Outcomes of Combined Heart-Kidney Transplantation in Older Recipients

Objectives The upper limit of recipient age for combined heart-kidney transplantation (HKT) remains controversial. This study evaluated the outcomes of HKT in patients aged ≥65 years. Methods The United Network of Organ Sharing (UNOS) was used to identify patients undergoing HKT from 2005 to 2021. Patients were stratified by age at transplantation: <65 and ≥ 65 years. The primary outcome was one-year mortality. Secondary outcomes included 90-day and 5-year mortality, postoperative new-onset dialysis, postoperative stroke, acute rejection prior to discharge, and rejection within one-year of HKT. Survival was compared using Kaplan–Meier analysis, and risk adjustment for mortality was performed using Cox proportional hazards modeling. Results HKT in recipients aged ≥65 significantly increased from 5.6% of all recipients in 2005 to 23.7% in 2021 (p=0.002). Of 2,022 HKT patients in the study period, 372 (18.40%) were aged ≥65. Older recipients were more likely to be male and white, and fewer required dialysis prior to HKT. There were no differences between cohorts in unadjusted 90-day, 1-year, or 5-year survival in Kaplan–Meier analysis. These findings persisted after risk-adjustment, with an adjusted hazard for one-year mortality for age ≥65 of 0.91 (95% CI (0.63–1.29), p=0.572). As a continuous variable, increasing age was not associated with one-year mortality (HR 1.01 (95% CI (1.00–1.02), p=0.236) per year). Patients aged ≥65 more frequently required new-onset dialysis prior to discharge (11.56% vs. 7.82%, p=0.051). Stroke and rejection rates were comparable. Conclusion Combined HKT is increasing in older recipients, and advanced age ≥65 should not preclude HKT.


Introduction
Rates of combined heart-kidney transplantations (HKTs) have increased dramatically over the last decade and at a higher rate than isolated heart transplantation (HT) [1][2][3]. Tis increase has been driven in part by coexisting renal disease among heart transplant recipients, which has demonstrated a negative impact on survival following isolated HT [3][4][5][6][7][8][9][10][11]. In addition, recent studies have confrmed the survival beneft of HKT in patients with coexisting heart and renal failure. Importantly, the demand for donor hearts continues to prolong waitlist times for isolated HT and increase the number of patients using mechanical circulatory support, increasing the likelihood of secondorgan failure [2,[12][13][14][15]. Kidney dysfunction afects the majority of patients awaiting HT, and severe dysfunction may not be reversible after isolated HT, necessitating consideration of HKT in these patients [2,14].
Advanced age is associated with worse posttransplant survival in isolated heart and isolated kidney transplants, but the relationship between age and post-HKT survival has not been elucidated [5]. However, due to the lack of clear selection criteria, many centers consider advanced age 65 years and older as a contraindication for combined heart-kidney transplantation. Tere are limited data regarding outcomes among older patients who undergo HKT. Te aim of this study was to evaluate trends and outcomes of HKT in patients aged 65 years or older compared to younger patients.

Study Design. Te United Network for Organ Sharing
(UNOS) is a database that records all solid organ transplantations performed in the United States. Te UNOS database was queried for all HKTs performed between January 1, 2005, and June 1, 2021. Only patients over 18 years of age were included in the analysis. Tis study was deemed exempt from review by the Medical University of South Carolina Institutional Review Board.
Patients were grouped by age, either <65 years or ≥65 years at the time of transplantation. Baseline characteristics of recipients, donors, and recipient-donor matching were compared between the two age groups. Te primary outcome was one-year mortality after HKT. Secondary outcomes included 90-day and 5-year mortality, postoperative new-onset dialysis, postoperative stroke, acute rejection prior to discharge, and rejection within one-year of HKT.

Statistical Analysis.
Categorical variables are summarized using counts and percentages. Pearson's chi-square tests were used to compare categorical variables, and Fisher's exact tests were used if the frequency of any variable was <5. All continuous variables were nonparametrically distributed and are presented as medians and interquartile ranges. Continuous variables were compared using Kruskal-Wallis tests.
Te Kaplan-Meier analysis was utilized to model 1-year survival, which was compared using log-rank tests and Wilcoxon-Breslow-Gehan tests. Multivariable Cox proportional hazards modeling was utilized to calculate the riskadjusted hazard for recipient age on 1-year mortality after HKT. Covariates associated with 1-year mortality on univariable analysis with p < 0.20 were included in the fnal multivariable model as well as those retained after backward stepwise selection with p < 0.05. Te threshold for statistical signifcance was two-sided p < 0.05. Analyses were performed using Stata, version 16.1 (StataCorp, TX, USA).

Patient Cohort.
In the observed study period, 2,022 patients underwent HKT. Te median age of the study population was 57 years, with 372 (18.4%) aged greater than 65 years. Te age distribution of patients undergoing combined HKT is shown in Figure 1. Tere was a signifcant increase in the annual frequency of HKT in recipients aged 65 years and older from 5.6% of all HKT recipients in 2005 to 23.7% of all recipients in 2021 (p � 0.002) ( Figure 2).

Baseline Characteristics of the Study Population.
Demographic characteristics for HKT recipients stratifed by age are summarized in Table 1

3.3.
Kaplan-Meier Survival after Heart-Kidney Transplantation. A Kaplan-Meier analysis of one-year survival after combined HKT stratifed by recipient age is shown in Figure 3. Te Kaplan-Meier analysis of 90-day and 5-year survival after combined HKT stratifed by recipient age is shown in Figure 4. Tere were no diferences between age groups in 90-day (92.0% in recipients aged <65 years vs. 91.7% in recipients aged ≥65 years, log-rank p � 0.889), 1-

One-Year
Survival following Heart-Kidney Transplantation. A multivariable Cox proportional hazards model for one-year mortality following combined HKT with age as a categorical variable is shown in Table 2. After risk adjustment, age ≥65 years was not associated with an increased risk for one-year mortality (HR 0.91, 95% CI, 0.63-1.29, p � 0.572). A multivariable Cox proportional hazards model for one-year mortality following combined HKT with age as a continuous variable is shown in Table 3. Increasing age was not associated with an increased risk for one-year mortality after HKT (HR 1.01 per year, 95% CI 1.00-1.02, p � 0.236). Increasing body mass index (BMI), increasing serum creatinine and bilirubin at time of HKT, mechanical ventilation prior to HKT, increasing heart ischemic time, and increasing donor age were found to independently predict one-year mortality after HKT.

Secondary Outcomes after Heart-Kidney Transplantation.
Secondary outcomes after combined HKT stratifed by age are shown in Table 4. Patients aged ≥65 years had higher rates of new-onset dialysis after HKT prior to discharge, though this relationship was not signifcant (11.56% vs. 7.82%, p � 0.051). Tere were no signifcant diferences in rates of stroke prior to discharge, rejection prior to discharge, and rejection treated within one-year posttransplant between age groups.

Discussion
Currently, there are few clearly defned recipient criteria for combined HKT and little data to suggest which recipients may beneft most from HKT compared to isolated HT [3,4].     Previous studies have explored the impacts of comorbidities, age, and other recipient characteristics on survival post-HKT in an attempt to generate guidelines for dual organ allocation [5,6,13,16,17]. Advanced age in particular is a well-described independent risk factor for early and late mortality after isolated HT, although its efect on HKT is less defned. Early outcomes, including 1-year survival, freedom from rejection at 1-year, and absence of major adverse cardiac events in HKT recipients aged ≥65 years, have been shown to be similar to outcomes of isolated HT in this patient group [5]. In addition, analyses of longer term outcomes found that 5-year and 15-year survival after HKT among patients aged ≥60 years was comparable to younger patients [6,13,16]. Other factors studied include a threshold eGFR to recommend combined HKT versus isolated HT, with the conclusion that HKT should be recommended in patients with an eGFR <37 mL/minute as it improves posttransplant survival in this group as compared with isolated HT [1]. LVAD implantation has been shown to transiently improve eGFR in patients awaiting heart transplantation, but this efect is temporary and has no impact on survival [18]. Terefore, HKT ofers a survival beneft to select patients with cardiorenal disease, which may extend to those of advanced age if selected appropriately. Peripheral vascular disease, recipient age >65 years, nonischemic heart failure, dialysis at the time of HKT, and mechanical circulatory support have previously been identifed as factors associated with reduced survival following HKT [17]. Te fndings presented in this analysis demonstrate similar early posttransplant outcomes among recipients aged ≥65 years compared to their younger counterparts. Tese fndings corroborate previous research that shows the lack of an adverse impact of advanced age on HKT outcomes. While one study by Reich et al. found that recipient age greater than 65 was associated with worse survival, the majority of previous studies found no diference in survival following HKT based on recipient age [5,6,13,16,17]. Te similar survival rates between younger and older patients in these studies may be attributed to several factors. In a recent analysis by Punnoose et al., recipient selection appeared to mitigate any potential negative impact of advanced age on post-HKT survival [16]. Older patients had fewer severe comorbidities than younger patients but higher incidences of ischemic cardiomyopathy, and younger patients more frequently had risk factors such as smoking, dialysis dependence prior to transplant, mechanical circulatory support prior to transplant, and increased pulmonary artery pressure [16]. Tese diferences illustrate the importance of comorbidities in predicting HKT outcomes rather than age alone. Another contributing factor to the similar overall outcomes of older patients could be related to the rates of graft rejection. Several studies have previously shown that older heart transplant recipients have lower rates of rejection and associated complications than younger recipients due to aging-related deterioration of the natural immune response [19,20]. Aging has been associated with fewer alloreactive T cells and an increased susceptibility to immunosuppressive agents, producing a reduced rejection rate [20]. Tis study found that advanced recipient  age was not associated with a similar incidence of rejection compared to age <65 years. Currently, there is a lack of guidelines regarding an upper limit of recipient age for HKTand minimal literature regarding this subject. Te fndings of the present study are consistent with the available literature on this matter, which recommend an individualized approach to HKT patient selection rather than a defned age cut-of [5]. Reich et al. recommended evaluation of factors, such as BMI, diabetic glycemic control, severe cerebral or peripheral vascular disease, frailty, social support, and severe cognitive-behavioral disabilities [5]. Additionally, Schafer et al. described dialysis dependence in patients awaiting HT as an indication for HKT as opposed to isolated HT [15]. Given the fndings of the present study that mechanical ventilation prior to HKT, increasing heart ischemic time, and increasing donor age independently predict 1-year mortality post HKT; these factors should also be considered in recipient evaluation and donor selection.
Limitations of this study include selection bias as recipients aged 65 years or older were more likely to be of male sex, white race, and have lower creatinine, representing favorable risk characteristics at baseline. Following risk-adjustment, however, recipient age had no impact on increased risk for one-year mortality when modeled as a continuous or categorical variable. In addition, this analysis considered posttransplant complications only occurring before discharge and rejection occurring only within 1-year of transplant. Complications occurring after 1-year posttransplant are not captured by this analysis as these data are not widely available in the UNOS registry. Terefore, diferences in longitudinal outcomes other than mortality between age groups are not analyzed here. Furthermore, registry data do not capture center-level practice diferences between programs performing HKT. It is possible that only high volume, experienced centers are performing HKT in older patients, leading to improved outcomes and further contributing to selection bias. Lastly, the registry does not contain granular information on patient-specifc factors such as perioperative care and postoperative transplant management that could impact survival.
Tis analysis of the UNOS registry determined that advanced age ≥65 is not predictive of mortality after HKT. Data collected from this cohort indicate that recipient aged ≥65 years is associated with similar one-and fve-year survival following HKT as compared with younger recipients. While comorbidities and other factors that are more common in older age may lead to negative outcomes, advanced age alone should not be used as an excluding variable for HKT candidacy.

Data Availability
Te data that support the fndings of this study are available on request to the United Network of Organ Sharing (UNOS) database.