The increase in patients with end-stage renal disease (ESRD) has primarily occurred in the elderly population. In 1985, 36% of the ESRD population was over 65 years of age. By 2009, the proportion had increased up to 48% according to United States Renal Disease System data [1]. In Korea, the number of people waiting for kidney transplantation (KT) has increased in the elderly population, and the number of people who have undergone KT has also increased. The proportion of patients over 60 years of age who underwent KT in 2006 was only 4.4%. However, it had increased to 21.9% in 2019 [2]. Elderly recipients are associated with a higher comorbidity. However, advanced age itself is not a contraindication of KT [3]. Previous studies have shown KT significantly reduces mortality compared to dialysis in a waiting-list elderly population with ESRD [3,4]. The elderly recipients have improved their quality of life after KT [5].

Aging affects all aspects of adaptive and innate immunities [6]. Immunosenescence gradually deteriorates the function of immune system, making the elderly susceptible to infection and malignancy, and eventually contributes to morbidity and mortality [7–9]. Hemmersbach-Miller et al. [10] reported that elderly recipients have a higher incidence of urinary tract infection (UTI) and more cytomegalovirus (CMV) reactivation, which usually occurs within 1 year after KT. Furthermore, Lim et al. [11] reported a significantly higher mortality rate from infection in elderly recipients compared to younger recipients. Modifications of T-cell function are the result of immunologic changes with aging and are a factor that reduces acute rejection in elderly recipients [8]. As such, the consequences of immunosenescence have a wide range of effects on organ transplants, and age-adaptive immunosuppression may be required in elderly recipients [12]. In previous studies, the comparison of induction agents has mainly focused on elderly patients. There have been reports suggesting that patient survival is worse when rabbit anti-thymocyte globulin (r-ATG) is used at a dose higher than 6 mg/kg [13]. Additionally, compared to a dose of 2.5 mg/kg, similar rejection rates were observed, but there was a higher incidence of infections [14]. Moreover, previous studies reported that using r-ATG at a dose higher than 4.5 mg/kg leads to a higher risk of infection compared to basiliximab (BSX) [15,16].

In this study, we evaluated the clinical outcomes, including rejection and infection rate when using BSX and r-ATG as induction agents, in elderly and young recipients with the same maintenance immunosuppressive agents.

This retrospective study was approved by the Institutional Review Board of Samsung Medical Center (No. 2020-12-045), and the need for informed consent was waived.

In this study, we observed similar occurrences of BPAR and most infections, except CMV antigenemia and UTI, within 6 months between the younger and older recipient groups when BSX was used as an induction agent. However, when r-ATG was used as an induction agent, BPAR within 6 months occurred less frequently in older recipients, while all infections within 6 months as well as deaths due to infection were more common in older recipients. In the older recipient group, BPAR within 6 months occurred less frequently, but CMV antigenemia within 6 months was more frequent when r-ATG was used as an induction agent compared to BSX. Furthermore, despite the older recipient receiving kidneys of poorer quality, there was no significant difference in death-censored graft survival compared to the younger recipient group. In multivariate analysis, recipient age equal to or over 60 years and the use of r-ATG as an induction agent were risk factors for viral infections such as CMV and BK virus within 6 months.

Worldwide, it is estimated that approximately 40% of patients with ESRD are 65 years of age or older, a proportion that is steadily increasing [18]. Previous studies have shown that for these elderly patients, undergoing KT could improve patient survival compared to remaining on the waiting list [19]. However, it should be noted that for elderly patients, the risk of mortality may be higher up to 1.8 years post-KT compared to remaining on dialysis [4]. Therefore, potential candidates for KT should be carefully evaluated considering comorbidities, frailty, and physical and cognitive function [19]. In addition, even in elderly patients undergoing KT, it is necessary to consider the modifications of induction agents due to alterations in the immune system caused by immunosenescence. Previous studies have reported an increased rate of infection and malignancy when using r-ATG as an induction agent in elderly recipients, compared to BSX [16,20]. In contrast, Goumard et al. [21] observed a higher incidence of BPAR when using BSX as an induction agent in sensitized elderly recipients.

Previous studies showed that the incidence of acute rejection decreased as the age of the recipient increased [22–24]. This reduction in acute rejection is directly related to age-related immune dysfunction as a part of immunosenescence [8]. The sensitization ability of the innate immune system as well as the response by the adaptive immune system are reduced with aging [12]. In contrast, old donors are reported to show increased acute rejection rates due to increased immunogenicity [12,25]. Rana et al. [24] reported that recipient age was a robust factor for acute rejection within 1 year regardless of the type of induction agent. Similarly, in our study, the incidence of BPAR within 6 months was lower in older recipients than in younger recipients. In addition, the incidence of BPAR within 6 months was less in the older group than the younger group when r-ATG was used as an induction agent. However, there was no difference in the incidence of BPAR within 6 months between the younger and older groups when BSX was used as an induction agent (Table 2). In multivariate analysis, young age and the use of BSX as an induction agent were risk factors for BPAR within 6 months (Supplementary Table 2, available online). In contrast, rejection-free graft survival was similar in the long-term between older and younger recipients regardless of the type of induction agent (Fig. 2B). Dreyer and de Fijter [18] reported that HLA class II mismatch influenced the formation of de novo DSA, leading to an increase in BPAR. Similarly, our results showed that HLA class II mismatch was an independent risk factor for BPAR within 6 months (Supplementary Table 2, available online).

In contrast to acute rejection, the incidence of infection increased as the age of the recipient increased [8,26]. In addition, the relative risk of death due to infection was considerably affected as the age of the recipient increased [22]. Dharnidharka et al. [27] reported that bacterial infection increases with age of the recipient, whereas viral infection decreases with age of the recipient. However, Pham et al. [16] reported that the incidence of viral infection as well as bacterial infection was higher in patients over 65 years of age within 1 year after KT. Hemmersbach-Miller et al. [10] reported that the incidence of UTI and CMV were significantly higher in older recipients within 1 year after KT, but the incidence of pneumonia and BSI did not differ according to age. In our study, bacterial, viral, and fungal infections were all higher in the older recipient group within 6 months after KT. However, the incidence of all infections was higher in older recipients when r-ATG was used as an induction agent, but only the incidences of CMV and UTI were higher in older recipients when BSX was used as an induction agent. In addition, patient death due to infection did not differ according to age when BSX was used as an induction agent, but it occurred more frequently in older recipients when r-ATG was used as an induction agent (Table 2). In multivariate analysis, old age and the use of r-ATG as an induction agent were risk factors for CMV antigenemia and BK viremia within 6 months (Table 3, 4).

Elderly patients who receive a kidney from an ECD demonstrate improved survival outcomes compared to those who remain on the waiting list in anticipation of a transplant from a higher-quality donor [28]. Doucet et al. [29] reported similar findings, with elderly patients more likely to receive kidneys from either ECD or elderly donors, according to data from the Australia and New Zealand Dialysis and Transplant Registry. Despite the lower quality of donors in elderly patients, there was no significant difference in death-censored graft survival compared to younger recipients. Heldal et al. [30] found that the 5-year death-censored graft survival rate of 89% in KT recipients aged over 70 years, which was comparable to that of senior patients aged 60–69 years and control patients aged 45–54 years. Faravardeh et al. [31] reported no significant difference in the 15-year death-censored graft survival among KT recipients aged under 50, 50–64, and 65 years and older. Similarly, in our study, older recipients were more likely to receive kidneys from donors of advanced age or ECDs, and these donors were more likely to have a history of DM, HTN, or higher terminal creatinine levels. Furthermore, our study showed no significant difference in death-censored graft survival between the younger and older recipient groups.

Clinical trials on the use of immunosuppression in the elderly are rare, so there are still no guidelines for age-adapted immunosuppression. Krenzien et al. [26] recommended the type and dose of induction therapy according to the immunologic risk in the elderly. For sensitized elderly recipients such as the second KT, 6 mg/kg of r-ATG was recommended. In non-sensitized elderly recipients, it is recommended to reduce the r-ATG up to 3 mg/kg for marginal organ quality such as ECD or ischemic time over 24 hours, and to use BSX for good organ quality such as a living donor or short ischemic time. Masset et al. [32] conducted a comparative study on the use of BSX and r-ATG at a dosage of 1.5 mg/kg/day for an average of 6.8 days in elderly KT recipients with low immunological risk. They found no significant difference between the two groups in the outcomes of graft and patient survival, BPAR, infection, and malignancy. However, they observed a lower incidence of posttransplant diabetes in the r-ATG group, which was attributed to the use of low-dose tacrolimus. In a study by Patel et al. [13] that divided patients into four groups based on age (60 years) and r-ATG 6 mg/kg, the patient survival rate was significantly lower when r-ATG over 6 mg/kg was used in patients over 60 years compared to other groups. Pham et al. [16] reported that the occurrence of CMV infection was significantly higher when r-ATG 4.5 mg/kg was used compared with when BSX was used in patients over 65 years of age. El-Hag et al. [15] reported that elderly recipient treated with 4.5 or 6 mg/kg r-ATG experienced a higher rate of infections such as CMV, BK, and UTI than the BSX and 3 mg/kg r-ATG groups. Yang et al. [14] reported that low-dose r-ATG (2.5 mg/kg) had a BPAR similar to that of 6 mg/kg r-ATG, but a statistically significantly lower incidence of infection. Cabrera et al. [33] reported that when extremely elderly recipients, 75 years of age and above, received kidneys from extremely aged deceased donors, interleukin-2 receptor antagonist was used as an induction agent in 91.9% of cases. In our study, when 4.5 mg/kg r-ATG was used as an induction agent in older recipients, the incidence of BPAR was low (Table 2), but the incidence of infection was high and more patients died from infection (Fig. 3). Thus, we speculate that 4.5 mg/kg of r-ATG might be a bit excessive in older recipients. A prospective study is needed to determine how much the r-ATG dose should be reduced.

This study is subject to similar limitations inherent to all retrospective studies, including missing data elements, protocol deviations, and selection bias. These problems can limit the ability to draw causal conclusions. To address potential confounders, we performed a multivariate analysis adjusting the recipient’s age, sex, and other relevant covariates. However, residual confounding may still exist, especially for the time point of BPAR and outcome events. Our results cannot be generalized to other centers using different induction strategies. In addition, the incidence of BPAR is relatively high because our center performs protocol biopsy in the second week. Thus, a prospective multicenter study is needed to confirm our findings.

In conclusion, when BSX was used as an induction agent, there were similar rates of BPAR and most infections between the younger and older recipient groups. Although CMV and UTI occurred more frequently in older recipients, infection-related mortality was comparable between the two groups. However, when 4.5 mg/kg of r-ATG was used as an induction agent in older KT recipients, not only did all infections occur more frequently, but the incidence of infection and death due to infection were higher compared with younger recipients. Considering the potential excessive dosage of 4.5 mg/kg for r-ATG in older recipients compared to younger recipients it may be necessary to use less intensive induction therapy for older recipients, of which dose reduction of r-ATG is one option.