Clinical frailty assessment might be associated with mortality in incident dialysis patients

Abstract

Introduction: Frailty is associated with mortality in maintenance dialysis patients. We investigated frailty using the clinical frailty scale (CFS) as related to mortality or hospitalization within two years in incident dialysis patients.

Methods: We retrospectively reviewed medical records of patients initiating hemodialysis or peritoneal dialysis during 2016–2018. Based on the medical records, two dialysis nurses independently used a 9-point CFS (1 = “Very fit” to 9 = “Terminally ill”) to assess each patient’s frailty at dialysis initiation. Patients with a mean CFS value of 5 or higher were classified as the frailty group.

Results: The analysis included 155 incident dialysis patients with mean age of 66.7±14.1 (71% male). Frailty was determined in 43 (28%) patients at dialysis initiation. Kaplan–Meier analyses showed that the survival and hospitalization-free rate within two years was significantly lower in the frailty group than in the non-frailty group (p < .01). Cox proportional hazards regression analyses revealed the CFS score as associated with the occurrence of a composite outcome, independently of age (hazard ratio 1.34, 95% confidence interval 1.04–1.72).

Conclusion: Frailty assessment based on clinical judgment using CFS might predict adverse outcomes in the dialysis-initiated patients.

Introduction

Frailty is recognized as a state of loss of reserves (energy, physical ability, cognition, and health) that engenders increased vulnerability.¹ Even minor stress in patients with frailty can degrade health and make it difficult to maintain life functions because of the decline in reserve capacity of physical and psychological functions caused by aging. Frail individuals deserve special attention because they experience adverse health outcomes at high rates.²

The problem of frailty is often applicable to dialysis patients, and currently discussed nowadays. Earlier studies have revealed high prevalence of frailty not only in older dialysis patients, but also in younger ones.³ In maintenance dialysis patients, frailty is reportedly an independent risk factor for poor outcomes such as mortality, hospitalization, falls, and discharge to an assisted care facility.^4,5 According to a retrospective study analyzing data from the Nationwide Inpatient Sample, hospitalized maintenance dialysis patients with frailty have twice the risk of in-hospital mortality and three times the risk of discharge to long-term facilities. They require higher in-hospital medical costs than non-frail dialysis patients.⁶ Frailty has severe effects on health not only in maintenance dialysis patients, but also in the incident dialysis patients.^7-9 Fitzpatrick et al. reported that frailty in incident hemodialysis patients is associated with 1.66-fold elevated mortality risk, even among patients with abdominal obesity.¹⁰

Various tools have been developed for frailty assessment. They are being used for clinical practice and research. Fried’s criteria are the most commonly used. Frailty is diagnosed when three or more of the five major physical components of frailty are identified: unintentional weight loss; low physical activity level; weakness (low grip strength); exhaustion; and slowness (slow gait speed)¹¹. However, this criterion, which requires equipment for physical measurements, is unsuitable for detailed assessment of the degree of frailty.

The Clinical Frailty Scale (CFS) developed by Rockwood et al. is a subjective tool that enables assessment of the degree of frailty based on clinical judgment¹. The original version of CFS was a 7-point scale with grading of the degree of frailty from 1 (very fit) to 7 (severely frail). In 2020, an updated version of CFS (CFS ver. 2.0) was introduced with revised level names. It was edited to level descriptions by 9 scales ranging from 1 (very fit) to 9 (terminally ill).¹² Using CFS, health-care professionals subjectively assess the level of frailty based on clinical information about patient activities of daily living such as mobility, dressing, and preparing meals. Silhouettes and descriptions of a typical patient in each CFS category are helpful for the proper classification of patients. For the screening of frailty, CFS is recognized as a reliable tool. Earlier reports have suggested that CFS is a predictor of mortality or adverse outcomes in people with various diseases.^13,14 However, because of the small number of studies of incident dialysis patients, it has not been well established whether the degree of frailty evaluated by CFS at dialysis initiation is associated with short-term adverse outcomes. In addition, only the 7-point CFS scale, not 9-point version, was used for those earlier studies.^7,8 The aim of this study is investigation of the relation between frailty as assessed by CFS on a 9-point scale at the time of dialysis initiation and adverse outcomes such as death or hospitalization within two years.

Materials and Methods

Patients and data collection

We conducted a retrospective cohort study of adult patients admitted to a tertiary care hospital and started chronic dialysis (either peritoneal dialysis or hemodialysis) as their first kidney replacement therapy between January 1, 2016 and December 31, 2018. In our clinical practice, all patients start dialysis under inpatient care. After discharge, they go to dialysis clinics near their home. This study, which was conducted in accordance with the principles outlined in the Declaration of Helsinki, was approved by the Institutional Review Board of The University of Tokyo (#2269). Written informed consent was obtained from all patients at dialysis initiation. The exclusion criteria were the following: (1) lost to follow up after discharge; (2) patients who only received dialysis transiently (<1 week); and (3) patients who had been hospitalized for more than 3 months before dialysis initiation (because long hospitalization might affect the degree of frailty). In addition, (4) one patient died suddenly during his first session of hemodialysis.

 The basic information of the patients was obtained from their medical records: age, gender, cause of end-stage renal disease, history of cardiovascular disease (CVD), and days of hospitalization in initiation of dialysis. Clinical (systolic and diastolic blood pressure, body mass index) and laboratory data from the time of dialysis initiation were also obtained from medical records: hemoglobin (Hb), blood urea nitrogen (BUN), serum creatinine (Cr), estimated glomerular filtration rate (eGFR), corrected calcium (cCa), phosphate (IP), total protein (TP), albumin (Alb), C-reactive protein (CRP), uric acid (UA), hemoglobin A1c (HbA1C), total cholesterol (T.chol), triglyceride (TG), and brain natriuretic peptide (BNP). 

Evaluation of CFS

To assess and quantify the level of frailty, CFS ver. 2.0 on a scale graded as 1–9 was used: 1, very fit; 2, fit; 3, managing well; 4, living with very mild frailty; 5, living with mild frailty; 6, living with moderate frailty; 7, living with severe frailty; 8, living with very severe frailty; 9, terminally ill.¹² We had applied to the licensor for the use of CFS ver. 2.0 translated into Japanese and had received kind permission. Two dialysis nurses, one with more than 10 years of nursing experience and the other with more than two years of working at our dialysis center, independently assessed frailty using CFS by reference to medical chart records on activities of daily living at the time of dialysis initiation. The mean value of the results of the two nurses’ assessments was defined as the patient’s CFS score. Patients with a mean CFS score of 5 or higher were classified as the frailty group; the remainder were the non-frailty group. 

Outcomes

The primary outcome was the composite of all-cause mortality and hospitalization within two years after dialysis initiation. The secondary outcome was all-cause mortality within two years after dialysis initiation. The occurrence and date of the first observed outcomes after the start of dialysis were investigated. A researcher other than the two nurses evaluating CFS was responsible for collecting prognostic data through medical records and telephone surveys. Patient survival was censored at kidney transplantation or the date of last follow-up. 

Statistical analysis

All statistical analyses were conducted using software (JMP®, Version<16.0>; SAS Institute Inc., Cary, NC, 1989–2021.). Continuous data were expressed as mean ± standard deviation or median (interquartile range). Student t-tests or Mann–Whitney U-tests were used to compare continuous variables. The chi-square test or Fisher’s exact test was used to compare categorical variables. The Kaplan–Meier method and the log-rank test were used to compare differences in primary and secondary outcomes between the frailty (mean CFS >=5) and non-frailty (mean CFS<5) groups. Univariate and multivariate Cox proportional hazards regression analyses were performed to examine significant factors associated with the primary outcome. A Spearman’s correlation test was performed on correlation between the CFS score and clinical factors. Values for which p was less than .05 were inferred as significant.

Results

Characteristics of Study Participants

Of the 170 patients who started dialysis during the study period, a total of 155 patients were included in the analysis (Fig. 1). Baseline characteristics and laboratory data of all subjects are presented in Table 1. The mean patient age was 66.7±14.1 years old and 110 (71%) were male. The overall 2-year mortality was 17% (27 deaths). The causes of death included malignancy (n=6, 22%), CVD (n=5, 18%), infection (n=4, 15%), others (n=5, 19%), and unknown (n=7, 26%). The causes of unexpected hospitalization (n=53) included CVD (n=16, 30%), infection (n=14, 26%), vascular access troubles (n=4, 8%), malignancy (n=8, 15%), and others (n=11, 21%). The most common primary kidney disease was diabetic kidney disease (n=61, 39%), followed by chronic glomerulonephritis (n=31, 20%) and nephrosclerosis (n=24, 16%). The number of patients with a mean CFS >=5 (frailty group) was 43 (28%) of all 155 patients.

Table 1 presents results of comparison between two groups with a mean CFS score above 5 and less. The group with mean CFS>=5 (frailty group) had higher 2-year mortality (37% vs. 10%, p < .01), hemodialysis patients, (100% vs. 85%, p < .01), CRP [0.91 (0.11, 5.59) vs. 0.16 (0.05, 0.52) mg/dl, p < .01], and BNP [458 (185, 1375) vs. 153 (61.0, 356) pg/ml, p < .01], compared with patients with CFS<5 (non-frailty group). Meanwhile, serum creatinine, total protein, and albumin level were significantly lower in frail group. More patients in the frailty group started dialysis urgently (planned initiation of dialysis; 26% vs. 72%, p < .01) and had a longer hospitalization period (26 days vs. 10 days, p < .01), than patients of the non-frailty group. 

Validity of CFS Scores

The distribution of the CFS results assessed by each of the two nurses is shown in Fig. 2. The mean value of the CFS scores reported by the two nurses was 4.03±1.25; 28% (N=43) of the patients were evaluated as mildly to severely frailty (mean CFS >=5). Agreement between the two nurses' evaluation whether the CFS score is more than 5 (living with mild to very severe frailty) or not was found in 133 (86%) of all cases. Table 2 displays the correlation found between mean CFS score obtained from subjective clinical judgement and objective parameters. Significant positive correlation was found between the mean CFS score and the hospitalization period (r=0.43, p < .01), CRP (r=0.41, p < .01), UA (r=0.25, p < .01), and BNP (r=0.33, p < .01). A significant negative correlation was found between the mean CFS score and Cr (r= -0.23, p < .01) TP (r= -0.20, p < .01), and Alb (r= -0.43, p < .01). 

Relation between Outcomes and CFS

The 2-year survival rate or hospitalization after the initiation of dialysis was compared between the frailty and non-frailty groups using Kaplan-Meier analysis and log-rank testing. (Fig.3A) Results showed that worse frailty (mean CFS score >=5) was associated with decreased 2-year survival or hospitalization-free rate within two years (p < .01, Fig. 3A). Similarly, the 2-year survival rate in CFS>=5 group was significantly lower than that in CFS<5 group (p < .01, Fig.3B). Cox proportional hazard models were used to evaluate the relation between 2-year mortality or hospitalization and mean CFS score. The analyses were adjusted for factors which were reported as associated with an increased risk of all-cause mortality: age, expected start of dialysis, systolic blood pressure, Cr, Alb, CRP, total cholesterol, and BNP (Tables 3 and 4).^15-19 Increase in the mean CFS score was found to be related significantly to 2-year mortality or hospitalization in all models (Table 4). Similarly, Cox regression analysis suggested that an increase in the mean CFS score was associated with death within two years from the initiation of dialysis (Supplementary Tables 1 and 2). Adjustment for age and planned initiation of dialysis revealed a nearly twofold higher risk of 2-year mortality for each 1-point increase in the mean CFS. The hazard ratio was also considerably higher when adjusted for each factor above (Supplementary Table 2).

Discussion

Results of this study demonstrated that frailty at the initiation of dialysis was associated with mortality or hospitalization within two years. To the best of our knowledge, this is the first study demonstrating predictive validity of 9-point CFS assessed by nurses for relatively short-term prognosis in incident dialysis patients. We also found correlation between the CFS score based on the nurses’ subjective assessment and several objective laboratory parameters such as CRP, Alb, Cr, and BNP.

In our study, 28% of the patients were classified into the frailty group when judged by the criterion of mean CFS score >= 5. The frequency of frailty in dialysis patients varies among reports. It seems to depend on the assessment method and patient background. Chu et al. demonstrated that frailty as assessed by Physical Frailty Phenotype (Fried’s criteria) was present in 71.4% among older incident hemodialysis patients and 47.3% in younger ones.²⁰ Alfaadhel et al. reported that frailty assessed using 7-point CFS existed in 26% of all incident hemodialysis patients⁷, which was compatible with our data.

Screening for frailty is important because frailty is associated with increased risk of hospitalization, mortality, and falls in individuals with chronic kidney disease.²¹ Increased frailty consequently engenders huge physical and mental burdens on patients. Alfaadhel et al. demonstrated that a higher CFS score at dialysis initiation was associated with higher mortality. Our findings are compatible with their results.⁷ CFS, easily can be assessed, may be a useful predictor of mortality in incident dialysis patients.

Although CFS is a subjective assessment tool for frailty based on the health-care providers’ judgment, it has been shown to have high inter-rater reliability.¹ In this study, the categorization (CFS score is above 5 or not) was consistent in 133 (86%) cases. The 9-point CFS was apparently reliable with small inter-rater differences in the clinical assessment of incident dialysis patients. Additionally, we calculated and used the mean of CFS scores from the two nurses for analyses in this study. We believe that the mean of the CFS scores from two nurses, who take care of patients under consideration of their conditions and daily lives, might increase the reliability of the results.

The correlation between CFS scores based on the clinician’s subjective judgement and various objective markers such as Alb, CRP, and BNP might support the reliability of CFS in our cohort. Serum albumin, known as an independent risk factor of mortality as well as a nutritional marker in end-stage renal disease (ESRD) patients, has been reported to be lower in frail individuals than in healthy ones.^15,22 The mean serum albumin level was low at 3.14±0.55 g/dl, which might reflect the condition of the patients, such as chronic malnutrition and exhaustive illness in ESRD patients. Frail patients often have comorbidities that can affect the inflammatory parameters.²³ Aggravation of inflammation can lead to structural damage to physiologic organs such as musculoskeletal, hematological (anemia), cardiovascular, and endocrine systems.²⁴ Consequently, it is not surprising that serum CRP was correlated significantly with the CFS score. Regarding BNP, it has been reported that elevated BNP (>= 100 pg/ml is significantly associated with frailty in the general elderly population (OR: 2.63, 95% confidence interval: 1.61–4.32).²⁵ Although the reasons for correlation between BNP levels and CFS scores in our study was not clear, it might be mediated by fluid overload and the presence of CVD, both of which are often seen in ESRD patients.

Patients of the frailty group (mean CFS >=5) had less planned dialysis initiation and longer hospitalization periods than patients of the non-frailty group (mean CFS <5). Although the reasons for these differences remain unclear, missing the appropriate timing to start dialysis can lead to an urgent start of dialysis and prolonged hospitalization, which is undoubtedly a great physical and medical cost burden for frail patients. This study found that eGFR at dialysis initiation was significantly higher in the frailty group, suggesting that eGFR based on serum creatinine might not reflect renal function in frail patients because of a loss of muscle mass, and that factors other than renal function (such as comorbidities) might have influenced the decision to initiate dialysis. Therefore, it might be necessary to consider not only objective clinical parameters but also frailty assessments based on clinical judgments to make decisions about dialysis initiation.²⁶

The present study had several limitations. First, we might not have investigated or collected sufficient data of unknown factors affecting the relation between frailty and prognosis. Second, based on the nature of retrospective studies, potential influences of prognostic information related to the CFS assessment was a concern. Therefore, the CFS evaluators made decisions based solely on information from the dialysis initiation period and were separated from the investigator for patient prognosis. Third, because this study was conducted at a single tertiary hospital, it remains unclear whether the results were generalizable or not. Fourth, clinicians might misclassify the severity of CFS based on limited descriptions included in medical chart information. We tried to reduce the misclassification of patients by calculating the mean of CFS from two dialysis nurses. Fifth, the change in CFS score before and after dialysis initiation was not investigated. Finally, cognitive function was not evaluated in this study although recognition of patients with dementia might help to adequate CFS classification. To address these limitations, a large and multicenter prospective cohort study with long-term follow-up must be undertaken as a future study.

In conclusion, results of this study demonstrated that frailty at the initiation of dialysis is related to death or hospitalization within two years. Used by nurses who are familiar with patient's living and physical conditions, CFS might become an effective tool for predicting the prognoses of incident dialysis patients.

Declarations

Acknowledgment

We are grateful to Fastek, Ltd. for assistance with English proofreading. 

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by R.O., Y.H., S.T., K.S., S.T., M.I., and Y.K. The first draft of the manuscript was written by R.O., Y.H., Y.M., R.M., K.D. and M.N. all provided substantial contributions to the revisions of the first draft of the manuscript. All authors read and approved the final manuscript. 

Funding

The authors declare that they have no relevant financial interests. 

Conflict of interest

The authors declare that they have no competing financial or other interest or personal relationship that could have influenced this paper or the study it describes. 

Ethical approval

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Institutional Review Board of The University of Tokyo (#2269). 

Data Availability Statement

The data which support the findings of this study are available from the corresponding author, [Y.H.], upon reasonable request.

References

1. Rockwood, K.et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 173, 489-495, doi:10.1503/cmaj.050051 (2005).
2. Clegg, A., Young, J., Iliffe, S., Rikkert, M. O. & Rockwood, K. Frailty in elderly people. Lancet 381, 752-762, doi:10.1016/s0140-6736(12)62167-9 (2013).
3. McAdams-DeMarco, M. A.et al. Frailty as a novel predictor of mortality and hospitalization in individuals of all ages undergoing hemodialysis. J Am Geriatr Soc 61, 896-901, doi:10.1111/jgs.12266 (2013).
4. Sy, J. & Johansen, K. L. The impact of frailty on outcomes in dialysis. Curr Opin Nephrol Hypertens 26, 537-542, doi:10.1097/mnh.0000000000000364 (2017).
5. Sood, M. M.et al. The role of functional status in discharge to assisted care facilities and in-hospital death among dialysis patients. Am J Kidney Dis 58, 804-812, doi:10.1053/j.ajkd.2011.06.017 (2011).
6. Jiang, X., Li, D., Shen, W., Shen, X. & Liu, Y. In-Hospital Outcomes of Patients on Maintenance Dialysis With Frailty: 10-year Results From the US National Inpatient Sample Database. J Ren Nutr 30, 526-534, doi:10.1053/j.jrn.2019.12.007 (2020).
7. Alfaadhel, T. A.et al. Frailty and mortality in dialysis: evaluation of a clinical frailty scale. Clin J Am Soc Nephrol 10, 832-840, doi:10.2215/CJN.07760814 (2015).
8. Clark, D.et al. Frailty Severity and Hospitalization After Dialysis Initiation. Can J Kidney Health Dis 8, 20543581211023330, doi:10.1177/20543581211023330 (2021).
9. Bao, Y., Dalrymple, L., Chertow, G. M., Kaysen, G. A. & Johansen, K. L. Frailty, dialysis initiation, and mortality in end-stage renal disease. Arch Intern Med 172, 1071-1077, doi:10.1001/archinternmed.2012.3020 (2012).
10. Fitzpatrick, J.et al. Frailty, body composition and the risk of mortality in incident hemodialysis patients: the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease study. Nephrol Dial Transplant 34, 346-354, doi:10.1093/ndt/gfy124 (2019).
11. Fried, L. P.et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56, M146-156, doi:10.1093/gerona/56.3.m146 (2001).
12. Rockwood, K. & Theou, O. Using the Clinical Frailty Scale in Allocating Scarce Health Care Resources. Can Geriatr J 23, 210-215, doi:10.5770/cgj.23.463 (2020).
13. Basic, D. & Shanley, C. Frailty in an older inpatient population: using the clinical frailty scale to predict patient outcomes. J Aging Health 27, 670-685, doi:10.1177/0898264314558202 (2015).
14. García-Blas, S.et al. Frailty Scales for Prognosis Assessment of Older Adult Patients after Acute Myocardial Infarction. J Clin Med 10, doi:10.3390/jcm10184278 (2021).
15. Ma, L. & Zhao, S. Risk factors for mortality in patients undergoing hemodialysis: A systematic review and meta-analysis. Int J Cardiol 238, 151-158, doi:10.1016/j.ijcard.2017.02.095 (2017).
16. Bian, Z., Gu, H., Chen, P. & Zhu, S. Comparison of prognosis between emergency and scheduled hemodialysis. J Int Med Res 47, 1221-1231, doi:10.1177/0300060518807092 (2019).
17. Fink, J. C.et al. Significance of serum creatinine values in new end-stage renal disease patients. Am J Kidney Dis 34, 694-701, doi:10.1016/s0272-6386(99)70395-1 (1999).
18. Li, Z.et al. The epidemiology of systolic blood pressure and death risk in hemodialysis patients. Am J Kidney Dis 48, 606-615, doi:10.1053/j.ajkd.2006.07.005 (2006).
19. Iseki, K., Yamazato, M., Tozawa, M. & Takishita, S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 61, 1887-1893, doi:10.1046/j.1523-1755.2002.00324.x (2002).
20. Chu, N. M.et al. Frailty Prevalence in Younger End-Stage Kidney Disease Patients Undergoing Dialysis and Transplantation. Am J Nephrol 51, 501-510, doi:10.1159/000508576 (2020).
21. Bohm, C., Storsley, L. & Tangri, N. The assessment of frailty in older people with chronic kidney disease. Curr Opin Nephrol Hypertens 24, 498-504, doi:10.1097/mnh.0000000000000163 (2015).
22. Honda, H.et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 47, 139-148, doi:10.1053/j.ajkd.2005.09.014 (2006).
23. Soysal, P.et al. Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing Res Rev 31, 1-8, doi:10.1016/j.arr.2016.08.006 (2016).
24. Li, H., Manwani, B. & Leng, S. X. Frailty, inflammation, and immunity. Aging Dis 2, 466-473 (2011).
25. Yao, S.et al. Association of BNP with Frailty in Elderly Population: Rugao Longevity and Ageing Study. J Nutr Health Aging 23, 73-78, doi:10.1007/s12603-018-1112-7 (2019).
26. Travers, J., Romero-Ortuno, R., Bailey, J. & Cooney, M. T. Delaying and reversing frailty: a systematic review of primary care interventions. Br J Gen Pract 69, e61-e69, doi:10.3399/bjgp18X700241 (2019).

Tables

Table 1

 Comparison between groups with mean CFS scores of more or less than 5

 Continuous data are presented as mean±SD or median (IQR): CVD, cardiovascular disease; Hb, hemoglobin; Cr, creatinine; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; Ca, calcium; IP, phosphate; TP, total protein; Alb, albumin; CRP, C-reactive protein; T.chol, total cholesterol; TG, triglyceride; UA, uric acid; HbA1C, hemoglobinA1C; BNP, brain natriuretic peptide 

Table 2

 Correlation between mean CFS scores obtained by subjective assessment and objective parameters

Table 3

 Results of univariate cox proportional hazards model analyses for 2-year mortality or hospitalization

Table 4

 Results from multivariate cox proportional hazards model for 2-year mortality or hospitalization