Age-specific impact of different immunosuppressive regimens on kidney transplant outcomes: clinical evidence from the scientific registry of transplant recipients

What was known

• Older kidney transplant recipients have increased susceptibility to infections, malignancies, and metabolic complications related to immunosuppression, but are underrepresented in clinical trials.
• Evidence comparing long-term outcomes of different immunosuppressive regimens in older recipients is limited and inconsistent.

This study adds

• In recipients ≥65 years, cumulative incidence of mortality was higher in patients on mTORi-MMF and CsA-MMF compared to Tac-MMF. In contrast, no increased mortality was observed in patients on Tac-mTORi compared to Tac-MMF.
• Tac–mTORi regimen showed comparable cumulative incidence of graft loss, acute rejection rate and trajectory of mean eGFR when compared to standard Tac–MMF regimen in older recipients.

Potential impact

• These findings support individualized immunosuppressive strategies for older kidney transplant recipients rather than uniform treatment approaches.
• Tac-mTORi regimen might represent an alternative to Tac-MMF in selected older patients balancing efficacy and tolerability.

Introduction

Kidney transplantation (KTx) is the most effective treatment to improve survival and quality of life in patients with end-stage renal disease (1, 2). In this context, the older patient population is becoming increasingly important, as the number of kidney transplant recipients (KTRs) being 65 years of age or older continues to grow in the United States (3). Older candidates face lower transplantation rates and higher waitlist attrition due to illness or mortality (4). Nevertheless, appropriately selected older transplant candidates may still achieve a significant survival benefit from KTx compared to remaining on dialysis (5, 6). Notably, the risk profile of older KTRs differs from younger cohorts. While immunosenescence results in lower acute rejection (AR) rates, older patients face a higher burden of comorbidities and susceptibility to immunosuppressive therapy–related side effects (7, 8). Furthermore, geriatric syndromes such as frailty have emerged as important prognostic factors, as they are associated with increased mortality and adverse outcomes after transplantation (9, 10). Consequently, assessing biological rather than chronological age is increasingly recommended for individualized recipient evaluation.

Immunosuppressive maintenance regimens for KTRs have evolved significantly, reducing rejection rates but introducing new challenges, particularly for older patients at higher risk for infections, malignancies, and diabetes. In this context, meticulous patient selection has become increasingly important (4). Older KTRs have an impaired immune function, a state also known as immunosenescence (11, 12). Since clinical trials for immunosuppressants traditionally focus on patients under 65 years of age (13), specific evaluations of graft lost risk in older patients are mostly lacking. An adaptation of immunosuppressive protocols according to the recipient’s age has rarely taken place (14). This leads to a gap in the scientific literature, making it difficult to determine the optimal treatment for older KTRs. Thus, the aim of this study was to evaluate whether recipient age (> 65 vs 18–65 years) is impacting the efficacy and safety profiles of different immunosuppressive maintenance regimens.

Materials and methods

Study population

This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donors, wait-listed candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. Our study included adult patients (age ≥ 18 years), who underwent their first KTx between January 1, 2010, and December 31, 2020. Patients were excluded if they had received multi-organ transplants and had received immunosuppressive regimens other than the protocols of interest (Figure 1).

Data collection

Baseline socio-demographic and clinical characteristics for both donors and recipients were recorded, including age at transplantation, sex, weight, BMI, and pre-existing comorbidities. Other variables collected were the number of human leukocyte antigen (HLA) mismatches, type of transplantation, induction and immunosuppressive maintenance regimens documented three months after KTx. Age was stratified in two groups (18–64 years and ≥ 65 years) based on the CDC (Centers for Disease Control and Prevention) classification of older adults (15). Immunosuppressive regimens were categorized into four groups: 1) Tac-MMF, 2) Tac-mTORi, 3) CsA-MMF and 4) mTORi-MMF. The analysis was restricted to these four dominant regimens to accurately reflect clinical practices during the study period. These regimens directly reflect international standard-of-care guidelines (16). Specifically, the KDIGO Clinical Practice Guidelines for the Care of Kidney Transplant Recipients recommend a calcineurin inhibitor (CNI; preferably Tacrolimus or CsA) as first-line therapy, combined with an antiproliferative agent (preferring Mycophenolate). KDIGO also recognizes mTOR inhibitors as important, tailored alternatives within maintenance strategies (17–19).

Endpoint definition

The primary outcome was the cumulative incidence of overall survival (OS), defined as death for any cause. Patients alive or lost to follow-up were right censored at the time of the last registered contact. The maximum follow-up was 10 years. Secondary outcomes included cumulative incidence of cause-specific mortality, graft loss (GL), 1-year acute rejection (AR) and kidney function. Kidney function was calculated using the estimated glomerular filtration rate (eGFR) calculated with the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation without race adjustment (20).

Statistical analysis

Baseline recipient and donor characteristics were analyzed using descriptive statistics. Nominal variables were summarized using absolute counts and percentages. Continuous variables were reported as mean ± standard deviation (SD) or median (interquartile range). Data distribution was evaluated by investigating kurtosis, skewness, as Q-Q plots, and histograms.

The statistical analyses were conducted utilizing a landmark cohort design. For the primary endpoint OS, Kaplan-Meier methods were used to estimate post-transplant survival probabilities. Proportional Cox regression models were applied to evaluate the association between age and immunosuppressive regimens on the outcome OS. Exposure variable selection was based on clinical reasoning (1, 5, 21–25) and supported by two approaches: univariate analysis and Survival Random Forest model (26–28) (Supplementary Figure 1). These selected covariable were subsequently included in the final multivariable Cox regression model. To evaluate whether age modified the effect of immunosuppressive maintenance regimens on the outcomes, an interaction term between age and immunosuppressive regimens was included. Where a significant interaction was detected, subgroup analyses were performed and reported with corresponding p-values; in the absence of significant interaction, only the effect sizes for the subgroups were reported. For all comparative analyses, Tac-MMF group was designated as the reference group, against which the other three regimens (Tac-mTORi, CsA-MMF, and mTORi-MMF) were compared.

The Aalen-Johansen estimator was used to calculate the cumulative incidence of the secondary endpoint GL. Sub-distribution Cox Proportional-Hazard models of Fine and Gray were used to assess association between GL across age and immunosuppressive regimens. Death was considered as competing risk. The Schoenfeld test and the goodness of fit test based on the cumulative sum of residuals (29) were used to assess the proportionality assumption required for Cox proportional and Subdistribution hazard modeling.

1-year AR was described using absolute frequencies and percentages. Binary logistic regression was performed to compare age and immunosuppressive regimens; odds ratios (OR) and two-sided 95% CI were calculated. The goodness of fit of the model was evaluated using the Hosmer-Lemeshow test. The effect of age and immunosuppressive regimen on the eGFR slope was analyzed by fitting a linear mixed model with random intercepts for each participant over time. The model included fixed effects for treatment, age and the interactions term of treatment with time.

Statistical significance was assumed for two-sided values of 0.05 or less. All statistical analyses were performed using R version 4.1.0 and SPSS for Windows version 28 (IBM).

Results

Demographics

Out of the 486, 697 recipients recorded in the SRTR database between 2010 and 2020, a total of 112, 952 (43.1%) were included in the final analysis (Figure 1). Mean age at the time of KTx was 52.2 years (SD ±13.8), with 89, 578 patients aged 18–64 years and 23, 374 patients aged ≥ 65 years. Patients´ characteristics stratified according to the respective age categories are shown in Table 1. When compared to the younger group, older patients (>65 years) had a higher prevalence of angina, diabetes and malignancies. The maintenance immunosuppressive regimens used three months after KTx were n = 110, 866 (98.2%) Tac-MMF, n = 500 (0.4%) Tac-mTORi, n = 1, 241 (1.1%) CsA-MMF, and n = 345 (0.3%) mTORi-MMF. A total of 75, 155 (66.5%) patients received steroid maintenance regimen, with no difference between age groups.

Table 1. Baseline characteristics stratified by age.

SMD, Standardized mean differences.

Overall survival

During a median follow-up of 3.67 years (95% CI: 3.61 to 3.72), a total of 12, 356 KTRs died. The OS was 95.6%, 93.7% and 87.6% at, 2-, 3- and 5-years post-transplant respectively (Figures 2a, b). The lowest OS was observed among KTRs age ≥65 years who received CsA-MMF and mTORi-MMF (see Supplementary Table). Results of the univariate analyses are shown in Supplementary Table 2. In multivariable analysis, patients receiving mTORi-MMF tended to a higher risk of all-cause mortality (aHR 1.46 95% CI 0.93 – 2.29 p-value = 0.099) compared with those receiving Tac-MMF. By contrast, the Tac-mTORi group was not associated with an increased risk of death (aHR 0.74, p-value 0.205) (Table 2). The effect of immunosuppressive regimens on OS was consistent across age subgroups, with no significant interaction per subgroup (p-value_interaction Tac-mTORi: 0.166, CsA-MMF: 0.658 and mTORi-MMF: 0.197). Figure 2c shows the subgroup analysis, indicating that the Tac-mTORi and Tac-MMF regimens were associated with comparable OS.

Table 2. Multivariable analysis of the endpoint all-cause of death, proportional hazard ratio model (n = 111, 570).

Multivariate model was adjusted for baseline recipient characteristics, including gender, BMI, pre-transplant dialysis status, pre-existing diabetes. Donor related variables including donor age and donor type (living, standard criteria deceased and expanded criteria deceased); and transplant-specific variables included: cold ischemia time, number of HLA mismatches, induction therapy and steroid maintenance therapy.

Cause-specific death

Hazard ratios for cause-specific death are presented in Table 3. Treatment with Tac-mTORi was not associated with an increased risk of cause-specific mortality compared with Tac-MMF. In contrast, KTRs receiving mTORi-MMF demonstrated a higher risk of death from infection (HR 2.64, p value <0.001). Subgroup analyses confirmed that this association was consistent across prespecified age groups (Figure 3).

Table 3. Proportional hazard ratio model of cause specific death (n = 111, 750).

Multivariate model was adjusted for baseline recipient characteristics, including gender, BMI, pre-transplant dialysis status, pre-existing diabetes. Donor related variables including donor age and donor type (living, standard criteria deceased and expanded criteria deceased); and transplant-specific variables included: cold ischemia time, number of HLA mismatches, induction therapy and steroid maintenance therapy.

Graft loss

GL was observed in 8, 654 out of 112, 952 patients, while 10, 080 patients died with a functioning graft. Cumulative incidences of death censored GL are show in Figures 4a, b. Supplementary Table 3, Supplementary Figure 2 show the cumulative incidence of GL and death with functioning graft across therapies and age groups. GL rates varied strongly between the different therapies and age categories, being highest in the older mTORi-MMF group. Two-year cumulative incidence of GL in patients ≥ 65 years was lowest with 1.0% in patients with Tac-mTORi and increased to 4.1% in patient with Tac-MMF and up to 8.4% in patients receiving mTORi-MMF (Supplementary Table 3).

In the multivariable subdistribution hazard ratio (sHR) analysis, the risk of graft loss (GL) was significantly higher in patients receiving CsA-MMF (sHR 1.65, 95% CI 1.42 – 1.92) and mTORi-MMF (sHR 2.11 95% CI 1.57 – 2.84) compared to patients with Tac-MMF (Table 4). By contrast, no significant difference in the risk of GL was observed for KTRs treated with Tac-mTORi (sHR 1.04 95% CI 0.77 – 1.41 p-value = 0.780). This association remained consistent by age groups (p-value_interaction CsA-MMF: 0.430, Tac-mTORi: 0.290 and mTORi-MMF: 0.670). The effect of the immunosuppressive regimens on GL was further evaluated across the two age groups. Here age did not appear to modify the effect of immunosuppressive regimen on GL (Figure 4c).

Table 4. Subdistribution hazard ratio model (Fine and Gray) of graft loss, death is considered as competing risk (n = 111, 570).

Multivariate model was adjusted for baseline recipient characteristics, including gender, BMI, pre-transplant dialysis status, pre-existing diabetes. Donor related variables including donor age and donor type (living, standard criteria deceased and expanded criteria deceased); and transplant-specific variables included: cold ischemia time, number of HLA mismatches, induction therapy and steroid maintenance therapy.

Acute rejection during the first year after KTx

Episodes of 1-year AR occurred in 7.7% of the total study cohort (8, 062/104, 788). Supplementary Table 4 and Figure 5a show the percentages of 1-year AR episodes stratified by immunosuppressive regimens and age categories. Here, mTORi-MMF was associated with highest incidences of acute rejection across both age categories, reaching the highest value in patients younger than 65 years (16.9%). By contrast, the lowest incidence of 1-year AR was observed in young patients when treated with Tac-MMF and in the older cohort upon treatment with Tac-mTORi. Multivariable binary logistic regression model was performed to assess the association between age, immunosuppressive regimens, and the risk of 1-year AR. KTRs of 18–64 years had a higher likelihood of rejection (OR 1.21 95% CI 1.13 – 1.28). Treatment with mTORi-MMF was associated with an increased risk of AR (OR: 2.39 95% CI 1.18 – 4.40), whereas Tac-mTORi was not significantly different from Tac-MMF (OR: 1.31 95% CI 0.58 – 2.55). Interaction terms between age and therapy were not statistically significant, suggesting that the effect of immunosuppressive regimens on AR episodes did not differ across age groups (Table 5). The effect of the immunosuppressive regimens on the endpoint 1-year AR was further evaluated across the two age groups. Here, age did not impact the effect of immunosuppressive regimens on 1-year AR (Figure 5b).

Table 5. Binary logistic regression model of acute rejection (n = 103, 668).

Multivariate model was adjusted for baseline recipient characteristics, including gender, BMI, pre-transplant dialysis status, pre-existing diabetes. Donor related variables including donor age and donor type (living, standard criteria deceased and expanded criteria deceased); and transplant-specific variables included: cold ischemia time, number of HLA mismatches, induction therapy and steroid maintenance therapy.

Kidney function

Figure 6 and Supplementary Table 5 present the trajectory of mean estimated glomerular filtration rate (eGFR) over the first five years after KTx, stratified by age group and immunosuppressive maintenance regimen. Among KTRs of 18–64 years, initial kidney function one month after KTx was significantly reduced in the mTORi-MMF group compared with Tac-MMF, with an estimated effect size of β = –7.719 [mean eGFR = 75.36], p-value < 0.001). A similar pattern was observed among older KTRs (≥65 years), where baseline eGFR was also lowest in the mTORi-MMF group (β = –9.985, [mean eGFR = 67.67, p-value < 0.001) (Table 6). No differences were observed in patients older than 65 years receiving Tac-mTORi or CsA-MMF.

Table 6. Linear mixed model of changes of mean eGFR over time (in years).

Adjusted for BMI, type of donor, induction therapy, steroid maintenance therapy, cold ischemic time and HLA mismatches.

Longitudinal trajectories of eGFR revealed age-specific differences. In the younger cohort (18–64 years), the mean annual decline in eGFR for patients receiving the Tac-MMF regimen was –0.234 mL/min/1.73 m² per year, representing the slowest rate of decline in this age group. In contrast, patients treated with other regimens exhibited significantly greater annual reductions: CsA-MMF (β = –0.674), Tac-mTORi (β = –0.971), and mTORi-MMF (β = –1.045). In the older cohort (≥65 years), a different pattern was observed. The mean annual decline in eGFR among patients treated with Tac-MMF was –0.309 mL/min/1.73 m² per year, broadly comparable to the trajectory seen in younger KTRs. However, in contrast to the younger cohort, no significant additional decline was observed in patients treated with either Tac-mTORi (β = 0.087) or mTORi-MMF (β = 0.191) (Figure 6).

Discussion

Although the number of KTRs being 65 years of age or older is steadily increasing in parallel with demographic changes in the general population (30, 31), we are still facing a substantial gap of knowledge on how different immunosuppressive regimens impact the clinical outcome after kidney transplantation in an age-specific fashion. To address this question, our study evaluated the age-stratified impact of different maintenance immunosuppressive regimens on post-transplant clinical outcomes. Our findings indicate that a Tac – mTORi based maintenance regimen may provide comparable therapeutic efficacy to Tac – MMF in terms of 1-year acute rejection, graft loss and overall survival, with no significant differences observed between patients aged 18–64 and those ≥ 65 years. These findings support the conclusion of Sanders et al. (32),, suggesting that both regimens may be effective options for older KTRs.

In detail, our analysis revealed a higher prevalence of angina, diabetes, and prior malignancy among older KTRs, consistent with previous literature (33, 34). Furthermore, the older cohort exhibited a significantly higher risk of mortality due to infection, cardiovascular disease and malignancies. Despite these elevated risks, our findings confirm that Tac-MMF remains the gold standard regimen across both age cohorts, utilized in 98.2% of all patients in this study. This high utilization rate of Tac - MMF indicates that older KTRs are exposed to potent immunosuppressive regimens, despite being more susceptible to drug associated complications like infections and malignances due to age related immune dysfunction (22). This observation is consistent with a previous study that analyzed integrated Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) records with Medicare billing claims (22). Here, the authors found a shift towards Tac-based regimens in both younger and older KTRs while the utilization of CsA- and mTORi-based regimens decreased over the analyzed period (Supplementary Table 3).

The OS in our cohort was 95.6% and 87.6% at 1- and 5-years, respectively, aligning with previous reports (8, 33). Among the other maintenance regimen evaluated, the highest 5-year cumulative incidence of death was observed in the CsA-MMF and mTORi-MMF groups across both age categories. This finding is consistent with previous studies reporting an increased risk of mortality among KTRs receiving CsA- and mTORi-based therapy (21, 22, 35).

Cause-specific analysis revealed a significantly higher risk of infectious death among older KTRs. Applying standard immunosuppressive regimens to this cohort may increase the risk of over-immunosuppression, contributing to death with a functioning graft (36–39). Furthermore, older KTRs are at a higher risk of developing cardiovascular events, including myocardial infarction, stroke, and heart failure (40). Since immunosuppressive regimens can exacerbate these risks by impairing the regulation of inflammation and oxidative stress, key drivers of vascular disease (41), the implementation of more individualized, tailored immunosuppressive strategies will be crucial for this particularly vulnerable population.

Given that immunosenescence decreases the overall risk of AR in older graft recipients (11), we found at slightly reduced 1-year AR rates in older KTRs when comparing to younger KTRs receiving the same immunosuppressive regimen. These findings are in line with a previous registry analysis (23), which demonstrated lower rejection rates in older KTRs (14% in ≥ 70 years vs. 28% in 18–29 years) under comparable immunosuppression. Notably, the Tac-mTORi combination showed AR rates similar to Tac-MMF, which is also supported by previous reports (42, 43). This finding might open the door for safe CNI-sparing to avoid nephrotoxicity in combination with mTORi.

Previous studies suggested that the lower rejection rates and higher infectious mortality in older patients stem from age-associated immune changes rather than differences in drug metabolism (44). Experimental research has shown that the diminished alloresponse in the elderly is linked to attenuated effector CD4+ T-cell activation, an increased pool of memory T cells, and preserved function of regulatory T cells, suggesting that immune aging modulates the balance between activation and tolerance (38). Moreover, age-related pharmacokinetic alterations, including reduced hepatic first-pass metabolism and altered drug clearance, may increase systemic exposure to immunosuppressive agents (45). These factors underline the importance of individualized dosing and close therapeutic drug monitoring in older KTRs. Similar to a recent study (33) which reported that intensified immunosuppressive regimens are associated with increased infection-related mortality in elderly KTRs, our results provide further evidence that standard immunosuppressive strategies may not be universally applicable to this subgroup. Collectively, these findings advocate for a precision-medicine approach, integrating biological age, frailty status, and pharmacokinetic variability into protocol selection.

Regarding kidney graft function, patients receiving mTORi-MMF presented the lowest mean eGFR at baseline after transplantation and throughout the follow-up period. These findings likely reflect intended CNI avoidance in grafts with poor initial function; however, consistent with previous studies, this group also exhibited a higher risk of AR (46). Longitudinal analysis revealed distinct age-specific eGFR trends: while Tac-MMF provided the most stable kidney function in younger KTRs, a different pattern emerged in the older cohort. Notably, older patients treated with Tac-mTORi showed no significant additional eGFR reduction over time. These results may be suggestive that mTORi-based regimens may offer an individual alternative to Tac-MMF in selected older patients balancing efficacy and tolerability.

The primary strength of our study is based on the utilization of the Scientific Registry of Transplant Recipients (SRTR), a national database that provided a large and diverse cohort of transplant recipients. These data allowed us to evaluate also less common immunosuppressive regimens, such as the tacrolimus–mTORi combination, which are often underrepresented in clinical trials. Furthermore, our study employed a robust variable selection process, incorporating traditional literature-based predictors (1, 5, 21–25) and Random Forest algorithms to identify and control relevant covariates. By specifically focusing on recipients aged ≥ 65 years, we addressed a critical gap in the literature regarding individualized immunosuppression in a rapidly growing and vulnerable patient population.

Despite these strengths, several limitations warrant careful consideration. First, as a retrospective registry analysis, this study is subject to inherent selection and confounding bias. The distribution of regimens was highly imbalanced; specifically, the mTORi-MMF group was significantly smaller than the Tac-MMF group. It is probable that patients in the mTORi-based groups represented a highly selected subgroup, which might have influenced the clinician’s choice of regimen. While we attempted to mitigate this by adjusting for baseline variables selected via literature evidence, univariate analysis, and Random Forest modeling, the SRTR lacks clinical data on frailty, cognitive status, and the specific clinical rationale behind regimen selection. Second, because this study relies on registry data, other clinical parameters were unavailable, including drug-specific side effects, toxicities, and medication adherence related to the immunosuppressive maintenance regimens. Third, the immunosuppressive regimen was defined solely at the therapy received three months after transplantation. Our analysis did not account for therapy “crossover” or modifications during follow-up, which may lead to exposure misclassification. Fourth, although we aimed to identify age-specific effects, the interaction analyses between age and treatment regimens did not reach statistical significance for several primary outcomes. Therefore, the differences observed between immunosuppressive regimens in older KTRs should be interpreted as explorative rather than definitive.

In conclusion, our analysis showed several critical implications of both mTORi- and CNI-based immunosuppressive protocols in older KTRs. As older patients develop immunosenescence, they usually require less aggressive immunosuppression while at the same time being vulnerable to severe adverse effects of immunosuppression including opportunistic infections, malignancies and metabolic toxicities. This is reflected in our results since the older cohort exhibited higher mortality due to infection, cardiovascular disease and malignancy when compared to recipients < 65 years. On the other hand, our findings demonstrated that Tac-mTORi and Tac-MMF regimens exhibited no significant differences when comparing clinical outcomes in both age groups. Therefore, the Tac–mTORi combination may represent an alternative, CNI-sparing strategy in selected older kidney graft recipients. Taken together, our study emphasizes the need for individualized immunosuppressive regimens in older KTRs to optimize clinical outcomes while minimizing the risk of adverse events at the same time calling for further prospective studies.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneph.2026.1886887/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: Tiago Sampaio, Federal University of Ceara, Brazil

Reviewed by: Alessandro Cesare Rosa, Regional Health Service of Lazio, Italy

Hina Khalid, Shandong University of Technology, China