Current status of the assessment of sarcopenia, frailty, physical performance and functional status in chronic kidney disease patients

Purpose of review Low physical function, frailty, and sarcopenia are common complications of chronic kidney disease (CKD). In this article, we review the epidemiology and pathogenesis of low physical function, as well as its associations with adverse outcomes in CKD patients. Additionally, we present various traditional and novel methods for assessment of physical function in CKD patients. Recent findings In nondialysis dependent (NDD) and dialysis-dependent CKD patients, the prevalence of low physical function, frailty, and sarcopenia are substantially higher than in the general population. The potential mechanisms of low physical function, frailty, and sarcopenia in CKD patients are due to various factors including underlying kidney disease, co-existing comorbidities, and certain therapeutic interventions utilized in CKD. Increasing evidence has also uncovered the ill effects of impaired physical function on clinical outcomes in CKD patients. Summary Routine assessment of physical function is an under-utilized yet important component in the management of CKD patients. Future studies are needed to determine how prescription of exercise and increased daily physical activity can be tailored to optimize the health and well-being of NDD and dialysis-dependent CKD patients in pursuit of successful aging.


INTRODUCTION
Epidemiologic studies show that the chronic kidney disease (CKD) population, including those receiving chronic dialysis therapy, is aging worldwide (e.g., mean age of incident end-stage renal disease [ESRD] patients in Japan is >70 years of age) [1].In parallel with aging, clinical studies also suggest that a growing proportion of the CKD population suffers from a decline in their activities of daily living (ADL), loss of independence, and need for long-term care, which has been deemed to be a form of 'unsuccessful aging [2].'There is compelling need for clinicians to not only prioritize 'longevity' but also 'health longevity' and 'successful aging' vis-a `-vis maintenance of physical function in patients with CKD.Indeed, physical function is defined as the ability to perform both basic and instrumental ADL's, and when impaired, has been associated with adverse outcomes such as hospitalization, nursing home admissions, loss of independence, poor healthrelated quality of life, and death.Additionally, frailty, ascertained by various validated instruments (i.e., Fried frailty index), is a common complication in advanced CKD patients, and is characterized by a decline in physical function and vulnerability to adverse outcomes (i.e., illness, hospitalization).
Frailty was originally described as a state of increased vulnerability to stresses ensuing from age-related decline in physical reserve and function across multiple physiological systems [18,19], The syndrome of frailty has now been characterized in other clinical conditions independent of aging, including CKD and ESRD.Frailty is reported to affect an even higher proportion of chronic dialysis patients than elderly patients without CKD, ranging from 24 to 78% [20].Indeed, muscle wasting and dysfunction are far more pervasive in dialysis patients [20][21][22][23][24] as compared with communitydwelling older adults not receiving renal replacement therapy (i.e., approximately 6.9% in older adults without CKD) [18].

Nondialysis dependent chronic kidney disease
Physical function decline is also observed in earlier stages of nondialysis dependent (NDD) CKD and becomes substantially worse as kidney disease progresses (Table 1).Various indicators of physical function, such as upper and lower strength, balance function, and walking speed, have been found to be significantly worse in patients with stages 4-5 CKD as compared to those with stages 2-3 CKD.Lower levels of estimated glomerular filtration rates (eGFRs) based on serum creatinine levels are associated with worse physical function [25].Overall, the prevalence of sarcopenia in NDD-CKD patients ranges from 5.9 to 50.0% [26][27][28][29][30][31], although estimates may vary based on age and severity of CKD stage [32].Similar to chronic dialysis patients, the prevalence of frailty in NDD-CKD patients is considerably higher compared to those without CKD.While estimates differ according to the type of frailty assessment tool, the prevalence of frailty defined by the Cardiovascular Health Study (CHS) criteria was found to range from 7.0 to 42.6% among NDD-CKD patients [33][34][35][36][37][38].In a study of Japanese community-dwelling older adults with varying levels of kidney function, there was a graded association between the prevalence of frailty and the severity of kidney disease: 8.0%, 10.8%, 18.0% and 32.8% among patients with eGFR levels of !60, 45-59, 30-44, <30 ml/min/1.73m 2 , respectively [37].Hence, there is a compelling need to conduct routine assessments of physical function even in the early stages of NDD-CKD as well as in ESRD patients.

LOW PHYSICAL FUNCTION, SARCOPENIA, AND FRAILTY AS PREDICTORS OF CLINICAL OUTCOMES
CKD patients are at high-risk for such adverse outcomes as death, progression to ESRD, cardiovascular disease, and frequent hospitalizations [45][46][47][48].An

KEY POINTS
There are various mechanistic underpinnings that have been proposed as potential contributors to low physical function in CKD patients, and these factors are largely due to two categories, namely 1) CKD in and of itself and its co-existing comorbidities, and 2) the treatment of CKD.
Routine assessment of physical function is an essential component in the optimal management of CKD patients.
The ideal characteristics of tools used to evaluate physical function and performance include (1) being easily measured, (2) not requiring expensive equipment, (3) and being portable to a wide variety of clinical settings.increasing body of evidence shows that low physical function is a major risk factor for these complications in both NDD-CKD and ESRD patients [49][50][51] (Table 2).

Mortality
Low levels of ADL's and impaired physical function have been identified as predictors of mortality in the MHD population.For example, in a study of 1233 MHD patients from the China Dialysis Outcomes and Practices Patterns Study cohort, those with greater limitations in performing moderate activities and in climbing stairs had a higher risk of mortality compared to patients with lesser degrees of limitation [52].Low muscle strength and slow gait speed have also been identified as predictors of higher mortality in MHD patients, with one study demonstrating a 1.7-fold and 2.3-fold higher death risk, respectively, among those affected by these conditions [41].Frailty has also been associated with higher death risk in the MHD population, even at more moderate levels of severity.For example, in a prospective study of 146 MHD patients from a single center, 50% of older (!65 years) and 35% of younger (<65 years) patients were frail, whereas 36% of older and 29% of younger patients were intermediately frail [23].Notably, this study found an increasingly    ① adjusted HR 2.03 (1.00-4.10)② adjusted HR 0.98 (0.56-1.74) ③ adjusted HR 1.06 (0.60-1.86) ④ adjusted HR 1.70 (0.94-3.05)Climbing stairs limited level Limited a little adjusted HR 0.574 (0.380-0.865)Not limited at all adjusted HR 0.472 (0.293-0.762) higher three-year mortality for incrementally severe frailty levels (16%, 34%, and 40% three-year mortality for nonfrail, intermediately frail, and frail patients) [23].In contrast, the results of studies of sarcopenia and mortality in MHD patients have been mixed.In a study of 330 incident MHD patients conducted by Isoyama et al., sarcopenia was found to be associated with higher mortality risk [9].However, other studies have not confirmed a relationship between sarcopenia and mortality in the MHD population [12,41,42  & ] In these latter studies, dynapenia (defined as presence low muscle strength without low muscle mass) was more strongly associated with mortality than sarcopenia (defined as presence of low muscle strength and low muscle mass) nor presarcopenia (defined as presence of low muscle mass without low muscle strength) [9,42  & ].These data suggest that the evaluation of muscle strength may be a more important factor in the prognostication of MHD patients as compared with assessment of muscle mass.
Among NDD-CKD patients, physical function has also been found to be an important predictor of mortality.In a study of patients with stages 2-4 NDD-CKD by Roshanravan et al., those with weak handgrip strength, slow gait speed, low 6-min walk distance (6MWD) (i.e., as an indicator of exercise capacity), and slow timed up and go (TUG) test (i.e., as an indicator of dynamic balance, which assesses the ability to maintain postural stability and orientation with center of mass over the base of support while the body parts are in motion) had higher mortality risk [53].Similar to the dialysis population, varying degrees of frailty have been associated with higher death risk in NDD-CKD patients.In a secondary analysis of patients from the Modification of Diet in Renal Disease study who underwent direct GFR measurement using iothalamate clearance (mGFR), as well as indirect GFR estimation based on the CKD-EPI creatinine (eGFR) and cystatin C (eGFRcys) equations, there was an inverse association between kidney function and selfreported frailty (i.e., defined as reporting three or more of the following: exhaustion, poor physical function, low physical activity, and low body weight) that was similar for mGFR, eGFR and eGFRcys [54].International data from CKD participants in the United Kingdom Biobank [55 && ] and among advanced CKD patients transitioning to ESRD from Japan [56] have corroborated significant associations between sarcopenia and low ADL levels with mortality risk.

Progression to end-stage renal disease and dialysis
Several studies in CKD patients have reported that higher levels of physical function, ascertained by handgrip strength and cardio-respiratory endurance, were significantly associated with lower risk of commencing dialysis [57,58].Sarcopenia and frailty have each been found to be independent predictors of progression to ESRD [55  && ,59].In one study of CKD participants from the United Kingdom Biobank, the presence of sarcopenia was associated with a two-fold higher risk of developing ESRD [55  && ].In another study of 165,461 patients with CKD and diabetes from the from the Longitudinal Cohort of Diabetes Patients in Taiwan who were evaluated with a modified version of the FRAIL scale, those with 1, 2, and !3 frailty components had a 1.13-, 1.18-, and 1.20-fold higher risk of developing ESRD, respectively [59].However, it remains unclear as to whether sarcopenia and frailty are causally associated with kidney disease progression, or are simply markers for those with more severe renal impairment [59].It bears mention that several meta-analyses have reported that physical exercise and activity are associated with maintenance and improvement in renal function [60][61][62].Further studies are needed to determine whether the prevention of low physical function, frailty, and sarcopenia may have favorable effects on CKD outcomes.

Other clinical outcomes
Impaired physical health has also been associated with other adverse sequelae in CKD patients.For example, physical function measured by maximum walking speed and 30-s chair stand test; sarcopenia; and frailty have each been associated with a higher incidence of cardiovascular events in both the NDD-CKD and chronic dialysis populations [39,59,61,63].One study by Chao et al. also reported that frailty was a predictor of hospitalizations and ICU admissions [59].Emerging data have shown that low physical function, as determined by low handgrip strength and/or low gait speed, is a risk factor for future cognitive decline in NDD-CKD patients [64].

MECHANISMS OF LOW PHYSICAL FUNCTION, FRAILTY, AND SARCOPENIA IN CHRONIC KIDNEY DISEASE
There are various mechanistic underpinnings that have been proposed as potential contributors to low physical function, frailty, and sarcopenia in CKD.These contributory factors are largely due to two categories of clinical characteristics, namely (1) CKD in and of itself and its co-existing comorbidities, and (2) the treatment of CKD (Fig. 1).
With regard to the former category, such comorbidities as diabetes mellitus (DM) and cardiovascular disease are prevalent complications of CKD that can engender a number of maladaptive physiological

Novel therapeutic approaches in nephrology and hypertension
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changes in the body.For example, chronic inflammation, uremia, and malnutrition are frequently observed in CKD patients, and can lead to increased muscle catabolism and decreased metabolism [65,66].In addition, vitamin D deficiency, high parathyroid hormone levels, low klotho levels, and a constellation of mineral and bone disorders in CKD, may contribute to loss of muscle strength and decreased muscle mass [67,68], exhaustion, and frailty [69].Furthermore, decreased exercise capacity and increased exhaustion are exacerbated by anemia [70,71].The interaction between muscle catabolism, low physical function, and exhaustion caused by CKD may consequently lead to low physical function, frailty, and sarcopenia.
In addition to CKD and its related comorbidities, the treatment of kidney disease may also lead to decline in physical condition.With respect to dietary interventions, protein restriction has a demonstrated benefit in slowing CKD progression [72,73], and has been recognized as an effective and safe treatment for conservative nondialytic management even among older adults with CKD [74], as long as patients maintain adequate calorie intake [75].However, in the real-world setting, this strategy may be difficult to adhere to, especially for some elderly CKD patients as well as older adults without CKD who have insufficient social support or suffer from functional decline [76  && ].Hence, there is potential risk that older patients with CKD who are prescribed a low protein diet may not consume enough calories, which may adversely affect their physical function and survival [77].Given that advanced CKD patients are at higher risk of death than of progressing to ESRD, which is particularly true for older adults [78], and that low physical function and frailty have ill effects on survival [53,54,55 && ], the nutritional management of kidney disease, including dietary protein restriction, should be tailored to individuals according to their underlying physical function, overall health status, and lifestyle/ preferences.

ASSESSMENTS OF PHYSICAL FUNCTION
There are a number of validated tools and instruments that can be utilized to assess physical function and performance, although each approach has inherent strengths and limitations.The ideal assessment tool should be (1) easily measured, (2) not require expensive equipment, and (3) be readily portable to a wide variety of clinical settings.In the section below, we describe various approaches that can be used to assess physical function.These are categorized into the domains of muscle strength, gait ability, balance function, muscle mass, exercise capacity, and general physical performance (Table 3) [79][80][81][82][83][84][85][86][87][88][89][90][91][92].

Muscle strength
Preservation of muscle strength is one of the most important aspects of preventing physical disability and adverse downstream sequelae.As a measure of upper limb strength, handgrip strength is one of the most convenient and useful indicators of muscle strength and sarcopenia.Although a handgrip dynamometer is required to conduct this assessment, the equipment is typically inexpensive.With respect to assessing lower limb strength, measurement of isometric and isokinetic knee extension strength by a trained physical therapist is considered the clinical gold-standard.However, these evaluations require specific equipment (i.e., isokinetic dynamometer) which may be expensive.Alternatively, assessments such as the 5-chair stand (i.e., tool to assess sit-tostand ability which measures the time taken to stand five times from a sitting position as rapidly as possible) and the 30-s sit-to-stand test require only a stopwatch and chair, and can be easily measured in screening decreased lower extremity muscle strength.If the abovementioned measured values fall below the recommended thresholds, and/or if patients cannot stand up due to very low muscle strength, we recommend that patients should be referred to a physical therapist for prescribed physical exercise training.

Gait ability
For the evaluation of mobility function, gait speed test is considered one of the most practical and objective indicators.There are two types of assessments, namely maximum gait speed and comfortable gait speed.Comfortable gait speed has, in fact, been incorporated into some definitions of frailty and sarcopenia.Typically, gait distances of 4, 5, or 10 m are considered acceptable.However, a gait speed of less than 1.0 m/s meets the threshold for some frailty criteria [93], and a speed of less than 0.8 m/s is considered a slow gait speed within the definition for sarcopenia [7].

Balance function
Balance function is typically categorized into static balance vs. dynamic balance.The one-leg stand (OLS) test is frequently used as a static balance test, and it is considered a useful predictor of future falls [82].In addition, the TUG Test has been utilized as an indicator of dynamic balance function.The TUG  www.co-nephrolhypertens.com Copyright © 2021 Wolters Kluwer Health, Inc.All reserved.
evaluation consists of several elements, such as standing up, walking, turning around, and sitting down, which are akin to the movements of daily living.The time that a patient requires to complete the TUG evaluation has been associated with future falls and decline of ADL's [94,95].A more complicated measurement tool, the Berg balance scale is commonly used among physical therapists as a screening test for general balance function [96].

Skeletal muscle mass
Imaging modalities such as magnetic resonance imaging and computed tomography (CT) are considered gold-standard methods for the assessment of skeletal muscle mass.However, these tools are not commonly used in real-world clinical settings because of their high cost, lack of portability, and requirement for highly trained personnel to conduct the tests [7,97].Dual-energy X-ray absorptiometry (DXA) and bioimpedance analysis (BIA) are more widely available tools used to assess muscle mass.However, it bears mention that the DXA text is typically utilized in specialty clinical settings, and may be challenging to conduct in a primary care clinical setting [7,97].In addition, measurements of DXA and BIA are affected by the hydration status of the patients [7].Hence, there may be potential risk of overestimating muscle mass in advanced CKD patients, particularly in ESRD patients with volume overload and edema.
If clinicians do not have access to the abovementioned equipment, there are alternative methods that can be used for evaluating muscle mass as a screening tool.For example, anthropometric measurements such as mid-arm muscle circumference (MAMC) and calf circumference (CC) are easily implemented in the clinical setting.These methods have been shown to correlate with muscle mass and are considered valid indicators of sarcopenia in older adults [85,98,99].In addition, these tools are used as assessments of body composition even in CKD and MHD patients [14,26,39,100].However, some experts have advised that these anthropometric measurements are not ideal for assessing muscle mass, such as in a statement by the EWGSOP2 [7].Hence, anthropometric measurements should be used as screening tools in scenarios where other muscle mass diagnostic methods are not available [7].Also, if accuracy is to be obtained, the anthropometrist must be well trained in the anthropological techniques that are to be used, and must be sensitive to the need for meticulous care in conducting these measurements.
It is well established that muscle mass can be estimated from serum and urinary creatinine levels.Creatinine is a chemical product of creatine phosphate in muscle, and therefore serum creatinine and the urinary excretion rate of creatinine can be used as proxy measures for estimating muscle mass [101].Serum creatinine can often be used to estimate muscle mass under steady-state conditions, including in the NDD-CKD and MHD populations  [80] Influenced by the patients volume overload and edema [102,103].Serum can also be used to calculate the creatinine index, which can be calculated from published formula-derived creatinine generation rates and kinetics-derived generation rates, and has been associated with survival in MHD patients [104].
In order to simplify the process of estimating net creatinine production, several recent studies have described a modified creatinine index that is calculated with the use of such variables as age, sex, predialysis serum creatinine, and Kt/V for urea.It is contended that this modified creatinine index is a fairly accurate surrogate of muscle mass and is also a predictor of adverse outcomes in MHD patients & ].However, the precise reference values for creatinine index in identifying patients with low muscle mass or sarcopenia are not clear.Moreover, the confidence intervals that define the  relationship between creatinine index and actual skeletal muscle mass need to be better defined.Further study of this assessment method is needed.
There are several other potentially major confounding factors that may limit the accuracy of using serum and urinary creatinine to estimate skeletal muscle mass.Mammalian meat also contains abundant creatine, and the quantity of striated muscle (i.e., skeletal and cardiac muscle) ingested will affect serum and urine creatinine.Cooking more readily converts the creatine in meat to creatinine.Currently, many people who are interested in being physically conditioned may regularly ingest creatine supplements which will also affect their serum and urine creatinine levels.Finally, creatinine is degraded by intestinal bacteria.The magnitude of intestinal creatinine degradation appears to be increased when serum creatinine levels are substantially elevated as in advanced CKD and ESRD patients.It is not known what factors, if any, may influence the rate of intestinal creatinine degradation.

Exercise capacity
Cardiopulmonary exercise testing (CPX) with ventilatory gas analysis is one of the most effective methods for determining exercise capacity.CPX can measure cardiorespiratory indicators such as oxygen uptake (VO2) and anaerobic threshold (AT), and these indicators can be used to prescribe exercise.In addition, CPX with an electrocardiogram can assess arrhythmias and ischemic electrocardiogram changes during exercise, and hence is useful for evaluating cardiac risk.However, CPX requires access to expensive equipment and must be conducted under the supervision of trained professionals.Hence, the applicability of CPX for broad segments of the NDD-CKD and ESRD populations may be limited.
The 6-min walk distance/test (6MWD/6MWT) is commonly used as a surrogate measure of exercise capacity in clinical setting.This is considered to be a simple and easy measurement, and the value of 6MWT has correlation with CPX indices [107].The 2-min walk distance/test (2MWD/2MWT) is an abbreviated version of the 6MWD/6MWT that may be even easier to implement among NDD-CKD and ESRD patients.

General physical performance
To assess physical function in a more global manner, such general physical performance tests as short Copyright © 2021 Wolters Kluwer Health, Inc.All rights reserved.
physical performance battery (SPPB) may be used [108].SPPB measurements comprised of a balance function, gait speed, and 5-chair stand test (Fig. 2), and have been used in the diagnosis of sarcopenia by EWGSOP2 [7] and AWGS2019 [80], as well as in the diagnosis of frailty (revised EWG-SOP2 and AWGS2019 criteria shown in Fig. 3).[40].SPPB is a simple assessment and does not require specialized equipment, and hence is commonly used in the clinical setting.However, the SPPB may not be ideal for evaluating physical performance in robust populations given that it has a ceiling effect in patients with high functional abilities, limiting its usefulness among those who are active and independent [109].

CONCLUSION
Low physical function, frailty, and sarcopenia are highly prevalent complications among patients with CKD, and are potent predictors of mortality, progression to ESRD, cardiovascular disease, and other adverse sequelae.Future studies are needed to determine how prescription of exercise and increased daily physical activity can be tailored to optimize the health and well-being of NDD-CKD and ESRD patients in pursuit of successful aging.

FIGURE 2 .
FIGURE 2. Short Physical Performance Battery in the assessment of physical performance [108].

FIGURE
FIGURE Revised European Working Group on Sarcopenia in Older People 2 (EWGSOP2) and Asian Working Group for Sarcopenia 2019 (AWGS2019) criteria.

Table 1 .
Epidemiologic studies of the prevalence of physical function, frailty, and sarcopenia in CKD and ESRD Physical performance in CKD Otobe et al.

Table 3 .
Assessments physical function