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ORIGINAL ARTICLE
a
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science,
Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
b
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk, Poland
KEYWORDS Summary
Muscle atrophy; Background & aims: Muscle wasting is considered the best marker of protein-energy wasting in
Inflammation; end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle
Dialysis; atrophy (MA) grading in relation to morbidity and mortality in ESRD patients.
Mortality; Methods: In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent
Sex hemodialysis patients), each patient’s degree of MA was visually graded by a trained nurse on
a scale from 1 to 4 as part of the subjective global assessment. This score was confronted with
inflammatory and nutritional indexes as well as objective measurements of muscle atrophy. Pa-
tients were then prospectively followed for up to four or six years, depending on the cohort.
Results: Thirty percent of the incident and 39% of the prevalent patients presented signs of MA.
Across worsening MA scale, nutritional and anthropometric markers of muscle loss were incre-
mentally poorer. Inflammation markers as well as the proportion of women became progres-
sively higher. Female sex, presence of cardiovascular disease, inflammation and low insulin-
like growth factor-1 levels were associated with increased significant odd ratios of MA in each
cohort. After adjustment for age, sex, inflammation, diabetes, cardiovascular disease,
Abbreviations: ESRD, end-stage renal disease; PEW, protein-energy wasting; MA, muscle atrophy; CKD, chronic kidney disease; SGA,
subjective global assessment; HD, hemodialysis; GFR, glomerular filtration rate; CRP, C-reactive protein; IL-6, interleukin-6; IGF-1, insulin
growth factor like-1; LBMI, lean body mass index; MAMC, midarm muscle circumference.
* Corresponding author. Division of Renal Medicine, K56, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden. Tel.: þ46
6693406
E-mail address: juan.jesus.carrero@ki.se (J.J. Carrero).
c
Both authors contributed equally to this work.
0261-5614/$ - see front matter ª 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
doi:10.1016/j.clnu.2008.04.007
558 J.J. Carrero et al.
glomerular filtration rate and/or time on hemodialysis, the hazard ratio of death for moderate/
severe MA was 2.62 (95% CI: 1.34, 5.13; p Z 0.001) and 3.04 (95% CI: 1.61, 5.71; p Z 0.0001) in
the incident and prevalent cohorts respectively.
Conclusion: Increased MA is more common in female dialysis patients and associated with in-
flammation, poor nutritional and anthropometric status, as well as a 3-fold increased 4e6 year
mortality. Our data support the use of frequent MA and/or nutritional assessments in the clinical
practice.
ª 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights
reserved.
The current study was performed in two different cohorts Anthropometric evaluation
of CKD-5 patients (the MIA and MIMICK cohorts) according to
protocols that have been described in detail elsewhere.16,17 Body mass index (BMI) was defined as the weight in
The Ethics Committee of the Karolinska University Hospital kilograms divided by the square of the height in meters.
in Huddinge, Stockholm, approved both study protocols, Body composition was assessed in both cohorts by using the
and informed consent was obtained from all patients. four skinfold thicknesses (biceps, triceps, subscapular, and
The first cohort16 consisted of 265 CKD-5 incident pa- suprailiac), measured with a conventional skinfold caliper
tients (162 (61%) men, median age 55 [inter quartile range (Cambridge Scientific Instruments, Cambridge, MA). Lean
44e64] years) from the Karolinska University Hospital at body mass (LBM) and fat body mass were estimated by
Huddinge, Stockholm, who were investigated close to means of dual-energy x-ray absorptiometry (in the pre-
the start of renal replacement therapy (median SD glo- dialysis cohort) using the DPX-L device (Lunar Corp, Madison,
merular filtration rate [GFR] 6.4 2.3 ml/min) during WI) or according to a theoretical formula (in the HD cohort)
Muscle atrophy and outcome in dialysis 559
based on skinfold thicknesses and body density.18 Lean albumin (bromcresol purple) and high-sensitivity C-reactive
body mass index (LBMI) was defined as the total lean body protein (CRP) (nephelometry) were performed by routine
mass in kilograms divided by the square of the height in procedures at the Department of Clinical Chemistry,
meters.19 Midarm circumference (MAC) was measured Karolinska University Hospital Huddinge. In both patient
with a plastic tape measurer and was normalized with materials plasma interleukin-6 (IL-6) and insulin growth
measurements from healthy subjects; midarm muscle cir- factor like-1 (IGF-1) concentrations were measured using
cumference (MAMC) was calculated by using the following commercial kits available for an Immulite Automatic Ana-
formula: MAMC Z MAC (3.1416 triceps skinfold thick- lyzer (Diagnostic Products Corporation, Los Angeles, CA).
ness/10).18 Handgrip strength was measured using a Harpen-
den Handgrip Dynamometer (Yamar, Jackson, MI) in the Statistical analysis
dominant hand (in the incident dialytic cohort) or in the
hand without fistula (in the HD group) and normalized Variables were expressed as means SD or median (inter-
with measurements from healthy subjects (see below). quartile range), as appropriate. Differences among the
These assessments were completed either at the time of muscle atrophy groups were analyzed with the Kruskale
or within 1 week of blood sample collection and after the Wallis analysis of variance followed by a post hoc Dunn’s
HD session in the prevalent cohort. test for non-parametric comparisons when assessing differ-
ences in inflammation markers. A c2 test was used for cat-
Nutritional status and muscle atrophy (MA) egorical variables. A multinomial logistic regression model
assessment was used to assess the predictors for muscle atrophy; this
model included the variables significantly associated with
Estimation of muscle atrophy is a part of the SGA question- muscle atrophy in univariate analysis or other variables
naire.20 This questionnaire includes six different compo- with a documented causal relationship (in this case age
nents: three subjective assessments that are performed and diabetes mellitus). Survival analyses used the Ka-
by the patients and that concern the patient’s history of planeMeier survival curve and the Cox proportional hazards
weight loss, incidence of anorexia, and incidence of vomit- model. The Cox proportional hazards model was used to
ing, and three objective assessments that are performed by examine survival differences after the analysis had been
the evaluators and that are based on the presence of mus- adjusted for potential confounding factors. Statistical sig-
cle atrophy (MA), the presence of edema and the loss of nificance was set at p < 0.05. All statistical analyses were
subcutaneous fat. The grading of MA was assessed by a spe- performed with SAS statistical software (version 9.1; SAS
cially trained nurse examining the temporalis muscle, the Institute Inc., Cary, NC).
prominence of the clavicles, the contour of the shoulders
(rounded indicates well-nourished; squared indicates mal- Results
nutrition), visibility of the scapula, the visibility of the
ribs, and interosseous muscle mass between the thumb MA scores for the patients included in the study are shown
and forefinger, and the quadriceps muscle mass. The signs in Fig. 1. After dichotomization into two major categories,
of MA were scored as follows: 1, no signs of MA; 2, mild signs 81 (30%) of the incident dialysis patients and 87 (39%) of the
of MA; 3, moderate signs of MA; 4, severe signs of MA. This HD patients showed some sign of MA (ranging from mild to
assessment was completed either at the time of or within severe). Since the sample sizes for the groups displaying
1 week of blood sample collection. moderate and severe signs of MA were small in both co-
Healthy subjects were recruited among the hospital horts, they were merged for comparative purposes.
staff. These individuals underwent a similar protocol as Demographic and laboratory data for the cohorts studied
above described. Anthropometric and handgrip values were and ratings of MA intensity are shown in Tables 1 and 2. In
used for normalization of the patient’s data. Individuals
younger than 18 and older than 70 years, or presenting with
clinically manifest disease were not included. A total of 44
healthy volunteers (24 men and 20 women, median age 44
[21e64] years) were recruited. None of these individuals
presented a history of CVD or diabetes. Also, none of these
individuals presented signs of malnutrition (SGA > 1), MA or
inflammation (C-reactive protein > 10 mg/l) at the time of
evaluation.
Laboratory analysis
Table 1 Clinical and biochemical characteristics in 265 incident CKD-5 patients starting dialysis according to their degree of
muscle atrophy (MA)
No signs of MA Mild MA Moderate/severe MA p
(N Z 184), 70% (N Z 59), 22% (N Z 22), 8%
Clinical characteristics
Age (years) 54 (43e64) 59 (48e65) 58 (49e66) n.s.
Sex (% male) 65 54 41 <0.05
Diabetes (%) 28 34 41 <0.01
CVD (%) 28 61 41 <0.001
GFR (ml/min) 6.7 2.3 5.7 1.9 6.4 2.7 n.s.
Nutritional parameters
BMI (kg/m2) 25.4 4.0 22.9 4.1 21.6 5.0 <0.0001
Weight (kg) 75.9 14.1 64.9 13.5 62.9 16.1 <0.0001
IGF-1 (ng/ml) 185 (129e246) 133 (89e94) 107 (55e192) <0.001
s-Creatinine (mmol/l) 775 259 627 183 516 223 <0.0001
s-Albumin (g/l) 33.5 6.2 31.6 7.2 30.5 5.2 <0.05
LBMI (kg/m2) 16.9 2.3 15.6 1.9 15.3 1.8 <0.001
Inflammation parameters
hsCRP (mg/l) 4.0 (1.5e12.8) 12.5 (2.5e24.5)* 6.1 (3.0e34.5) <0.01
IL-6 (pg/ml) 5.5 (3.3e9.2) 9.7 (5.6e17)* 9.3 (5.0e20.5)* <0.001
Data presented as mean standard deviation or median (interquartile range). n.s., not significant; CVD, cardiovascular disease; BMI,
body mass index; IGF-1, insulin-like growth factor-1; LBMI, lean body mass index; hsCRP, high-sensitivity C-reactive protein; IL-6, inter-
leukin 6.
*p < 0.05, different from the group with no signs of MA.
both cohorts the proportions of women became progres- i.e., IGF-1 levels, lean body mass index (LBMI), handgrip
sively and significantly higher as the MA scale worsened. strength and MAMC were progressively decreased (Fig. 2).
Also, across worsening MA scale, nutritional parameters Furthermore, inflammation parameters (e.g. CRP and IL-6)
and anthropometric measurements tended to be poorer. became gradually higher. However, some differences be-
Clinical and biochemical reflections of muscle wasting, tween the two cohorts turned out, probably due to
Table 2 Clinical and biochemical characteristics in 221 prevalent hemodialysis patients according to their degree of muscle
atrophy (MA)
No signs of MA Mild MA Moderate/severe MA p
(N Z 134), 61% (N Z 57), 26% (N Z 30), 13%
Clinical characteristics
Age (years) 62 (47e72) 70 (58e77) 68 (58e78) <0.01
Sex (% male) 67 42 40 <0.001
Diabetes (%) 24 26 27 n.s.
CVD (%) 59 75 67 n.s.
Dialysis vintage (months) 29 (16e57) 29 (15e61) 27 (8e78) n.s.
Nutritional parameters
BMI (kg/m2) 24.8 4.8 24.0 5.0 23.6 7.1 n.s.
Dry weight (kg) 74.6 12.2 67.3 13.9 65.7 17.2 <0.01
IGF-1 (ng/ml) 182 (124e256) 143 (94e225) 138 (79e206) <0.01
s-Creatinine (mmol/l) 838 207 691 143 639 212 <0.0001
s-Albumin (g/l) 35.5 4.2 33.8 4.7 31.5 4.3 <0.0001
LBMI (kg/m2) 16.8 2.6 15.6 2.4 15.8 3.1 <0.01
Inflammation parameters
hsCRP (mg/l) 5.5 (2.3e17.0) 7.3 (2.3e17.5)* 25.5 (6.0e46.3)* 0.001
IL-6 (pg/ml) 7.4 (4.2e11.7) 9.2 (6.2e15.8)* 16.0 (9.5e31.3)* <0.0001
Data presented as mean standard deviation or median (interquartile range). n.s., not significant; CVD, cardiovascular disease; BMI,
body mass index; IGF-1, insulin-like growth factor-1; LBMI, lean body mass index; hsCRP, high-sensitivity C-reactive protein; IL-6, inter-
leukin 6.
*p < 0.05, different from the group with no signs of MA.
Muscle atrophy and outcome in dialysis 561
Hangrip strength CVD in the incident dialysis cohort, such relations were
Incident dialysis patients
not observed in the prevalent HD patients, possibly because
of the inclusion of older subjects in the HD cohort.
% of age-matched controls
Table 3 Odds ratios and 95% confidence intervals (CI) for muscle atrophy after dichotomization into two main groups: no pres-
ence vs. presence of muscle atrophy (from mild to severe) in each of the cohorts studied
Incident dialysis patientsa Hemodialysis patientsb
Odds ratio (95% CI) p Odds ratio (95% CI) p
Intercept of presence of muscle atrophy <0.01 <0.01
Age (>55 [in CKD-5] or 66 [in HD] years) 0.86 (0.39e1.88) n.s. 1.54 (0.81e2.90) n.s.
Diabetes (presence) 1.37 (0.67e2.82) n.s. 1.00 (0.48e2.13) n.s.
Sex (men) 0.43 (0.21e0.86) <0.01 0.31 (0.16e0.56) <0.0001
Cardiovascular disease (presence) 3.08 (1.43e6.65) <0.01 1.17 (0.92e2.23) n.s.
Inflammation (IL-6 > 6.5 [in CKD-5] or 8.6 [in HD] pg/ml) 2.81 (1.33e5.91) <0.001 2.55 (1.38e4.70) <0.01
IGF-1 (<163 [in CKD-5] or 161 [in HD] ng/ml) 1.94 (0.86e3.89) <0.05 1.82 (0.95e3.32) <0.05
The models included muscle atrophy gradation as the dependent variable and factors either significantly associated with the dependent
variable in univariate analysis or with a documented causal relationship. Age, IL-6 and IGF-1 groups were defined according to the me-
dian value in each cohort. n.s., not significant; CRP, C-reactive protein; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6.
a
Pseudo r2 Z 0.18, p < 0.0001.
b
Pseudo r2 Z 0.17, p < 0.0001.
562 J.J. Carrero et al.
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