Frailty is defined as a state of decreased cognitive and physiological reserve with a poor ability to respond to stressors . Initially described in the geriatric population, frailty is a marker of unsuccessful aging and is associated with increased disability, risk of falls, hospitalization, and death . As a predictor of poor outcomes, the identification of frail status can help direct treatment decisions and identify a segment of the population that could benefit from ‘de-frailing’ interventions such as physical activity programming. In the frail population, such treatments have the potential to improve health-related quality of life (HRQOL) and outcomes.
FRAILTY IN CHRONIC KIDNEY DISEASE
The prevalence of frailty is high in both old and young individuals with chronic kidney disease (CKD). This prevalence increases with age and with declining renal function [2,3]. Using data from the Cardiovascular Health Study (CHS), which enrolled community dwelling individuals aged 65 or older, Shlipak et al. showed that elderly individuals with CKD were two to three times more likely to be frail than those with normal renal function even when adjusted for confounders. Using data from the Third National Health and Nutrition Examination (NHANES III), Wilhelm-Leen et al. demonstrated that even younger adults with CKD were two to six times more likely to be frail than those without CKD. In this cross-sectional study, the prevalence of frailty increased as CKD progressed . Frailty was identified in 6% of individuals with Stage 1–2 CKD and 21% of those with moderate-severe CKD (Stage 3b–5), respectively. The persistence of this relationship even when adjusted for multiple potential modifiers such as sarcopenia, comorbidities, medications, anemia, and inflammation indicates that frailty is a distinct syndrome independent from other common complications and comorbidities seen in CKD. The highest proportion of frailty is seen in individuals with end-stage renal disease (ESRD) who require dialysis; in this subset, the prevalence is 26–68%, depending on study group characteristics and the frailty measures that were used [4,5,6▪▪].
Frailty has been associated with an increased risk of hospitalization, mortality, and falls in individuals with CKD [2,5,7–9]. In view of its high prevalence in individuals with CKD and association with adverse outcomes, the identification of frailty has significant potential to impact treatment decisions and modify interventions in this population. The ultimate goal of such directed interventions would be to improve HRQOL, minimize disability, and reduce adverse outcomes.
FRAILTY MEASURES USED IN CHRONIC KIDNEY DISEASE
Although the frailty concept is well accepted, its definition and measurement is somewhat more controversial and various frailty measures incorporating diverse domains exist. Although early frailty measures predominately incorporated physical performance measures, several recently proposed measures have added cognitive, comorbidity, and disability criteria. Some of these tools have been evaluated in individuals with CKD. An overview of the most common measures of frailty, the evidence linking each measure to outcomes in the CKD population and a summary of each tool's strengths and limitations is provided below (Table 1).
The Fried frailty definition was originally developed in a community living elderly population participating in the CHS, and includes the following subdomains: weight loss/sarcopenia, slowness, weakness, exhaustion/low energy, and low physical activity (Table 2) . Identification of a deficit in each of these five areas is scored as one point and total deficit points are summed. Individuals who score 3 or more out of a total of five points are considered frail . Those who have only one or two criteria present are classified as intermediate risk or prefrail .
Strengths and evidence linking measure to outcomes
This well-validated tool incorporates objective, reliable, and reproducible criteria making it useful for studying large populations and for conducting clinical research. As evidence of this, the Fried criteria have been extensively used in diverse populations and are predictive of 1.5-fold to 3-fold increased risk of falls, mortality, and institutionalization in the ESRD population [5,7]. In addition, various studies in the CKD and dialysis population have used criteria for frailty that are based on, but slightly modified from the original Fried criteria (discussed in next section) [1–4].
Criticisms of the Fried criteria include a focus predominately on physical deficits. The lack of inclusion of cognitive function or comorbidities, both of which are extremely prevalent in the CKD population, may provide a less comprehensive assessment of frailty than other measures. Another potential source of error exists with the Fried weight loss criterion. This is particularly important in the later stages of CKD and at dialysis initiation in which weight changes may indicate fluids shifts rather than gain or loss of true body weight. Finally, the categorical nature of this tool may fail to identify small changes in frailty status over time, potentially missing earlier opportunities for intervention, as even small changes to frailty status have been associated with change in outcomes [11,12,14].
Modified Fried frailty criteria based on self-report
Retaining the original Fried criteria for weight loss, exhaustion, and physical activity, this version of the tool measures slowness and weakness using the physical function scale (PFS) score as determined from the Short Form-36 (SF-36), a self-reported HRQOL questionnaire. A PFS score of less than 75 is indicative of significant deficits in the slowness and weakness categories, and results in the scoring of one point for each of these domains . Overall scoring and definition of frailty is the same as in the original Fried criteria with a score of 3 or more (out of a total possible score of 5) indicating frail status (Table 2).
Strengths and evidence linking measures to outcomes
Originally described using data from the Women's Health Initiative observational study, these modified Fried criteria were predictive of hip fracture, disability, mortality, and hospitalization in a population of community dwelling women over age 65 . Frailty as defined by these modified Fried criteria has also been associated with a 1.5-fold to 2-fold increased risk of death in incident hemodialysis patients [4,8]. As the SF-36 is a HRQOL measure that is commonly used, such a definition offers advantages in both clinical and research settings in which it may be difficult to obtain objective physical performance measures to assess frailty. In large population-based studies, other self-reported frailty measures, also modified from the original Fried criteria, have been predictive of mortality in individuals with CKD (Table 2) [2,9].
The use of an identical definition for two domains in this frailty measure is problematic and may lead to false positive frailty classifications. Indeed, several reports suggest that measurement of frailty using self-reported measures may result in a higher proportion of individuals being identified as frail than when using objective criteria . In a study comparing self-reported physical function with physical performance measures for the determination of frailty in 771 maintenance hemodialysis patients, 53% were frail by the self-reported definition and 29% were frail by the performance-based definition [16▪]. Sensitivity of the self-reported definition of frailty was 90% and specificity was 64% when using the performance-based definition as a gold standard [16▪]. Similarly, in a population of 188 prevalent hemodialysis patients, Painter demonstrated that 78.2% of individuals were frail using self-report as compared with 34% frail using physical performance measures . Agreement with both methods used in this study only occurred in 44 individuals . Modifying the thresholds for self-reported function and scoring to improve overall fit with the performance-based definition improved the diagnostic performance of the self-reported criteria when compared with the gold standard [16▪]. However, the risk of over-identification of frail status with the use of self-reported criteria remains.
In contrast to the focus on physical frailty with the Fried criteria, the Frailty Index applies an inventory of deficits in activities of daily living, cognition, comorbidities, and clinical and neurological abnormalities noted on examination [13,17]. The Frailty Index is calculated by dividing the number of identified deficits by the total number of deficits listed in the inventory . Stratifying patients into quintiles based on frailty index score indicates frailty status. Thus, no strict definition of frailty is used. The original Frailty Index used a 70-item deficit inventory based on objective clinical assessment and patient self-report [13,18].
Strengths and evidence linking measures to outcomes
Since its first validation, multiple studies in diverse populations have demonstrated the utility of using a lower total number (usually 20–40 in total) or slightly different deficit inventory, making this measure more practical for a clinical environment . These indices are well validated in the community dwelling elderly and are predictive of mortality [12,19].
The Frailty Index has not been extensively used or validated in individuals with CKD. In addition, the lack of standardization in different populations because of the use of different criteria is problematic and makes comparison between studies and different populations difficult. This, coupled with the fact that CKD is not included as one of the conditions in the Frailty Index  despite its significant association with frailty, make the utility of this measure in individuals with CKD uncertain.
Short physical performance battery
Multiple measures of frailty are heavily influenced by deficits in physical function. It is well established that physical function declines with age and with progression of renal disease in individuals with CKD . Poor performance on physical performance measures (regardless of type) has been associated with both frailty and worsening kidney function in multiple studies [3,22]. Thus, a rapidly administered test to measure physical function objectively may be an effective screening tool for frailty in this population. The short physical performance battery (SPPB) has been identified and used as one such tool in the general population .
The SPPB uses a composite score derived from objective balance (side by side; semitandem, and tandem tests), timed chair-stand (five repetitions), and gait speed testing to assess degree of impairment to physical function . Scores can range from 0 (worst) to 12 (best), with scores less than 10 indicating frail status .
Strengths and evidence linking measures to outcomes
Lower SPPB score has been associated with a graded increase in the risk of hospitalization, mortality, and disability in diverse populations [11,23,24]. An SPPB score below 9 has been correlated with the frailty phenotype in several distinct elderly populations and a clinically significant difference in SPPB score has been established in older adults [25–27]. This facilitates the interpretation of longitudinal observations with this tool. In patients with CKD, SPPB score declines with worsening renal function, paralleling findings with other frailty measures. Using data from the Chronic Renal Insufficiency Cohort, Reese et al. showed that individuals with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 had a significantly lower SPPB score when compared with those with an eGFR greater than 60 ml/min and this decline worsened with increasing renal dysfunction. The SPPB incorporates several key measures used in other frailty criteria (gait speed and strength) and has potential as a rapid and objective screening tool for frailty in the CKD population that could be applied longitudinally in both research and clinical settings.
The SPPB has not been compared with other validated definitions for identifying frailty in individuals with CKD. Thus, its performance for this purpose is uncertain. In the study by Reese et al. mentioned above, 66% of participants had an SPPB of 9 or less, but only 7% were frail as defined by the Fried criteria . This suggests that the SPPB threshold for frailty in the CKD population may not be the same as that observed in the general elderly population. In addition, the association between frailty as identified by SPPB and adverse outcomes in individuals with CKD is unknown. Therefore, prior to the adoption of this tool as a routine measure of frailty in CKD, further validation studies are required.
Clinical frailty scale
Using clinical judgment based on key descriptors for each level of frailty, the clinical frailty scale (CFS) is a brief tool that can be easily applied in clinical practice. The CFS uses a 7-point scale based on level of disability that ranges from 1 (very fit/robust and active) to 7 (severely frail/completely dependent on others) .
Strengths and evidence linking measures to outcomes
The CFS has been validated in a large Canadian community dwelling elderly population and has been shown to have excellent construct validity and some evidence of interrater reliability . The CFS was also found to be predictive of mortality and institutionalization in the elderly population and this was similar to the utility of other frailty measures . The CFS has also been shown to predict mortality in individuals with ESRD. In 468 individuals commencing hemodialysis in a Canadian tertiary care center with mean age 63 years old, 26% were identified as frail (ranging from mild to severe) and an additional 27% were identified as ‘vulnerable’ [6▪▪]. Each 1-point increase in CFS score was associated with a hazard ratio for mortality of 1.22 (95% confidence interval 1.04–1.43) [6▪▪]. This relationship did not seem to be modified by advanced age, comorbidity, and dialysis modality [6▪▪].
The CFS is subjective and clinicians may not necessarily use a standardized set of patient characteristics in their application of this tool. This results in questionable reliability across different time periods or with different assessors. One problematic issue identified with the above study and the use of the CFS in dialysis patients is that based on the criteria identified, individuals with ESRD on hemodialysis should consistently score at least 3 or higher (Well: with treated comorbid disease) because all have at least one comorbid disease (CKD). Despite this, 25% of individuals in the above mentioned study scored either one or two demonstrating the potential subjectivity of this tool [6▪▪]. As this is the first report of the use of the CFS in CKD, further validation studies in this population are required.
Clinical impression of frailty
The tools described above are not yet routinely used in the clinical setting. However, physiological vulnerability and ability to withstand clinical stress is often assessed on an individual patient basis during clinical interactions using provider and patient perception and experience . Whether this interpretation is similar to what would be concluded with a validated measure of frailty is uncertain and an ongoing source of debate. To study this question, Salter et al.[30▪] compared frailty as measured using the original Fried criteria and frailty as perceived by nephrologists, nurse practitioners, and the patients themselves in 146 prevalent patients with hemodialysis. Of those individuals who were determined to be frail using the Fried criteria, nephrologists and nurse practitioners perceived only 42 and 49%, respectively to be frail [30▪]. Self-perception of frailty was also shown to be inaccurate as only 5% of patients identified as frail using the objective criteria self-identified as frail [30▪]. This indicates that clinical impression or self-report alone is an inadequate and unreliable method of identifying frailty in the CKD population.
Although many validated measures of frailty exist, the ideal tool for use in the CKD population has not yet been determined and may vary depending on the setting. In addition, studies investigating the measures of frailty in CKD have been cross-sectional in nature and the utility and responsiveness of these tools for longitudinal measurement of frailty are not yet clear. More extensive validation studies in the CKD population are required for many of these tools. In the interim, careful attention to the domains within each specific tool, the setting in which the tool is to be used and the strengths and weaknesses of each tool will help clinicians and researchers alike determine which measurement method is best for each particular situation.
N.T. is supported by the KRESCENT New Investigator Award and the Research Manitoba Establishment Award. The KRESCENT Award is a joint initiative of the Kidney Foundation of Canada, the Canadian Institute of Health Research, and the Canadian Society of Nephrology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest,
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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