Median donor age was 52 years (41–62 years). One hundred fifteen donors were 70 years or older (13.60%). Donation after circulatory death (DCD) donors accounted for 12% of LTs. In DCD, total donor warm ischemia time was 19 minutes (15–25 minutes). Cold ischemia time was 7.88 hours (6.23–9.50 hours). No difference in the duration of cold ischemia time was observed between D < 70 and D ≥ 70 (Table 1).
Compared to younger donors, D ≥ 70 were more often female, died more frequently of cerebrovascular events, had shorter hospitalization in intensive care before donation, higher DRI [D ≥ 70: 2.63 (2.43–2.87), D < 70: 1.89 (1.56–2.22); P < 0.0001], and were more frequently procured by our own team. DCDs were less common in D ≥ 70 (1.70%) than in D < 70 (13.60%, P < 0.0001). Predonation peak-transaminases were lower in D ≥ 70 (Table 1).
Recipients were aged 57 years (49–64 years) and were transplanted with a median laboratory MELD at the time of LT of 15 points (11–23). The two most frequent indications for transplantation were hepatocellular carcinoma (HCC; 30.27%) and postethyl cirrhosis (12.60%) (Table 1).
The median follow-up was 5.26 years (2.38–9.35 years). Patient survival was 90% at 1 year and 75.60% at 5 years after transplantation, whereas graft survival was 97.80% and 90% at 1 and 5 years after LT, respectively (Table 2).
Older Recipients Are at Higher Risk of Death Independently of Age Matching
Figure 1A depicts the interpolation plot for patient survival, in which divergent interpolation lines suggest the existence of significant interaction of age. In univariate analysis, recipient age was associated with higher risk of death after transplantation (HR, 1.04 per additional year; 95% confidence interval [CI], 1.02-1.05, P < 0.0001), whereas patient survival was not influenced by D ≥ 70 (HR, 5.96; 95% CI, 0.45-79.09; P = 0.18) or age interaction (HR, 0.97; 95% CI,: 0.93-1.01; P = 0.17).
The effect of older donors, recipient age, and age interaction on patient survival was further tested against other predictors in multivariate Cox regression (Table 3). Among the variables significantly associated with worse patient survival in univariate analysis, the United Network for Organ Sharing score, transplantation for HCC, redo-LT, and cold ischemia remained independent predictors for patient's death in multivariate analysis. Donors in which thoracic organs were also donated (either heart, lungs, or heart and lungs) were associated with better survival after transplantation. D ≥ 70 did not affect patient survival (adjusted HR, 2.15; 95% CI, 0.14-34.26; P = 0.59). In contrast, recipient's age independently increased the risk of death after transplantation (adjusted HR, 1.03 per additional year; 95% CI, 1.02-1.05; P < 0.0001), but matching older donors to older recipients did not confer additional risk (adjusted HR of the interaction product, 0.98; 95% CI, 0.94-1.03, P = 0.47) (Table 3).
Results remained unchanged when introducing the era of the transplant in the multivariate model, which had no effect on patient survival (adjusted HR, 0.98; 95% CI, 0.93-1.03; P = 0.35).
After stratification per recipient age, the adjusted risk of patient's death was significant for patients aged 60 to 69 years (HR, 1.995; 95% CI, 1.40-2.85; P < 0.0001) and for recipients 70 years or older (HR, 2.001; 95% CI, 1.10-2.66; P = 0.02) (Figure 2; SDC, Table S1, http://links.lww.com/TXD/A197). The adjusted negative effect of recipient age on patient survival was significant already 6 months (HR, 1.06 per additional year; 95% CI, 1.03-1.09; P = 0.00008) and 1 year after transplantation (HR, 1.06 per additional; 95% CI, 1.03-1.09, P = 0.00003) (SDC, Table S2, http://links.lww.com/TXD/A198).
Five-year patient survival in recipients 70 years or older transplanted with grafts from D ≥ 70 years was 72.60%. The absolute difference on 5-year patient survival of recipients transplanted with grafts procured from younger or older donors was similar between recipients younger than 60 years (7%) or 70 years or older (8%, P = 0.53), further confirming the absence of significant interaction of donor and recipient age (Figure 3).
Older Recipients Are Not at Higher Risk of Graft Loss
Figure 1B depicts the interpolation plot for graft survival, in which divergent interpolation lines suggested the existence of significant interaction of age. However, in univariate analysis, the risk of graft loss was not associated with recipient age (HR, 1.02 per additional year; 95% CI, 0.997-1.04; P = 0.09), D ≥ 70 (HR, 1.56; 95% CI, 0.11-222.57; P = 0.86), or age interaction (HR, 0.99; 95% CI, 0.91-1.07; P = 0.75).
The effect of older donors, recipient age, and age interaction on graft survival was further tested against other predictors in multivariate Cox regression (Table 3). Among the predictors associated with graft loss in univariate analysis, retransplantation and recipient with a history of diabetes remained significant predictors in multivariate regression, whereas the risk of graft loss was not influenced by D ≥ 70 (adjusted HR, 1.09; 95% CI, 0.01-88.01; P = 0.97), recipient age (adjusted HR, 1.02; 95% CI, 0.996-1.04; P = 0.11), or age interaction (adjusted HR, 0.993; 95% CI, 0.92-1.07; P = 0.85) (Table 3).
Older Recipients Exhibited a Low-risk Profile Pretransplantation
To identify predictors of worse outcomes in older recipients, donor and recipient demographics, transplant characteristics, and postoperative complications were compared post hoc between the age group showing the best outcomes, that is, recipients younger than 60 years (R < 60, n = 514 LT), and the 2 age groups showing a significantly increased risk of death after LT, that is, recipients of 60 to 69 years (R60-69, n = 289 LT) and recipients 70 years or older (R ≥ 70, n = 46 LT).
Both R60-69 and R ≥ 70 were transplanted with grafts procured from older donors. Cold ischemia was significantly shorter in both R60-69 (7.64 hours [6.02–9.34], P = 0.002) and R ≥ 70 (6.55 hours [5.14–8.27], P = 0.002) than R < 60 (8.03 hours [6.45–9.67]). DCD grafts were more frequently transplanted in R60-69 (17.30%) than R < 60 (9.30%, P = 0.004) (Table 4).
Older recipients had a more stable disease when compared to R < 60. Indeed, both R60-69 and R ≥ 70 were transplanted more frequently for HCC within Milan criteria,26 had lower laboratory MELD score at the time of LT [R < 60: 16 (11–25); versus R60-69: 14 (11–21), P = 0.004; versus R ≥ 70: 12 (8–25), P = 0.004], and were less frequently admitted to the intensive care at the time of organ offer (R < 60: 16.90%; versus R60-69: 8.40%, P = 0.02; versus R ≥ 70: 4.50%, P = 0.06). Additionally, R60-69 needed renal replacement therapy before LT less frequently than R < 60 (Table 4).
There was no difference between groups in the incidence of primary nonfunction, early allograft dysfunction,25 acute kidney injury, and nonanastomotic biliary strictures. R60-69 and R ≥ 70 showed higher frequencies of diabetes than R < 60, and R60-69 showed a higher frequency of arterial hypertension. Nevertheless, there was no difference in death rate caused by either cardiac or cerebrovascular events, nor a more prevalent cause of death in R60-69 or R ≥ 70 could be identified (Table 4).
An explorative analysis of risk factors for patient death in older recipients (R ≥ 60, n = 335 LT) identified hospitalization in the intensive care at the time of organ offer as the only predictor of poor patient survival (adjusted HR, 2.91; 95% CI, 1.53-5.52; P = 0.001), whereas D ≥ 70 did not influence the risk of death after LT (adjusted HR, 0.66; 95% CI, 0.39-1.11; P = 0.12) (SDC, Table S3, http://links.lww.com/TXD/A199).
This single-center retrospective analysis of 849 deceased-donor LTs shows that matching older donor livers to older liver transplant recipients does not affect long-term outcomes because there was no synergic amplification of age-related risks when other risk factors are minimized. Advanced recipient age was an independent predictor of patient's death but did not influence the risk of graft loss. Lastly, older donors were not associated with worse outcomes, in contrast with results from large registry studies12,13 but in line with previously published single-center analyses.7,14-17
Previous studies have assessed the risk of death/graft loss of transplants with different combinations of donor and recipient age.27-29 In a large retrospective analysis, Chapman et al27 did not observe any difference in patient and graft survival in LTs matched or mismatched per age, but the actual interaction product of donor and recipient age was not considered. Using a similar approach, Pagano et al28 observed worse graft and patient survival in multivariate analysis in age mismatched LT, but the absence of correction for donor and recipient age, the small sample size, and small number of events do not allow to draw any solid conclusion on the relevance of age interaction. Very recently, Bittermann and Goldberg29 observed in a large-registry analysis that the detrimental effect of increasing donor age was greater in younger (<40 years) than older recipients (≥60 years), and younger recipients transplanted with older grafts (≥60 years) had significantly worse outcomes in multivariate analysis. These results led the authors to conclude that donor and recipient age have a significant synergic interaction influencing outcomes after LT, although it is not clear if recipient age was a risk factor for death and if analyses were adjusted for donor age. In the absence of such adjustment, a higher risk of death/graft loss in transplants in which older grafts are used might reflect the detrimental effect of advanced donor age rather than indicating a significant effect of true interaction of age. Furthermore, in the study by Bitterman and Goldberg, donors younger than 40 years constituted almost 50% of the donor pool, and only 17% were older donors (≥60 years), whereas in our cohort, they accounted for 20% and 30% of LTs, respectively. Such difference in the donor pool resulted in a more stringent selection of older donors in our population (shorter hospitalization, small number of DCDs with shorter warm ischemia time, and more frequent local procurement/allocation), making direct comparison of results difficult. When clustering the transplants according to different age matches similarly to the study by Bittermann and Goldberg, our results did not change: older recipients were at higher risk of death independently from various combinations of donor and recipient age (SDC, Table S4, http://links.lww.com/TXD/A200).
Despite the fact that older patients were at higher risk of death, our adjusted analysis showed that LT in older recipients achieves 5-year patient survival more than 80% (Figure 2), which is in line with the best achievable results identified in a recent benchmark analysis in LT.30 Although the benefit in years-gain after LT should be quantified based on the expected survival on the waiting list rather than on the absolute value of post-LT survival,6 our data justify the conclusion that LT in older candidates can achieve excellent results. Indeed, their remarkable 80% patient survival at 5 years after transplantation is likely to be superior to the expected 5-year survival of age peers suffering from end-stage liver disease still on the waiting list and is substantially greater than the 60% cutoff generally accepted as threshold to overcome the harm of a futile transplant.31 Therefore, older candidates should not be excluded from LT a priori based on “chronological” age; rather, a more comprehensive risk stratification and evaluation of their health status should guide the decision for listing.
Older recipients exhibited a pretransplant profile, suggesting a high likelihood of success (they were transplanted mostly for HCC within Milan criteria,26 with a low laboratory MELD score, and short cold ischemia), yet they had higher risk of death. Although the effect of recipient age remained largely unexplained in our analyses, it did not seem related to graft failure since recipient age did not influence death-censored graft survival. We do acknowledge, however, that our analysis may have been less precise for this outcome due to the small number of graft loss observed in our cohort (n = 87). Lastly, the adjusted effect of recipient age on patient's death was significant as early as 6 months after LT; therefore, the negative effect of recipient age cannot be related solely to the expected inferior longevity of older recipients.
Cardiovascular diseases have been associated with mortality after solid organ transplantation in older patients2 but did not seem to play a major role in our series. The incidence of the most common risk factors for cardiovascular events was similar in older and younger recipients, with the exception of diabetes mellitus. We could not evaluate the incidence of risk factors for metabolic syndrome,32 which is closely related to the risk of both cardiac and cerebrovascular events.33,34 Nevertheless, patients of advanced age in this series underwent full cardiological assessment (including MIBI myocardial perfusion image test or coronary angiography when appropriate) on single-case basis before listing, and we did not observe higher incidence of fatal cardiac or cerebrovascular accidents in older recipients.
Recipient's age may be a surrogate marker of other factor(s) not adequately captured in our analysis. For instance, recipient's global fitness and functional reserves rather than “chronological age” may determine the increased risk of death observed in older recipients. “Physical frailty” is a syndrome of the geriatric population characterized by increased vulnerability to external stressors and predisposes to adverse outcomes and death.35 The loss of muscular mass, the impairment of muscular performance, and the malnutrition almost invariably associated with liver cirrhosis are also hallmarks of the frailty syndrome.36 The recently developed “liver frailty index,” which evaluates the extrahepatic manifestation of cirrhosis (nutritional status, extremity strength, and neuromotor function) with 3 straightforward performance tests (grip strength, chair stands, and balance),37 quantifies patient's functional reserves, predicts waitlist mortality better than MELD,37 and, more importantly, correlates with post-LT mortality in preliminary studies.38,39 We hypothesize that older recipients in our cohort suffered from unknown degrees of physical frailty, which, in turn, might have predisposed them to worse outcomes despite the favorable pretransplant profile. Indeed, an explorative analysis identified hospitalization in intensive care as the only predictors of patient's death in recipients 60 years or older (SDC, Table S3, http://links.lww.com/TXD/A199), which may also reflect the more fragile phenotype of these patients. To date, the pretransplant assessment of (older) candidates suffering from end-stage liver disease focuses mostly on quantifying their probability to survive surgery mainly by stratifying their risk of cardiovascular events.2 The systematic and objective quantification of functional reserves of older transplant candidates might allow us not only to improve risk stratification and selection of older recipients but also to prompt targeted rehabilitation therapies aiming to improve their global fitness and endurance before LT, ultimately improving results in the long-term.
Our study is a single-center retrospective analysis in which donors ≥70 years with a low-risk profile were selected and, as such, donor-related risk factors as donor type and warm ischemia were not associated with worse outcomes. It may be argued that an unequal distribution between younger and older DCD donors in our cohort may confound our findings on the safety of using well-selected older donors. However, DCD grafts of 50 or older or 60 years or older can be safely used without impact on long-term graft survival, provided that other risk factors are minimized.40,41 We repeated our analysis excluding DCD liver transplants, and the results did not change (SDC, Table S5, http://links.lww.com/TXD/A201).
The low median laboratory MELD of the transplants included in our study (15 [11–23]) may also be considered as a limitation to the generalizability of our results. However, de Boer et al analyzing the utilization of older grafts for LTs performed within the Eurotransplant region in the same period considered in our study (2000–2015) reported a similar median laboratory MELD score of 16 points (11–27). Therefore, we believe that the LTs included in our study are a fair representation of the current practice in LTs in the majority of Europe.
Older recipients had more stable disease than younger patients, and the intrinsic effect of recipient's age after adjustment for other predictors in our analysis might have been underestimated. Additionally, the effects of other factors, such as the severity of hepatic steatosis and physical deconditioning and malnutrition, were not considered in this study, and we might have overestimated the effect of recipient's age on long-term outcomes. Therefore, some degree of caution is warranted while interpreting our results.
We acknowledge that the experience of our center with older donors17 may partially influence the good results obtained with this type of graft and that carefully selecting and matching older donors and recipients may limit the generalizability of our study. Nonetheless, this strategy reflects a real-life practice aiming to use older donor grafts without jeopardizing outcomes by minimizing other risk factors well known to influence long-term results. For example, we preferably but not exclusively accept D ≥ 70 with normal liver function tests predonation, a short intensive care stay (≤3 days), procured by our own team allowing us to minimize the duration of cold ischemia. Similar observations have been made in 2 registry analyses. Indeed, Halazun et al observed that adjusting for cold ischemia (>8 hours) and some recipient characteristics (>60 years, hepatitis C, pretransplant hospitalization, retransplantation, previous abdominal surgery) resulted in similar patient survival after transplantation of ≥70 and <70 years donor grafts.20 Similar to our findings, Segev et al identified a subgroup of “low-risk” recipients (nonurgent first transplant for HCC or indications other than hepatitis C, >45 years, cold ischemia <8 hours) in which posttransplant outcomes were not affected by older donor age.5 Such findings were recently confirmed in a Eurotransplant registry analysis.42 However, our results also highlight that older “low-risk” recipients have a considerable increased risk of death independent of age matching, stressing the emergent need to improve the preoperative risk stratification of these patients.
In conclusion, older livers can be safely used in older recipients without jeopardizing graft and patient survival if other risk factors are minimized. However, carefully selected older recipients have higher risk of death after LT, although their 5-year survival can be excellent. The preoperative evaluation of older liver transplant candidates should include the objective assessment of their global fitness and functional reserves because it might improve stratification of risks, allow targeted pretransplant rehabilitation, and ultimately further ameliorate long-term outcomes.
An abstract of this manuscript was presented during the 27th international congress of The Transplantation Society (Madrid, June 30, 2018, to July 5, 2018).
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