Research Progress on Cognitive Frailty in Older Adults with Chronic Kidney Disease Open Access

With the continuing rise in life expectancy globally, it is estimated that the population of people aged ≥60 years will increase to 420 million by 2035 [1]. China is experiencing a particularly noticeable ageing population, with the number of people aged ≥65 years exceeding 200 million by the end of 2021, accounting for 14.2% of the country’s total population [2]. Older adults are susceptible to chronic kidney disease (CKD), which is a common condition in which the structure and function of the kidneys are damaged for various reasons. Statistics show that 10.8% of patients with CKD in China are aged >60 years, with end-stage renal disease (ESRD) incidence of up to 1 in 100,000 [3]. Older adults are also a high-risk group for cognitive impairment and frailty [4, 5]. In 2013, the International Association of Gerontology and Geriatrics pointed out that cognitive frailty includes physical frailty and cognitive impairment, which is a heterogeneous clinical syndrome in older adults [6]. This study reviews the research progress in epidemiology, pathogenesis, screening methods, prevention, and treatment of cognitive frailty in older adults, particularly those with CKD.

Frailty is a common clinical syndrome in older adults characterised by an age-associated decline in the physiological reserve capacity across multi-organ systems. In turn, this results in vulnerability in the body’s anti-stress ability, thereby increasing the risk of clinical outcomes such as death, hospitalisation and disability [4]. According to the Chinese Experts Consensus on Assessment and Intervention of Older Patients with Frailty, the prevalence of frailty among older patients in China is 4.9–83.4% [4]. Older patients with CKD have a higher prevalence of frailty. A systematic review of patients with CKD reveals a prevalence of frailty in patients with CKD aged >65 years who are not undergoing dialysis of 43%, compared with 73% in patients with CKD [7] who are undergoing dialysis. Frailty, a predictor of adverse health outcomes, can increase the risk of cardiovascular events, all-cause death and acute kidney injury and accelerate the progress of renal function in older patients with CKD [8]. One of its reliable signs is sarcopenia, and patients with CKD are prone to this condition due to long-term loss of appetite, insufficient intake of protein, micro-inflammation, and energy consumption [9]. The incidence of sarcopenia among older patients with CKD is as high as 20–44% [10]. Sarcopenia has a close bearing on cognitive frailty [11], which may be related to the effects of mitochondrial dysfunction, epigenetic changes, and oxidative stress on metabolism, stress response, endocrine and neuromuscular systems [12].

Cognitive frailty refers to the simultaneous presence of physical frailty and cognitive impairment, which is one of the subtypes of weakness. In 2013, the International Academy on Nutrition and Aging (IANA) and the International Association of Gerontology and Gerontology (IAGG) jointly organised an International Consensus Group on Cognitive Frailty, which, for the first time, defined “cognitive frailty” as a heterogeneous clinical manifestation characterised by the following: (1) physical frailty and cognitive impairment, defined by a Clinical Dementia Rating of ≥0.5; and (2) exclusion of concurrent Alzheimer’s disease or other forms of dementia [6]. Cognitive frailty may give rise to the decline of the reserve function of multiple physiological systems and the destruction of homoeostasis, the increase of human vulnerability, and the decrease of resistance to stressors, thus increasing the risk of adverse health outcomes such as falls, hospitalisation, and death. Cognitive frailty is fundamentally about the cognitive impairment of older patients with frailty. Cognitive impairment is a defect, ranging from mild to severe, in one or more key brain function, such as memory, learning, concentration and decision-making. A syndrome of cognitive impairment or cognitive decline that affects independent living is called dementia [13]. Patients with CKD suffer from a significantly increased risk of cognitive impairment, with prevalence rates as high as 10–40% at different stages of CKD. Among them, patients with ESRD on maintenance haemodialysis (MHD) have the highest prevalence [5]. Studies have shown that patients with sarcopenia have improved physical function after treatment, which effectively slows the progression of cognitive impairment [14].

The core feature of cognitive frailty is cognitive decline. The panel of experts of the IANA-IAGG suggested that a comprehensive cognitive function assessment should be conducted to identify cognitive frailty effectively with assessment scales, mainly including the Mini Mental State Examination Scale [15] and the Montreal Cognitive Assessment Scale [16]. Various tools exist for evaluating different cognitive functions: The Stroop colour word test and letter-number sorting can be used to assess attention function; the fluency test, digital symbol substitution test, alternate connection test, and the Wisconsin card sorting test can assess the executive function; the Rey complex figure test, Rey auditory vocabulary learning test, and the Wechsler memory scale can assess memory function; language function can be assessed by the word fluency test and the Boston naming test [17]. Moreover, the Neuropsychiatric Inventory and the Geriatric Depression Scale can also be used to assess the severity of patients’ behavioural disorders [15].

Physical frailty is a necessary condition for the diagnosis of cognitive frailty [18], which is commonly assessed with Fried’s Phenotypic Frailty Scale [17], the Fatigue, Resistance, Ambulation, Illness and Loss of Weight Scale [19] and the Frailty Index Scale [20]. Measures such as calf circumference, waist circumference, body mass index, and gait can also be used to assess frailty [21‒23].

The core feature of cognitive frailty in older patients is cognitive impairment. The causes of cognitive impairment in patients with CKD are multifactorial [24], but they mainly include traditional cardiovascular and cerebrovascular risk factors and CKD-related factors.

Patients with CKD often suffer from multiple diseases. Therefore, the causes of cognitive impairment in such patients are also multifactorial [25]. First, patients with CKD often have complications such as diabetes, hypertension, dyslipidaemia, and other cardiovascular disease risk factors, which are also traditional risk factors of cerebrovascular disease [26‒28]. Second, the clinical cerebrovascular diseases of patients with CKD include stroke and transient ischaemic attack. A study of 1,382 patients undergoing MHD showed that the incidence of stroke was significantly higher than that of the general population (41.5/1,000 vs. 50.1/1,000 patient years), and diabetes and an age >65 years were related factors of stroke [26]. Third, cerebrovascular disease in patients with CKD often has subclinical manifestations, showing small vessel infarction, lacunar, and white matter disease on imaging [29]. Cognitive impairment related to cerebrovascular diseases in patients with CKD is mainly manifested as executive dysfunction [30]. Furthermore, patients with CKD often have impaired automatic regulation of cerebral blood flow, resulting in decreased cerebral blood flow. Studies have shown that CKD-related perivascular cell dysfunction can be manifested as a high intensity of focal white matter on magnetic resonance imaging (MRI), which is mainly due to focal ischaemia and blood flow reduction caused by vasoconstrictor peptides [31]. The decrease in cerebral blood flow is also one of the mechanisms of cognitive impairment [32].

Neurological complications, such as cognitive impairment, uraemic encephalopathy and anxiety, have been reported in patients with CKD. Early in the disease, uraemic metabolites begin to accumulate. The clearance of medium and large molecular metabolites by dialysis membrane is much lower than that of small molecular metabolites [33]. Despite the gradual reduction of uraemia-related severe cognitive impairment (uraemic encephalopathy) with the application of high-throughput dialysis membranes to remove uraemic toxins [34], studies have shown that a variety of medium and large molecular uraemic toxins, including phenylalanine, benzoic acid, and glutamic acid phase metabolites, may be markers of cognitive impairment related to patients with CKD [35]. Cognitive impairment in patients with CKD may involve several factors, including haemodynamic disorders and blood-brain barrier (BBB) impairment. The BBB guarantees the exchange of solutes between the blood and the brain through a complex cellular organisation and a diverse range of transport proteins. This study hypothesises that the increased exposure of the brain to protein-bound uraemic toxins is involved in BBB disruption and induces a perturbation in the activity of endothelial membrane transporters. This phenomenon could play a part in the evolution of neurological disorders driven by this kidney-brain crosstalk impairment [36]. The potential for uraemic toxin clearance to improve cognitive function should be further assessed in future studies.

Cognitive function can be impaired by dialysis [37‒39]. Haemodynamic instability in haemodialysis (HD) may lead to insufficient cerebral perfusion in patients undergoing HD, which is the cause of cognitive impairment in patients with ESRD [37]. Wolfgram et al. demonstrated that monitoring cerebral perfusion in patients undergoing HD may delay cognitive frailty [40]. Findlay et al. measured the cerebral blood flow of 97 patients undergoing MHD by transcranial Doppler ultrasonography and found that the average blood flow velocity decreased significantly during dialysis, which was related to the ultrafiltration volume [41]. Cerebral microbleeds may be another risk factor for cognitive impairment related to HD; they are commonly seen in patients undergoing HD, which may have a close bearing on anticoagulants, such as heparin, during treatment. A study involving 180 patients undergoing HD showed a clear correlation between severe cerebral microbleeds and cognitive impairment, involving overall cognitive function, memory, language ability, and executive function [42]. Cerebral microbleeds can also increase the risk of intracranial haemorrhage. Haemorrhagic stroke, as one of the common types of cerebrovascular diseases, is also one of the causes of cognitive impairment [43]. In addition, dialysate temperature and ultrafiltration rate will affect cerebral blood flow and then affect cognitive function [44]. The impact of the dialysis dose on cognitive function remains uncertain, particularly in the current era of increased dialysis dose and flux. One study explored the cross-sectional relationship between dialysis adequacy and cognitive function in a cohort of patients undergoing MHD [45]. The study found no association between a lower Kt/V value and poorer cognitive performance. Future studies should address the longitudinal relationship between dialysis adequacy and cognitive function to confirm these findings.

Patients with CKD often also experience anaemia, which may be closely related to the occurrence of cognitive impairment [46, 47]. However, cause-and-effect relationships are difficult to assess because it is not clear whether anaemia affects cognition directly (perhaps through decreased perfusion/oxygenation) and/or indirectly (by increasing the risk of cerebrovascular events, including stroke) or whether it is simply a sign of a higher risk phenotype for comorbid conditions, including cognitive impairment. In patients with CKD, the correction of anaemia from low values (<9 g/dL) improves several aspects of quality of life (including breathlessness and physical performance), which in turn may be beneficial for cognitive function [48, 49]. Aluminium brain deposition was once considered a factor leading to dementia in dialysis patients [50]. It has been found that the administration of the chelating agent desferrioxamine to patients with ESRF exposed to aluminium results in elevated plasma concentrations and may cause neuropsychiatric symptoms [51]. However, it is unclear how much of this toxicity is related to desferrioxamine itself. At present, such a situation is largely eliminated by stringent water testing and limiting the use of aluminium-based phosphorus adhesives; nevertheless, this is still worthy of attention.

An inverse correlation between higher serum parathyroid hormone (PTH) levels and poorer cognitive function has been observed in the general population, although the level of evidence was variable [52]. Secondary hyperparathyroidism (SHPT) can potentially interfere with neurotransmission by increasing calcium levels in the brain; hence, controlling SHPT with calcimimetics may help to improve cognitive function [53]. According to a recent study that assessed the risk of dementia in older patients (age ≥66 years) with SHPT, the treatment for SHPT was linked to a 42% lower risk of dementia compared with untreated patients [54].

Patients with CKD often have calcium and phosphorus metabolism disorder, with the levels of PTH and fibroblast growth factor 23 (FGF23) increased, whereas the levels of α-Klotho and calcitriol are low. The disorder of calcium and phosphorus metabolism may give rise to vascular calcification and endothelial dysfunction, which in turn lead to an increase in the incidence of cerebrovascular diseases and related cognitive impairment [55, 56]. The disorder of calcium and phosphorus metabolism is also related to cerebral small vessel disease, which is a risk factor for cerebral small vessel disease stroke and causes cognitive impairment by cerebral small vessel disease [57]. Higher FGF23 levels are associated with a higher risk of dementia [58]. A study of 263 patients undergoing MHD showed that FGF23 was associated with poor performance of comprehensive memory score [59]. The expression of α-Klotho was the highest in the kidney and parathyroid gland, followed by that in the brain. The level of α-Klotho in the circulation, kidney, and parathyroid gland of patients with CKD is down-regulated [60]. A study based on MRI found that the decrease in circulating α-Klotho level is related to the increased risk of dementia and deep white matter lesions in the brain [61] and also related to the risk of B2 microglobulin-related amyloidosis and dementia [62].

Depression or depressive disorder, including clinical and subclinical depression, may lead to cognitive impairment and may also limit the cognitive impairment test results of people with normal cognitive function. A study involving 241 patients undergoing HD revealed that depression is related to cognitive frailty [63]. One study found that depression was an independent risk factor for cognitive decline and that people with depression were 2.5 times more likely to develop the disorder than people who were not depressed [64]. In this regard, Rivan et al. analysed a population of Malaysian seniors in a 5-year follow-up study [65] and discovered that the prevalence of cognitive frailty was 7.1%, with depression being one of the major risk factors. Depression is strongly associated with cognitive dysfunction and frailty, which may be due to common risk factors and similar pathological basis, including oxidative stress, chronic inflammation, cerebral white matter lesions, and mitochondrial dysfunction [66, 67]. Polypharmacy of CKD may also lead to cognitive impairment. The high risk of cognitive impairment may be increased by a large number of drugs, potential drug interaction, and impaired renal clearance function. Sleep (or decreased sleep quality) may also play a role in cognitive impairment (CI) [68, 69]. A study including 613 older patients undergoing HD showed that CI in middle-aged and older patients undergoing HD was related to poor sleep quality, particularly sleep disorder, daytime dysfunction, and long sleep time [70, 71].

The well-being of older patients with frailty requires comprehensive intervention in many aspects, including nutrition, multi-component exercise and drugs. Aerobic exercise, strength training, explosive-force training, flexibility training, balance training, and multi-component intervention can all improve the degree of sarcopenia in older patients [72]. A study involving 1,494 older patients showed that the intervention of resistance training, aerobic exercise, and balance training can improve the walking speed, muscle strength, exercise ability, and physical function of weak patients [73]. Strength training can improve skeletal muscle strength and is an important way to prevent skeletal muscle attenuation and falls; it is also a key factor in maintaining the functional ability of older people. Multi-component exercise intervention refers to the integration of aerobic exercise, strength training, balance training, and functional training in the process of debilitating intervention, which can stimulate and promote the benign adaptation of many physiological systems, such as neuromuscular and cardiovascular, thus improving senile debilitating syndrome, and its effect is significantly better than any single-mode intervention [74]. Research from the SPRINTT project on patients with CKD showed that CKD and patients with ESRD are in a state of chronic inflammatory reaction energy consumption for a long time, and combined exercise and nutrition intervention is beneficial to maintain their mobility; this intervention is recommended to protect the mobility of older adults at risk of disability [75].

In patients with mild to moderate CKD, the application of renin-angiotensin system (RAS) blockers may slow down the decline of cognitive function by controlling blood pressure, reducing proteinuria, or improving vascular conditions. Research from the SPRINT MIND trial showed that the incidence of cognitive impairment in the intensive treatment group (the target systolic blood pressure was controlled <120 mm Hg) was lower than that in the standard treatment group (the target systolic blood pressure was controlled <140 mm Hg) [76]. Patients undergoing MHD are more likely to have serious cognitive impairment, and a certain dialysis frequency, dialysis adequacy, and dialysate temperature may improve their cognitive function. Cooling dialysate may benefit cognitive status, and increasing dialysate temperature may affect cognitive function. A study by Eldehni et al. included 73 patients with MHD. The dialysate temperature in the control group and intervention group were set at 37° and 0.5° lower than the core body temperature, respectively. After 1 year, the changes of white matter in the intervention group did not change, whereas the control group showed obvious white matter changes [44]. In addition, renal transplantation may improve the cognitive impairment of patients with ESRD. Studies have shown that the cognitive function of both adults and children can be continuously improved 1 year after renal transplantation [77]. Another study showed that the cerebral blood flow and the concentration of neurochemicals choline and inositol tended to be normal after renal transplantation [78], suggesting that some brain abnormalities of CKD were reversible and normalised with renal transplantation.

Cognitive frailty, as a vital subtype of weakness, is a group of heterogeneous clinical syndromes in older adults. At its core, it is associated with cognitive impairment in older patients with physical frailty. The follow-up population is ageing, and the incidence of CKD in older patients is increasing gradually; the cognitive frailty of older patients with CKD has become an area of intense research. The pathogenesis of cognitive frailty may be closely related to traditional cerebrovascular diseases, cardiovascular and cerebrovascular risk factors, uraemic metabolites, and anaemia. Exercise intervention, nutrition intervention, multi-component intervention and drug intervention can reduce the weakness of older patients with CKD. The application of RAS blockers and changes in dialysis conditions, such as kidney transplantation, dialysis membrane, dialysis frequency, and temperature, may play a positive role in improving cognitive impairment of older patients with CKD. This review provides a more comprehensive analysis of the concept, epidemiology, screening methods, preventive measures, and pathogenesis of cognitive frailty in older patients with CKD. Timely intervention by clinicians can significantly improve cognitive function, improve self-management ability, and quality of life of older patients with CKD, and reduce the incidence of complications.

This study was conducted in accordance with the declaration of Helsinki. The protocol of this study was approved by the Ethics Committee of Beijing Chaoyang Hospital. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication was not needed.

The authors declare that they have no conflict of interest.

This research did not receive any funding support.

Yuan Y. designed and wrote the manuscript; Chang J. searched literature; Sun Q. searched literature and wrote the manuscript; and all authors have read and approved the manuscript.

All articles referred to in this study are included in this study. Further enquiries can be directed to the corresponding author.