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Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study
Clinical Nutrition xxx (xxxx) xxx
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Original article
Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study Yasuharu Tabara a, *, Katsuhiko Kohara b, Yoko Okada c, Yasumasa Ohyagi c, Michiya Igase d a
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Regional Resource Management, Faculty of Collaborative Regional Innovation, Ehime University, Matsuyama, Japan Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Toon, Japan d Department of Anti-aging Medicine, Ehime University Graduate School of Medicine, Toon, Japan b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 3 May 2019 Accepted 22 July 2019
Background: Sarcopenia increases mortality risk in older adults. Loss of skeletal muscle mass is a cardinal feature of sarcopenia. The creatinine-to-cystatin C ratio (CCR) has been suggested as a marker of muscle mass. The present study investigated the usefulness of CCR in discriminating the risk of low muscle mass and weak muscle strength in an elderly population. Methods: The present cross-sectional study included 1,329 apparently healthy community residents aged 60 years or older. The cross-sectional area (CSA) of muscle in the mid-thigh was measured using computed tomography. Clinical data recorded at routine medical check-ups were obtained from each participant's medical record. Results: Mean muscle CSA was 109 ± 24 cm2. CCR by quartiles according to sex was strongly associated with muscle CSA (Q1: 104 ± 22, Q2: 108 ± 24, Q3: 110 ± 23, and Q4: 114 ± 25 cm2, F ¼ 10.38, P < 0.001). This association was independent of major covariates (Q1: reference, Q2: b ¼ 0.06, P < 0.001, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.17, P < 0.001) even in a sex-separated analysis. Although creatinine alone was independently associated with muscle CSA (F ¼ 5.81, P < 0.001), the association was weaker than that of CCR, particularly in the individuals with renal functional decline. Also, CCR was associated with grip strength independently of muscle CSA. Conclusion: CCR was a simple marker of low muscle mass and weak muscle strength in older community-dwelling adults. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Creatinine Cystatin C Skeletal muscle Sarcopenia General population
1. Introduction Sarcopenia in the elderly is known to increase the risks of falls [1] and death [2e4]. Although sarcopenia is a composite phenotype defined by a combination of low skeletal muscle mass, weak muscle strength, and decreased physical function, excessive loss of muscle mass remains the cardinal feature. Several methods are recommended for the assessment of muscle mass, including dual x-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging [5]. However, these methods require
* Corresponding author. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. Fax: þ81 75 751 4167. E-mail address: [email protected] (Y. Tabara).
specific devices and are therefore burdensome to adopt it in a primary care setting that aims to identify at-risk elderly individuals. Creatinine is an end product of muscle catabolism, and its generation is proportional to muscle mass. The circulating level of creatinine has thus been considered a potential marker reflecting systemic muscle mass. However, because its level varies with renal function, it is not useful in practice [6]. Creatinine is eliminated by filtration across the glomerulus and secreted by the proximal tubules into the urine; hence, a functional decline in glomerular filtration results in an increased circulating creatinine level. Cystatin C is another marker of glomerular filtration. It is produced in all nucleated cells and is thus not affected by muscle mass. Furthermore, approximately 99% of the filtered cystatin C is reabsorbed at the proximal tubule and is completely catabolized. Therefore, the circulating cystatin C level may more accurately
https://doi.org/10.1016/j.clnu.2019.07.027 0261-5614/© 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027
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represent the glomerular filtration rate (GFR) than creatinine [6]. Given this background, the creatinine-to-cystatin C ratio (CCR), also known as the sarcopenia index, was recently suggested as a marker of muscle mass. A cross-sectional study of patients in the intensive care unit reported a significant association between CCR and muscle mass measured by abdominal computed tomography (CT) [7]. This association was superior than that of creatinine and the estimated GFR (eGFR) calculated using either creatinine or cystatin C values [8]. Similar results were observed in kidney transplant recipients [9] and patients with type 2 diabetes [10], whose muscle mass was measured by DXA. However, the sample size of these studies [7e10] was as small, with some evaluating fewer than 300 patients. A recent study including approximately 700 community-dwelling individuals [11] also reported a significant association between CCR and sarcopenia, although this study used an indirect method (bioelectrical impedance analysis) to assess muscle mass. To further clarify the utility of CCR as a marker of muscle mass decline in a general population, we analyzed a dataset from the anti-aging study cohort (AASC), a longitudinal study of adults living independently, where CT-measured femoral muscle mass data was available for analysis. 2. Methods 2.1. Study participants We analyzed a dataset from the AASC [12,13], a longitudinal study cohort of the Shimanami Health Promoting Program (JSHIPP study). The J-SHIPP study, conducted by Ehime University Graduate School of Medicine, aims to evaluate factors relating to cardiovascular disease, dementia, and death. The J-SHIPP study involves several cohorts of the general population in Ehime Prefecture, Japan. AASC includes apparently healthy, middleaged to elderly participants in the medical check-up program at the Ehime University Hospital Anti-Aging Center. This medical check-up was provided to general residents of Ehime Prefecture for evaluation of age-related disorders, such as atherosclerosis, cardiovascular diseases, physical dysfunction, and cognitive impairment. From a total of 2,127 individuals who participated from February 2006 to December 2018, we analyzed a dataset of 1,329 elderly (60 years) individuals with available relevant clinical data, including CT-measured femoral muscles crosssectional area (CSA). Those with severe renal function decline (i.e., eGFR <30 mL/min/1.73 m2 or urinary albumin 300 mg/ day) were excluded. Clinical data used in this study were obtained from health records completed as part of the medical check-up program. All study procedures were approved by the ethics committee of Ehime University Graduate School of Medicine (30-K6). Written informed consent was obtained from all participants. 2.2. Measurement of femoral muscle CSA CSA of the femoral muscles, including quadriceps, adductors, and hamstrings were measured on CT images (LightSpeed VCT, GE Healthcare, Tokyo, Japan) at the midpoint between the lower margin of the femoral condyles and upper margin of the greater trochanter [14]. CT measurements of femoral muscle CSA and abdominal obesity at the check-up program were provided upon patient's request. With an attenuation range of 0e100 Hounsfield units for muscle, the CSA was computed using OsiriX software [15]. CT images with a minimal slice thickness of 5 mm were obtained. The utility of CT-measured muscle CSA in the assessment of skeletal muscle mass has been reported elsewhere [14].
2.3. Measurement of hand grip strength Hand grip strength was measured using a digital grip dynamometer (TKK5401, Takei Scientific Instruments Co., Ltd., Niigata, Japan), which reports grip strength to one decimal place. Measurements were made once for each hand with the person standing with arms down. The mean of the two measurements was used for the analysis as a representative value. Grip strength data were only available for 768 individuals who had the medical check-up after July 2007. 2.4. Basic clinical parameters Basic clinical parameters used in this study such as the creatinine level were obtained from the participants’ clinical record from the medical check-up. The homeostasis model assessment index for insulin resistance (HOMA-IR) was calculated as (insulin glucose)/ 405. Cystatin C was measured by latex agglutination-turbidimetric immunoassay (IATRO Cys-C; LSI Medience Co. Ltd., Tokyo, Japan), while leptin was measured by radioimmunoassay (Leptin HL-81K; Linco Research Inc., St. Charles, Mo., USA), using blood specimens stored at 80 C. The fasting blood specimens were drawn in the morning of the medical check-up day. CCR was calculated as [creatinine (mg/dL)/cystatin C (mg/L)] 10. eGFR was calculated from the creatinine level by using the MDRD [16] and CKD-EPI [17,18] equations modified by multiplying with the Japanese coefficient: eGFR MDRD ¼ 194 creatinine1.094 age0.287 0.739 (if female); eGFR CKD-EPI ¼ 141 min (creatinine/k, 1)a max (creatinine/k, 1)1.209 0.993age 1.018 (if female), where k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is the minimum of creatinine/k or 1, and max is the maximum of creatinine/k or 1. 2.5. Statistical analysis Values are expressed as mean ± standard deviation. Quartiles were calculated separately for men and women to avoid potential sex differences. When the participants were not equally divisible into quartiles due to a mismatch between the cut-off value of the quartiles and the discontinuity point of the variable using quartile calculation, participants with the same cut-off value were randomly assigned to adjacent quartiles. Group differences in numeric variables were assessed by analysis of variance. Factors independently associated with femoral muscle CSA were identified using a liner regression analysis. A P-value lower than 0.05 was considered as statistically significant. Statistical analyses were performed using JMP Pro 14.2.0 software (SAS Institute Inc., Cary, NC, USA). 3. Results Clinical characteristics of the study participants are summarized in Table 1. The CCRs in this population were similar to those observed in previous studies [10,11]. Figure 1 shows the differences in the femoral muscle CSA by quartiles of several clinical traits calculated by serum creatinine and cystatin C levels. The most significant association was observed between CCR and femoral muscle CSA (Fig. 1A). A similar association was seen in the sex-separated analysis (men, Q1:124 ± 18 cm2, Q2: 131 ± 18 cm2, Q3: 132 ± 16 cm2, and Q4: 141 ± 15 cm2, P < 0.001; women, Q1: 91 ± 14 cm2, Q2: 91 ± 12 cm2, Q3: 96 ± 13 cm2, and Q4: 97 ± 12 cm2, P < 0.001). Although creatinine was also significantly associated with CSA (Fig. 1B), this association was slightly weaker than that of CCR. In contrast, no significant
Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027
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reference, Q2: b ¼ 0.05, P ¼ 0.046, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.19, P < 0.001). Although creatinine quartiles also showed an
Table 1 Clinical characteristics of the participants.
N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)x Glucose (mg/dL) Insulin (mU/mL) HOMA-IR Leptin (ng/mL) Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio eGFR MDRD (mL/min/1.73 m2) eGFR CKD-EPI (mL/min/1.73 m2) Urinary albumin (mg/day)
3
Men
Women
533 69.6 ± 6.1 23.8 ± 2.8 132 ± 18 35.9 ± 6.1 108 ± 20 6.1 ± 3.9 1.7 ± 1.2 4.8 ± 3.5 0.88 ± 0.15 0.83 ± 0.16 10.7 ± 1.6 68.4 ± 12.4 69.6 ± 9.0 28 ± 45
796 68.8 ± 5.7 22.7 ± 3.0 94 ± 13 21.5 ± 4.0 101 ± 15 5.6 ± 3.5 1.4 ± 1.0 9.4 ± 6.5 0.64 ± 0.12 0.76 ± 0.14 8.6 ± 1.3 71.7 ± 14.4 73.4 ± 8.5 27 ± 39
Values are mean ± standard deviation. x Data of 768 participants were available. Homeostasis model assessment index for insulin resistance (HOMA-IR) was calculated as (insulin glucose)/405. Estimated glomerular filtration rate (eGFR) was calculated from creatinine level by the following MDRD and CKD-EPI equations modified by multiplying with the Japanese coefficient: eGFR MDRD ¼ 194 creatinine1.094 age0.287 0.739 (if female) eGFR CKD-EPI ¼ 141 min(creatinine/k, 1)a max(creatinine/k, 1)1.209 0.993Age 1.018 (if female) 0.813, where k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is the minimum of creatinine/k or 1, and max is the maximum of creatinine/k or 1. BMI: body mass index, CSA: cross-sectional area.
association was found in the analysis of cystatin C (Fig. 1C) and eGFR (Fig. 1D,E). Differences in other clinical factors among the quartiles of CCR and femoral muscle CSA are summarized in Tables 2 and 3, respectively. Although several factors particularly age, sex, and body mass index were significantly associated with both CCR and femoral muscle CSA, the results of multiple linear regression analysis adjusted for the possible covariates (Table 4) indicated that the CCR quartiles were independent determinants of muscle CSA (Model 1). This association was also significant in the separate analysis based on sex (Models 2 and 3) and age (Models 4 and 5), as well as in participants with decreased renal function (eGFR MDRD <60 mL/ min/1.73 m2 or urinary albumin 30 mg/day, n ¼ 497) (Q1:
independent association with CSA in the regression analysis of the total population that included the same covariates as Model 1 (Q1: reference, Q2: b ¼ 0.05, P ¼ 0.001, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.12, P < 0.001), the association was weaker than that of CCR, particularly in the analysis of participants 70 years old (Q1: reference, Q2: b ¼ 0.03, P ¼ 0.265, Q3: b ¼ 0.08, P ¼ 0.002, and Q4: b ¼ 0.12, P < 0.001) and those with renal functional decline (Q1: reference, Q2: b ¼ 0.04, P ¼ 0.132, Q3: b ¼ 0.04, P ¼ 0.153, and Q4: b ¼ 0.16, P < 0.001). In addition, the quartiles of CCR were associated with grip strength (Model 6) independently of the femoral muscle CSA. When the lowest quartile of femoral muscle CSA was defined as low muscle mass, the frequency of low muscle mass was increased in inverse proportion to the CCR quartiles (Fig. 2). Crude odds ratios of the CCR quartiles for low muscle mass were calculated using the highest CCR quartile as a reference. 4. Discussion In the present cross-sectional study of community-dwelling elderly, we found that CCR was an independent marker of CTmeasured femoral muscle CSA. The CCR was also significantly associated with grip strength independently of the femoral muscle CSA. To the best of our knowledge, this is the first study showing CCR to be an independent marker of skeletal muscle mass in more than 1,000 community residents. Although creatinine alone was significantly associated with muscle CSA, the association was weaker than that of CCR, particularly in individuals with renal functional decline. Because the circulating levels of creatinine partially depend on GFR, the creatinine levels in individuals with a low eGFR might not accurately reflect the amount of skeletal muscle. The weak association with creatinine in participants 70 years old who were more likely to have a lower eGFR might due to the same reason. The association between CCR and femoral muscle CSA was confirmed in both sexes irrespective of the large sex differences in these factors. We previously reported that leptin, an adipocytederived protein that may have adverse effects in skeletal muscle
Fig. 1. Differences in femoral muscle cross-sectional area (CSA). Values are expressed as means. Quartiles were calculated separately by sex. The number of study participants in each quartile is shown in the columns. Statistical significance was assessed by analysis of variance.
Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027
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Table 2 Differences in clinical characteristics by the quartiles of the creatinine-to-cystatin C ratio. Quartiles of creatinine-to-cystatin C ratio
Men
Women
N Age (years) BMI (kg/m2) Grip strength (kg)a Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio Urinary albumin (mg/day) N Age (years) BMI (kg/m2) Grip strength (kg)a Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio Urinary albumin (mg/day)
P
Q1
Q2
Q3
Q4
132 72.4 ± 6.5 24.0 ± 3.2 32.5 ± 6.2 0.81 ± 0.15 0.93 ± 0.18 8.71 ± 0.83 40 ± 56 196 71.0 ± 5.9 23.4 ± 3.4 19.9 ± 4.1 0.58 ± 0.13 0.82 ± 0.17 7.09 ± 0.56 38 ± 50
133 70.2 ± 5.7 23.8 ± 2.9 35.9 ± 5.9 0.86 ± 0.15 0.85 ± 0.14 10.18 ± 0.31 26 ± 40 193 69.5 ± 5.7 22.6 ± 2.9 21.0 ± 4.0 0.62 ± 0.10 0.76 ± 0.12 8.17 ± 0.22 26 ± 36
134 69.1 ± 6.2 23.8 ± 2.9 36.1 ± 5.8 0.90 ± 0.15 0.81 ± 0.14 11.17 ± 0.31 29 ± 44 204 67.7 ± 5.4 22.8 ± 2.8 21.8 ± 4.2 0.65 ± 0.10 0.73 ± 0.11 8.91 ± 0.23 22 ± 34
134 66.7 ± 4.5 23.8 ± 2.4 38.4 ± 5.4 0.94 ± 0.13 0.74 ± 0.10 12.64 ± 0.85 19 ± 35 203 67.1 ± 4.9 22.2 ± 2.7 22.9 ± 3.3 0.71 ± 0.11 0.71 ± 0.12 10.17 ± 1.09 21 ± 32
<0.001 0.845 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Values are mean ± standard deviation. Statistical significance was assessed by analysis of variance. a Data of 306 men (Q1: 67, Q2: 75, Q3: 77, Q4: 87) and 462 women (Q1: 100, Q2: 108, Q3: 131, Q4: 123) were available.
Table 3 Differences in clinical characteristics by the quartiles of femoral muscle CSA. Quartiles of Femoral muscle CSA
Men
Women
N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)a HOMA-IR Leptin (ng/mL) N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)a HOMA-IR Leptin (ng/mL)
P
Q1
Q2
Q3
Q4
133 73.3 ± 6.3 21.6 ± 2.6 109 ± 8 32.1 ± 4.8 1.3 ± 1.2 4.1 ± 3.2 199 70.8 ± 6.3 20.6 ± 2.5 78 ± 6 19.1 ± 3.4 1.2 ± 0.8 8.3 ± 6.7
134 69.7 ± 6.1 23.6 ± 2.3 126 ± 4 35.8 ± 5.5 1.7 ± 1.3 4.8 ± 2.8 199 69.2 ± 5.6 22.1 ± 2.3 89 ± 2 21.5 ± 3.4 1.3 ± 0.8 8.5 ± 5.4
133 68.2 ± 5.0 24.4 ± 2.4 138 ± 3 36.6 ± 6.0 1.7 ± 1.2 5.1 ± 4.5 199 67.4 ± 4.9 23.3 ± 2.2 98 ± 3 22.2v3.5 1.4 ± 0.9 9.5 ± 5.1
133 67.2 ± 5.1 25.8 ± 2.3 154 ± 9 39.0 ± 6.1 2.0 ± 1.2 5.1 ± 3.1 199 67.6 ± 5.1 25.0 ± 2.9 110 ± 8 23.5 ± 4.5 1.8 ± 1.3 11.4 ± 7.8
<0.001 <0.001 <0.001 <0.001 <0.001 0.054 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Values are mean ± standard deviation. Statistical significance was assessed by analysis of variance. HOMA-IR: homeostasis model assessment index for insulin resistance, BMI: body mass index, CSA: cross-sectional area. a Data of 306 men (Q1: 78, Q2: 71, Q3: 75, Q4: 82) and 462 women (Q1: 124, Q2: 122, Q3: 114, Q4: 102) were available.
Table 4 Multiple linear regression analysis of femoral muscle CSA and grip strength. Femoral muscle CSA Model 1
Age (years) Sex (men) BMI (kg/m2) HOMA-IR (log normalized) Leptin (ng/mL) Femoral muscle CSA (cm2) Creatinine-to-cystatin C ratio Q1 Q2 Q3 Q4
Grip strength Model 2
Model 3
Model 4
Model 5
Model 6
Total
Men
Women
<70 years old
70 years old
N ¼ 1,329
N ¼ 533
N ¼ 796
N ¼ 734
N ¼ 595
N ¼ 768
b
P
b
P
b
P
b
P
b
P
b
P
0.14 0.67 0.41 0.02 0.10
<0.001 <0.001 <0.001 0.205 <0.001
0.26
<0.001
0.16
<0.001
0.68 0.05 0.17
<0.001 0.189 <0.001
0.65 0.09 0.15
<0.001 0.004 <0.001
0.03 0.68 0.39 0.02 0.12
0.046 <0.001 <0.001 0.221 <0.001
0.13 0.67 0.44 0.01 0.07
<0.001 <0.001 <0.001 0.677 0.001
0.14 0.59 0.01 0.03 0.03 0.29
<0.001 <0.001 0.670 0.106 0.241 <0.001
Reference 0.06 <0.001 0.10 <0.001 0.17 <0.001
Reference 0.13 <0.001 0.15 <0.001 0.31 <0.001
Reference 0.06 0.084 0.17 <0.001 0.23 <0.001
Reference 0.04 0.079 0.09 <0.001 0.17 <0.001
Reference Reference 0.08 <0.001 0.06 0.09 <0.001 0.06 0.16 <0.001 0.10
0.011 0.015 <0.001
Quartiles of creatinineecystatin C ratio were calculated separately by sex. b: standardized regression coefficient, CSA: cross-sectional area, BMI: body mass index, HOMA-IR: homeostasis model assessment index for insulin resistance.
Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027
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Fig. 2. Crude odds ratio for lower 25 percentile of femoral muscle CSA. The number of participants in each subgroup is shown in the columns. CCR: creatinineecystatin C ratio, CSA: cross-sectional area, OR: odds ratio. #P < 0.001, xP ¼ 0.003, ¶P ¼ 0.063.
and contribute to sarcopenia, was an independent inverse determinants of femoral muscle CSA in a portion of that study population [19]. However, in the present study, the association between CCR and muscle CSA was also independent of the leptin level. Given the large coefficient of CCR in the regression model as well as the high odds ratio of lower CCR quartiles to low muscle mass, it would be helpful to consider using CCR in a primary care setting and public health practice aiming to estimate individual risk of low muscle mass. Given the creatinine and cystatin C levels in each CCR quartile, a disproportionately low creatinine level in comparison with cystatin C and urinary albumin levels may be a clue to identify individuals with low muscle mass. CCR was also associated with grip strength independently of muscle CSA. Although we only measured mid-thigh muscle CSA, not upper-arm muscle CSA, the results strongly support the possibility that CCR may indicate not only muscle quantity but also muscle quality. In a longitudinal study of older individuals [3], muscle strength was more important than muscle quantity in estimating the mortality risk. This possible association between CCR and muscle strength and quality deserves further investigation. The strength of this study was the use of CT-measured muscle mass as a dependent variable rather than a surrogate measure based on bioelectrical impedance analysis. This technique enabled an accurate assessment of the relationship between CCR and muscle mass. In a longitudinal study, mid-thigh muscle CSA was a better predictor of death than body mass index in patients with chronic obstructive pulmonary diseases [20], supporting the superiority of using muscle CSA as an outcome measure. Furthermore, as we measured both muscle CSA and grip strength in the same population, we could clarify CCR as a representative marker not only of muscle mass but also of muscle function. Another strength of this study was the large population size. There are several limitations that should be mentioned. First, because we did not have data on walking speed, a measure of skeletal muscle function that is required to diagnose sarcopenia [21], we could not directly investigate a relationship between CCR and sarcopenia. However, given the association between CCR and
grip strength independent of muscle mass, CCR may have potential as a marker of not only low muscle mass but also of sarcopenia. Second, we did not consider dietary intake of meat or exercise habits. These two factors could increase the circulating levels of creatinine and probably have a positive influence on muscle mass. Also, we did not exclude participants taking drugs such as cimetidine [22] that increase the creatinine level independently of muscle mass and renal function. Third, our study participants were Japanese. Since the body size of Asians is smaller than that of Europeans [23], further studies among other populations are required to extrapolate our present findings. Fourth, the present study had a cross-sectional design. Further investigation is required to clarified whether CCR predicts longitudinal loss of muscle mass and quality. In summary, CCR may be useful as a marker identifying elderly individuals with low muscle mass. Authorship contributions Study design: YT; data acquisition: YT, KK, YoO, YaO, MI; statistical analysis and interpretation of data: YT, KK; drafting manuscript: YT, KK. All authors reviewed and edited the manuscript, and approved the final version to submit. Conflict of interest The Department of Anti-aging Medicine at Ehime University is funded by endowments from Nitta Gelatin Incorporated to Ehime University. Financial support The work was supported by the Grant-in-Aid for Scientific Research (20018020, 19659163, 20390185, 23659382, 24390084, 23659352, 25293141, 26670313, 17H04123) from Ministry of Education, Culture, Sports, Science and Technology, Japan; research grant from the Japan Atherosclerosis Prevention Found, Japan; National Cardiovascular Research Grants, Japan; and Research Promotion Award from Ehime University, Japan.
Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027
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Acknowledgment The authors are deeply indebted to the staff members of the JSHIPP study. We also thank the editors of Enago for the English language review.
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Original article
Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study Yasuharu Tabara a, *, Katsuhiko Kohara b, Yoko Okada c, Yasumasa Ohyagi c, Michiya Igase d a
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Regional Resource Management, Faculty of Collaborative Regional Innovation, Ehime University, Matsuyama, Japan Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Toon, Japan d Department of Anti-aging Medicine, Ehime University Graduate School of Medicine, Toon, Japan b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 3 May 2019 Accepted 22 July 2019
Background: Sarcopenia increases mortality risk in older adults. Loss of skeletal muscle mass is a cardinal feature of sarcopenia. The creatinine-to-cystatin C ratio (CCR) has been suggested as a marker of muscle mass. The present study investigated the usefulness of CCR in discriminating the risk of low muscle mass and weak muscle strength in an elderly population. Methods: The present cross-sectional study included 1,329 apparently healthy community residents aged 60 years or older. The cross-sectional area (CSA) of muscle in the mid-thigh was measured using computed tomography. Clinical data recorded at routine medical check-ups were obtained from each participant's medical record. Results: Mean muscle CSA was 109 ± 24 cm2. CCR by quartiles according to sex was strongly associated with muscle CSA (Q1: 104 ± 22, Q2: 108 ± 24, Q3: 110 ± 23, and Q4: 114 ± 25 cm2, F ¼ 10.38, P < 0.001). This association was independent of major covariates (Q1: reference, Q2: b ¼ 0.06, P < 0.001, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.17, P < 0.001) even in a sex-separated analysis. Although creatinine alone was independently associated with muscle CSA (F ¼ 5.81, P < 0.001), the association was weaker than that of CCR, particularly in the individuals with renal functional decline. Also, CCR was associated with grip strength independently of muscle CSA. Conclusion: CCR was a simple marker of low muscle mass and weak muscle strength in older community-dwelling adults. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Creatinine Cystatin C Skeletal muscle Sarcopenia General population
1. Introduction Sarcopenia in the elderly is known to increase the risks of falls [1] and death [2e4]. Although sarcopenia is a composite phenotype defined by a combination of low skeletal muscle mass, weak muscle strength, and decreased physical function, excessive loss of muscle mass remains the cardinal feature. Several methods are recommended for the assessment of muscle mass, including dual x-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging [5]. However, these methods require
* Corresponding author. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. Fax: þ81 75 751 4167. E-mail address: [email protected] (Y. Tabara).
specific devices and are therefore burdensome to adopt it in a primary care setting that aims to identify at-risk elderly individuals. Creatinine is an end product of muscle catabolism, and its generation is proportional to muscle mass. The circulating level of creatinine has thus been considered a potential marker reflecting systemic muscle mass. However, because its level varies with renal function, it is not useful in practice [6]. Creatinine is eliminated by filtration across the glomerulus and secreted by the proximal tubules into the urine; hence, a functional decline in glomerular filtration results in an increased circulating creatinine level. Cystatin C is another marker of glomerular filtration. It is produced in all nucleated cells and is thus not affected by muscle mass. Furthermore, approximately 99% of the filtered cystatin C is reabsorbed at the proximal tubule and is completely catabolized. Therefore, the circulating cystatin C level may more accurately
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represent the glomerular filtration rate (GFR) than creatinine [6]. Given this background, the creatinine-to-cystatin C ratio (CCR), also known as the sarcopenia index, was recently suggested as a marker of muscle mass. A cross-sectional study of patients in the intensive care unit reported a significant association between CCR and muscle mass measured by abdominal computed tomography (CT) [7]. This association was superior than that of creatinine and the estimated GFR (eGFR) calculated using either creatinine or cystatin C values [8]. Similar results were observed in kidney transplant recipients [9] and patients with type 2 diabetes [10], whose muscle mass was measured by DXA. However, the sample size of these studies [7e10] was as small, with some evaluating fewer than 300 patients. A recent study including approximately 700 community-dwelling individuals [11] also reported a significant association between CCR and sarcopenia, although this study used an indirect method (bioelectrical impedance analysis) to assess muscle mass. To further clarify the utility of CCR as a marker of muscle mass decline in a general population, we analyzed a dataset from the anti-aging study cohort (AASC), a longitudinal study of adults living independently, where CT-measured femoral muscle mass data was available for analysis. 2. Methods 2.1. Study participants We analyzed a dataset from the AASC [12,13], a longitudinal study cohort of the Shimanami Health Promoting Program (JSHIPP study). The J-SHIPP study, conducted by Ehime University Graduate School of Medicine, aims to evaluate factors relating to cardiovascular disease, dementia, and death. The J-SHIPP study involves several cohorts of the general population in Ehime Prefecture, Japan. AASC includes apparently healthy, middleaged to elderly participants in the medical check-up program at the Ehime University Hospital Anti-Aging Center. This medical check-up was provided to general residents of Ehime Prefecture for evaluation of age-related disorders, such as atherosclerosis, cardiovascular diseases, physical dysfunction, and cognitive impairment. From a total of 2,127 individuals who participated from February 2006 to December 2018, we analyzed a dataset of 1,329 elderly (60 years) individuals with available relevant clinical data, including CT-measured femoral muscles crosssectional area (CSA). Those with severe renal function decline (i.e., eGFR <30 mL/min/1.73 m2 or urinary albumin 300 mg/ day) were excluded. Clinical data used in this study were obtained from health records completed as part of the medical check-up program. All study procedures were approved by the ethics committee of Ehime University Graduate School of Medicine (30-K6). Written informed consent was obtained from all participants. 2.2. Measurement of femoral muscle CSA CSA of the femoral muscles, including quadriceps, adductors, and hamstrings were measured on CT images (LightSpeed VCT, GE Healthcare, Tokyo, Japan) at the midpoint between the lower margin of the femoral condyles and upper margin of the greater trochanter [14]. CT measurements of femoral muscle CSA and abdominal obesity at the check-up program were provided upon patient's request. With an attenuation range of 0e100 Hounsfield units for muscle, the CSA was computed using OsiriX software [15]. CT images with a minimal slice thickness of 5 mm were obtained. The utility of CT-measured muscle CSA in the assessment of skeletal muscle mass has been reported elsewhere [14].
2.3. Measurement of hand grip strength Hand grip strength was measured using a digital grip dynamometer (TKK5401, Takei Scientific Instruments Co., Ltd., Niigata, Japan), which reports grip strength to one decimal place. Measurements were made once for each hand with the person standing with arms down. The mean of the two measurements was used for the analysis as a representative value. Grip strength data were only available for 768 individuals who had the medical check-up after July 2007. 2.4. Basic clinical parameters Basic clinical parameters used in this study such as the creatinine level were obtained from the participants’ clinical record from the medical check-up. The homeostasis model assessment index for insulin resistance (HOMA-IR) was calculated as (insulin glucose)/ 405. Cystatin C was measured by latex agglutination-turbidimetric immunoassay (IATRO Cys-C; LSI Medience Co. Ltd., Tokyo, Japan), while leptin was measured by radioimmunoassay (Leptin HL-81K; Linco Research Inc., St. Charles, Mo., USA), using blood specimens stored at 80 C. The fasting blood specimens were drawn in the morning of the medical check-up day. CCR was calculated as [creatinine (mg/dL)/cystatin C (mg/L)] 10. eGFR was calculated from the creatinine level by using the MDRD [16] and CKD-EPI [17,18] equations modified by multiplying with the Japanese coefficient: eGFR MDRD ¼ 194 creatinine1.094 age0.287 0.739 (if female); eGFR CKD-EPI ¼ 141 min (creatinine/k, 1)a max (creatinine/k, 1)1.209 0.993age 1.018 (if female), where k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is the minimum of creatinine/k or 1, and max is the maximum of creatinine/k or 1. 2.5. Statistical analysis Values are expressed as mean ± standard deviation. Quartiles were calculated separately for men and women to avoid potential sex differences. When the participants were not equally divisible into quartiles due to a mismatch between the cut-off value of the quartiles and the discontinuity point of the variable using quartile calculation, participants with the same cut-off value were randomly assigned to adjacent quartiles. Group differences in numeric variables were assessed by analysis of variance. Factors independently associated with femoral muscle CSA were identified using a liner regression analysis. A P-value lower than 0.05 was considered as statistically significant. Statistical analyses were performed using JMP Pro 14.2.0 software (SAS Institute Inc., Cary, NC, USA). 3. Results Clinical characteristics of the study participants are summarized in Table 1. The CCRs in this population were similar to those observed in previous studies [10,11]. Figure 1 shows the differences in the femoral muscle CSA by quartiles of several clinical traits calculated by serum creatinine and cystatin C levels. The most significant association was observed between CCR and femoral muscle CSA (Fig. 1A). A similar association was seen in the sex-separated analysis (men, Q1:124 ± 18 cm2, Q2: 131 ± 18 cm2, Q3: 132 ± 16 cm2, and Q4: 141 ± 15 cm2, P < 0.001; women, Q1: 91 ± 14 cm2, Q2: 91 ± 12 cm2, Q3: 96 ± 13 cm2, and Q4: 97 ± 12 cm2, P < 0.001). Although creatinine was also significantly associated with CSA (Fig. 1B), this association was slightly weaker than that of CCR. In contrast, no significant
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reference, Q2: b ¼ 0.05, P ¼ 0.046, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.19, P < 0.001). Although creatinine quartiles also showed an
Table 1 Clinical characteristics of the participants.
N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)x Glucose (mg/dL) Insulin (mU/mL) HOMA-IR Leptin (ng/mL) Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio eGFR MDRD (mL/min/1.73 m2) eGFR CKD-EPI (mL/min/1.73 m2) Urinary albumin (mg/day)
3
Men
Women
533 69.6 ± 6.1 23.8 ± 2.8 132 ± 18 35.9 ± 6.1 108 ± 20 6.1 ± 3.9 1.7 ± 1.2 4.8 ± 3.5 0.88 ± 0.15 0.83 ± 0.16 10.7 ± 1.6 68.4 ± 12.4 69.6 ± 9.0 28 ± 45
796 68.8 ± 5.7 22.7 ± 3.0 94 ± 13 21.5 ± 4.0 101 ± 15 5.6 ± 3.5 1.4 ± 1.0 9.4 ± 6.5 0.64 ± 0.12 0.76 ± 0.14 8.6 ± 1.3 71.7 ± 14.4 73.4 ± 8.5 27 ± 39
Values are mean ± standard deviation. x Data of 768 participants were available. Homeostasis model assessment index for insulin resistance (HOMA-IR) was calculated as (insulin glucose)/405. Estimated glomerular filtration rate (eGFR) was calculated from creatinine level by the following MDRD and CKD-EPI equations modified by multiplying with the Japanese coefficient: eGFR MDRD ¼ 194 creatinine1.094 age0.287 0.739 (if female) eGFR CKD-EPI ¼ 141 min(creatinine/k, 1)a max(creatinine/k, 1)1.209 0.993Age 1.018 (if female) 0.813, where k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is the minimum of creatinine/k or 1, and max is the maximum of creatinine/k or 1. BMI: body mass index, CSA: cross-sectional area.
association was found in the analysis of cystatin C (Fig. 1C) and eGFR (Fig. 1D,E). Differences in other clinical factors among the quartiles of CCR and femoral muscle CSA are summarized in Tables 2 and 3, respectively. Although several factors particularly age, sex, and body mass index were significantly associated with both CCR and femoral muscle CSA, the results of multiple linear regression analysis adjusted for the possible covariates (Table 4) indicated that the CCR quartiles were independent determinants of muscle CSA (Model 1). This association was also significant in the separate analysis based on sex (Models 2 and 3) and age (Models 4 and 5), as well as in participants with decreased renal function (eGFR MDRD <60 mL/ min/1.73 m2 or urinary albumin 30 mg/day, n ¼ 497) (Q1:
independent association with CSA in the regression analysis of the total population that included the same covariates as Model 1 (Q1: reference, Q2: b ¼ 0.05, P ¼ 0.001, Q3: b ¼ 0.10, P < 0.001, and Q4: b ¼ 0.12, P < 0.001), the association was weaker than that of CCR, particularly in the analysis of participants 70 years old (Q1: reference, Q2: b ¼ 0.03, P ¼ 0.265, Q3: b ¼ 0.08, P ¼ 0.002, and Q4: b ¼ 0.12, P < 0.001) and those with renal functional decline (Q1: reference, Q2: b ¼ 0.04, P ¼ 0.132, Q3: b ¼ 0.04, P ¼ 0.153, and Q4: b ¼ 0.16, P < 0.001). In addition, the quartiles of CCR were associated with grip strength (Model 6) independently of the femoral muscle CSA. When the lowest quartile of femoral muscle CSA was defined as low muscle mass, the frequency of low muscle mass was increased in inverse proportion to the CCR quartiles (Fig. 2). Crude odds ratios of the CCR quartiles for low muscle mass were calculated using the highest CCR quartile as a reference. 4. Discussion In the present cross-sectional study of community-dwelling elderly, we found that CCR was an independent marker of CTmeasured femoral muscle CSA. The CCR was also significantly associated with grip strength independently of the femoral muscle CSA. To the best of our knowledge, this is the first study showing CCR to be an independent marker of skeletal muscle mass in more than 1,000 community residents. Although creatinine alone was significantly associated with muscle CSA, the association was weaker than that of CCR, particularly in individuals with renal functional decline. Because the circulating levels of creatinine partially depend on GFR, the creatinine levels in individuals with a low eGFR might not accurately reflect the amount of skeletal muscle. The weak association with creatinine in participants 70 years old who were more likely to have a lower eGFR might due to the same reason. The association between CCR and femoral muscle CSA was confirmed in both sexes irrespective of the large sex differences in these factors. We previously reported that leptin, an adipocytederived protein that may have adverse effects in skeletal muscle
Fig. 1. Differences in femoral muscle cross-sectional area (CSA). Values are expressed as means. Quartiles were calculated separately by sex. The number of study participants in each quartile is shown in the columns. Statistical significance was assessed by analysis of variance.
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Table 2 Differences in clinical characteristics by the quartiles of the creatinine-to-cystatin C ratio. Quartiles of creatinine-to-cystatin C ratio
Men
Women
N Age (years) BMI (kg/m2) Grip strength (kg)a Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio Urinary albumin (mg/day) N Age (years) BMI (kg/m2) Grip strength (kg)a Creatinine (mg/dL) Cystatin C (mg/L) Creatinine-to-cystatin C ratio Urinary albumin (mg/day)
P
Q1
Q2
Q3
Q4
132 72.4 ± 6.5 24.0 ± 3.2 32.5 ± 6.2 0.81 ± 0.15 0.93 ± 0.18 8.71 ± 0.83 40 ± 56 196 71.0 ± 5.9 23.4 ± 3.4 19.9 ± 4.1 0.58 ± 0.13 0.82 ± 0.17 7.09 ± 0.56 38 ± 50
133 70.2 ± 5.7 23.8 ± 2.9 35.9 ± 5.9 0.86 ± 0.15 0.85 ± 0.14 10.18 ± 0.31 26 ± 40 193 69.5 ± 5.7 22.6 ± 2.9 21.0 ± 4.0 0.62 ± 0.10 0.76 ± 0.12 8.17 ± 0.22 26 ± 36
134 69.1 ± 6.2 23.8 ± 2.9 36.1 ± 5.8 0.90 ± 0.15 0.81 ± 0.14 11.17 ± 0.31 29 ± 44 204 67.7 ± 5.4 22.8 ± 2.8 21.8 ± 4.2 0.65 ± 0.10 0.73 ± 0.11 8.91 ± 0.23 22 ± 34
134 66.7 ± 4.5 23.8 ± 2.4 38.4 ± 5.4 0.94 ± 0.13 0.74 ± 0.10 12.64 ± 0.85 19 ± 35 203 67.1 ± 4.9 22.2 ± 2.7 22.9 ± 3.3 0.71 ± 0.11 0.71 ± 0.12 10.17 ± 1.09 21 ± 32
<0.001 0.845 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Values are mean ± standard deviation. Statistical significance was assessed by analysis of variance. a Data of 306 men (Q1: 67, Q2: 75, Q3: 77, Q4: 87) and 462 women (Q1: 100, Q2: 108, Q3: 131, Q4: 123) were available.
Table 3 Differences in clinical characteristics by the quartiles of femoral muscle CSA. Quartiles of Femoral muscle CSA
Men
Women
N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)a HOMA-IR Leptin (ng/mL) N Age (years) BMI (kg/m2) Femoral muscle CSA (cm2) Grip strength (kg)a HOMA-IR Leptin (ng/mL)
P
Q1
Q2
Q3
Q4
133 73.3 ± 6.3 21.6 ± 2.6 109 ± 8 32.1 ± 4.8 1.3 ± 1.2 4.1 ± 3.2 199 70.8 ± 6.3 20.6 ± 2.5 78 ± 6 19.1 ± 3.4 1.2 ± 0.8 8.3 ± 6.7
134 69.7 ± 6.1 23.6 ± 2.3 126 ± 4 35.8 ± 5.5 1.7 ± 1.3 4.8 ± 2.8 199 69.2 ± 5.6 22.1 ± 2.3 89 ± 2 21.5 ± 3.4 1.3 ± 0.8 8.5 ± 5.4
133 68.2 ± 5.0 24.4 ± 2.4 138 ± 3 36.6 ± 6.0 1.7 ± 1.2 5.1 ± 4.5 199 67.4 ± 4.9 23.3 ± 2.2 98 ± 3 22.2v3.5 1.4 ± 0.9 9.5 ± 5.1
133 67.2 ± 5.1 25.8 ± 2.3 154 ± 9 39.0 ± 6.1 2.0 ± 1.2 5.1 ± 3.1 199 67.6 ± 5.1 25.0 ± 2.9 110 ± 8 23.5 ± 4.5 1.8 ± 1.3 11.4 ± 7.8
<0.001 <0.001 <0.001 <0.001 <0.001 0.054 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Values are mean ± standard deviation. Statistical significance was assessed by analysis of variance. HOMA-IR: homeostasis model assessment index for insulin resistance, BMI: body mass index, CSA: cross-sectional area. a Data of 306 men (Q1: 78, Q2: 71, Q3: 75, Q4: 82) and 462 women (Q1: 124, Q2: 122, Q3: 114, Q4: 102) were available.
Table 4 Multiple linear regression analysis of femoral muscle CSA and grip strength. Femoral muscle CSA Model 1
Age (years) Sex (men) BMI (kg/m2) HOMA-IR (log normalized) Leptin (ng/mL) Femoral muscle CSA (cm2) Creatinine-to-cystatin C ratio Q1 Q2 Q3 Q4
Grip strength Model 2
Model 3
Model 4
Model 5
Model 6
Total
Men
Women
<70 years old
70 years old
N ¼ 1,329
N ¼ 533
N ¼ 796
N ¼ 734
N ¼ 595
N ¼ 768
b
P
b
P
b
P
b
P
b
P
b
P
0.14 0.67 0.41 0.02 0.10
<0.001 <0.001 <0.001 0.205 <0.001
0.26
<0.001
0.16
<0.001
0.68 0.05 0.17
<0.001 0.189 <0.001
0.65 0.09 0.15
<0.001 0.004 <0.001
0.03 0.68 0.39 0.02 0.12
0.046 <0.001 <0.001 0.221 <0.001
0.13 0.67 0.44 0.01 0.07
<0.001 <0.001 <0.001 0.677 0.001
0.14 0.59 0.01 0.03 0.03 0.29
<0.001 <0.001 0.670 0.106 0.241 <0.001
Reference 0.06 <0.001 0.10 <0.001 0.17 <0.001
Reference 0.13 <0.001 0.15 <0.001 0.31 <0.001
Reference 0.06 0.084 0.17 <0.001 0.23 <0.001
Reference 0.04 0.079 0.09 <0.001 0.17 <0.001
Reference Reference 0.08 <0.001 0.06 0.09 <0.001 0.06 0.16 <0.001 0.10
0.011 0.015 <0.001
Quartiles of creatinineecystatin C ratio were calculated separately by sex. b: standardized regression coefficient, CSA: cross-sectional area, BMI: body mass index, HOMA-IR: homeostasis model assessment index for insulin resistance.
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Fig. 2. Crude odds ratio for lower 25 percentile of femoral muscle CSA. The number of participants in each subgroup is shown in the columns. CCR: creatinineecystatin C ratio, CSA: cross-sectional area, OR: odds ratio. #P < 0.001, xP ¼ 0.003, ¶P ¼ 0.063.
and contribute to sarcopenia, was an independent inverse determinants of femoral muscle CSA in a portion of that study population [19]. However, in the present study, the association between CCR and muscle CSA was also independent of the leptin level. Given the large coefficient of CCR in the regression model as well as the high odds ratio of lower CCR quartiles to low muscle mass, it would be helpful to consider using CCR in a primary care setting and public health practice aiming to estimate individual risk of low muscle mass. Given the creatinine and cystatin C levels in each CCR quartile, a disproportionately low creatinine level in comparison with cystatin C and urinary albumin levels may be a clue to identify individuals with low muscle mass. CCR was also associated with grip strength independently of muscle CSA. Although we only measured mid-thigh muscle CSA, not upper-arm muscle CSA, the results strongly support the possibility that CCR may indicate not only muscle quantity but also muscle quality. In a longitudinal study of older individuals [3], muscle strength was more important than muscle quantity in estimating the mortality risk. This possible association between CCR and muscle strength and quality deserves further investigation. The strength of this study was the use of CT-measured muscle mass as a dependent variable rather than a surrogate measure based on bioelectrical impedance analysis. This technique enabled an accurate assessment of the relationship between CCR and muscle mass. In a longitudinal study, mid-thigh muscle CSA was a better predictor of death than body mass index in patients with chronic obstructive pulmonary diseases [20], supporting the superiority of using muscle CSA as an outcome measure. Furthermore, as we measured both muscle CSA and grip strength in the same population, we could clarify CCR as a representative marker not only of muscle mass but also of muscle function. Another strength of this study was the large population size. There are several limitations that should be mentioned. First, because we did not have data on walking speed, a measure of skeletal muscle function that is required to diagnose sarcopenia [21], we could not directly investigate a relationship between CCR and sarcopenia. However, given the association between CCR and
grip strength independent of muscle mass, CCR may have potential as a marker of not only low muscle mass but also of sarcopenia. Second, we did not consider dietary intake of meat or exercise habits. These two factors could increase the circulating levels of creatinine and probably have a positive influence on muscle mass. Also, we did not exclude participants taking drugs such as cimetidine [22] that increase the creatinine level independently of muscle mass and renal function. Third, our study participants were Japanese. Since the body size of Asians is smaller than that of Europeans [23], further studies among other populations are required to extrapolate our present findings. Fourth, the present study had a cross-sectional design. Further investigation is required to clarified whether CCR predicts longitudinal loss of muscle mass and quality. In summary, CCR may be useful as a marker identifying elderly individuals with low muscle mass. Authorship contributions Study design: YT; data acquisition: YT, KK, YoO, YaO, MI; statistical analysis and interpretation of data: YT, KK; drafting manuscript: YT, KK. All authors reviewed and edited the manuscript, and approved the final version to submit. Conflict of interest The Department of Anti-aging Medicine at Ehime University is funded by endowments from Nitta Gelatin Incorporated to Ehime University. Financial support The work was supported by the Grant-in-Aid for Scientific Research (20018020, 19659163, 20390185, 23659382, 24390084, 23659352, 25293141, 26670313, 17H04123) from Ministry of Education, Culture, Sports, Science and Technology, Japan; research grant from the Japan Atherosclerosis Prevention Found, Japan; National Cardiovascular Research Grants, Japan; and Research Promotion Award from Ehime University, Japan.
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Acknowledgment The authors are deeply indebted to the staff members of the JSHIPP study. We also thank the editors of Enago for the English language review.
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Please cite this article as: Tabara Y et al., Creatinine-to-cystatin C ratio as a marker of skeletal muscle mass in older adults: J-SHIPP study, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.07.027