Targeted Non-Pharmacological Interventions for People Living with Frailty and Chronic Kidney Disease

: Frailty is highly prevalent within people living with chronic kidney disease (CKD) and is associated with the increased risk of falls, hospitalisation, and mortality. Alongside this, individuals with CKD report a high incidence of depression and reduced quality of life. The identiﬁcation of frailty within nephrology clinics is needed to establish comprehensive management plans to improve clinical outcomes and quality of life for people with CKD. Current research exploring the role of non-pharmacological management has primarily focussed on exercise and physical activity interventions in the frail CKD population. However, there is a growing evidence base and interest in this area. This review provides an up-to-date overview of the literature into frailty assessment in CKD and subsequent non-pharmacological treatment approaches.


Introduction
Frailty, a reduction in physiological reserve and multi-system imbalance, when exposed to stressors, is highly prevalent in people with chronic kidney disease (CKD) [1]. Several studies have shown the association between individuals living with chronic disease and frailty, for example, cardiovascular [2] and neurological diseases [3], cancer [4], and diabetes [5]. Alongside this, individuals who live with multiple chronic diseases, known as multi-morbidity, have been shown to have a higher incidence of frailty, shown by increasing disability, hospitalisation, mortality, and healthcare utilisation [6].
Within CKD, recent systematic reviews estimate the prevalence of frailty in the haemodialysis and pre-transplant CKD populations to be 46% and 17%, respectively [7,8].
Outcomes are poor for people with frailty and CKD, including increased risk of mortality, hospitalisation, falls, high symptom burden, health care utilisation, reduced health-related quality of life (HRQoL), and depression [9,10]. Other geriatric impairments, including impaired functional status, mobility, cognition, and mood, are also highly prevalent and similarly associated with adverse outcomes [11,12]. A holistic multi-disciplinary approach is needed to identify and manage frailty and associated geriatric impairments and to address preventable risk factors for frailty.
Frailty is not a static state, and a transition between frailty states is possible, particularly in those classed as 'pre-frail' [11][12][13]. Such findings suggest that at least some factors associated with frailty may be reversible or responsive to change. Abundant guidance advocates a life course approach to the management of frailty, by promoting healthy lifestyles in those with risk factors for frailty and enhancing access to proactive, integrated, and personalised care for those with established frailty [14][15][16][17][18]. Existing reviews of nonpharmacological interventions in the frail CKD population have primarily focussed on physical activity and exercise interventions. The majority of included interventions have been extrapolated from robust populations in the absence of research focussing specifically on people with frailty and CKD. Table 1 summarises the current research being undertaken in this area. Despite limited previous research, there is a growing evidence base in this area, and the aim of this review is to provide an updated overview of frailty identification and assessment and subsequent self-management, physical activity, and dietary and psychological interventions for people with frailty and CKD.

Frailty Phenotype
To study the potential effects of multi-modal prehabilitation as a prognostic variable to predict the 90-day primary endpoint based on clinical and functional outcomes achieved in frail and non-frail KT candidates.
Multi-modal exercise intervention with nutritional supplementation.
To be determined-this is a protocol paper. To explore the risk factors related to frailty in elderly CKD patients without dialysis.
To investigate the effect of individualised interventions of frailty on the prognosis of elderly patients with CKD who did not undergo dialysis.
Nutrition, psychology, and exercise intervention.
To be determined-this is a protocol paper.

Frailty Identification and Assessment
First and foremost, the proactive identification of frailty, prompting the timely consideration of targeted interventions, is essential to improving outcomes for this vulnerable population. Clinical acumen alone is unreliable when identifying frailty in people with CKD; frailty measures that can either replace or guide clinical judgement can improve the accuracy of assessment [19]. Most frailty screening tools and measures used in clinical practice are derived from two conceptual models of frailty, the Frailty Phenotype [1] and the deficit accumulation model, also known as the Frailty Index [20,21]. The Frailty Phenotype is defined as a clinical syndrome of physical frailty involving at least three of the following criteria: unintentional weight loss, self-reported exhaustion, weakness (measured by grip strength), slow walking speed, and low physical activity [1]. It has been most well studied in CKD populations [22] and is predictive of adverse outcomes [23,24]. However, it can be unwieldy outside the research environment, requiring a combination of self-report questionnaires and objective assessments. A frailty index takes a more holistic approach to frailty assessment, considering deficits across various domains, including disease states, physical function, cognition, and functional status [20,21]. It is predictive of adverse outcomes in CKD [25], although its use in clinical practice is hampered by the volume of data required to generate a frailty index score. The electronic Frailty Index (eFI) has circumnavigated this limitation within the general older population by using existing electronic primary care health record data to generate a score [26]. Additional validation studies are needed before its use can be recommended within routine nephrology practice; however, preliminary data suggests that the eFI has prognostic value in CKD populations [27].
Multiple frailty screening tools have been evaluated in CKD populations and perform reasonably well [28][29][30][31][32]. Notably, the widely cited Clinical Frailty Scale (CFS) [21,33], a global 9-point scale that guides the clinical judgement of an individual's frailty status, has been shown to be associated with adverse outcomes in Australian, Canadian, Japanese, South Korean, and UK CKD populations [34][35][36][37][38][39][40][41][42][43][44]. A limitation of the CFS is that it relies on a healthcare professional to make a subjective assessment, albeit an informed one. The screening tool selected for use in clinical practice will be influenced by the familiarity of local geriatric medicine and primary care services, given the importance of communicating readily interpretable frailty status assessments in the multi-disciplinary and multi-professional management of people living with frailty. Arguably, it is more important that frailty is proactively identified, regardless of the method used, rather than delaying the implementation of frailty screening within nephrology services as a consequence of over-deliberation.
Once frailty is identified, a holistic assessment can inform the implementation of targeted interventions. Comprehensive Geriatric Assessment (CGA) is considered the 'gold standard' of care for older adults [45]. CGA is defined as 'a multidimensional, multidisciplinary process which identifies medical, social and functional needs, and the development of an integrated/co-ordinated care plan to meet those needs' [46]. CGA or modified versions, which often involve one assessor performing a multi-domain assessment, have been used to successfully identify geriatric impairments in older adults with advanced CKD [36,47,48]. Using a structured geriatric assessment, van Loon et al. [47] demonstrated that nearly half of older people starting dialysis had three or more geriatric impairments. Voorend et al. [49] demonstrated that geriatric assessment was useful to identify trends in geriatric domains and provided a reason to set targeted interventions. In addition, geriatric assessment helped to initiate dialogue on treatment decisions, including prompting the consideration of different treatment options [49]. It is not yet known if CGA leads to improved outcomes in people with CKD; however, studies are underway [49][50][51]. Existing evidence suggests that CGA or modified versions can be used to assess people with frailty and CKD to identify associated geriatric impairments, which in turn can guide future targeted interventions. Figure 1 details a pathway for the identification, assessment, and management of frailty in CKD. Physical activity, exercise and rehabilitation

Self-Management Interventions
Self-management comprises of three core tasks (medical management, role or behavioural management, and emotional management) [52], which are underpinned by five key processes (decision making, utilising resources, forming partnerships with healthcare professionals, problem solving, and taking action) [53]. Lightfoot et al. described these core tasks and processes in detail, outlining them in a figure [54]. For people with CKD, self-management behaviours range from the management of medication adherence, health monitoring, and symptom monitoring to lifestyle modifications (e.g., increasing physical activity and eating an appropriate diet) and learning to live and cope with the emotional consequences associated with CKD [54].
Self-management consists of a diverse repertoire of cognitive and behavioural abilities to manage resources for fulfilling needs and managing losses [55]. The ability to appropriately self-manage is important for people with long-term conditions but becomes especially so when there are changes in health associated with frailty [55,56]. Declines in physical and cognitive condition can negatively impact an individual's ability to manage their health, potentially leading to further deterioration [57]. Whilst frailty is not a significant predictor of self-care behaviours [58], impaired self-management abilities are negatively associated with physical, psychological, and social frailty [59].
Individuals who are vulnerable to or have established frailty may have a lack of reserves in important resources (e.g., health, social support, social roles, etc.) or have losses in such resources [55]. Supported self-management can prevent dependence and increase one's ability to adapt and self-manage long-term condition(s) and their associated consequences [57]. There is a dearth of evidence specifically relating to the benefits of supported self-management in people with frailty and CKD. However, interventions that influence the physical, psychological, and social dimensions of frailty are likely to be beneficial in delaying the onset of frailty or reducing the risk of adverse outcomes associated with it [60,61]. Support should target problem-solving skills, self-efficacy, and coping skills [55]. Future interventions should aim to strengthen the self-management abilities of people with CKD to prevent or delay the onset of frailty. As self-management abilities can be influenced by psychological health, socio-economic factors, and health literacy, interventions need to be tailored to the individual.

Physical Activity and Exercise-Based Rehabilitation
Addressing sedentary behaviour, encouraging physical activity, and supporting participation in structured exercise are key components in the holistic care of people with frailty and CKD at all stages and levels of severity, although the focus and aims of these interventions may differ, as outlined within  Observational data support the high prevalence of physical frailty characteristics, particularly sarcopenia and physical inactivity, in the CKD population, underlining the possible mediating role of physical activity and exercise in the development and progression of frailty [12,62]. National and international guidance recommend that all people with CKD undertake exercise for cardiovascular and HRQoL benefits [63,64]. In addition, exercise is particularly recommended for older people with CKD because of its positive impact upon function [32].
Despite these recommendations, to date, only three feasibility trials focusing on exercise interventions have been conducted with people with frailty and CKD [65,66]. A small non-randomised pilot of 12 weeks of IDC combined with lower limb strengthening during dialysis in older people aged 75-95 found that those who exercised had improved Fried phenotype scores and function measured by the sit-stand 5 test, although clinically, the significance of these findings is unclear [67,68].  found that six months of moderate-intensity, thrice-weekly intradialytic cycling (IDC) was safe and feasible for frail people receiving HD and may allay deterioration in exercise capacity, endurance, and function [66,67]. Participants, however, described IDC as limited and wanted a more comprehensive programme. Nevertheless, the intradialytic period offers an attractive opportunity to encourage activity without increasing burden. Suzuki et al. (2019) are undertaking a cross-over trial examining the effects of intradialytic electrical muscle stimulation, which may offer a useful adjunct for frailer people who find exercise challenging [69].
A more varied programme comprising twelve weeks of home-based, moderateintensity resistance, aerobic, and balance training was also feasible and safe for people with frailty and CKD stages 3-5, leading to potential improvements in function and symptoms [65]. Similar programmes are known to be effective in older people with frailty in the general population [70][71][72][73][74]. These findings suggest that, irrespective of stage of CKD and mode of RRT, a focus on a range of exercises may be more effective and acceptable to frailer people who can undertake exercise. Within these programmes, progressive resistance training to enhance muscle mass, strength, and function is of particular importance [75]. Compelling evidence from community-dwelling older populations indicates that strength training alongside balance exercise significantly reduces the rate and number of falls [76]. To date, a limited number of studies have explored the impact of exercise upon falls and falls-related outcomes in the CKD population [77][78][79][80].
Evidence to date highlights the challenges of exercise for this population [65,66]. Reducing sedentary behaviour and increasing light physical activity may represent a more achievable first step and segue into exercise for frailer people [81,82]. Levels of sedentary behaviour and physical inactivity are high across the spectrum of CKD and are also key characteristics of frailty [12,[83][84][85][86]. Several studies indicate that walking is a feasible and acceptable form of physical activity for people with CKD, which can lead to the preservation of muscle mass and improvements in exercise capacity and function, even in older participants [87,88]. Whether walking interventions are acceptable to those with frailty, who may be particularly functionally impaired, remains to be explored. Qualitative evidence suggests that people with CKD and frailty prefer activity with 'purpose' [66]. Increasing functional daily activities may be easier to incorporate into daily routines and is more likely to be viewed as purposeful, potentially promoting sustained change [89]. For those unable to achieve this, even regular standing to break up sedentary periods can lead to functional improvement, and preliminary evidence indicates that this approach is useful for those with CKD [81,90].
Admission to hospital and the transition to end-stage kidney disease represent two significant health stressors, which can trigger increasing dependence and the onset of additional support needs [91]. The introduction of exercise programmes to prevent or allay this decline is an area of growing interest. One small study regarding four weeks of thriceweekly inpatient exercise training led to improvements in fatigue [92], whilst an ongoing study will explore the feasibility and preliminary efficacy of a tailored inpatient exercise intervention on frailty levels, length of stay, readmissions, HRQoL, and function [93]. How to effectively support frail people to regain function and fitness post-hospital discharge is also an area requiring further research. For those making decisions regarding RRT, 'prehabilitation', which aims to improve tolerance to an upcoming physiologic stressor, may be beneficial [94]. Existing prehabilitation studies have predominantly focused on those awaiting transplant or approaching dialysis, concluding that prehabilitation has a positive influence on physical activity, frailty status, function, and strength [95][96][97]. Further definitive trials are required; an ongoing study by Perez-Saez et al. will provide additional information on the role of prehabilitation, specifically in frail kidney transplant candidates [98]. Interestingly, no research has been conducted for those opting for conservative care. In other conditions, palliative prehabilitation helps maintain independence and supports symptom management and the achievement of meaningful goals, as well as reducing carer and family burden [99,100].

Nutrition
Poor nutritional status has been identified as a key contributor, and potentially modifiable risk factor, for frailty [1,101,102]. Malnutrition, poor quality diet, and the low intake of specific macro-or micronutrients have been associated with frailty [102,103]. For people with advanced CKD, nutritional status and diet quality may be negatively impacted by a reduced dietary intake driven by uraemic symptoms (e.g., anorexia, nausea, and taste disturbance), financial constraints, low mood, or poor dentition [101,104]. Dietary restrictions may further compromise intake; as such, guidelines on the management of older people with CKD recommend that preserving nutritional status should take precedence over these [32]. Intercurrent illnesses, nutrient losses into dialysate, inflammation, and acidaemia may also be superimposed on reduced dietary intake and further contribute to protein-energy wasting and frailty [104,105].
Screening for risk of malnutrition is recommended for people at risk of frailty [106]. The identification of those at risk of malnutrition can then prompt further nutrition assessment and intervention. For adults with CKD, no gold standard nutrition screening tool exists; however, modified tools are available [107,108]. Comprehensive nutrition assessment (using tools such as the Subjective Global Assessment) can then be conducted to provide a more in-depth assessment of an individual's nutritional state and to help guide a treatment plan [107,108].
Interventions to correct nutritional deficits and weight loss may present the opportunity to reverse or modify frailty in people with CKD. However, currently, there is a paucity of studies exploring the effectiveness of nutritional interventions (nutrition education and/or supplementation) for people with frailty and CKD. Within older populations with frailty, evidence of the benefits of nutritional intervention is also lacking. International guidelines on the management of frailty recommend the use of protein/calorie supplementation when undernutrition or weight loss has been diagnosed, although the low certainty of the evidence on which this recommendation is based is highlighted [109]. Evidence from systematic reviews have suggested that although nutritional interventions delivered in isolation may not show a beneficial effect [110], when used as part of multi-component interventions incorporating physical exercise, they may provide an additive effect, yielding greater improvement in frailty status and physical functioning [111]. For people with frailty and CKD, several such trials are currently underway and will begin to shed light on the impact of multi-component interventions on frailty in people with CKD stage 3-5 [51], those receiving haemodialysis [112], and in kidney transplant recipients [98].

Non-Pharmacological Interventions for Depression
Depression is commonly experienced by people with CKD and is associated with poorer health-related outcomes, including increased mortality [113][114][115]. Across the spectrum of advanced CKD, the prevalence of depression is estimated to be between 26.5 and 39.3% depending on CKD severity and modality [116].
In community settings, depression and frailty often co-occur [117]. The relationship between frailty and depression appears reciprocal since both are associated with the incidence and prevalence of each other [117]. It is likely that both depression and frailty have shared risk factors, including multi-morbidity and chronic inflammation, particularly in the context of CKD. For example, recent meta-analytic evidence found that higher interleukin-6 and lower albumin were associated with the prevalence and severity of depression in people with CKD [118]. Furthermore, symptom clusters of both depression and frailty overlap, including the presence of fatigue, weight loss, and decreased activity [1], which can complicate the assessment of both conditions. Among people with CKD, both frailty and depression are significant determinants of HRQoL [38,119]. Cross-sectional data from both dialysis and kidney transplant recipients found that depression symptoms are associated with a respective 2.14 and 3.97 increase in the odds of frailty [120,121]. In a prospective study regarding people receiving dialysis, Sy et al. [120] found that depression symptoms were associated with the incidence of frailty, whereas frailty was not found to predict incident depression. In the same study, both frailty and depression were independent predictors of mortality in time-varying survival models [120]. A study regarding kidney transplant recipients found that those with co-existing depression and frailty had a 6.20-fold increased risk of death-censored graft failure and a 2.62-fold increased risk of all-cause mortality, compared to non-depressed non-frail recipients [121]. Furthermore, data from a relatively small study regarding people receiving peritoneal dialysis showed poorer nutritional status and greater hospitalisation and mortality in those with co-existing depression and frailty [122]. A more recent study showed that the association between depression and mortality was attenuated once frailty was adjusted for [123]. Taken together, both depression and frailty appear to be associated with adverse clinical outcomes, with some evidence to suggest that comorbid frailty and depression are particularly important prognostic factors.
Despite the co-occurrence of frailty and depression in CKD, little research has focused on psychosocial and behavioural interventions to support management. Whilst recent meta-analytic evidence suggests that exercise training improves symptoms of depression in people receiving HD, further research is needed to understand the psychosocial factors associated with frailty in order to inform multi-component interventions designed to improve symptoms of frailty and depression. There is a particular need to understand how people with CKD think and respond to symptoms of frailty and how these factors are associated with subsequent self-management behaviours, symptom severity, and impairment. In kidney transplant recipients, psychological resilience has been found to be associated with frailty [124], and in community-dwelling older adults, self-efficacy and a sense of mastery have been found to reduce the odds of functional decline [125]. Such factors are also commonly associated with depression. Improving the early identification and treatment of depression might help reduce functional decline in people with CKD. Future research is needed to develop and test multi-component interventions, which include elements designed to help support the management of both depression and frailty and the impact these symptoms have on HRQoL. At present, there are three multi-component research trials underway, which will go some way to addressing this gap [51,98,112].

Digital Health Interventions
With increasing burden placed upon healthcare systems, there is a growing focus on leveraging digital technology as a means of delivering health interventions [126]. Digital technologies may increase synergy across healthcare systems and empower people to manage their long-term physical and mental health [127]. As the number of individuals with frailty and CKD increases, it is imperative that access to appropriately tailored healthcare interventions, irrespective of geographical location, is widened. Digital health interventions (DHIs) are defined as services delivered electronically to deliver health and health-related care [128] and have the potential to improve access to services and reduce health inequalities [129].
There has been an increase in the number and types of DHIs in recent years. DHIs may increase capacity, drive efficiencies, and improve clinical outcomes [129]. DHIs specifically designed for people with frailty is a growing area of interest. DHIs can support frailty detection and the assessment and monitoring of health status and enhance communication between healthcare professionals and people with frailty. They have also been used to provide falls prevention and rehabilitation interventions [130]. To our knowledge, there is limited evidence that specifically focusses on DHIs to support lifestyle interventions for people with frailty and CKD.
The delivery of physical activity and exercise rehabilitation may be particularly amenable to online or app-based delivery. Research indicates that DHIs have the potential to reduce barriers to participating in physical activity, increasing physical activity levels in the shorter term [131][132][133][134][135]. This is particularly relevant within the context of the ongoing coronavirus-19 (COVID-19) pandemic. Frail older adults' levels of physical activity reduced during this time, with a resultant negative impact upon deconditioning and falls [136], and physical activity levels in shielding adults with ESKD also declined [137]. A newly established online platform, which aims to enhance physical activity and emotional wellbeing in people with CKD, 'Kidney Beam', may prove beneficial for people with frailty and CKD [138]. Indeed, a 6-month clinical pilot demonstrated an increase in the number of participants self-reporting that they were meeting national physical activity guidelines, as well as demonstrating an increase in perceived energy levels [139]. A multi-centre, randomised, controlled trial is currently underway to evaluate the clinical effectiveness of this digital platform for individuals living with CKD.
The potential of DHIs for individuals with frailty and CKD is clear; however, is it essential that further research is undertaken to understand how best to tailor DHIs for those living with CKD and frailty. Whilst people with CKD have described their experiences of DHIs as positive [137], some found the loss of non-verbal communication associated with remote telemedicine challenging [137]. Additionally, current DHIs typically provide general advice and feedback, which people with frailty and CKD feel is not always appropriate for their complex needs [140]. DHI designed specifically for this population may benefit from a co-design approach to ensure the content and methods of delivery are in line with users' needs [130].

Considerations
This review provides an overview of current evidence on the importance of identifying frailty in those with CKD, alongside targeted non-pharmacological interventions. Individualised holistic assessment and management is required to provide care for this group, to maximise HRQoL, support independence, and minimise the risk of adverse health outcomes.
Frailty is a dynamic state, and frailty status can improve as well as worsen in people with advanced CKD. McAdams-DeMarco et al. [13] demonstrated an improvement in frailty scores three months following transplantation. A recent study by Rampersad et al. [141] found that there is an accelerated decline in physical function with transition to dialysis for older adults. However, Johansen et al. [12] demonstrated that frailty status can fluctuate in the prevalent haemodialysis population, and whilst in some cases, the severity increases, and many also improve. Hospitalisation was associated with worsening frailty status over time [12], highlighting the importance of minimising unplanned hospitalisations. Management strategies should be proactive, aiming to maintain or improve nutritional and functional status, minimise fall risk, and promptly treat infection. Advanced care planning should also be considered, particularly for those with more severe frailty.
Non-pharmacological interventions can prevent or delay dependence. However, it is important to note that prioritising such interventions can be challenging, particularly for those with complex healthcare needs [142,143]. Decisions about which care tasks or activities to prioritise can be influenced by social and economic factors [144], and individuals who are more highly educated or from a higher socio-economic status have more resources available to enable them to manage their conditions and the impacts of frailty [56,58]. Greater health and technology literacy [58] may also support the use of DHIs to support self-management [145]. Self-management abilities may also be made more challenging in this group by high levels of depression and emotional distress as well as physical and cognitive impairments [142,146,147]. Therefore, disadvantaged groups may require additional support to ensure they achieve the best possible outcomes.
To date, research has focussed primarily on exercise interventions to address the impact of physical frailty and CKD. Future research should focus on understanding the role of multi-component interventions that aim to target the multiple drivers of frailty. This may include a combination of exercise, nutritional, pharmacological, and psychological interventions and could logically lead to greater improvements in outcomes. Evidence for the effectiveness of combined interventions in the general older population appears to be inconclusive, although exercise seems be a key component [70,94,111]. Beetham et al. [147] recently demonstrated the benefits of a multi-component lifestyle intervention, which also included an exercise component, for people with CKD. There are three ongoing studies utilising exercise programmes in conjunction with nutrition and psychological components that will provide further evidence for the frail CKD population [51,98,112].
Current research has identified the need for a holistic, multi-disciplinary approach to both frailty identification and management. Promisingly, there is a growing evidence base in this area, but whilst further research is awaited, there are several practical applications that can be implemented into routine kidney care. These are highlighted in Table 2. Future research should focus on establishing interventions to manage the complications and components of frailty that are specific to the complex needs of those with CKD, particularly those from disadvantaged backgrounds. Table 2. Practical applications to support the care of people with frailty and CKD.

Areas of Focus Practical Applications
Frailty identification and assessment Exercise/physical activity • Routinely discuss the importance of exercise and physical activity for maintaining independence, especially during episodes of physiological stress (e.g., initiation of dialysis, hospitalisation, or transplantation). • Dependent upon needs and resources, provide opportunities to become more physically active, and refer into existing strength-and balance-based fall prevention programmes. • Sign-post to local physical activity and exercise groups within the community.

•
For those unable to undertake exercise, consider supporting them to increase daily physical activity within their usual routine or to reduce sedentary behaviour. • Sign-post to DHIs that are specific to frailty and CKD populations. • Identify those who would benefit from the use of DHIs, such as low physical activity levels, psychological wellbeing needs, or specific educational or peer support needs.

•
Embed the use of renal-specific DHIs within Kidney Units. • Assign Digital Champions within units to promote appropriate resources, educate on safe and researched specific DHIs, and support individuals to access these platforms with digital devices.

Conclusions
Frailty is highly prevalent in individuals with CKD and is directly linked to poor HRQoL, reduced physical function, risk of hospitalisation, and mortality. It is therefore essential that individuals are screened in kidney clinics to identify frailty and facilitate discussions around future treatment plans, and that holistic treatment pathways for management are established. Frailty identification and management in CKD is complex and requires a multi-disciplinary approach. Non-pharmacological interventions are a promising area for routine clinical implementation, and future research should focus on targeted interventions for those with frailty and CKD.

Conflicts of Interest:
The authors declare no conflict of interest.