Abstract
Introduction:
The relationship between donor age and adolescent heart transplant outcomes remains incompletely understood. We aimed to explore the effect of donor-recipient age difference on survival after adolescent heart transplantation.
Methods:
The United Network for Organ Sharing database was used to identify 2,855 adolescents aged 10– 17 years undergoing isolated primary heart transplantation from 1/1/2000 to 12/31/2022. The primary outcome was 10-year post- transplant survival. Multivariable Cox regression identified predictors of mortality after adjusting for donor and recipient characteristics. A restricted cubic spline assessed the non-linear association between donor-recipient age-difference and the adjusted relative mortality hazard.
Results:
The median donor-recipient age-difference was +3 (range −13 to +47) years, and 17.7% (n=504) of recipients had an age- difference >10 years. Recipients with an age-difference >10 years had a less favorable pre-transplant profile, including a higher incidence of priority status 1A (81.6%, n=411 versus 73.6%, n=1730; p=0.01). The 10-year survival rate was 54.6% (95% confidence interval (CI) 48.8– 60.4) among recipients with a donor-recipient age-difference >10 years and 66.9% (95% CI 64.4–69.4) among those with an age-difference ≤10 years. An age-difference >10 years was an independent predictor of mortality (hazard ratio 1.43, 95% CI 1.18–1.72, p<0.001). Spline analysis demonstrated that the adjusted mortality hazard increased with increasingly positive donor-recipient age-difference and became significantly higher at an age-difference of 11 years.
Conclusion:
A donor-recipient age-difference >11 years is independently associated with higher long-term mortality after adolescent heart transplantation. This finding may help inform acceptable donor selection practice for adolescent heart transplant candidates.
INTRODUCTION
Insufficient donor availability contributes to high pediatric heart transplant waitlist mortality, which approaches 8 deaths per 100 waitlist years in adolescent patients.1,2 Extended donor criteria have been employed in adults as a means to reduce waitlist mortality, and a cautious center donor acceptance practice has been associated with higher waitlist mortality in this cohort.3,4 Utilizing older adult donor hearts in adolescent recipients is a possible avenue for similarly increasing the donor pool for pediatric heart transplantation, and this practice is already being utilized in Europe.5 However, donor age greater than 25 years has been shown to be associated with worse survival in pediatric heart transplant recipients, particularly among adolescent recipients.6 It is uncertain whether this association is primarily being driven by the increased hazard of donors much older than 25 years, and the relationship between donor age and adolescent heart transplant outcomes remains incompletely understood.
We therefore aimed to explore the effect of donor-recipient age-difference on long-term survival in adolescent orthotopic heart transplantation recipients aged 11–17 years, in whom adult hearts are most likely to be used.
MATERIALS AND METHODS
Data source
The analysis for this study was performed using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research file as of January 1, 2022, which includes data for transplants performed in the United States up to December 31, 2022. The file was used to identify all patients aged 10–17 years that underwent heart transplantation from January 1, 2000 to December 31, 2021 (n=3,273). Patients that underwent repeat heart transplantation (n=318) or multi-organ transplantation (n=119) were excluded (Supplemental Figure 1).
All baseline characteristics, operative variables and post-transplant outcomes were defined according to the standard UNOS definitions. The donor-recipient weight ratio was used to quantify degree of size mismatch, this was calculated by dividing donor weight by recipient weight. A donor-recipient weight ratio <0.8 or >2.0 was considered size mismatched.7 The donor-recipient age difference was calculated by subtracting the recipient age from the donor age, such that a positive difference denotes an older donor than recipient and a negative difference a younger donor than recipient. Recipients were stratified by donor-recipient age-difference into those with <10 years difference and those with ≥10 years difference for an initial comparative analysis, donor-recipient age-difference was then analyzed as a continuous variable to further explore its relationship with post-transplant survival.
This study was approved by the Institutional Review Board at Cedars-Sinai Medical Center, approval included a waiver of informed consent.
Primary and secondary outcomes
The primary outcome was 10-year post-transplant survival. Secondary outcomes were repeat heart transplantation, post-transplant length of stay, and selected in-hospital outcomes (mortality, post-transplant dialysis, stroke, and permanent pacemaker implant). Follow-up was censored at 10 years post-transplant.
Statistical analyses
Continuous variables were not normally distributed and were reported as median and interquartile range (IQR). Categorical variables were reported as proportions. Between-group comparisons were performed using Kruskal-Wallis test for continuous variables and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Post-transplant survival curves were derived using the Kaplan-Meier method and groups were compared using the log-rank test. The cumulative incidence of repeat transplantation was assessed with death treated as a competing risk and groups were compared using Gray’s test.
A multivariable Cox regression analysis was performed to evaluate for independent predictors of post-transplant mortality. Covariates with a p-value of less than 0.25 on univariate analysis and those with clinical relevance were entered into the initial multivariable model alongside the dichotomous donor-recipient age-difference variable. Variables with a p-value <0.05 and those with clinical relevance were retained in the final model. Variables that violated the proportional hazards assumption were treated as time dependent covariates. Donor-recipient age-difference was then modeled as a continuous variable, using restricted cubic splines with 5 knots, in a cox regression model with the same covariates to assess the non-linear relationship between donor-recipient age-difference and the adjusted relative hazard of mortality. Observations with missing data were presented as proportions for categorical variables and marked as missing for continuous variables, those with >5% missing data were not used in the multivariable model but were included in the descriptive analysis.
All tests were two-tailed with an alpha level of 0.05. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina).
RESULTS
Baseline Characteristics
A total of 2,855 adolescents aged 10–17 years undergoing isolated heart transplantation comprised the final study cohort, including 82.3% of recipients with a donor-recipient age-difference ≤10 years (n=2351) and 17.7% of recipients with an age-difference >10 years (n=504). The median donor age was 17 (range 4 to 59) years, and the median donor-recipient age-difference was +3 (range −13 to +47) years. The proportion of recipients with a donor-recipient age-difference >10 years was similar between recipients aged 10–13 years (17.6%, n=214) and those aged 14–17 years (17.7%, n=290) (p=0.98). The relationship between recipient and donor age is provided in Figure 1.
Figure 1:
Box plot demonstrating the relationship between donor and recipient age among adolescents undergoing heart transplantation
Whiskers represent minimum and maximum values; boxes represent first quartiles, median values and third quartiles; diamonds represent mean values; circles represent outlying values.
The recipients’ pre-transplant characteristics are provided in Table 1A. Adolescent recipients with a donor-recipient age-difference >10 years were of similar age (median 14 versus 14 years, p=0.99) but weighed more (median 55kg versus 50kg, p<0.001) than those with an age-difference ≤10 years. Overall, 39.7% (n=1134) of recipients were female and 47.3% were non-white (n=1,350), with similar proportions between the two groups (Table 1A). The proportion of patients with cardiomyopathy (63.8%, n=1,821) and congenital heart disease (32.0%, n=914) were also similar between the two groups (Table 1A). Adolescent recipients with a donor-recipient age-difference >10 years had a less favorable pre-transplant profile than those with an age-difference ≤10 years: they were more likely to be listed under priority status 1A (81.6%, n=411 versus 73.6%, n=1730; p=0.01) and more likely to be hospitalized in ICU at the time of transplantation (50.2%, n=253 versus 38.3%, n=900; p<0.001), with a higher rate of extracorporeal membrane oxygenation (5.6%, n=28 versus 2.2%, n=52; p<0.001) and ventilator dependency (10.5%, n=53 versus 5.5%, n=130; p<0.001).
Table 1:
Recipient and donor characteristics for adolescent patients undergoing heart transplantation, stratified by degree of donor-recipient age mismatch.
| Donor-Recipient Age-difference ≤ 10 Years (N=2351) | Donor-Recipient Age-difference >10 Years (N=504) | P-value | |
|---|---|---|---|
| A. Recipient Characteristics | |||
| Age, years (IQR) | 14 (12–16) | 14 (12–16) | 0.66 |
| Female (%) | 945 (40.2) | 189 (37.5) | 0.26 |
| Weight, kg (IQR) | 49.9 (38.1–63.0) |
55.3 (43.4–72.0) |
<0.001 |
| Ethnicity (%) | 0.15 | ||
| White | 1245 (53.0) | 260 (51.6) | |
| Black | 528 (22.5) | 134 (26.6) | |
| Hispanic | 421 (17.9) | 85 (16.9) | |
| Other | 157 (6.7) | 25 (5.0) | |
| Primary etiology (%) | 0.44 | ||
| Cardiomyopathy | 1487 (63.3) | 334 (66.3) | |
| Congenital | 764 (32.5) | 150 (29.8) | |
| Other | 100 (4.3) | 20 (4.0) | |
| Diabetes mellitus (%) | 28/2324 (1.2) | 3/500 (0.6) | 0.24 |
| Dialysis since listing (%) | 56/2337 (2.4) | 19/501 (3.8) | 0.08 |
| UNOS priority status (%) | 0.001 | ||
| 1A | 1730 (73.6) | 411 (81.6) | |
| 1B | 408 (17.4) | 57 (11.3) | |
| 2 | 213 (9.1) | 36 (7.1) | |
| Hospitalization status (%) | <0.001 | ||
| Hospitalized in ICU | 900 (38.3) | 253 (50.2) | |
| Hospitalized not in ICU | 508 (21.6) | 104 (20.6) | |
| Not hospitalized | 943 (40.1) | 147 (29.2) | |
| Ventilator dependent (%) | 130 (5.5) | 53 (10.5) | <0.001 |
| Extra corporeal membrane oxygenation (%) | 52 (2.2) | 28 (5.6) | <0.001 |
| Intra-aortic balloon pump (%) | 17 (0.7) | 6 (1.2) | 0.29 |
| Inotropes (%) | 1070 (45.5) | 248 (49.2) | 0.13 |
| Ventricular assist device in situ (%) | 621/2188 (28.4) | 146/460 (31.7) | 0.15 |
| Time on the waitlist, days (IQR) | 44 (14–123) | 31 (9–88) | <0.001 |
| B. Donor Characteristics | |||
| Age | 16 (13–18) | 29 (26–34) | <0.001 |
| Female Gender | 862 (36.7) | 253 (50.2) | <0.001 |
| Donor-recipient gender mismatch (%) | 989 (42.1) | 214 (42.5) | 0.87 |
| Donor-recipient weight ratio* (IQR) | 1.2 (1.0–1.4) | 1.2 (1.0–1.5) | 0.04 |
| ABO match level (%) | 0.89 | ||
| Identical | 1886 (80.2) | 403 (80.0) | |
| Compatible | 465 (19.8) | 101 (20.0) | |
| Diabetes mellitus (%) | 22/2346 (0.9) | 18/503 (3.6) | <0.001 |
| Hypertension (%) | 21/2345 (0.9) | 56/502 (11.2) | <0.001 |
| Blood Infection (%) | 190 (8.1) | 36 (7.1) | 0.48 |
| Left ventricular ejection fraction*, % (IQR) | 63 (59–68) | 60 (58–65) | <0.001 |
| Cause of death (%) | 2349 | 504 | <0.001 |
| Head trauma | 1524 (64.9) | 249 (49.4) | |
| Anoxia | 594 (25.3) | 124 (24.6) | |
| Stroke | 168 (7.2) | 111 (22.0) | |
| Other | 63 (2.7) | 20 (4.0) | |
| Ischemic time, hours* (IQR) | 3.5 (2.9–4.1) | 3.4 (2.6–4.1) | 0.001 |
There were 4 patients with missing values for donor-recipient weight ratio, 85 patients with missing values for left ventricular ejection fraction and 77 patients with missing values for ischemic time
ADL = activities of daily living; IQR = interquartile range; ICU = intensive care unit; UNOS = United Network for Organ Sharing.
Donor characteristics are provided in Table 1B. The median donor-recipient weight ratio was 1.2 (IQR 1.0–1.5) among recipients with a donor-recipient age-difference >10 years and 1.2 (IQR 1.0–1.5) among those with an age-difference ≤10 years (p=0.04). The rate of donor-recipient weight mismatch was 10.5% (n=53) in recipients with an age-difference >10 years and 7.1% (n=167) in those with an age-difference ≤10 years (p=0.01). The proportion of female donors was higher among recipients with a donor-recipient age-difference >10 years (50.2%, n=252) than those with an age-difference ≤10 years (36.7%, n=862) (p<0.001), but there was no difference in the frequency of donor-recipient gender mismatch (42.5%, n=214 versus 42.1%, n=989; p=0.87). Compared to donors for recipients with a donor-recipient age-difference ≤10 years, donors for those with an age-difference >10 years had a lower median left ventricular ejection fraction (60% versus 63%, p<0.001) and were more likely to have hypertension (11.2%, n=56 versus 0.9%, n=21; p<0.001) and diabetes mellitus (3.6%, n=18 versus 0.9%, n=22; p<0.001). Donors for recipients with an age-difference >10 years were also more likely to have died of a stroke (22.0%, n=111 versus 7.2%, n=168) and less likely to have died from head trauma (49.4%, n=249 versus 64.9%, n=1524) than those for recipients with an age-difference ≤10 years (p<0.001).
Outcomes
In-hospital and short-term outcomes are provided in Supplemental Table 1. Recipients with a donor-recipient age-difference >10 years had higher rates of in-hospital renal failure requiring dialysis (9.0%, n=45 versus 5.9%, n=137; p=0.01), stroke (4.0%, n=20 versus 2.1%, n=49; p=0.01) and pacemaker insertion (2.2%, n=11 versus 1.0% n=24; p=0.009) than recipients with a donor-recipient age-difference ≤10 years.
Median follow-up was 5.6 years (IQR 2.6–9.5) for the entire cohort. The cumulative incidence of repeat transplantation at 10 years for the entire cohort was 6.3% (95% confidence interval 5.2–7.5). The cumulative incidence of repeat transplantation at 1, 5 and 10 years was 0.6% (95% CI 0.2–1.8), 3.8% (95% CI 2.1–6.1) and 6.7% (95% CI 4.1–10.1) respectively among recipients with a donor-recipient age-difference >10 years and 0.4% (0.2–0.8), 2.9% (95% CI 2.2–3.8) and 6.2% (95% CI 5.0–7.6) respectively among recipients with an age-difference ≤10 years (Gray’s Test, p=0.73) (Supplemental Figure 2). The 10-year survival rate for the entire cohort was 65.2% (95% CI 62.9–67.5). The 1, 5 and 10-year survival rate was 91.3% (95% CI 88.8–93.8), 76.3% (95% CI 72.2–80.5) and 55.1% (95% CI 49.3–60.9) respectively among recipients with a donor-recipient age-difference >10 years and 94.5% (95% CI 93.6–95.5), 84.0% (95% CI 82.4–85.6) and 67.4% (95% CI 64.8–69.9) respectively among recipients with an age-difference ≤10 years (p<0.001) (Figure 2). In the multivariable model adjusting for donor and recipient characteristics, including age and donor-recipient weight ratio, a donor-recipient age-difference >10 years was an independent predictor of long-term mortality (HR 1.43, 95% CI 1.18–1.74, p<0.001). Other variables associated with long-term mortality on multivariable analysis are provided in Supplemental Table 2.
Figure 2:
Post-transplant survival up to 10 years following adolescent heart transplantation, stratified by donor age.
Restricted cubic spline analysis demonstrated a non-linear relationship between donor-recipient age-difference and the adjusted 10-year post-transplant mortality hazard (p<0.001). The adjusted mortality hazard increased with increasingly positive donor-recipient age-difference and became significantly higher at a donor-recipient age-difference of +11 years (Figure 3). The use of a younger donor was not associated with an increased adjusted mortality hazard. Relative to a donor-recipient age-difference of 0, the adjusted hazard ratio for 10-year post-transplant mortality at +5, +10, +15, +20 and +25 years of donor-recipient age-difference were 1.14 (95% CI 0.91–1.43), 1.22 (95% CI 0.98–1.52), 1.43 (95% CI 1.15–1.79), 1.74 (95% CI 1.38–2.20) and 2.12 (95% CI 1.57–2.85) respectively.
Figure 3:
The relationship between donor-recipient age-difference and the adjusted relative hazard of 10-year mortality following adolescent heart transplantation in Cox regression with restricted cubic splines.
Blue line represents hazard ratio; shaded area represents 95% confidence interval.
The hazard ratio becomes significant where the lower confidence interval crosses the horizontal gray reference line.
DISCUSSION
This national analysis delineating the association between donor-recipient age-difference and long-term survival among adolescents aged 10–17 years undergoing heart transplantation has several important findings. The use of older adult donor hearts is not limited to the oldest adolescents, as there was no relationship between donor and recipient age and a donor heart aged >40 years had been used in recipients of all ages (Figure 1). Adolescents receiving hearts with a greater donor-recipient age-difference were generally sicker, with a higher priority status, and were more likely to receive extended criteria donor hearts. After adjusting for recipient and donor factors in the multivariable regression analysis; including transplant year, pre-operative ECMO support and donor left ventricular ejection faction; donor-recipient age-difference was an independent predictor of long-term survival. The adjusted restricted cubic spline analysis demonstrated a dose-response relationship between donor-recipient age-difference and mortality hazard: adolescents receiving a heart from a donor aged 11 years older or greater were at increased risk of long-term mortality and this risk increased with increasing age-difference.
The association between older donor age and worse pediatric heart transplant outcomes has been demonstrated in analyses of national and international datasets, and the present study further explores this relationship. A recent International Society for Heart and Lung Transplantation (ISHLT) annual report identified donor age as a continuous risk factor for 10-year mortality following pediatric heart transplant.8 However, use of donor age alone does not account for the relative age of the recipient. For example, this approach would not differentiate between a 13-year-old and a 17-year old recipient receiving a 20-year old donor heart. An analysis of the UNOS database by Westbrook and colleagues used donor-recipient age-difference to better describe this relationship. The authors demonstrated that a donor-recipient age-difference of >5 years older was associated with worse late survival among age-matched children, particularly among adolescent recipients and those receiving hearts from donors >25 years old.6 This study was subject to important limitations. The authors limited their analysis to weight matched children with a donor-recipient weight ratio 0.8–1.5, which accounts for only 75% of adolescents undergoing transplantation in the US. Previous studies have not found a weight ratio of 0.6–3.0 to be associated with adverse outcomes,9–11 and in the present study, size ratio and recipient age are instead included as covariates in the multivariable regression. Westbrook and colleagues also used categorization with 5-year cut offs to identify age-matched, younger and older donors which may oversimplify the relationship between age-difference and post-transplant outcomes, as any age-difference >5 years would be considered identical for the purpose of the analysis.6 Using restricted cubic splines to model donor-recipient age-difference as a continuous variable from −13 years through +47 years, we demonstrated that the use of younger donors and donors aged up to 11 years older than the recipient did not impact 10-year post-transplant survival. Adolescents receiving a donor heart greater than 11 years older were at increased risk of long-term mortality – this risk was present among recipients of donor hearts aged 11 years older and increased with increasing donor-recipient age-difference (Figure 1). These findings support donor-recipient age mismatch as a risk factor in adolescent heart transplantation.
Limitations
The strengths of this study lie in the use of a national transplant registry, including adult and pediatric recipients, robust longitudinal follow up, yet it is subject to several limitations. The analysis was limited to variables available at the start of the study period, so more recently added variables such as specific ventricular assist device and the presence of structural abnormalities could not be accounted for. There was also no information available on recipients’ declined donor hearts and whether these were used by adult heart transplant candidates. The age-mismatched patients had a higher priority status and were more likely to have risk factors for post-transplant mortality. Although donor and recipient characteristics were accounted for in the adjusted analysis, there may be some residual selection bias.
CONCLUSION
Our study focusing on adolescent heart transplant outcomes identified a significant association between increasing donor-recipient age-difference and the adjusted hazard of long-term mortality. Recipients of a heart from a donor aged greater than 11 years older were at increased risk of long-term mortality and this risk increased with increasing age-difference. These findings may help inform acceptable donor selection practice for adolescent patients undergoing heart transplantation.
Supplementary Material
ACKNOWLEDGEMENTS
This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Qiudong Chen is supported by a grant from the National Institutes of Health for advanced heart disease research (T32HL116273). Jason Thomas is supported in part by the Office of Scholarly Engagement, Harvard Medical School.
Abbreviations:
- UNOS
United Network for Organ Sharing
- ISHLT
International Society of Heart and Lung Transplantation
Footnotes
DISCLOSURE STATEMENT
Dr Emerson discloses Abiomed speakers bureau. All other authors have no relevant conflicts of interest to disclose.
Data statement
The data that support the findings of this study are available from United Network for Organ Sharing. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of United Network for Organ Sharing.
REFERENCES:
- 1.Zafar F, Castleberry C, Khan MS, et al. Pediatric heart transplant waiting list mortality in the era of ventricular assist devices. J Hear Lung Transplant. 2015;34(1):82–8. [DOI] [PubMed] [Google Scholar]
- 2.Colvin M, Smith JM, Ahn Y, et al. OPTN/SRTR 2019 Annual Data Report: Heart. Am J Transplant. 2021; Suppl 2:356–440. [DOI] [PubMed] [Google Scholar]
- 3.Davies RR, Bano M, Butts RJ, Jaquiss RDB, Kirk R. Donor organ turn-downs and outcomes after listing for pediatric heart transplant. J Heart Lung Transplant. 2019;38(3):241–251. [DOI] [PubMed] [Google Scholar]
- 4.Hess NR, Seese LM, Sultan I, Wang Y, Thoma F, Kilic A. Impact of center donor acceptance patterns on utilization of extended-criteria donors and outcomes. J Card Surg. 2021;36(11):4015–4023. [DOI] [PubMed] [Google Scholar]
- 5.Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:1037–1046. [DOI] [PubMed] [Google Scholar]
- 6.Westbrook TC, Morales DLS, Khan MS, et al. Interaction of older donor age and survival after weight-matched pediatric heart transplantation. J Hear Lung Transplant. 2017;36(5):554–558. [DOI] [PubMed] [Google Scholar]
- 7.Kirk R, Dipchand AI, Davies RR, et al. ISHLT consensus statement on donor organ acceptability and management in pediatric heart transplantation. J Heart Lung Transplant. 2020. Apr;39(4):331–341. [DOI] [PubMed] [Google Scholar]
- 8.Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant. 2019;38(10):1056–1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tang L, Du W, Delius RE, L’Ecuyer TJ, Zilberman MV. Low donor-to-recipient weight ratio does not negatively impact survival of pediatric heart transplant patients. Pediatr Transplant. 2010;14(6):741–745. [DOI] [PubMed] [Google Scholar]
- 10.Patel A, Bock MJ, Wollstein A, Nguyen K, Malerba S, Lytrivi ID. Donor-recipient height ratio and outcomes in pediatric heart transplantation. Pediatr Transplant. 2016;20(5):652–657. [DOI] [PubMed] [Google Scholar]
- 11.Singh TP, Colan SD, Gauvreau K. Matching Donor and Recipient Size in Pediatric Heart Transplantation. Transpl Int. Published online Feb 7, 2022. 10.3389/ti.2021.10039. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from United Network for Organ Sharing. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of United Network for Organ Sharing.