Abstract
Background Skeletal muscle wasting is common and insidious in patients who are undergoing hemodialysis. However, the association between lower extremity muscle strength and all-cause mortality remains unclear in this population.
Objective The purpose of this study was to investigate the prognostic significance of lower extremity muscle strength on 7-year survival in a cohort of patients who were clinically stable and undergoing hemodialysis.
Design A prospective cohort study was conducted.
Methods A total of 190 Japanese outpatients who were undergoing maintenance hemodialysis 3 times per week at a hemodialysis center were followed for up to 7 years. Lower extremity muscle strength was evaluated using a handheld dynamometer at the time of patient enrollment in the study. Muscle strength data were divided by dry weight and expressed as a percentage. A Cox proportional hazards regression model was used to assess the contribution of lower extremity muscle strength to all-cause mortality.
Results The median age (25th and 75th percentiles) of this study population was 64 years (57 and 72 years), 53.2% of the patients were women, and the time on hemodialysis was 39.0 months (15.9 and 110.5 months) at baseline. During a median follow-up of 36.0 months, there were 30 deaths. With a multivariate Cox model, the hazard ratio in the group with a knee extensor strength of <40% was 2.73 (95% confidence interval=1.14–6.52) compared with that in the ≥40% group.
Limitations This was a small-scale observational study, and the mechanisms underlying the higher mortality risk in patients with poor muscle strength undergoing hemodialysis than in other patients undergoing hemodialysis remain to be elucidated.
Conclusions Decreased lower extremity muscle strength was strongly associated with increased mortality risk in patients undergoing hemodialysis.
Skeletal muscle wasting, which is associated with impaired physical performance, is common and insidious in patients undergoing hemodialysis. Previous studies have shown that lower extremity muscle strength in patients undergoing hemodialysis was poorer than in healthy age- and sex-matched individuals.1,2 Sterky and Stegmayr3 reported that muscle strength in patients undergoing hemodialysis was only about half that of healthy adults. In general, muscular weakness is believed to be associated with lower levels of physical performance, such as in walking ability and standing balance function. Recently, impaired physical performance was reported to predict not only adverse health-related events but also death. In a meta-analysis of community-dwelling populations by Cooper et al,4 a strong association was found between impaired physical performance and high risk of all-cause mortality.
The mortality rate among patients undergoing hemodialysis is very high despite continual improvements in dialysis technology. To date, the determinants of mortality in patients undergoing maintenance hemodialysis include older age, body mass, comorbid conditions, and markers of nutrition and inflammation.5–8 However, the association between lower extremity muscle strength and all-cause mortality in this patient population remains unclear.
In this study, we investigated the prognostic significance of lower extremity muscle strength, evaluated using a handheld dynamometer, in relation to physical performance and survival in a cohort of patients who were clinically stable and adequately dialyzed.
Method
Participants
Between October 2002 and February 2012, outpatients at the Hemodialysis Center at Sagami Junkanki Clinic who were clinically stable were assessed for eligibility for inclusion in this prospective study. Those patients who were undergoing maintenance hemodialysis therapy 3 times per week were included in the study. According to data gathered by the Japanese Society for Dialysis Therapy, this is the most common hemodialysis regimen in Japan. Patients were excluded from our study if they had been hospitalized within the previous 3 months; had a recent myocardial infarction or angina pectoris; had uncontrolled cardiac arrhythmias, hemodynamic instabilities, uncontrolled hypertension, or renal osteodystrophy with severe arthralgia; or required walking assistance. Oral consent was obtained from all patients by their physicians.
Demographic and Clinical Factors
Information on demographic factors (age, sex, time on hemodialysis) and physical constitution (body mass index [BMI], primary kidney disease, and comorbid conditions such as cardiac disease and diabetes mellitus) was collected at the time of study enrollment. Data for serum albumin and C-reactive protein levels were obtained from patient hospital charts. To quantify comorbid illnesses, we used a comorbidity index that was developed specifically for patients undergoing dialysis and can give a single-value summary for the following: primary causes of end-stage renal disease, atherosclerotic heart disease, congestive heart failure, cerebrovascular accident/transient ischemic attack, peripheral vascular disease, dysrhythmia, other cardiac diseases, chronic obstructive pulmonary disease, gastrointestinal bleeding, liver disease, cancer, and diabetes. This comorbidity score was calculated using the method previously described and performed in a survival analysis of patients undergoing hemodialysis.9
Lower Extremity Muscle Strength
Maximum voluntary isokinetic knee extensor strength was assessed with a handheld dynamometer (μTas MT-1, Anima, Japan). The dynamometer pad is 56 × 56 mm, and its front side is curved to fit the shape of the areas to be measured on the extremities. The measurement range of this dynamometer is 0 to 100 kg, with a recording interval of 0.1 kg. The accuracy and reliability of this instrument have been reported in previous studies.10,11
For knee extensor strength assessment, participants were seated on a bed in an upright posture with their feet over the side of the bed, hands on the bed, and knees flexed to 90 degrees. The dynamometer pad was placed perpendicular to the leg just above the malleoli. Before testing, all participants received instruction from the physical therapists regarding the appropriate evaluation of knee extensor muscle strength. Participants were told to push against the dynamometer pad by attempting to straighten their knees for a period of 5 seconds. The physical therapists asked the participants to increase force gradually to maximum voluntary effort. During the tests, the dynamometer pad was stabilized by the examiner's hand. Isokinetic knee extensor strength was measured 3 times on each side, and the highest value for the right and left legs was used to calculate the average knee extensor muscle strength. Furthermore, to adjust for the difference in physical constitution among patients, knee extensor strength was divided by dry weight and expressed as a percentage.12,13 Lower extremity muscle strength was measured by 6 testers. All testers in our study were Japanese physical therapists who were instructed in the assessment of muscle strength by a supervisor and had received sufficient training before measuring muscle strength in patients. Previous studies have demonstrated that intrarater and interrater reliability of handheld dynamometry in measuring maximal isometric knee strength is very high.14,15
Physical Performance
Maximum gait speed and functional reach were used in our study for evaluation of physical performance. Maximum gait speed is one of the indexes of walking ability. First, participants were asked to walk down a 10-m gait lane with acceleration area at their usual speed to prepare for measurement of the maximum gait speed. Second, they were instructed to walk safely as fast as possible without running. Previous studies have demonstrated high reliability and validity of the 10-Meter Walk Test.12,16,17 Maximum gait speed was defined as the higher value of 2 attempts12 and reflected by the ratio of distance to time (cm/s).
Functional reach is one of the indexes of standing balance ability. Participants were asked to stand comfortably next to a wall and raise their dominant arm until it was parallel to the floor (position 1). The position of the end of the third metacarpal was recorded on the wall. Participants were then asked to reach as far forward as they could without losing their balance (position 2), and the position of the end of the third metacarpal was again recorded. Functional reach was defined as the distance between position 1 and position 2,18 and the higher value of 2 attempts (in centimeters) was used. The reliability and validity of this test have been reported in previous studies.18–21
Data Analysis
Data are presented as median (25th percentile, 75th percentile) or number (percentage) and were tested by the Mann-Whitney U test or chi-square test. The Pearson product moment correlation was used to explore the correlation between lower extremity muscle strength and physical performance. For the Kaplan-Meier estimate of survival curves, we truncated the data for the 7-year follow-up period to avoid an insufficient number of patients at risk. Participants were categorized into 2 groups by a lower extremity muscle strength cutoff value of 40%, and the difference between groups was tested using a log-rank test. In a previous study, this cutoff value defined whether patients were able to walk independently or dependently,22 and it is commonly applied to patients and elderly individuals in Japan.
The 7-year cumulative survival probability was estimated using the life table method with the interval length set at 1 month. To assess the predictive ability of knee extensor muscle strength, gait speed, and functional reach for mortality, we used values of area under the receiver operating characteristic (ROC) curve. A Cox proportional hazards regression analysis was performed to estimate the independent prognostic effect of lower extremity muscle strength on survival after adjustment for confounders. Within the present study sample, there were 30 all-cause deaths, which allowed for a maximum of 3 variables to be included in the multivariate Cox model. If the multivariate Cox model includes more than 3 covariates, it has the potential to cause overfitting. To avoid overfitting, all potential confounding factors of lower extremity muscle strength, which include age, sex, BMI, time on hemodialysis, comorbidity score, and serum albumin and serum C-reactive protein levels, were reduced to one composite characteristic by applying a propensity score.23 The propensity score reflects the likelihood of a study participant being assigned to the knee extensor strength <40% or ≥40% group. Once a propensity score is calculated, the score can be used in a multivariate Cox model as an independent variable. Probability values <.05 were considered statistically significant. Analyses were performed using IBM SPSS software, version 12.0 (IBM Corp, Armonk, New York).
Results
Baseline Characteristics, Lower Extremity Muscle Strength, and Physical Performance
A total of 430 Japanese outpatients were assessed for their eligibility for inclusion. A total of 101 patients who did not satisfy the inclusion criteria were excluded, and 139 patients declined to participate in the study. As a result, 190 patients undergoing hemodialysis were recruited (Fig. 1).
Flow diagram of the participant selection and exclusion process.
Demographic and clinical characteristics of the participants are summarized in Table 1. The study participants were 89 men and 101 women aged 35 to 88 years (median age=64). Time on hemodialysis was 39.0 months (25th percentile, 75th percentile=15.9 months, 110.5 months) at baseline. The most common underlying kidney disease in the study sample was diabetic nephropathy (33.7%), and the next most common was glomerulonephritis (32.1%). The comorbidity score was 5.0 (25th percentile, 75th percentile=3.0, 7.0). Knee extensor muscle strength was 40.7% (25th percentile, 75th percentile=32.1%, 49.1%). A total of 47.4% of participants were included in the group with <40% knee extensor strength, which was chosen as a cutoff value for lower extremity muscle strength. Maximum gait speed was 147.1 cm/s (25th percentile, 75th percentile=122.4 cm/s, 173.0 cm/s), and functional reach was 30.5 cm (25th percentile, 75th percentile=27.0 cm, 35.0 cm).
Patient Characteristics, Lower Extremity Muscle Strength, and Physical Performance at Baselinea
Table 2 shows baseline characteristics of the participants according to knee extensor strength (<40% or ≥40%). The percentage of women in the ≥40% group was significantly lower than in the <40% group (P<.001). Serum albumin levels in the ≥40% group were significantly higher than in the <40% group (P=.007). The maximum gait speed and functional reach in the ≥40% group were significantly higher than in the <40% group (P<.001, respectively). Other baseline characteristics did not significantly differ between the groups.
Baseline Characteristics by Knee Extensor Strength (<40% or ≥40%)a
Lower Extremity Muscle Strength and Physical Performance
Figure 2 shows the associations between knee extensor strength and physical performance. Knee extensor strength significantly correlated with maximum gait speed (r=.55, P<.001) and functional reach (r=.42, P<.001).
Correlation between lower extremity muscle strength and physical performance. Scatter plots reflect the correlation between knee extensor strength and maximum gait speed or functional reach.
Kaplan-Meier Estimate of Patient Survival
Participants were followed for up to 7 years. Overall follow-up duration ranged from 2 to 84 months (X̅=36). A total of 30 participants died by the end of the follow-up period: 16 of cardiovascular disease, 5 of infection, 1 of cerebrovascular disease, 1 of gastroenterologic disease, and 7 of unknown causes. The 7-year cumulative survival rates were 92.0% in the ≥40% group and 75.6% in the <40% group. More than half of the participants in each group were alive at the end of follow-up. Twenty-five percent of participants with low knee extensor strength died after 45 months. However, the mortality rate of participants with high knee extensor strength at the end of the follow-up period was <25%. This finding indicates superior survival in patients with high knee extensor strength (P=.003) (Fig. 3).
Kaplan-Meier analysis of survival for 190 patients undergoing hemodialysis. Participants with knee extensor strength above the median value of 40% (thick dark line) at baseline had significantly better survival than those with a lower value (dotted line) (P=.003 by log-rank test).
Effect of Lower Extremity Muscle Strength on Survival Using a Cox Proportional Hazards Regression Analysis
The area under the ROC curve was 0.66 (95% confidence interval [CI]=0.55–0.77, P=.005) for knee extensor muscle strength, 0.74 (95% CI=0.64–0.84, P<.001) for gait speed, and 0.68 (95% CI=0.58–0.77, P=.002) for functional reach. With a Cox proportional hazards model, the crude hazard ratio (HR) in the <40% group was 3.20 (95% CI=1.42–7.20, P=.005) compared with that in the ≥40% group, indicating that low muscle strength of the lower extremities was associated with an elevation in all-cause mortality risk (Tab. 3). After adjustment for the effects of age, sex, BMI, time on hemodialysis, comorbidity score, and serum albumin and C-reactive protein levels, the HR became 3.71 (95% CI=1.46–9.40, P = 0.006). An analysis with the propensity score, performed to adjust for the effect of knee extensor strength by transforming all other confounding variables into a single estimator, revealed that after adjustment, low knee extensor strength still had a significant negative effect on survival (HR=2.73, 95% CI=1.14–6.52, P=.02).
Univariate and Multivariate Cox Models for the Effects of Lower Extremity Muscle Strength on Survivala
Discussion
In this prospective study, we examined all-cause mortality in a cohort of 190 patients undergoing hemodialysis. After an observation period of up to 7 years, 15.8% of the patients had died, and cardiovascular disease was the leading cause of death. The main finding of this study is the significant effect of lower extremity muscle strength at study entry on mortality in patients undergoing hemodialysis. The effect was independent of age, sex, BMI, time on hemodialysis, comorbid conditions, and markers of nutrition and inflammation. To our knowledge, this is the first study showing the association between lower extremity muscle strength and mortality in patients undergoing hemodialysis. On the basis of our findings, participants with severely decreased lower extremity muscle strength (<40%) had a 2.7-fold higher risk of death than those with high lower extremity muscle strength (≥40%).
In our study, we used a handheld dynamometer to evaluate knee extensor muscle strength. It was previously reported that intrarater and interrater reliability of values with the handheld dynamometer were very high.14,15,24 Piao et al25 reported that measurements of knee extensor muscle strength with a handheld dynamometer were generally consistent with values derived using a gold-standard device (Kin-Com, Chattecx Corp, Harrison, Tennessee). In this study, we evaluated patients' lower extremity muscle strength using a similar handheld dynamometer. In addition, we used knee extensor muscle strength instead of handgrip strength as an index of muscle strength because handgrip strength of patients undergoing hemodialysis is decreased by the presence of the hemodialysis shunt in the arm and, in some cases, because of carpal tunnel syndrome, cubital tunnel syndrome, or destructive cervical spondylosis due to dialysis-related amyloidosis. Knee extensor muscle strength is not directly influenced by the hemodialysis shunt or these comorbidities in the upper extremities.
We examined the association of knee extensor muscle strength with physical performance in order to reconfirm the validity of the handheld dynamometer in our study. Bohannon17 reported that knee extensor muscle strength was significantly correlated with maximum gait speed in healthy individuals. Furthermore, Kutsuna et al12 assessed knee extensor muscle strength and other physical performance parameters in patients undergoing maintenance hemodialysis, who demonstrated significant effects of knee extensor muscle strength on maximum gait speed, independent of clinical characteristics and physical activity levels. Knee extensor muscle strength significantly correlated with physical performance tests in our study, and our findings agree with those of prior studies. However, although knee extensor muscle strength is a good indicator of gait ability and balance function in patients undergoing hemodialysis, evaluation of muscle strength in the clinical setting alone is not sufficient. A comprehensive assessment of physical function is necessary for predicting outcomes such as disabilities or survival.
We categorized patients into 2 groups on the basis of knee extensor muscle strength using a cutoff value of 40%. In Japan, people with values under this cutoff point may need assistance with walking. However, although all patients in our study population walked unassisted, approximately half of them had muscle strength lower than the cutoff value. Yamamoto et al26 reported that knee extensor strengths evaluated using a handheld dynamometer in elderly patients with a first acute myocardial infarction and community-dwelling elderly adults were 47.6% and 60.2%, respectively. Because knee extensor muscle strength in our study participants was 40.7%, knee extensor muscle strength may be lower in patients undergoing hemodialysis than in other populations. This finding is consistent with previous studies that reported muscle weakness in patients undergoing hemodialysis1–3 and highlights the necessity for an objective evaluation of muscle strength even though patients may not display gait abnormality. Decreased muscle strength may already be present in patients undergoing hemodialysis before they exhibit difficulty in walking. In our study, decreased lower extremity muscle strength predicting a worse prognosis in this patient population without severe difficulty in walking was of clinical significance.
Risk factors that may be associated with low muscle strength in patients undergoing hemodialysis include systemic inflammation, protein energy malnutrition, and comorbid conditions, which are all common in this patient population.27 In addition, a sedentary lifestyle has a negative effect on muscle strength. Many resistance training trials have been conducted with these patients. The majority of these trials demonstrated that prolonged exercise is safe and beneficial for this patient population. In 2005, Cheema and Singh28 systematically reviewed trials of exercise training involving adult patients undergoing hemodialysis and showed the positive effects of high-intensity exercise training on muscle strength. Recently, the benefits of resistance training during dialysis sessions have been reported.29–31 Although the association of muscle strength improvement with survival remains unclear, improvement in lower extremity muscle strength in this patient population is believed to be associated with improved quality of life, improvement in activities of daily living, and increased exercise tolerance.30–32 Based on these findings, it may be important to include exercise therapy in routine care for patients undergoing hemodialysis.
With respect to our results, several possibilities may be considered. First, previous studies have shown that decreased muscle strength was associated with decreased walking ability and standing balance function,12,30,33 as was the case in our study. Patients with impaired physical performance are considered to be at increased risk for falls, and falls can predict hospitalization, the need for long-term institutional care, or bedridden status.34–36 In addition, Cooper et al4 reported that in a meta-analysis, people in community-dwelling populations with impaired physical performance were at a high risk for death. In our study, physical performance parameters such as gait speed and functional reach were significantly associated with mortality, and prognosis prediction ability of physical performance tests was higher than knee extensor muscle strength, which is one of the factors affecting gait ability and balance function. Therefore, impaired physical performance would have a potentially detrimental effect on mortality, not only in general populations but also in patients undergoing hemodialysis.
Second, physical activity in patients with lower muscle strength who are undergoing hemodialysis may be less frequent than in other patients. Kutsuna et al12 reported that knee extensor muscle strength evaluated with a handheld dynamometer correlated with objectively measured physical activity in patients undergoing hemodialysis. Previous studies have established the strong benefits of increased physical activity on mortality in the general population, older patients with cardiovascular disease, and patients with chronic kidney disease.37–40 Furthermore, we previously reported the prognostic significance of habitual physical activity, evaluated using an accelerometer (gold standard), on survival in a cohort of patients undergoing hemodialysis.41 Engaging in physical activity improves the risk factors for cardiovascular disease,42–46 which is the primary cause of death in hemodialysis populations. In particular, we had previously examined the association of physical activity measured by accelerometer with high-density lipoprotein cholesterol (HDL-C) level in Japanese patients undergoing hemodialysis and reported the significant effect of physical activity on HDL-C level.47 Therefore, physical inactivity might increase the risk of mortality, whereas increasing physical activity improves muscle strength. Lower extremity muscle strength and physical activity parameters may interact.
Third, patients with adequate muscle strength often have good nutrition. Malnutrition is a predictor of mortality in patients undergoing dialysis.48 Wang et al49 reported that muscle strength may be used as a nutrition-monitoring tool. The participants in the current study with poor lower-extremity muscle strength may have had malnutrition, which could have contributed to a poor outcome.
Fourth, muscle strength is associated with insulin resistance. Shinohara et al50 reported that insulin resistance was a strong risk factor for cardiovascular mortality in patients with end-stage renal disease, and Rasic-Milutinovic et al51 reported an association between muscle wasting and insulin resistance in patients undergoing hemodialysis. In a previous study, exercise interventions improved the insulin sensitivity of patients with lifestyle-related diseases such as type 2 diabetes and hypertension.52 However, in another study, although patients with hemodialysis engaged in exercise classes twice weekly for 3 months, the intervention had no effect on insulin resistance.45 The reason for this finding was discussed in the same article; the duration and frequency of exercise appeared to be inadequate.
Our study had some limitations. First, because it was a small-scale observational study, the results of our study might lack general versatility. The percentage of women in the high muscle strength group was significantly lower than in the low strength group. Thus, the accuracy of results might be improved by analyzing the data for each sex separately. Further large-scale prospective cohort studies are needed. However, we analyzed the association of lower extremity muscle strength with survival after adjustment for the effect of sex and other factors.
Second, we adopted the method used for propensity scoring to avoid overfitting and neglect of all observed covariates. For observational, nonrandomized studies, propensity scores appear to represent one of the best available methods to adjust for differences of patients. However, the differences of patient characteristics attributed to knee extensor strength <40% versus ≥40% in our study were adjusted by only observed factors. Therefore, we may need to obtain additional information regarding patient characteristics that potentially affect lower extremity muscle strength in patients undergoing maintenance hemodialysis.
Third, because we measured muscle strength only at baseline, we did not consider the change of muscle strength in our participants. Ideally, muscle strength would have been evaluated at differing time points. However, the patients in our study were in relatively stable condition within a general dialysis population and were not treated with any regular exercise therapies. As stated above, dramatic fluctuations of muscle strength over time would not be observed in our study participants unless they started muscle strengthening exercise on their own during the observational period. Therefore, we believe that the measurement of muscle strength at baseline fairly accurately predicts the future value.
Fourth, although we reported that participants with poor muscle strength experienced a higher mortality risk than the other participants, the underlying mechanisms remain to be elucidated.
In conclusion, decreased lower extremity muscle strength is strongly associated with survival in patients undergoing hemodialysis who are clinically stable. Future studies are needed to determine the potential mechanisms underlying this association.
Footnotes
Mr Matsuzawa, Dr Matsunaga, Dr Yamamoto, Dr Kutsuna, and Dr Takahira provided concept/idea/research design. Mr Matsuzawa and Dr Wang provided writing. Mr Matsuzawa, Dr Matsunaga, Dr Kutsuna, Ms Ishii, Mr Abe, and Mr Yoneki provided data collection. Mr Matsuzawa, Dr Matsunaga, Dr Wang, and Dr Kutsuna provided data analysis. Dr Matsunaga and Dr Takahira provided project management. Dr Takahira provided fund procurement. Mr Abe and Dr Yoshida provided study participants. Dr Yoshida provided facilities/equipment. Dr Matsunaga, Dr Wang, Dr Yoshida, and Dr Takahira provided consultation (including review of manuscript before submission). The authors thank the renal staff for their support and the patients for giving their time to complete the research protocol.
This study was approved by the Kitasato University Allied Health Sciences Research Ethics Committee.
- Received December 26, 2013.
- Accepted February 20, 2014.
- © 2014 American Physical Therapy Association
References
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