Population ageing and an increasing incidence of chronic disease have led to a growing number of patients with kidney failure being considered for kidney transplantation (KT) [1, 2]. KT is recognised as the most effective treatment option for kidney failure patients and offers significant advantages over haemodialysis treatment in terms of mortality, graft function and quality of life [3–5]. As a result, the demand for grafts is steadily increasing worldwide while the number of available donor organs has been stagnating [6, 7]. Consequently, the demand for kidney transplants considerably exceeds the number of available grafts, which underlines the importance of optimising pre- and post-KT procedures and outcomes. Age significantly impacts transplant results, were individuals of similar age may present with different physical and cognitive conditions. Thus, chronological age (counted in years) alone is an inaccurate representation of patients' functional abilities [8, 9]. Physical frailty, a better predictor of biological age, and MCI were both found to be strong independent predictors of adverse health outcomes and functional decline in ESRD as well as KT recipients [5, 7, 9]. Nevertheless, there is limited evidence on how these two conditions develop long term and how they interact after KT. Therefore, studies that investigate the prevalence, the evolution, and the interrelation of both conditions over time represent an important area of research to contribute informing clinical and policy decision making.

Physical frailty is defined as a state of vulnerability and a decline in functioning across multiple physiological body systems [10, 11]. The Fried Frailty phenotype (FFP) offers the most common way for determining physical frailty in transplantation [12]. This phenotype is based on the five components weakness, slowed walking speed, low level of physical activity, exhaustion, and chronic undernutrition [10, 11]. Depending on the presence of these components, a patient is classified as non-frail; pre-frail; or frail. Although the FFP was initially designed to identify older adults at increased risk for adverse health outcomes, it is presently utilized as a predictive tool for such detrimental health effects across diverse patient populations [10, 13]. For improving its predictive validity, the FFP components have been adapted for KT patients (e.g., chronic undernutrition is measured by asking for loss of appetite instead of asking for weight loss) [14, 15].

In addition to physical frailty, MCI has been shown to significantly influence KT outcomes; MCI is characterized as a syndrome involving cognitive decline that exceeds normative expectations for an individual’s age and educational background, yet does not substantially impair activities of daily living [12, 16]. Physical frailty and MCI are common in patients with chronic kidney disease (CKD) [17–22]. Studies have demonstrated that up to 78% of patients with kidney failure and as many as 58% of KT candidates at the time of transplantation exhibit signs of frailty [18, 19, 22–25]. Both conditions are strong and independent predictors of adverse health outcomes such as postoperative complications, increased rate of early hospital readmission or mortality in chronically ill adults of all ages [22, 26–30]. A study on changes in frailty after kidney transplantation revealed that the prevalence of physical frailty initially increased from 20% immediately after transplantation to 33% 1 month post-transplantation, but subsequently decreased to 27% at 2 months and 18% at 3 months. The findings indicate that physical frailty in kidney transplantation patients is not a stagnant condition, but rather a dynamic physiological state [31].

MCI has in parallel been found to be a strong and independent predictor of increased rates of hospitalization and mortality in different populations [20, 21, 26, 30, 32]. It also adversely affects patients’ decision-making, the adoption of healthy lifestyle behaviours and adherence to medication regimens and can in turn negatively influence health outcomes in the KT population [20, 27, 33]. The prevalence of MCI in CKD patients is high, with figures up to 75%. Therefore, several studies suggest regular screening for MCI in the CKD population to allow early detection [20, 21, 26, 30, 34]. Moreover, physical frailty and mild cognitive impairment appear to contribute to a cycle of physical and cognitive decline and reduced quality of life [20, 35]. Dysregulation of multiple biological and stress-response systems has been implicated in the development of both frailty and cognitive impairment. The coexistence of these conditions may further increase vulnerability and accelerate functional decline [36, 37]. Additionally, physical frailty has been associated with lower cognitive function and poorer cognitive outcomes following the initiation of haemodialysis and after KT [24, 38, 39]. However, despite increasing recognition of the clinical importance of both conditions, little is known about their longitudinal evolution after kidney transplantation or the directionality of their relationship. Understanding whether frailty and cognitive impairment improve, worsen, or influence one another over time may provide important insights into patient recovery following transplantation and may help identify potential targets for intervention. Consequently, the identification and management of frailty and cognitive impairment have become increasingly important in kidney transplantation [19, 20]. While the associations between frailty, MCI, and adverse transplant outcomes have been well documented, substantially less is known about how these conditions evolve following transplantation and whether they influence one another over time. A better understanding of their longitudinal trajectories and interrelationship may help identify mechanisms underlying post-transplant recovery and inform the development of targeted interventions aimed at improving patient outcomes.

The objective of this study was to assess the prevalence of physical frailty and MCI among adult KT recipients at the time of transplantation and to describe their longitudinal evolution and interrelationship during the first 2 years following KT. Given the established associations of both conditions with adverse transplant outcomes, a better understanding of their trajectories may support risk stratification, guide the development of targeted interventions, and inform future studies investigating their impact on long-term transplant outcomes.

The current study presents results of the multicenter, prospective cohort study GERAS (ExplorinG frailty and mild cognitive impairmEnt in adult kidney tRansplant recipients to enhance risk prediction for biochemicAl, psychosocial, and health cost outcomeS) [40]. GERAS is nested in the Swiss Transplant Cohort Study (STCS), a long-term open prospective cohort study that has enrolled more than 95% of all KT recipients in Switzerland since 2008 [41, 42]. The GERAS study was approved as a multicenter study by the responsible ethics committee (EKNZ: 2015-235). Figure 1 illustrates the study design, data resources and variables of the GERAS Study. The GERAS study protocol has been published elsewhere [40].

During the recruitment phase, 563 adults underwent kidney transplantation across the five participating Swiss transplant centers. Of these, 348 were assessed for eligibility and 230 fulfilled the inclusion criteria and were enrolled in the study. The discrepancy between the total number of transplant recipients and those screened was primarily attributable to logistical constraints during transplantation procedures, particularly when multiple transplantations occurred simultaneously. If several transplantations were planned simultaneously, recruitment of all recipients was not always possible. 230 KT recipients across the five participating Swiss transplant centers fulfilled the inclusion criteria and were included in the study (Figure 2). As center-specific differences were not part of the study objectives, participants from all centers were analysed as a single multicenter cohort and results are reported for the pooled sample. Table 2 provides an overview of the sample characteristics. The study participant’s mean age was 53.0 years (SD ± 14.4, range 20–75), 25.2% were aged ≥65 years and 31.7% were female.

The objective of this study was to evaluate the prevalence of physical frailty and MCI among adult KT recipients at the time of transplantation and to describe their evolution up to 2 years post-KT. We found that in our study population, the prevalence of physical frailty amounted to 8.3% and that of MCI to 42.6%.

The prevalence of physical frailty in KT patients in our study was lower than that reported in the literature (8% compared to up to 20%) [6, 8, 9, 18, 44, 54]. In contrast, the percentage of patients with physical pre-frail status was higher than values previously reported in an international study (54% compared to 33%) [44, 45]. This finding might result from the fact that healthcare systems differ among countries, making direct comparisons difficult. Nevertheless, the average time on the waitlist for KT in Switzerland was 2.6 years in 2018, which is low compared to other European countries and the US (Swisstransplant, ERA-EDTA, UNOS). A shorter waiting time has been shown to be beneficial in various studies, whereas a prolonged time on the waitlist has been associated with negative outcomes after KT [3, 55]. The relatively short waiting time may be one factor explaining why many patients were only in the physical pre-frail stage and not yet further advanced. Interestingly, pre-frailty was more prevalent among pre-emptive transplant recipients than among patients receiving haemodialysis. This difference was not explained by age in our cohort and may instead reflect other patient characteristics or selection factors that were not investigated in the present study. A further notable finding was the lower prevalence of physical frailty among recipients aged 65–75 years compared with those aged 20–64 years. Although this observation appears counterintuitive, it is likely explained by the selection process for kidney transplantation. Older transplant recipients represent a highly selected population who have undergone extensive medical and functional evaluation and are therefore more likely to have preserved physiological reserve than older individuals with kidney failure in the general population [6]. In contrast, younger recipients may accumulate a substantial burden of chronic disease, dialysis-related complications, and multimorbidity that contribute to frailty despite their younger chronological age [56]. This observation further supports the concept that chronological age alone is an insufficient surrogate for biological age in kidney transplantation and reinforces the importance of incorporating frailty assessment into transplant evaluation irrespective of age [3, 6, 12, 54]. Nevertheless, given the relatively small number of frail participants in our cohort, this finding should be interpreted with caution and warrants confirmation in larger prospective studies. Similarly, although physical frailty appeared to be more prevalent among participants with a higher educational background, this finding should be interpreted cautiously, as participants with higher educational attainment were proportionally overrepresented in our cohort and this imbalance may have influenced the observed distribution.

This study revealed a high prevalence of MCI among kidney transplant recipients immediately prior to transplantation, consistent with previous reports [20, 36, 57, 58]. Although pre-transplant anxiety related to the anticipated transplantation procedure may have influenced cognitive performance in some individuals, baseline assessments were conducted under standardized and calm clinical conditions as part of routine pre-transplant evaluations. The observed reduction in MCI prevalence following transplantation aligns with longitudinal studies demonstrating improvements in cognitive function after kidney transplantation, particularly during the first postoperative year, although residual cognitive impairment remains common [20, 36]. Therefore, the observed trajectory is more likely to reflect genuine post-transplant cognitive recovery than a transient effect of perioperative stress. Evidence regarding longer-term cognitive trajectories is less consistent, with some studies reporting persistent impairment or late cognitive decline, whereas others demonstrate sustained improvement or stabilization [20, 57]. Consistent with recent longitudinal evidence, we observed a decline in MCI prevalence from 42.6% before transplantation to 29.8% at 12 months, followed by stable prevalence at 24 months. These findings suggest that cognitive impairment after KT is not necessarily progressive but rather reflects an early phase of cognitive recovery followed by relative stability over the first two years after transplantation. Despite this favourable trajectory, persistent cognitive impairment remained common, highlighting the importance of integrating cognitive screening and tailored support into routine post-transplant care to optimize self-management, medication adherence, and long-term clinical outcomes [20]. Although frailty improved and cognitive function remained relatively stable over time, these findings should be interpreted in light of the observed attrition. Participants with poorer baseline cognitive function and greater physical frailty were more likely to have missing 24-month follow-up assessments, which may have resulted in a modest overestimation of the observed longitudinal improvements.

Post-KT, the study observed a marked decline in the prevalence of physical frailty, decreasing to between 1% and 2% at the six, twelve, and twenty-four-month follow-ups. Similarly, pre-frailty levels decreased significantly, from 43.4% at six months to 27.6% at twenty-four months. This trend aligns with existing literature suggesting that rehabilitation and supportive care post-transplant can lead to improved physical outcomes. Studies have demonstrated that structured rehabilitation programs can improve physical functioning in kidney transplant recipients. Recent studies further indicate that structured exercise-based prehabilitation can improve exercise capacity, muscle strength, physical performance, and muscle morphology in kidney transplant candidates, including those with frailty. These findings support the integration of individualized exercise interventions into multidisciplinary care across the kidney transplantation pathway [59, 60]. In terms of cognitive health, MCI prevalence also decreased over time, dropping from 35.0% at six months to 31.3% at twenty-four months. This reduction, although less pronounced than that observed in physical frailty, indicates that cognitive function can improve post-transplant, possibly due to enhanced physical health and psychosocial factors.

Regression analyses further revealed a significant association between cognitive function and frailty, suggesting that cognitive decline precedes subsequent physical resilience. This is important in identifying patients at risk. Moreover, if this would constitute a causal pathway, then physical frailty may respond to interventions targeting cognitive function, thus early cognitive assessments in kidney transplant patients may help mitigate frailty progression over time.

The strength of this study lies in its prospective, longitudinal design, which encompassed a 24-month follow-up period post-KT and employed a multicentric approach. However, two significant limitations of this study are the reliance on a convenience sample, which led to a considerable number of missed patients, and the presence of missing data at several follow-up time points particularly in later visits, reduced the statistical power to detect weaker associations and may have introduced bias, which could not be addressed by the use of less missingness-sensitive random-effects models (i.e., because of convergence problems). The follow-up duration may also have been insufficient to capture the long-term impact of frailty on cognitive decline. Further, the potential attrition bias should be considered when interpreting the longitudinal findings, although the mixed-effects models included all available observations and were therefore able to accommodate intermittent missing follow-up data. Future studies should aim to extend the follow-up period and incorporate more detailed assessments of both cognitive and physical function, such as domain-specific neuropsychological tests and further objective frailty measures. Moreover, interventional studies investigating whether improving cognitive function can mitigate frailty progression in kidney transplant recipients would be valuable.

In conclusion, this study underscores the dynamic nature of physical frailty in kidney transplant recipients, demonstrating significant improvements over time, while MCI remained more stable. These findings highlight the critical importance of ongoing monitoring of both physical frailty and MCI in clinical settings. This study further provides evidence that cognitive function plays a significant role in frailty progression among kidney transplant patients, whereas frailty does not appear to substantially impact cognitive decline within the observed timeframe. These findings highlight the importance of early cognitive screening and intervention strategies to improve long-term outcomes in this patient population. Healthcare providers should implement routine assessments of frailty and cognitive function to identify at-risk patients early to adapt how healthcare services are being provided. Additionally, developing targeted interventions aimed at reducing frailty and improving cognitive health is essential to enhance patient outcomes and overall quality of life post-KT. By prioritizing these aspects of patient care, clinicians can better support the long-term wellbeing of kidney transplant recipients.