点击显示 收起
1 From the Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka and Miyaji Hospital, Shimizu, Japan.
2 Supported by a grant from Shizuoka Research and Education Foundation, Shizuoka, Japan.
3 Address reprint requests to H Kumagai, Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422, Japan. E-mail: kumagai{at}u-shizuoka-ken.ac.jp.
ABSTRACT
Background: Quantification of muscle mass, which represents the largest protein pool in the body, is important for nutritional assessment but is difficult to achieve with conventional methods in hemodialysis patients.
Objective: We measured the cross-sectional area of the thigh occupied by muscle by using computed tomography and compared this with other muscle mass indicators.
Design: Thigh muscle area (TMA) was examined and correlated with creatinine production and various nutritional indexes in 163 patients undergoing hemodialysis. Where appropriate, TMA was expressed relative to bone area in the thigh (TBA) to avoid the influence of body size.
Results: TMA was highly correlated with creatinine production as measured in the spent dialysate (r = 0.85, P < 0.001), indicating that TMA substantially reflects total-body muscle mass. TMA standardized for TBA was negatively correlated with age and positively correlated with other nutritional indicators including body weight, body mass index, serum albumin, serum transthyretin, and protein catabolic rate. Multiple regression analysis revealed that of these variables, age, serum albumin, and protein catabolic rate independently predicted TMA standardized for TBA. By using correlations with various nutritional indicators, we concluded that patients with a value <10.0 for TMA standardized for TBA were likely to be malnourished whereas those with a value >13.0 were likely to be well nourished.
Conclusions: These results indicate that TMA standardized for TBA, measured by computed tomography, is a reliable indicator of muscle mass that could be used for nutritional assessment of hemodialysis patients.
Key Words: Nutritional assessment • muscle mass • computed tomography • thigh muscle area • malnutrition • creatinine • hemodialysis patients • kidney disease
INTRODUCTION
Protein-energy malnutrition is prevalent in hemodialysis patients and is associated with increased morbidity and mortality (1, 2). Serum concentrations of albumin, transthyretin, and transferrin reflect visceral protein stores and are widely used for nutritional assessment of hemodialysis patients. Serum albumin (3–5) and transthyretin (6) have been reported to be the best predictors of mortality in these patients. Yet, although such data are easy to obtain, they fall short of indicating the global state of protein nutrition in the body.
The largest protein reservoir in the body is muscle, accounting for 60% of total-body protein content (7). Heymsfield et al (8) evaluated the significance of muscle mass for nutritional assessment and showed it to be a reliable indicator of protein-energy malnutrition and clinical outcome. Lowrie and Lew (3) reported that predialysis serum creatinine concentration, an indirect indicator of muscle mass, was a strong predictor of mortality in hemodialysis patients. The most widely used anthropometric parameter for measuring muscle mass is midarm muscle circumference (MAMC), whereas common biochemical indicators are 24-h urinary creatinine and urinary 3-methylhistidine.
In patients with renal failure, the metabolic fate of creatinine differs from that in subjects with normal renal function. Mitch et al (9) reported that in renal failure, a substantial amount of creatinine is recycled to creatine or is metabolized to products other than creatine to be excreted via an extrarenal route. Furthermore, large amounts of the creatinine and 3-methylhistidine generated in the body are lost in the dialysate. Because collection of dialysate for biochemical measurements is not practical in a clinical setting, routine measurement of creatinine and 3-methylhistidine production is difficult in hemodialysis patients. Some attempts to evaluate the creatinine production rate have used creatinine kinetic models that require only one predialysis and one postdialysis blood sample (10, 11); these methods have not yet been fully validated. In comparison, measurement of MAMC depends on the skill of the evaluator and there may be excessive variation among repeated measurements performed by the same individual.
Several investigators have developed an accurate method of measuring skeletal muscle mass by using computed tomography (CT) (12–14). Mitsiopoulos et al (15) recently evaluated a CT method for measuring muscle mass in cadavers and reported that the fat-free skeletal muscle area measured by CT was strongly correlated with values obtained directly (r = 0.99, P < 0.001). In the present study, we evaluated midthigh adipose-tissue-free muscle area by CT and examined its correlation with the creatinine production rate and plasma proteins. We propose a new index, a ratio of midthigh muscle area to midthigh bone area, as an indicator of muscle mass for the nutritional assessment of hemodialysis patients.
SUBJECTS AND METHODS
Subjects
A total of 163 patients (109 males and 54 females) with various renal diseases who had been undergoing hemodialysis for 6 mo were evaluated. Because this study was performed in outpatient facilities, bed-bound or disabled patients, who might be particularly likely to have muscle atrophy in the lower limbs, were not included. The patients were maintained on a regular hemodialysis regimen (3 times/wk for 4–5 h) with hollow-fiber dialyzers and a bicarbonate-buffered dialysate (Kindaly AF-3P, Fuso, Osaka, Japan). The blood flow rate was in the range of 150–250 mL/min, with a dialysate flow rate of 500 mL/min. Blood samples were drawn at the start of the dialysis session. Serum was separated immediately and stored at -82°C until analyzed.
Measurement of thigh muscle area and the femoral bone area
CT of the thigh was performed when patients were undergoing abdominal CT for various indications. Each patient was examined in the supine position with the thigh muscles relaxed. An axial CT image was obtained at the midpoint of a line extending from the superior border of the patella to the greater trochanter of the femur. The thickness of the slice was 10 mm. The radiographic film was digitally scanned for analysis with a personal computer. The adipose-tissue-free thigh muscle area (TMA), bone area in the thigh (TBA), subcutaneous fat area (SFA), and intermuscular fat area (IMFA) were measured with use of a public domain planimetry program, NIH IMAGE (written by Wayne Rasband of the National Institutes of Health, Bethesda, MD).
Anthropometric measurements
Body weight was measured before and after each dialysis, with the postdialysis body weight used as the dry weight. Body mass index (BMI) was calculated as dry weight in kg divided by the square of the height in m. Midarm circumference (MAC) and triceps skinfold thickness (TSF) were measured with Harpenden skinfold calipers (Holtain, Crymych, United Kingdom) on the limb not used for vascular access. MAMC was calculated by using the equation:
RESULTS
Subject characteristics and nutritional indexes are shown in Table 1. Mean age, duration of hemodialysis, BMI, and serum albumin and transthyretin concentrations were not significantly different between males and females, whereas protein catabolic rate and Kt/
View this table:
TABLE 1.. Characteristics and nutritional indexes of the study population1
Relations between creatinine production and both TMA and MAMC in anuric hemodialysis patients are shown in Figure 1. A strong positive correlation was found between TMA and creatinine production, whereas MAMC had a significant but weaker association with creatinine production.
FIGURE 1. . Correlations between creatinine production and both thigh muscle area and midarm muscle circumference.
When creatinine production is used to estimate lean body mass for the purpose of nutritional assessment, the ratio of creatinine to ideal body weight or the creatinine–height index (18) are the preferred forms of data expression because the values are usually not affected by height. Because TMA may be associated with overall body size, it should also be standardized. The diameters of long bones are unlikely to change significantly after cessation of growth, and TBA could be measured simultaneously with TMA in the same image. TBA was strongly correlated with height in hemodialysis patients <55 y (r = 0.82, P < 0.0001). To compare the advantages of standardization by height and by TBA, these measures were evaluated by age and sex (Table 2). The findings indicated that height was significantly lower in older subjects, whereas TBA was fairly constant and independent of age in both males and females.
View this table:
TABLE 2.. Bone area in the thigh and height in hemodialysis patients by age group and sex1
Correlations of MAMC, TMA, and TMA standardized for TBA with other clinical variables are shown in Table 3. MAMC was negatively correlated with age in males but not in females. However, TMA and TMA standardized for TBA showed significant negative correlations with age in both males and females. MAMC, TMA, and TMA standardized for TBA were all significantly correlated with body weight and BMI in both sexes. MAMC and TMA were also dependent on height, although TMA was no longer correlated with height after standardization for TBA. Concentrations of albumin and transthyretin, both indexes of visceral protein, were significantly correlated with TMA and TMA standardized for TBA in both males and females, whereas these variables were not associated with MAMC in either sex.
View this table:
TABLE 3.. Correlations between muscle indexes and other clinical variables1
For variables that were significantly correlated with TMA standardized for TBA by univariate analysis (Table 3), a forward stepwise multiple regression analysis was performed to identify independent predictors of TMA standardized for TBA. Sex was included in the analysis as an independent variable. Age, serum albumin concentration, and protein catabolic rate were independent predictors of TMA standardized for TBA (Table 4) and this regression model explained 70% of the variation in TMA standardized for TBA.
View this table:
TABLE 4.. Multiple regression analysis with TMA standardized for TBA as the dependent variable1
After the hemodialysis patients were divided into 3 groups according to TMA standardized for TBA, the groups were compared with regard to various nutritional indicators (Table 5). These 3 groups were defined by cutoff points for TMA standardized for TBA as follows: low, <10.0; medium, 10.0–13.0; and high, >13.0, with the groups including 13%, 34%, and 53% of patients, respectively. These percentages are quite similar to reported prevalences of severe malnutrition, moderate malnutrition, and mild or no malnutrition in dialysis patients (19). Patients with a high TMA standardized for TBA (>13.0) were likely to be well nourished according to other nutritional indexes. In contrast, patients with a low TMA standardized for TBA (<10.0) had significantly lower dry weight, BMI, TMA, thigh subcutaneous fat area, MAMC, serum albumin, and protein catabolic rate than patients with a high TMA standardized for TBA, whether male or female. Thus, a low TMA standardized for TBA suggested the presence of malnutrition.
View this table:
TABLE 5.. Comparisons of nutritional variables in patients with low (<10.0), medium (10.0–13.0), and high (>13.0) TMA standardized for TBA1
DISCUSSION
Anthropometric determination of MAMC is a method frequently used for measuring muscle volume. However, CT studies have shown inaccuracies in the MAMC method, even when measurements were performed by skilled technicians (20, 21). Factors related to such error include variable subcutaneous fat thickness, an irregular cross-sectional outline of the muscle mass, and compression of the skinfold by the calipers. In addition, MAMC does not account for bone, neurovascular bundles, or interstitial adipose tissue, all of which can lead to overestimation of arm muscle volume (22). Prediction of total-body muscle volume from measurement of MAMC alone would be difficult. In the present study, we found that the correlation of MAMC with creatinine production was limited (r = 0.64) and that MAMC was not significantly correlated with serum albumin or transthyretin concentrations. Although Qureshi et al (23) concluded that MAMC was correlated with serum albumin in their large cross-sectional study of hemodialysis patients, the correlation coefficient was only 0.24.
In contrast, we found that TMA measured by CT was more valid than MAMC for nutritional assessment. First, the correlation of TMA with creatinine production was much stronger than that of MAMC. The difference may reflect the fact that the lean mass of the lower extremities represents more than one-third of total-body muscle volume, far more than that of the upper extremities. The finding that muscle area could be measured accurately while excluding adipose tissue and bone is also an important factor. In measuring muscle area, TBA and IMFA were eliminated easily. These tissues represent a substantial part of the area between thigh muscles at the level studied [13.8 ± 3.7% of cross-sectional area for males (range: 7–25); 16.4 ± 4.9% for females (range: 8–29)]. Second, TMA and TMA standardized for TBA were also significantly correlated with serum albumin and transthyretin. In contrast, MAMC was not sufficiently sensitive to show such correlations, even though close associations between visceral and somatic proteins would be expected.
Häggmark et al (12) were the first to report the usefulness of CT scanning for measuring TMA. In 9 healthy subjects, these authors performed muscle biopsies at the level at which CT examination was performed. Mean muscle fiber diameter was closely correlated with the cross-sectional area of the same muscle. Lerner et al (13) applied this method to 14 pediatric patients receiving total parenteral nutrition and reported that TMA was a better predictor of muscle mass than was midarm muscle area. A recent study of cadavers showed that CT and magnetic resonance imaging for measurement of skeletal muscle area excluding adipose tissue were accurate and agreed well with direct tissue measurement (15).
Measurement of total body nitrogen by prompt neutron activation analysis has been shown to be a precise and reproducible indicator of muscle mass, but this method requires massive equipment and remains experimental. Dual-energy X-ray absorptiometry and bioelectrical impedance analysis have been used recently to quantify fat mass and lean body mass in healthy subjects. Although these methods can be applied easily to patients and they accurately estimate fat-free mass, constituents of the lean tissue compartment such as water and protein cannot be differentiated from one another. Therefore, these methods of estimating lean body mass are not well suited to dialysis patients, who have marked variation in fluid status.
When used for nutritional assessment, TMA must be suitably standardized for body size, which is a strong determinant of muscle volume. For example, when urinary creatinine is evaluated as an index of lean body mass, it is divided by ideal body weight as a function of height (24). Because lean body mass declines with age and differs between males and females, normal values for creatinine excretion are published according to age and sex. However, height can decrease with age because of multiple factors such as gravitational effects, osteoporosis, kyphosis, and other deformities of the vertebral column (25). Dialysis patients are particularly likely to lose height because they frequently manifest renal osteodystrophy and other osteoarticular complications. In contrast, the length and thickness of long bones appear less likely to change, even in elderly dialysis patients. In contrast with height, TBA was not affected by age in our study population, although it was significantly dependent on body size and would be affected by growth in proportion to muscle size in youth. Once an individual develops malnutrition, muscle size could decrease rapidly without any change in bone length or thickness. Therefore, for assessing hemodialysis patients, we advocate use of TMA standardized for TBA as a new indicator of muscle mass that avoids any need to adjust for height.
TMA standardized for TBA was significantly correlated with other nutritional indicators in univariate analyses. Multiple regression analysis also indicated that serum albumin and protein catabolic rate were independent predictors of TMA standardized for TBA. Furthermore, patients with a TMA standardized for TBA <10.0 were malnourished by other criteria, whereas patients with a value >13.0 were considered well nourished. These results indicate that TMA standardized for TBA should be a useful indicator for nutritional assessment of hemodialysis patients.
Although we used creatinine production as a reference indicator of muscle mass in this study, this variable might not be suitable for nutritional assessment in some specific diseases. Heymsfield et al (26) pointed out that urinary creatinine excretion can be affected by age, diet, exercise, stress, the menstrual cycle, renal function, and factors associated with critical illness. This suggests that creatinine production may not fully reflect muscle mass in all hemodialysis patients. Moreover, collecting spent dialysate is cumbersome and not suited to routine clinical assessments. In contrast, measurement of TMA standardized for TBA requires only one CT slice. Hemodialysis patients are increasingly being examined with abdominal CT as a surveillance measure to detect renal and extrarenal cancers. Many authors recommend that patients treated with hemodialysis for >3 y should be screened for renal cancer by using CT at 1- to 2-y intervals (27, 28). We therefore suggest that addition of TMA measurement for nutritional assessment would be desirable.
In summary, the fat-free muscle area in the thigh as evaluated by CT was significantly correlated with creatinine production as measured from spent dialysate, and thus TMA is likely to reflect lean body mass. The index TMA standardized for TBA was independent of height and was correlated more closely with concentrations of serum proteins, such as albumin, than were TMA or MAMC. This new index is particularly easy to determine and may prove more useful than other methods for evaluating muscle mass in the nutritional assessment of hemodialysis patients.
ACKNOWLEDGMENTS
We are grateful to Masaaki Takizawa of Miyaji Hospital for his helpful assistance in examining CT scans.
REFERENCES