Hasjim BJ, Chen SY, Hlaing NK, Ichii H, Redfield RR, Imagawa DK, Bhat M. Donor-recipient age mismatch and outcomes in liver transplantation: A scientific registry of transplant recipients database analysis. World J Transplant 2025; 15(4): 108376 [DOI: 10.5500/wjt.v15.i4.108376]
Corresponding Author of This Article
Bima J Hasjim, Department of Surgery, UC Irvine, 3800 Chapman Ave, Orange, CA 92868, United States. bjhasjim@gmail.com
Research Domain of This Article
Transplantation
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Hasjim BJ, Chen SY, and Bhat M participated in the concept, design of the study, provided administrative, technical, or material support; Hasjim BJ, Chen SY, Hlaing NKT, Ichii H, Redfield RR, Imagawa DK, and Bhat M assisted in the acquisition, analysis, or interpretation of data, and provided critical revision of the manuscript for important intellectual content; Hasjim BJ and Chen SY drafted the manuscript; Chen SY conducted the statistical analysis; Bhat M supervised the project; and all authors approved the final version of the manuscript that was submitted.
Institutional review board statement: This study was approved by the Medical Ethics Committee of University of California, approval No. #4474.
Informed consent statement: The need for signed informed consent was waived by the Institutional Review Board at University of California.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bima J Hasjim, Department of Surgery, UC Irvine, 3800 Chapman Ave, Orange, CA 92868, United States. bjhasjim@gmail.com
Received: April 15, 2025 Revised: May 23, 2025 Accepted: July 2, 2025 Published online: December 18, 2025 Processing time: 217 Days and 4.7 Hours
Abstract
BACKGROUND
Old donor allografts in liver transplantation (LT) account for 25% of all allografts, and their utilization is projected to increase with the aging general population. Older allografts are associated with higher rates of all-cause mortality and graft failure; however, there is limited literature exploring the specific phenotypic changes (e.g., functional status, cause-specific mortality) observed in different donor:recipient age pairs.
AIM
To investigate differences in functional impairment and cause-specific mortality between different donor:recipient age pairs.
METHODS
This was a retrospective analysis of LT patients from the Scientific Registry of Transplant Recipients from 2002 to 2022. Donors were categorized into younger age donors, ≤ 45-years (YAD), middle-aged donors, 46-69-years (MAD), and older age donors, ≥ 70-years (OAD). Recipients were categorized into younger age recipients, ≤ 55-years (YAR) and older age recipients, > 55-years (OAR) age recipients. Multivariate Fine-Gray competing risk and logistic regression analyses identified independent risk factors for cause-specific mortality and improvements in functional status, respectively.
RESULTS
Overall, 126185 patients were included in the analysis: YAD:YAR (32.7%), YAD:OAR (25.2%), MAD:YAR (17.5%), MAD:OAR (20.7%), OAD:YAR (1.3%), and OAD:OAR (2.7%). Compared to YAD:YAR, OAD pairs had the lowest likelihoods of improved functional status 5 years post-LT (OAD:YAR odds ratio 0.53, 95% confidence interval 0.42-0.67, P < 0.001; OAD:OAR odds ratio 0.67, 95% confidence interval 0.51-0.89, P = 0.006). Donor:recipient age pairs with older donors had higher rates of graft- and infection-related mortality compared to those with younger donors (P < 0.001). Meanwhile, donor:recipient age pairs with older recipients had higher cardioneurovascular- or malignancy-related deaths compared to those with younger recipients (P < 0.001).
CONCLUSION
Donor:recipient age mismatch was associated with differences in cause-specific mortality and functional status. These insights could potentially inform age-matched organ allocation strategies, though future work is warranted.
Core Tip: The aging general population has led to changes in liver transplant (LT) recipient and donor demographics. In addition to older recipient age, older allografts are increasingly utilized to keep up with the demand for LT. In this study, we found that older donor:recipient age pairs were associated with a lower likelihood of improving functional status and distinct patterns of cause-specific mortality. Notably, graft- and infection-related mortality were strongly dependent on allograft age, whereas cardioneurovascular- and malignancy-related mortality were more linked with recipient age. These findings highlight the importance of age dynamics in LT and may inform age-matched organ allocation strategies.
Citation: Hasjim BJ, Chen SY, Hlaing NK, Ichii H, Redfield RR, Imagawa DK, Bhat M. Donor-recipient age mismatch and outcomes in liver transplantation: A scientific registry of transplant recipients database analysis. World J Transplant 2025; 15(4): 108376
The aging population is projected to impact various facets of healthcare, including liver transplantation (LT). By 2030, one in five Americans is projected to be ≥ 65-years-old and will outnumber the population of children for the first time in United States history by 2034[1]. Utilization of liver allografts from donors ≥ 60 years old has increased by nearly 4-fold since 1990 and makes up nearly 25% of all allografts[2,3]. These rates will likely continue to increase as older individuals increasingly make up the donor pool, while also serving as a means for LT centers to meet the growing demand for LT.
While LT is the only definitive treatment of underlying liver disease, it is challenging for patients to return to baseline[4-8]. This may be especially true for elderly recipients as the characteristic changes of aging make them prone to frailty, illness, and diminished cognitive functioning[9]. Additionally, allografts from older donors may promote cellular senescent phenotypes (e.g., decreased spatial learning, cognitive function, and physical ability) in recipients and can adversely affect transplant outcomes[9]. While it is well-established that utilizing allografts from older donors is associated with higher rates of all-cause mortality and graft failure[10-13], there is limited literature exploring the phenotypic changes observed in different donor:recipient age pairs.
To this end, we aimed to clarify the differences in donor:recipient age pair outcomes, focusing on variations in functional status and cause-specific mortality. Understanding these differences is crucial for optimizing donor and recipient selection criteria and improving post-LT care to enhance patient outcomes.
MATERIALS AND METHODS
Data source
This was a retrospective cohort study of all patients from the Scientific Registry of Transplant Recipients (SRTR) who received a liver transplant from June 1, 2002, to May 29, 2022. The SRTR database is a national dataset of all donor, wait-listed transplant candidates, and transplant recipients in the United States submitted by members of the Organ Procurement and Transplantation Network[14]. The STROBE guidelines were used to report our findings (Supplementary Table 1). This study was approved by the Institutional Review Board at the University of California, approval No. #4474.
Study design
All patients [pediatric (< 18 years old) and adults (≥ 18 years old)] receiving LT were included in this study. Patients receiving transplantation of multiple organs (n = 13268; 8.8%), those with a history of a previous transplant (n = 7662; 5.1%) human immunodeficiency virus (n = 654; 0.4%) and pre-listing malignancy other than hepatocellular carcinoma (HCC) (n = 3644; 2.4%) were excluded from the analysis (Supplementary Figure 1).
Clinical variables and survival outcomes
Donors were divided into three groups according to donor age based on prior literature: Younger age donors, ≤ 45-years (YAD), middle-aged donors, 46-69-years (MAD), and older age donors, ≥ 70-years (OAD)[10,11,15]. Recipient age groups were dichotomized into two groups based on prior literature[16,17] and to yield the most balanced sample sizes across subpopulations: Younger age recipients, ≤ 55-years (YAR) and older age recipients, > 55-years (OAR) at the time of listing. Furthermore, we conducted additional sensitivity analyses with a donor age cutoff of 65 years (Supplementary Tables 2 and 3).
Donor characteristics of interest included sex, race, comorbidities, causes of death, donation after cardiac death (DCD) vs donation after brain stem death, and cold ischemia time (hours). Recipient characteristics included age, sex, race, comorbidities, functional status, primary diagnosis for transplant, and model for end-stage liver disease (MELD)/pediatric end-stage liver disease model (PELD) score at waitlisting. Functional status was defined by the Karnofsky Performance Scale and categorized into “Independent”, “Mildly Dependent”, and “Totally Dependent”. Improvements in functional status were determined as those being categorized as “Independent” at 5 years post-LT after being “Mildly Dependent” or “Totally Dependent” at the time of LT.
The primary outcomes of interest were long-term, post-LT survival (5 years) and cause-specific mortality: Graft-, infection-, cardioneurovascular-, malignancy-, and renal-related. Secondary endpoints included all-cause mortality and long-term improvement of functional status between different donor:recipient age pairs.
Statistical analyses
Descriptive analyses compared demographic and clinicopathological variables between donor age groups. Counts and proportions were calculated for categorical variables, whereas mean and median, with corresponding mean ± SD and ranges, respectively, were provided for continuous variables. Differences between donor age groups were compared using Fisher’s exact tests or χ2 tests for categorical variables. Analysis of variance tests and Kruskal-Wallis tests were used to compare continuous variables. For all results, two-sided P-values were used, and those with an alpha level < 0.05 were considered statistically significant.
The Kaplan-Meier method was used to estimate overall survival and each cause of death. Cumulative incidence curves were plotted for different causes of mortality, and these plots were stratified by donor:recipient age groups. Univariable and multivariable Fine-Gray competing risk regression analyses were used to identify independent risk factors for different causes of death at 5- and 10-year follow-up. When analyzing one specific cause of mortality, deaths due to other causes were treated as competing risk events. Results were reported as subdistribution hazard ratios (sHR), 95% confidence intervals (CI), and P values. Univariable and multivariable logistic regression models were also conducted to examine the associations between risk factors and improvement of functional status post-transplant. Improvement in functional status was measured at the time of LT to 5 years of follow-up. Results were reported as odds ratios (OR), 95%CI, and P values. Multivariate analyses were performed with variables selected from the backward selection method and include donor-recipient age pairs, recipient diabetes, recipient diagnosis, recipient functional status, living donor liver transplantation (LDLT) vs deceased donor LT, and MELD/PELD. Clinically important variables, regardless of their statistical significance, and variables with P < 0.05 from the univariable analyses were considered and included. Data processing and analysis were performed using SAS 9.4 software (Cary, NC, United States).
RESULTS
Cohort characteristics
A total of 126185 donors were included in the analysis and were categorized into six donor:recipient age pairs: YAD:YAR, n = 41202; 32.7%, YAD:OAR, n = 31737; 25.2%, MAD:YAR, n = 22124; 17.5%, MAD:OAR, n = 26164; 20.7%, OAD:YAR, n = 1587; 1.3%, and OAD:OAR, n = 3371; 2.7%. There were 7677 (6.1%) DCD donors and 7128 (5.6%) LDLT donors. Female donors comprised 39.7% of the total cohort, with the proportion of female donors increasing significantly with age (P < 0.001). The leading causes of death among donors were anoxia (32.5%), cerebrovascular accident (33.9%), and head trauma (33.2%), with significant differences observed across age groups (P < 0.001). Cerebrovascular accident was the most common cause of death in older donors (YAD 16.4% vs MAD 55.1% vs OAD 72.2%), while anoxia (YAD 37.1% vs MAD 28.0% vs OAD 12.8%) and head trauma (YAD 46.0% vs MAD 16.6% vs OAD 14.9%) were more prevalent in younger donors (P < 0.001; Figure 1). Common comorbidities, such as diabetes and hypertension, were more prevalent in older donors (P < 0.001). The average cold ischemia time was 6.3 ± 3.3 hours (Table 1, Figure 1).
Figure 1 Donor characteristics and comorbidities by donor:recipient type.
There were differences in donor characteristics between donor:recipient age pairs. The most common causes of death in donors were cerebrovascular accident, while anoxia and head trauma were more common in younger donors (P < 0.001). Older donors had higher rates of comorbidities such as diabetes and hypertension. High-risk organ donors, donation after cardiac death, and living donor liver transplantation were more likely to be of younger donor:recipient age pairs (P < 0.001). YAD: Younger age donors, ≤ 45-years; MAD: Middle-aged donors, 46-69-years; OAD: Older age donors, ≥ 70-years; YAR: Younger age recipients, ≤ 55-years; OAR: Older age recipients, > 55-years; CVA: Cerebrovascular accident; DCD: Donation after cardiac death; LDLT: Living donor liver transplantation.
Table 1 Donor and recipient demographics stratified by donor:recipient pairs, n (%).
Recipients receiving older donor allografts were older (YAD 47.3 ± 18.9 years vs MAD 54.5 ± 10.5 years vs OAD 57.9 ± 9.4 years, P < 0.001) and had higher rates of diabetes (YAD 21.3% vs MAD 26.4% vs OAD 32.1%, P < 0.001), hypertension (YAD 20.3% vs MAD 24.9% vs OAD 27.2%, P < 0.001), and chronic obstructive pulmonary disease (YAD 1.9% vs MAD 2.2% vs OAD 2.5%, P = 0.020). OAD:OAR had the highest rates of patients with independent functional status (49.7%) and the lowest rates of totally dependent functional status (10.5%) at transplant (P < 0.001). YAD:YAR had the highest rates of totally dependent (30.5%) patients, and those with biliary (19.8%), idiopathic (20.9%), and autoimmune hepatitis (3.5%). YAD:YAR patients had the lowest rates of HCC, 6.0%, and metabolic dysfunction-associated steatohepatitis (5.2%). OAD:OAR had the highest rates of HCC (24.6%), metabolic dysfunction-associated steatohepatitis (17.6%), and the lowest rates of hepatitis C virus (HCV, 13.1%), and mean MELD/PELD (16.7 ± 7.2) (P < 0.001) (Table 1).
Multivariable logistic regression analysis for improvement in functional status: Older donor:recipient pairs had lower likelihoods of improving functional status
Donor age was independently associated with improvement of functional status, regardless of recipient age (Table 2). Compared to YAD:YAR pairs, incrementally older donors and their respective recipient pairs had less likelihoods of observing an improvement in functional status within 5-years post-LT: YAD:OAR (OR = 0.89, 95%CI: 0.83-0.96, P = 0.003), MAD:YAR (OR = 0.83, 95%CI: 0.77-0.90, P < 0.001), MAD:OAR (OR = 0.80, 95%CI: 0.73-0.87, P < 0.001), OAD:YAR (OR = 0.53, 95%CI: 0.42-0.67, P < 0.001), and OAD:OAR (OR = 0.67, 95%CI: 0.51-0.89, P = 0.006). Other notable independent risk factors include biliary etiology (OR = 0.77, 95%CI: 0.70-0.86, P < 0.001), HCC (OR = 0.56, 95%CI: 0.49-0.64, P < 0.001), HCV (OR = 0.73, 95%CI: 0.67-0.79, P < 0.001), and LDLT (OR = 0.77, 95%CI: 0.64-0.93, P = 0.005; Table 2). Sensitivity analyses utilizing an age cutoff of 65 years also found that odds of improving functional status were least likely in OAD:OAR (vs YAD:YAR; OR = 0.69, 95%CI: 0.88-1.03), followed by OAD:YAR (vs YAD:YAR; OR = 0.69, 95%CI: 0.67-0.82) (Supplementary Table 2).
Table 2 Multivariable logistic regression analysis for odds of improving functional status at 5 years of post-transplant follow-up.
Survival analysis: YAD:YAR pairs had the highest median survival
YAD:YAR pairs had the highest median survival [5.3 (5.1-5.5) years], while MAD:OAR pairs had the lowest median survival [4.2 (4.1-4.3) years] (Supplementary Figure 2). Higher donor age had the highest rates of graft- and infection-related mortality regardless of recipient age (Figure 2A and B). Though there were differences among donor age group pairs, older recipients independently had higher cardioneurovascular-, malignancy, and renal-related mortality (P < 0.001; Figure 2C-E).
Figure 2 Post-liver transplantation survival of patients stratified by each pairing of donor and recipient age.
Incrementally increasing donor age in each respective donor:recipient pair had increasing rates of graft- and infection-related mortality. Conversely, cardioneurovascular-, malignancy, and renal-related mortality were largely driven by recipient age as incrementally increasing recipient age in each respective donor:recipient pair had increased rates of these outcomes. A: Graft-related; B: Infection-related; C: Cardioneurovascular-related; D: Malignancy-related; E: Renal-related mortality. YAD: Younger age donors, ≤ 45-years; MAD: Middle-aged donors, 46-69-years; OAD: Older age donors, ≥ 70-years; YAR: Younger age recipients, ≤ 55-years; OAR: Older age recipients, > 55-years.
When assessing the cumulative incidence for competing causes of mortality by each donor:recipient age pair, infection-, graft-, and cardioneurovascular-related mortality were most prevalent within 1.5 years of follow-up (Figure 3). Malignancy-related mortality begins to rise, surpassing other causes of death earlier in follow-up among older recipients (Figure 3D-F). Malignancy-related mortality does not surpass graft-related mortality among MAD:YAR and OAD:YAR cohorts (Figure 3B and C). Supplementary Table 4 reports the distribution of common immunosuppression drugs and their associations with various cause-specific mortality.
Figure 3 Competing risk cumulative incidence curves for post-liver transplantation, cause-specific mortality by each donor:recipient age pair.
Cause-specific mortality and alternative causes of death were treated as competing risks. Within each donor:recipient subgroup, infection-, graft-, and cardioneurovascular-related mortality were most prevalent within the first 1.5 years of follow-up. Rates of graft- and Infection-related mortality rise with incremental increases of donor age among young recipients. Malignancy-related mortality begins to rise at later follow-up endpoints and eventually surpasses most causes of death. Among older recipients (younger age donors, ≤ 45-years (YAD): Older age recipients, > 55-years (OAR), middle-aged donors, 46-69-years: OAR: Older age donors, ≥ 70-years: OAR), malignancy-related mortality surpasses other causes of death sooner in follow-up. A: YAD: Younger age recipients, ≤ 55-years; B: Middle-aged donors, 46-69-years: YAR; C: Older age donors, ≥ 70-years: Younger age recipients, ≤ 55-years; D: YAD: OAR; E: Middle-aged donors, 46-69-years: OAR; F: Older age donors, ≥ 70-years: OAR. YAD: Younger age donors, ≤ 45-years; MAD: Middle-aged donors, 46-69-years; OAD: Older age donors, ≥ 70-years; YAR: Younger age recipients, ≤ 55-years; OAR: Older age recipients, > 55-years.
Older donor:recipient age groups had a higher risk of graft- and infection-related mortality: Overall, older donor:recipient age pairs had higher subdistribution hazards of all-cause mortality compared to YAD:YAR (P < 0.001). Donor:recipient age pairs had differing associations of cause-related mortality at 5- and 10-year follow-up (Table 3 and Supplementary Table 5). Older donor:recipient age pairs had higher subdistribution hazards of infection-related mortality compared to YAD:YAR, with the highest being among OAD:OAR (sHR = 3.06, 95%CI: 2.50-3.74). Other independent risk factors for infection-related death include: Recipient diabetes (sHR = 1.13, 95%CI: 1.03-1.24), HCV (sHR = 1.24, 95%CI: 1.10-1.41), and worse functional status (mildly dependent sHR = 1.34, 95%CI: 1.21-1.49; totally dependent sHR = 2.02, 95%CI: 1.78-2.30). Older recipients of donor:recipient age pairs had lower subdistribution hazards of graft-related mortality (YAD:OAR sHR = 0.68, 95%CI: 0.60-0.77; MAD:OAR sHR = 0.87, 95%CI: 0.76-0.98), while younger recipients had higher subdistribution hazards of graft-related mortality (MAD:YAR sHR = 1.42, 95%CI: 1.27-1.59; OAD:YAR sHR = 1.72, 95%CI: 1.32-2.25). LDLT was independently associated with graft-related survival (sHR = 0.67, 95%CI: 0.51-0.89).
Table 3 Multivariate Fine-Gray competing risk regression analysis identifying independent risk factors for different causes of death within 5-year outcomes.
Older recipients had higher risks of cardioneurovascular-, malignancy-, and renal-related mortality: Donor:recipient age pairs with older recipients had higher subdistribution hazards for cardioneurovascular-, malignancy-, and renal-related mortality (P < 0.001; Table 3). Compared to YAD:YAR, older donors (YAD:OAR, sHR = 1.46, 95%CI: 1.32-1.62; MAD:OAR sHR = 1.45; 95%CI: 1.30-1.61) had higher risks of cardioneurovascular-related mortality. Similarly, older donors had higher risks of malignancy- (YAD:OAR, sHR = 1.36, 95%CI: 1.22-1.51; MAD:OAR sHR = 1.31; 95%CI: 1.17-1.45) and renal-related (YAD:OAR, sHR = 1.58, 95%CI: 1.07-2.29; MAD:OAR sHR = 1.90; 95%CI: 1.29-2.79; OAD:OAR sHR = 2.49, 95%CI: 1.37-4.53) mortality. These associations were replicated in a sensitivity analysis utilizing a donor age cutoff of 65 years (Supplementary Table 3).
DISCUSSION
Not surprisingly, older donor:recipient age pairs were associated with higher rates of all-cause mortality. However, there were differences in late causes of mortality between donor:recipient age pairs. Patients receiving allografts ≥ 70 years had higher risks of graft- and infection-related mortality. In contrast, recipient age had a more significant impact on cardioneurovascular-, malignancy, or renal-related deaths. Additionally, regardless of recipient age, patients receiving allografts ≥ 70 years have a lower likelihood of improving their functional status at 5 years post-LT. These findings suggest varying risks of morbidity with different donor:recipient age pairs, which may hold important implications for decisions on organ offer acceptance.
The utilization of older allografts is an important strategy for expanding the donor pool for LT to meet its demand. In this study, even when allocated to younger recipients, older donor allografts were associated with higher risks of graft- and infection-related mortality. Prior studies similarly show that older allografts were more susceptible to graft-related complications, especially when other risk factors such as cold ischemia time, steatosis, and recipient comorbidities are present[15,18]. In addition to “inflammaging”, the result of an imbalance between a chronically inflamed state and oxidative stress that occurs throughout life, older allografts may also be more prone to ischemic reperfusion injury (IRI) that can manifest as graft- or infection-related complications[19,20]. IRI from extended cold or warm ischemia time may result in nonanastomotic biliary complications and up to 10% of all early allograft failures[21-23]. Recent advances in preservation methods across all solid organ transplantation have aimed to reduce IRI[24-26]. Particularly in DCD donors, where the incidence of biliary complications is 3 times as high as donation after brain stem death donors[27,28], hypothermic machine perfusion has been shown to reduce the risk of non-anastomotic biliary strictures by nearly 75% in the hypothermic oxygenated machine perfusion-DCD randomized controlled trial (NCT02584283)[29]. Future work to mitigate IRI, as advances in normothermic or hypothermic machine perfusion will be important to mitigate the risks of graft- and infection-related complications associated with older and other high-risk allografts.
Poor outcomes among older donor:recipient age pair mismatch can also be observed through secondary endpoints such as compromised physical and cognitive function[9]. Functional status is a known powerful predictor of mortality in LT[30-33], and we found that patients receiving older allografts had lower odds of improvements in post-LT functional status, regardless of recipient age. Compared to YAD:YAR, young and old recipients of OAD had lower odds of improving their functional status post-LT by 47.3% and 32.6%, respectively. These findings build upon the existing literature that found that older patients had lower improvements in functional status over time. In an analysis of the United Network for Organ Sharing database, older age was already independently associated with higher probabilities of having no improvements in functional status after LT[30]. Patients without improvements in functional status between 3-12 months after LT only had a 33% one-year survival rate compared to 91%-99% of patients who had improvements in functional status[30]. Our study further identifies a subset of vulnerable LT patients who were already at high risk of frailty and further highlights the importance of pre-habilitative interventions prior to LT to improve outcomes. Exercise training in LT candidates and recipients improves health-related quality of life, cardiorespiratory, and muscular fitness[34-37]. Timing of such interventions, determination of consensus clinical endpoints, and adherence to pre-/rehabilitation programs should be incorporated in future research to optimize outcomes in this at-risk population[38].
While donor age was associated with graft- and infection-related mortality, recipient age was the primary link to cardioneurovascular- or malignancy-related mortality. These results underscore the nuances of competing risks of specific causes of death. In these scenarios, different causes of death preclude the occurrence of other causes[39]. Because older allografts have higher rates of graft- and infection-related mortality, they inherently will have lower rates of other causes of death, such as cardioneurovascular or malignancy. Particularly in malignancy-related mortality, its rates begin to surpass those of other causes of death among recipients of younger donor allografts only after 1.5 years post-LT. In contrast, recipients of older donor allografts experience higher rates of non-malignancy-related mortality until approximately 3 years post-LT. Depending on both donor and recipient age, these findings may help clinicians and patients anticipate the differential risks of cause-specific mortality over time.
Currently, the liver allocation policy prioritizes the distribution of age-matched pediatric liver donors to pediatric LT candidates over their adult counterparts[40]. However, this age-matched allocation advantage does not apply after patients enter young adulthood. Large donor:recipient age gaps have been associated with increased risks of mortality by as much as 97% among those with differences spanning ≥ 20 years[41]. Given the projected increasing availability of older allografts, their potential interactions with increasing utilization of organ donation after DCD, other extended criteria, and advances in organ preservation through machine perfusion, it may be prudent to revisit the role of age matching in organ allocation[42,43]. We found that donors in older donor:recipient age pairs had higher rates of comorbidities such as diabetes and hypertension. Despite this, older LT recipients who received organs from older donors have demonstrated comparable long-term survival compared to older LT recipients of younger donors[44]. In these cases, matching older recipients to older allografts may offer a survival benefit, particularly when the liver offer might otherwise fall below the typical threshold for transplantation[45]. Conversely, high-risk organs, DCD, and LDLT from younger donors may be matched with younger recipients to optimize the survival benefit of an allograft. Moving from the “sickest first” allocation policy established by the MELD to a policy that is grounded on allograft utility and maximizing the total lifespan saved by LT may have major epidemiological ramifications[46]. Among younger patients who are not in emergent need of LT, preferential allocation of a younger-aged donor offers could optimize organ utility by increasing postoperative graft survival time[42]. Investigating the impact of age-matched policies within the context of current advances in expanding the donor pool is warranted.
There were several limitations to our study. First, because this was a retrospective review, we must caution from assuming causality in the observed associations we found. Second, this study only accounts for donor characteristics from the United States, which may vary from those of international cohorts. Second, the present analysis did not account for differences in immunosuppression therapy. Different post-LT immunosuppressive strategies (e.g., mTOR inhibitors vs. calcineurin inhibitors) have been associated with differences in late outcomes (e.g., de novo malignancies)[47-49]. Unfortunately, these variables had significant amounts of missingness, low sample sizes at long-term endpoints in the SRTR dataset, and could not account for differences in immunosuppression strategies that prevented further investigation or biostatistical analysis. Third, perioperative characteristics such as operating time, transfusion requirements, and hemodynamic instability were not accounted for in our analyses since these data were not available in the SRTR. While these factors may influence immediate perioperative outcomes, their impact on long-term outcomes - the primary focus of our study - is less substantial[50,51]. Lastly, the Karnofsky Performance Scale to measure functional status may not map perfectly to frailty (e.g., liver frailty index) and has been subject to wide-ranging interrater reliability[52,53]. However, the Karnofsky Performance Scale can still provide valuable insights between functional status and mortality[8,30,54]. Future work assessing biomarkers of cellular senescence among LT patients and their associations with key clinical endpoints such as mortality, quality of life, frailty, and cognitive function will be essential to advance the field. Longitudinal, prospective study designs can also mitigate these limitations.
CONCLUSION
In conclusion, our study provides insight into differences in late, cause-specific post-LT mortality between donor:recipient age pairs. Older donors, even among those paired with younger recipients, were associated with higher rates of all-cause, graft-, and infection-related mortality. Additionally, these patients had a lower likelihood of improving functional status. Among cardioneurovascular-, malignancy, and renal-related mortality, older recipient age was more strongly associated with poor outcomes than donor age. Organ acceptance of older allografts should be performed in carefully selected patients, and further investigation of other LT endpoints in the aging donor and/or recipient is warranted.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Transplantation
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade C
Novelty: Grade A, Grade B, Grade D
Creativity or Innovation: Grade A, Grade A, Grade C
Scientific Significance: Grade A, Grade B, Grade C
P-Reviewer: Matsusaki T; Patel B S-Editor: Bai Y L-Editor: A P-Editor: Zhang YL
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