Abstract
Objectives
Older adults with frailty are vulnerable to cardiovascular event and subsequent mortality. Frailty and albuminuria share atherosclerotic risk factors. The present study investigated the association of frailty and albuminuria among elderly Chinese inpatients.
Design
Cross-sectional study.
Settings and participants
A total of 202 patients aged over 60 years from the Center of Gerontology and Geriatric, West China Hospital.
Measurements
Frailty was defined using the five-item FRAIL scale. This included measurements of fatigue, resistance, ambulation, illness, and loss of weight. We further determined the random urine albumin/ creatinine ratio (UACR) of all patients. Random UACR ≥30 mg/g was defined as albuminuria, and < 30mg/g as normoalbuminuria. The relationship between albuminuria and frailty was assessed through multiple regression analysis.
Results
The 202 participants (156 men, 77.2%) had an average age of 78.99±7.60 years, which ranged from 60 to 95. Compared to those without albuminuria, elderly patients with albuminuria were of an older age, had a higher prevalence of diabetes and poorer renal function. The prevalence of frailty, pre-frailty and ambulation (one of the FRAIL components) were higher in the albuminuria group than the normoalbuminuria group (23.9% vs. 12.2%, 47.9% vs.37.4%, 33.8% vs. 16.0%, respectively, P<0.05). Following the adjustment for age, eGFR, hypertension, diabetes and using ACEI/ARB, being frail or pre-frail led to an enhanced risk of albuminuria (OR frail 2.60, 95% CI frail 1.01–6.72; OR pre-frail 2.14, 95% CI pre-frail 1.03–4.44).
Conclusions
Frailty is independently associated with albuminuria when adjusted for classic cardiovascular risk factors.
Key words: Frailty, albuminuria, older individuals, ambulation, urine albumin/creatinine ratio
Introduction
Frailty is a prevalence geriatric syndrome characterized by a decline in function across multiple physiological systems. This syndrome is also predictive of an array of adverse outcomes, including but not limited to, hospitalization, disability, falls and mortality (1, 2). Frailty afflicts 4 to 59% of all community-dwelling elderly individuals (3) and 18% to 40% of hospitalized elderly patients (4). Frailty presents as variable features including reduced physical function, cognition, comorbidities, unintentional weight loss, exhaustion, muscle weakness, and physiological dysfunction. Recent studies have reported that frailty is associated with an increased risk of the causative factors of cardiovascular disease (5, 6, 7).
Albuminuria can act as a surrogate measure of endothelial dysfunction in clinical or subclinical cardiovascular disease. Albuminuria additional represents a risk factor for cardiovascular disease due to alterations in the urine albumin/ creatinine ratio (UACR) (8). In the US population survey, albuminuria was independently associated with older age, diabetes, hypertension and chronic kidney disease (9).
Frailty and albuminuria have common cardiovascular risk factors that can combine to increase disease occurrence. In this study, we investigated the relationship between frailty and albuminuria. Our aim was to explore the hypothesis that albuminuria is a clinical marker of frailty though a cross-sectional analysis of the in-hospital population.
Methods
Study design and population
This cross-sectional study was performed in the Center of Gerontology and Geriatrics, West China Hospital from September 2015 to December 2018. The study was approved by the Research Ethics Committee of Sichuan University. Informed consent was provided by all participants.
Patients were included upon satisfying the following criteria: 1) aged ≥ 60 years; 2) those who had independent mobility. Exclusion patients were as follows: 1) unable to communicate with the interviewer; 2) life expectancy ≤ 6 months; 3) chronic kidney disease (CKD) stage 5 (estimated GFR <15 ml/min/1.73 m2 or receiving dialysis).
Clinical and laboratory data collection
Medical history and present medication data were obtained from face to face interviews and medical files-including sex, age, tobacco usage, hypertension and diabetes. We further monitored the use of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). All physical assessments were performed by trained nurses, and included height, body weight, systolic blood pressure (SBP), and diastolic blood pressure (DBP) assessments. Laboratory data included total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density (LDL) cholesterol, triglyceride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), estimated glomerular filtration rate (eGFR), fasting plasma glucose (FPG), and random UACR. Data were collected 3 days post-admission. Random UACR ≥30 mg/g was defined as albuminuria, and < 30mg/g as normoalbuminuria.
Frailty definition
Frailty was defined using the five-item FRAIL scale. This included measurements of fatigue, resistance, ambulation, illness, and loss of weight as previously described (10). A single point was assigned to each item. Participants with a score of 0 were defined as robust, 1 to 2 as pre-frail and 3 to 5 as frail.
Statistics
Data analysis was performed using SPSS version 20.0. Continuous data are shown as the mean ± standard deviation (SD). Categorical data are shown as percentages and absolute numbers. Normoalbuminuria and albuminuria were compared through paired or unpaired Student t test or Chi square test, as appropriate. The association between frailty status and albuminuria were assessed through Binary logistic regression. Logistic regression analysis was used to measure the Odds ratios (ORs) and 95% confidence intervals (CIs). P-values less ≤0.05 were considered significant.
Results
Patients
The average age of the 202 participants (156 men, 77.2%) was 78.99±7.60 years, ranging from 60 to 95. The prevalence of albuminuria was 35.1% (71 of 202). The descriptive characteristics of participants, categorized by the degree of albuminuria, are shown in Table 1. Subjects with albuminuria were of an older age than those without albuminuria (mean age 81.59 vs. 77.58, P=0.000). The albuminuria group had a higher prevalence of diabetes than normoalbuminuria group (88.7% vs. 76.3%, P=0.033). Furthermore, compared to the individuals without albuminuria, those with albuminuria exhibited poorer renal function (eGFR). There were no differences in patient gender, smoking status, hypertension, ACEI/ARB usage, body mass index (BMI), blood pressure, and routine blood biochemical values between the groups.
Table 1.
Clinical characteristics of study subjects with or without albuminuria
| Normoalbuminuria N=131 | Albuminuria N=71 | P* | |
|---|---|---|---|
| Male, n (%) | 98 (74.8%) | 58 (81.7%) | 0.266 |
| Age, years | 77.58±7.93 | 81.59±6.19 | 0.000 |
| History of smoking, n (%) | 63 (48.1%) | 37 (52.1%) | 0.585 |
| Hypertension, n (%) | 54 (41.2%) | 34 (47.9%) | 0.362 |
| Diabetes, n (%) | 100 (76.3%) | 63 (88.7%) | 0.033 |
| Using ACEI/ARB, n (%) | 48 (36.6%) | 27 (38.0%) | 0.846 |
| Height, cm | 165.47±7.41 | 166.25±5.99 | 0.447 |
| Body weight, kg | 65.56±10.47 | 64.65± 11.22 | 0.563 |
| BMI, kg/m | 23.89±3.21 | 23.34±3.56 | 0.259 |
| SBP, mmHg | 129.37±13.64 | 129.59±12.41 | 0.911 |
| DBP, mmHg | 72.89±10.50 | 71.28±8.43 | 0.267 |
| Total cholesterol, mmol/L | 3.94±1.21 | 3.81±1.22 | 0.462 |
| LDL cholesterol, mmol/L | 2.26±0.92 | 2.20±1.02 | 0.624 |
| HDL cholesterol, mmol/L | 1.19±0.38 | 1.22±0.41 | 0.551 |
| Triglyceride, mmol/L | 1.49±0.96 | 1.29±0.52 | 0.057 |
| AST, U/L | 23.50±17.15 | 22.87± 11.86 | 0.783 |
| ALT, U/L | 24.13±23.15 | 20.34±18.17 | 0.233 |
| eGFR, ml/min/1.73 m2 | 82.79±38.14 | 65.36±25.43 | 0.001 |
| FPG, mmol/L | 6.94±3.07 | 7.33±3.53 | 0.409 |
* Analysis using an independent two-sample t test or the χ2 test, as appropriate; ACEI=angiotensin converting enzyme inhibitor; ALT = alanine aminotransferase; ARB=angiotensin receptor blocker; AST = aspartate aminotransferase; BMI=body mass index; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; FPG = fasting plasma glucose; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SBP = systolic blood pressure.
Frailty status according to albuminuria
Both the prevalence of frailty and pre-frailty were higher in the albuminuria group vs. normoalbuminuria group (23.9% vs. 12.2%, 47.9% vs.37.4%, respectively, P=0.005). The prevalence of FRAIL scale components according to albuminuria categories are shown in Table 2. Compared to normoalbuminuria, ambulation rates were higher in the albuminuria group (33.8% vs. 16.0%, P=0.004). In addition, subjects with albuminuria were more likely to show fatigue, and have comorbidities; however, differences were not statistically significant.
Table 2.
Comparison of frailty status and FRAIL scale criteria between normoalbuminuria and albuminuria
| Normoalbuminuria N=131 | Albuminuria N=71 | P | |
|---|---|---|---|
| Frailty status | 0.005 | ||
| Robust | 66 (50.4%) | 20 (28.2%) | |
| Pre-frail | 49 (37.4%) | 34 (47.9%) | |
| Frail | 16 (12.2%) | 17 (23.9%) | |
| FRAIL scale criteria | |||
| Fatigue | 35 (26.7%) | 27 (38.0%) | 0.096 |
| Resistance | 28 (21.4%) | 23 (32.4%) | 0.085 |
| Ambulation | 21 (16.0%) | 24 (33.8%) | 0.004 |
| Illness | 15 (11.5%) | 15 (21.1%) | 0.065 |
| Loss of weight | 18 (13.7%) | 9 (12.7%) | 0.832 |
Relationship between frailty and albuminuria
As shown in Table 3, both frailty and pre-frailty were significantly associated with albuminuria through univariate logistic regression analysis. After adjusting for age, eGFR, hypertension, diabetes and using ACEI/ARB, being frail or pre-frail was associated with a higher risk of albuminuria (OR frail 2.60, 95% CI frail 1.01–6.72; OR pre-frail 2.14, 95% CI pre-frail 1.03–4.44).
Table 3.
Association between frailty status and albuminuria using binary logistic regression
| Robust | Pre-frail | P | Frail | P | |
|---|---|---|---|---|---|
| Unadjusted | Reference | 2.29 (1.18–4.45) | 0.015 | 3.51 (1.50–8.17) | 0.004 |
| Model 1 | Reference | 2.52 (1.27–5.01) | 0.008 | 3.54 (1.49–8.40) | 0.004 |
| Model 2 | Reference | 2.14 (1.03–4.44) | 0.041 | 2.60 (1.01–6.72) | 0.048 |
Model 1: adjusted by hypertension, diabetes and using ACEI/ARB ; Model 2: adjusted by model 1 + age and eGFR.
Discussion
The present study showed that frailty or pre-frailty defined using the FRAIL scale was associated with albuminuria in older Chinese patients. This relationship existed after adjusting for various factors associated with albuminuria. We also analyzed the prevalence of FRAIL scale components in participants with or without albuminuria. Compared to those without albuminuria, subjects with albuminuria were more likely to report having difficulty in ambulation.
Studies assessing the relationship between frailty and albuminuria are sparse. Ballew et al. reported a moderate associated of frailty with albuminuria and renal function based on the analysis of the Atherosclerosis Risk in Communities (ARIC) Study (11). Cross-sectional analysis using the I-Lan Longitudinal Aging Study data showed that low-grade albuminuria (UACR < 30mg/g) was associated with prefrailty/frailty, and the prevalence of prefrailty/frailty and its components increased across the UACR quartiles (12). Our study also found that albuminuria was independently associated with prefrailty/frailty older adults in hospital after adjustment for various confounders, which was consistent with the previous two community studies.
We employed the FRAIL scale to assess frailty in older Chinese patients (10). Among the five criteria of the scale, ambulation was the most significant parameter associated with albuminuria in our study. The main cause of ambulation decline in the elderly is a loss of skeletal muscle mass and strength, which is the key component of frailty. Previous studies in the Korean population from Kim et al. (13) found that the prevalence of albuminuria was higher in those with lower skeletal muscle index (SMI) compared to those with a normal SMI. The OR for albuminuria risk in the lower SMI group was 2.93 (1.46–5.88). In other studies, Han et al. (14) found that low skeletal muscle mass was associated with albuminuria following the adjustment for diabetes, hypertension and other confounders. Furthermore, in patients with type 2 Diabetes, sarcopenia which is characterized by a decline of skeletal muscle mass and strength, was associated with progression of albuminuria (15). A longitudinal study with 4 years follow-up showed that low skeletal muscle mass predicted the future development of albuminuria (16).
The pathophysiological mechanisms linking the frailty/ loss of muscle mass and albuminuria are unclear. Albuminuria is a known risk factor for cardiovascular events (17, 18), and frailty can increased the risk factor of cardiovascular disease and death (6, 19). The mechanisms underlying the occurrence of cardiovascular disease, namely a loss of endothelial function, insulin resistance, Renin-angiotensin-aldosterone system (RASS) activation, and inflammatory responses may govern the association between albuminuria and frailty observed (13, 16, 20, 25). Albuminuria and frailty share cardiovascular risk factors including advance age, hypertension, diabetes, hyperlipemia and chronic kidney disease. In this study, patients with albuminuria were of an older age, had a high prevalence of diabetes and lower eGFR. Furthermore, after adjustment for age, hypertension, diabetes, using RASS antagonists and eGFR, being frail/pre-frail were independently associated with albuminuria. Frailty may therefore have a direct association with albuminuria via a non-cardiovascular mechanism. Albuminuria can also be used as a marker of frailty in clinical practice. Future studies are required to evaluate this causal relationship between albuminuria and frailty.
Some limitations in the study should be note. Firstly, this was a cross-sectional study, designed to demonstrate the causal relationship between albuminuria and frailty. Secondly, the frailty was defined through five self-evaluation questions lacking objective physical measurements such as gait speed and grip strength. Furthermore, the participants were inpatients in a single university hospital and appeared to possess a higher number of comorbidities that influenced the urinary albumin excretion rates compared to those of the general population. These limitations limit the clinical application of our study.
Conclusion and implications
In this cross-sectional study of older inpatients, the prevalence of frailty/pre-frailty was higher in patients with albuminuria than those without albuminuria. Frailty was independently associated with albuminuria when adjusted for age, hypertension, diabetes, and renal function. Albuminuria as opposed to the classic cardiovascular risk factors therefore represents a novel marker of frailty and/or muscle decline, suggesting that therapeutic interventions for albuminuria may slow the progression of frailty.
Acknowledgments
The authors are grateful to the staff of the Center of Gerontology and Geriatrics, West China Hospital, Sichuan University and all participants for their support.
Conflicts of Interest
All authors have no conflicts of interest to disclose relevant to this paper.
Funding
This study was partly supported by the National Natural Science Foundation of China (81501197), Sichuan Province Science and Technology Support Program (2019YFG0194, 2020YFG0086), Research Project on Healthcare in Sichuan Province (Chuanganyan ZH2019-101, Chuanganyan 2019-105), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20191010), and Special Fund Project for Science and Technology Cooperation of Sichuan University and Zigong City, Sichuan Province (2019CDZG-25).
Author contributions
Ying Li led the development of the study concept. Xue Yang and Yangyang Jiang, Mengxuan Yang assisted with health data collection and frailty assessment. Birong Dong helped in study concept and design. Junxi Li, and Ying Liu helped in data analysis and manuscript writing.
Ethical standards
This study was approved by the research ethics committee of Sichuan Universtiy, and all patients or their appropriate proxies had provided written informed consent.
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