627 renal transplant recipients aged ≥50 yr at time of transplantation, we found most outcomes to be similar in recipients ≥65 yr in comparison to their 60- to 64- and 50- to 59-yr-old peers. Short-term outcomes such as primary nonfunction, delayed graft function, in-hospital mortality, and length of hospital stay did not differ among the age groups; neither did renal function among those discharged alive. Compared with transplant recipients ≥65 yr, those between 60 and 64 yr at time of the procedure had similar mortality (HR = 1.07; 95% CI, 0.66 to 1.74) and comparable rates of graft loss (HR = 1.28; 95% CI, 0.82 to 2.02). The youngest age group in this study (50 to 59 yr) demonstrated a clear trend toward lower mortality compared with those ≥65 yr (HR = 0.66; 95% CI, 0.43 to 1.03), but statistical power was limited to discover a survival difference between these two groups. However, graft survival was clearly not different between these two groups (HR = 1.02; 95% CI, 0.68 to 1.53). These results arose from analyses that simultaneously controlled for a large number of potential confounders of these associations. We are confident that the assessment of risk factors of mortality and graft loss that may confound the associations of age with these outcomes is the most thorough effort thus far. Hence, these findings have important implications for the discussion about who should have access to the limited pool of donor organs.
Successful kidney transplantation is the treatment of choice for patients with ESRD. There is an increasing gap between supply and demand for donor organs as the incidence of ESRD patients is growing worldwide. In addition, the proportion of patients older than 65 yr in need of renal replacement therapy has increased dramatically over the past decades. Long-term patient survival in the elderly has been shown to be significantly better in transplanted patients versus patients on dialysis, regardless of the dialytic modality (20,21). For patients aged 60 to 74 yr, the projected lifespan while being on the wait list for a transplant is 6 yr, whereas it is 10 yr for those with a transplanted kidney (22). Quality of life is also significantly better in transplanted patients compared with patients on the wait list among the elderly (21,23).
The literature on long-term outcomes of elderly patients after kidney transplantation is inconclusive (9,11,14,20,24–29). In particular, assessment and inclusion of information on comorbid conditions in previous analyses of long-term outcomes is limited at best. To fill this void, we retrospectively assessed 5-yr patient and graft survival in elderly patients compared with patients in the adjacent age groups at our institution and collected information on many possible confounding factors.
Our findings that undesired short-term outcomes did not differ among the three age groups are novel. Interestingly, neither delayed graft function nor primary-non function differed among the age groups, although donor age tended to be higher in the oldest recipient-group, which is likely attributable to the initiation of the Eurotransplant Senior Program in 1999 (30). Surgical complications, transplant nephrectomy, discharge on HD, and death during initial hospitalization were also not different among the three age groups; neither was renal function at discharge. Our finding that average hospital length of stay did not differ among the age groups confirms previous findings (31).
Crude 5-yr patient survival was superior for those aged 50 to 59 yr at transplantation compared with those in the older age groups (Figure 1). Our findings that, after multivariate adjustment, survival was similar between patients aged 60 to 64 and ≥65, and only nonsignificantly better in recipients 50 to 59 compared with those ≥65 yr of age at transplantation, require further comment. Although similar survival between patients aged 60 to 65 and those older than 65 may appear intuitive, nondifferential survival between the oldest group and those patients between 50 and 60 yr at transplantation is not. However, the statistical power to detect mortality differences between these groups was rather limited in our study. Kappes et al. (11) reported a significantly reduced 5-yr patient survival in recipients over the age of 60 (80%) compared with patients under the age of 60 (95%). This survival difference was mainly attributable to cardiovascular deaths: although cardiac complications were less frequent in older compared with younger recipients, the case fatality was much higher in the older group. Another study reported significantly lower survival over 2 yr of follow-up in recipients older than 60 (90%) compared with patients younger than 60 yr (96%) (32). In this study, cardiovascular events were also the leading cause of death. In contrast to the standardized workup implemented at our center, patients in this study were evaluated with a thallium scan only. However, age-related mortality due to cardiovascular disease is still twice as high in patients on the wait list compared with transplanted patients, suggesting that patients have an increased benefit in terms of cardiovascular mortality from transplantation with higher age (33).
In congruence with our results, Cantarovich et al. (34) reported similar 5-yr patient survival (80%) between transplant recipients ≥60 yr and those between 50 to 59 yr, whereas patients aged 20 to 29 yr at time of transplantation had a significantly better 5-yr survival (94%). Cardiovascular death rates were not different among the age groups, which might explain the similar survival rates observed among the two older groups. In this study, the rate of fatal cardiovascular events in elderly transplant recipients was roughly the same as in the French population aged 55 to 74 yr. The authors concluded that elderly patients, if correctly selected, did not have an increased risk of death due to cardiovascular events compared with the age-matched general population. When comparing life expectancy of transplanted patients of all Austrian transplant centers to the Austrian general population, approximation was achieved only for patients older than 65 yr (35). With respect to relative life expectancy compared with the general population, patients older than 60 yr at time of transplantation may have the largest benefit from receiving a kidney transplant (34).
Another important cause of death in elderly recipients are infectious complications. With conventional immunosuppressive regimens, the risk of infectious death in older recipients increases exponentially because there is a general trend toward increased infectious vulnerability in the elderly population. In the group of patients aged 18 to 29, the incidence of death due to infectious complications was 0.8%, whereas the incidence increased to 4.8% in patients older than 65 (33,36).
From the Kaplan-Meier curves of 5-yr graft survival, the combined end point of graft loss or patient death (Figure 2), we learned that at least for the first 3 yr of follow-up, the survival curves for the three age groups were virtually superimposed; only beyond 3 yr did patients between 50 and 59 yr appear to experience better graft survival. However, because Kaplan-Meier plots convey unadjusted information such analyses are crude and do not take into account any confounding factors. Formal multivariate analyses confirmed that graft survival was not different at all among the three age groups. These findings are in congruence with the literature. Cantarovich et al. (34) found 5-yr graft survival not to differ between the youngest (20 to 29 yr) and the oldest patients (>60), and Kappes et al. (11) found that 5-yr graft survival was even superior in the older recipients (90%) compared with the younger ones (82%). This effect may be due to less acute rejection in elderly patients given that the immune system weakens as age increases (37). Doyle et al. (10) discriminated between low-risk and high-risk recipients among the elderly and found graft survival in low-risk recipients to be equivalent to that of younger patients, with a 10-yr graft survival of 50% in the older compared with 53% in the younger ones. Graft survival in the high-risk patients was significantly worse than in the low-risk older and the younger patients, with a 10-yr graft survival of 15%. An explanation for this phenomenon may be a lower nephron mass or increased glomerular sclerosis in kidneys retrieved from older donors (5). Older kidneys have fewer functioning nephrons (38). The parenchymal cells of grafts from older donors might also undergo premature senescence as a result of multiple injuries such as reperfusion (39). Furthermore, kidneys from old donors also seem to have an impaired ability to restore tissue (39).
In our study, donor age was also an important determinant of graft loss, as described previously by Doyle and others (10): graft survival in low-risk recipients was equivalent to that of younger patients, with a 10-yr graft survival of 50% in the older compared with 53% in the younger ones. Graft survival in the high-risk patients was significantly worse than in the low-risk older and the younger patients, with a 10-yr graft survival of 15%. Although an association between donor age and graft loss seems intuitive, the association with mortality is not. It is possible that, especially in elderly patients, graft loss is often associated with a high risk of subsequent patient death as described elsewhere (10).
A positive history of CAD was highly associated with an increased risk of death or graft failure in our cohort, even though all patients were thoroughly screened for CAD before being placed on the wait list. Patients with a history of CAD are only registered, if the lesion is not significant (e.g., stenosis <70% in any coronary artery), or after appropriate intervention. Although CAD is an important predictor of mortality in the general population, it is likely that this effect is accentuated in transplant recipients with a history of CAD by the known acceleration of the disease associated with various immunosuppressive agents, such as corticosteroids (40–42) or calcineurin inhibitors (43).
Our findings that presence of any gastrointestinal comorbidities was highly associated with both patient death and graft loss has not been reported to date. A rationale for this effect may be the high prevalence of corticosteroid treatment in this population. It is well known that high dose corticosteroids aggravate preexisting gastric ulcers (44) and so may lead to gastric hemorrhage, perforated ulcer disease or spontaneous rupture of diverticula. Appropriate screening for gastrointestinal disease and consistent medical prophylactic therapy after transplantation seem obligatory (34).
From the analyses of 5-yr patient and graft survival, it becomes apparent that application of a standard selection process leads to a convergence of outcomes across age groups. Thus, the patients studied are carefully selected and the study population is rather homogenous. Although age can be assumed to still be a risk factor for mortality, everything else being equal, it is possible that the contribution of death on graft loss is counterbalanced by other forces, such as less immunological graft rejection, that lead to a net rate of graft loss in older recipients that is at least equal to the one observed in relatively younger patients.
The study presented here has certain limitations. First, it may not be generalizable to other centers or countries, because of the special situation in Austria with a higher organ supply compared with most other industrialized countries. Furthermore, patient selection algorithms may differ across centers and countries despite general guidelines. However, such concerns don’t invalidate our results. From our data, we cannot assess the age-specific rates of ESRD patients being evaluated for a transplant, being added to the wait list, and finally receiving a transplant. It can be assumed, though, that the degree of preselection increases with age, and fewer patients finally receive a transplant as age increases. Also, residual confounding of our findings is still possible, mainly as a result of crude dichotomization of comorbidities into present versus absent. Such categorization fails to capture any information on the severity of each condition. Nevertheless, we are confident that the study presented here excels with thorough confounding control compared with previous analyses on the topic of interest. Finally, the study period was limited to 5-yr of follow-up. Studies with long-term follow-up beyond 5 yr are warranted.
In summary, our findings suggest that kidney transplantation can be offered even to very elderly patients on renal replacement therapy once they have undergone a thorough pretransplant workup and received treatment of preexisting comorbidities, where possible. Transplantation is a safe procedure regardless of recipient age. Five-year patient survival was similar and graft survival was at least equal in the elderly when compared with relatively younger patients. Thus, our findings provide good evidence that age per se is not associated with a lower return on investment when distributing a scarce donor organ. Thus, discriminating on the basis of age is not supported by the medical research and is thus not justified in the discussion of who should have preferred access to the limited supply of donor kidneys.
Drs. Fabrizii and Winkelmayer contributed equally to this study.
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