Clinical Nutrition (2008) 27, 557e564

available at www.sciencedirect.com

http://intl.elsevierhealth.com/journals/clnu

ORIGINAL ARTICLE

Muscle atrophy, inflammation and clinical outcome

in incident and prevalent dialysis patients
s Carrero a,*,c, Michal Chmielewski a,b,c, Jonas Axelsson a,
Juan Jesu
ra
ny a,
rger a, Peter Ba
Sunna Snaedal a, Olof Heimbu
Mohamed E. Suliman a, Bengt Lindholm a, Peter Stenvinkel a,
Abdul Rashid Qureshi a
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

Received 22 February 2008; accepted 17 April 2008

KEYWORDS
Muscle atrophy;
Inflammation;
Dialysis;
Mortality;
Sex

Summary
Background & aims: Muscle wasting is considered the best marker of protein-energy wasting in
end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle
atrophy (MA) grading in relation to morbidity and mortality in ESRD patients.
Methods: In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent
hemodialysis patients), each patients 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. Patients 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 incrementally poorer. Inflammation markers as well as the proportion of women became progressively higher. Female sex, presence of cardiovascular disease, inflammation and low insulinlike 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.: 46
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 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 inflammation, 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.
2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights
reserved.

Introduction
Protein-energy wasting (PEW) is the term proposed1 to describe the state of decreased body stores of protein and energy fuels (body protein and fat masses) in chronic kidney
disease (CKD). PEW is present in 18e75% of CKD patients.2,3
Muscle wasting is considered one of the most valid markers
of PEW in CKD,4e6 especially because of the limitations of
assessing changes in body weight in patients with impaired
salt and water regulation. Catabolic factors that accelerate
muscle wasting in this patient population are numerous and
include acidosis, comorbid illnesses, corticosteroid use, hemodialysis (HD) treatment, and sedentary lifestyle.1,7,8 Indeed, the severity of muscle wasting increases as kidney
function worsens (independently of age and main comorbidites),9 directly contributing to asthenia and to the reduction in physical activity and quality of life.10
The development of muscle wasting may also be a result
of chronic low-grade inflammation,6 linked to protein
breakdown.11 As recent investigations documented a powerful association between muscle wasting and mortality in patients with CKD,12,13 even in the presence of overweight,14
early detection may allow the implementation of appropriate therapeutic measures. However, there are currently no
clinically useful, uniform and reproducible measures for assessing the presence of accelerated muscle protein catabolism.15 The objective of the present study was thus to study
determinants of muscle wasting in a dialysis population and
to assess whether using a simple subjective visual evaluation of muscle atrophy (done as a part of the subjective
global assessment (SGA) questionnaire) could be used to
predict outcome in two large CKD populations.

Methods
Patients
The current study was performed in two different cohorts
of CKD-5 patients (the MIA and MIMICK cohorts) according to
protocols that have been described in detail elsewhere.16,17
The Ethics Committee of the Karolinska University Hospital
in Huddinge, Stockholm, approved both study protocols,
and informed consent was obtained from all patients.
The first cohort16 consisted of 265 CKD-5 incident patients (162 (61%) men, median age 55 [inter quartile range
44e64] years) from the Karolinska University Hospital at
Huddinge, Stockholm, who were investigated close to
the start of renal replacement therapy (median  SD glomerular filtration rate [GFR] 6.4  2.3 ml/min) during

1994e2005. Patients younger than 18 and older than

70 years, with HIV, hepatitis B and signs of acute infection
or unwilling to participate were excluded. The causes of
kidney disease were diabetic nephropathy (31%), chronic
glomerulonephritis (27%), polycystic kidney disease (11%)
and other or unknown causes (31%). Clinical history of diabetes mellitus or CVD (obtained from the patients medical
records) was documented in 30% and 36% of the patients,
respectively. CVD was defined by clinical history or signs
of ischemic cardiac disease, and/or presence of peripheral
vascular disease and/or cerebrovascular disease. The patients were followed up for up to 5 years from inclusion in
the study. Follow-up was censored on transplantation and
no patient was lost to follow-up. Although the original material consisted of 330 patients, 65 patients refused or
could not attend the nutritional evaluation visits.
The second cohort17 consisted of 221 prevalent HD patients (126 (57%) men, median age 66 [IQR 51e74] years)
from the Karolinska University Hospital at Huddinge, Stockholm (including four satellite dialysis units), Danderyds Hospital and Uppsala Academic Hospital. Patients were
enrolled from October 2003 through March 2004. The only
exclusion criteria were patients with HIV, hepatitis B or unwillingness to participate. The causes of kidney disease
were diabetic nephropathy (17%), chronic glomerulonephritis (18%), polycystic kidney disease (12%), nephrosclerosis
(15%) and other or unknown causes (38%). Clinical history
of DM or CVD (obtained from the patients medical records)
was documented in 24.9% and 64.3% of the patients, respectively. CVD was defined by clinical history or signs of ischemic cardiac disease, and/or presence of peripheral
vascular disease and/or cerebrovascular disease. The patients were followed-up for up to 4 years from inclusion in
the study. Follow-up was censored on transplantation and
no patient was lost to follow-up. Although the original material consisted of 228 patients, 7 patients refused or could
not attend the nutritional evaluation visits.

Anthropometric evaluation
Body mass index (BMI) was defined as the weight in
kilograms divided by the square of the height in meters.
Body composition was assessed in both cohorts by using the
four skinfold thicknesses (biceps, triceps, subscapular, and
suprailiac), measured with a conventional skinfold caliper
(Cambridge Scientific Instruments, Cambridge, MA). Lean
body mass (LBM) and fat body mass were estimated by
means of dual-energy x-ray absorptiometry (in the predialysis cohort) using the DPX-L device (Lunar Corp, Madison,
WI) or according to a theoretical formula (in the HD cohort)

Muscle atrophy and outcome in dialysis

based on skinfold thicknesses and body density.18 Lean
body mass index (LBMI) was defined as the total lean body
mass in kilograms divided by the square of the height in
meters.19 Midarm circumference (MAC) was measured
with a plastic tape measurer and was normalized with
measurements from healthy subjects; midarm muscle circumference (MAMC) was calculated by using the following
formula: MAMC Z MAC  (3.1416  triceps skinfold thickness/10).18 Handgrip strength was measured using a Harpenden Handgrip Dynamometer (Yamar, Jackson, MI) in the
dominant hand (in the incident dialytic cohort) or in the
hand without fistula (in the HD group) and normalized
with measurements from healthy subjects (see below).
These assessments were completed either at the time of
or within 1 week of blood sample collection and after the
HD session in the prevalent cohort.

Nutritional status and muscle atrophy (MA)

assessment
Estimation of muscle atrophy is a part of the SGA questionnaire.20 This questionnaire includes six different components: three subjective assessments that are performed
by the patients and that concern the patients history of
weight loss, incidence of anorexia, and incidence of vomiting, and three objective assessments that are performed by
the evaluators and that are based on the presence of muscle atrophy (MA), the presence of edema and the loss of
subcutaneous fat. The grading of MA was assessed by a specially trained nurse examining the temporalis muscle, the
prominence of the clavicles, the contour of the shoulders
(rounded indicates well-nourished; squared indicates malnutrition), visibility of the scapula, the visibility of the
ribs, and interosseous muscle mass between the thumb
and forefinger, and the quadriceps muscle mass. The signs
of MA were scored as follows: 1, no signs of MA; 2, mild signs
of MA; 3, moderate signs of MA; 4, severe signs of MA. This
assessment was completed either at the time of or within
1 week of blood sample collection.
Healthy subjects were recruited among the hospital
staff. These individuals underwent a similar protocol as
above described. Anthropometric and handgrip values were
used for normalization of the patients 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.

559
albumin (bromcresol purple) and high-sensitivity C-reactive
protein (CRP) (nephelometry) were performed by routine
procedures at the Department of Clinical Chemistry,
Karolinska University Hospital Huddinge. In both patient
materials plasma interleukin-6 (IL-6) and insulin growth
factor like-1 (IGF-1) concentrations were measured using
commercial kits available for an Immulite Automatic Analyzer (Diagnostic Products Corporation, Los Angeles, CA).

Statistical analysis
Variables were expressed as means  SD or median (interquartile range), as appropriate. Differences among the
muscle atrophy groups were analyzed with the Kruskale
Wallis analysis of variance followed by a post hoc Dunns
test for non-parametric comparisons when assessing differences in inflammation markers. A c2 test was used for categorical variables. A multinomial logistic regression model
was used to assess the predictors for muscle atrophy; this
model included the variables significantly associated with
muscle atrophy in univariate analysis or other variables
with a documented causal relationship (in this case age
and diabetes mellitus). Survival analyses used the KaplaneMeier survival curve and the Cox proportional hazards
model. The Cox proportional hazards model was used to
examine survival differences after the analysis had been
adjusted for potential confounding factors. Statistical significance was set at p < 0.05. All statistical analyses were
performed with SAS statistical software (version 9.1; SAS
Institute Inc., Cary, NC).

Results
MA scores for the patients included in the study are shown
in Fig. 1. After dichotomization into two major categories,
81 (30%) of the incident dialysis patients and 87 (39%) of the
HD patients showed some sign of MA (ranging from mild to
severe). Since the sample sizes for the groups displaying
moderate and severe signs of MA were small in both cohorts, they were merged for comparative purposes.
Demographic and laboratory data for the cohorts studied
and ratings of MA intensity are shown in Tables 1 and 2. In

Laboratory analysis
Blood samples were collected after an overnight fast in the
pre-dialysis cohort and before the dialysis session in the HD
cohort (morning or afternoon rounds). Plasma samples were
kept frozen at 70  C if not analyzed immediately. Glomerular filtration rate (GFR) in the pre-dialysis cohort was estimated as the mean of urea and creatinine clearances. In
both cohorts, routine determinations of creatinine, serum

Figure 1 Prevalence of muscle atrophy (MA) in ESRD patients

as derived from the subjective global assessment.

560

J.J. Carrero et al.

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
(N Z 184), 70%

Mild MA
(N Z 59), 22%

Moderate/severe MA
(N Z 22), 8%

Clinical characteristics
Age (years)
Sex (% male)
Diabetes (%)
CVD (%)
GFR (ml/min)

54 (43e64)
65
28
28
6.7  2.3

59 (48e65)
54
34
61
5.7  1.9

58 (49e66)
41
41
41
6.4  2.7

n.s.
<0.05
<0.01
<0.001
n.s.

Nutritional parameters
BMI (kg/m2)
Weight (kg)
IGF-1 (ng/ml)
s-Creatinine (mmol/l)
s-Albumin (g/l)
LBMI (kg/m2)

25.4  4.0
75.9  14.1
185 (129e246)
775  259
33.5  6.2
16.9  2.3

22.9  4.1
64.9  13.5
133 (89e94)
627  183
31.6  7.2
15.6  1.9

21.6  5.0
62.9  16.1
107 (55e192)
516  223
30.5  5.2
15.3  1.8

<0.0001
<0.0001
<0.001
<0.0001
<0.05
<0.001

Inflammation parameters
hsCRP (mg/l)
IL-6 (pg/ml)

4.0 (1.5e12.8)
5.5 (3.3e9.2)

12.5 (2.5e24.5)*
9.7 (5.6e17)*

6.1 (3.0e34.5)
9.3 (5.0e20.5)*

<0.01
<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, interleukin 6.
*p < 0.05, different from the group with no signs of MA.

both cohorts the proportions of women became progressively and significantly higher as the MA scale worsened.
Also, across worsening MA scale, nutritional parameters
and anthropometric measurements tended to be poorer.
Clinical and biochemical reflections of muscle wasting,

i.e., IGF-1 levels, lean body mass index (LBMI), handgrip

strength and MAMC were progressively decreased (Fig. 2).
Furthermore, inflammation parameters (e.g. CRP and IL-6)
became gradually higher. However, some differences between 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
(N Z 134), 61%

Mild MA
(N Z 57), 26%

Moderate/severe MA
(N Z 30), 13%

Clinical characteristics
Age (years)
Sex (% male)
Diabetes (%)
CVD (%)
Dialysis vintage (months)

62 (47e72)
67
24
59
29 (16e57)

70 (58e77)
42
26
75
29 (15e61)

68 (58e78)
40
27
67
27 (8e78)

<0.01
<0.001
n.s.
n.s.
n.s.

Nutritional parameters
BMI (kg/m2)
Dry weight (kg)
IGF-1 (ng/ml)
s-Creatinine (mmol/l)
s-Albumin (g/l)
LBMI (kg/m2)

24.8  4.8
74.6  12.2
182 (124e256)
838  207
35.5  4.2
16.8  2.6

24.0  5.0
67.3  13.9
143 (94e225)
691  143
33.8  4.7
15.6  2.4

23.6  7.1
65.7  17.2
138 (79e206)
639  212
31.5  4.3
15.8  3.1

n.s.
<0.01
<0.01
<0.0001
<0.0001
<0.01

Inflammation parameters
hsCRP (mg/l)
IL-6 (pg/ml)

5.5 (2.3e17.0)
7.4 (4.2e11.7)

7.3 (2.3e17.5)*
9.2 (6.2e15.8)*

25.5 (6.0e46.3)*
16.0 (9.5e31.3)*

0.001
<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, interleukin 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

not observed in the prevalent HD patients, possibly because
of the inclusion of older subjects in the HD cohort.
Logistic regression estimated odds ratios (ORs) and 95%
confidence intervals (CIs) for presence vs. absence of MA,
after dichotomization of the MA categories into two main
groups, are shown in Table 3. In the incident dialysis cohort,
female sex, inflammation, low IGF-1 levels and a clinical
history of CVD were associated with higher ORs to present
signs of MA. In prevalent HD cohort female sex, inflammation and low IGF-1 levels, but not clinical history of CVD,
were associated with higher ORs to present signs of MA. In
both models, age and DM did not contribute.
During the follow-up periods, 88 (33%) and 85 (38%)
patients died in the incident and prevalent cohorts, respectively. In unadjusted KaplaneMeier curves, a worsening
on MA scales was associated with a higher mortality in both
cohorts (Fig. 3). These differences persisted after adjustment for potential confounding factors by using the Cox
proportional hazards model (Table 4). Thus, patients with
mild signs of MA showed a non-significant trend towards
an increased mortality risk in the incident cohort, that attained statistical significance in the prevalent cohort (Hazard ratio [HR] 1.76 [95% CI: 1.02, 3.01; p Z 0.03]). The HR
of death for moderate/severe MA was 2.62 (95% CI: 1.34,
5.13; p Z 0.001) in the incident dialysis patients and 3.04
(95% CI: 1.61, 5.71; p Z 0.0005) in the prevalent HD
patients (Table 4).

% of age-matched controls

Incident dialysis patients

Prevalent hemodialysis patients

P<0.0001 in
both cohorts

% of age-matched controls

Mid arm muscle circumference

P<0.0001 in
both cohorts
No muscle
atrophy

Mild muscle
atrophy

Discussion

Moderate/severe
muscle atrophy

The present study, performed in two independent ESRD

patient cohorts, demonstrates that a simple subjective
assessment of MA is significantly associated with patient
survival, as well as with multiple measures of inflammatory
and nutritional status. Furthermore, even after adjustment
for confounders, mortality was significantly higher in
patients assessed as having MA.
Although several methods exist to assess the degree of
muscle wasting (from simple ones like MAMC, handgrip
strength or creatinine generation to more sophisticated
including CT-scanning and magnetic resonance), their

Figure 2 Handgrip strength and mid-arm muscle circumference across muscle atrophy categories in 265 incident dialysis
patients and in 221 prevalent hemodialysis patients.

different cohort designs and inclusion criteria. Whereas

worsening MA scores were associated with increasing age
in the HD cohort, such relations were not observed in the
incident dialysis cohort in which age >70 years constituted
an exclusion criterion. Also, whereas worsening MA scores
were associated with increasing prevalence of DM and

Table 3 Odds ratios and 95% confidence intervals (CI) for muscle atrophy after dichotomization into two main groups: no presence vs. presence of muscle atrophy (from mild to severe) in each of the cohorts studied

Intercept of presence of muscle atrophy

Age (>55 [in CKD-5] or 66 [in HD] years)
Diabetes (presence)
Sex (men)
Cardiovascular disease (presence)
Inflammation (IL-6 > 6.5 [in CKD-5] or 8.6 [in HD] pg/ml)
IGF-1 (<163 [in CKD-5] or 161 [in HD] ng/ml)

Incident dialysis patientsa

Hemodialysis patientsb

Odds ratio (95% CI)

Odds ratio (95% CI)

0.86
1.37
0.43
3.08
2.81
1.94

<0.01
n.s.
n.s.
<0.01
<0.01
<0.001
<0.05

1.54
1.00
0.31
1.17
2.55
1.82

<0.01
n.s.
n.s.
<0.0001
n.s.
<0.01
<0.05

(0.39e1.88)
(0.67e2.82)
(0.21e0.86)
(1.43e6.65)
(1.33e5.91)
(0.86e3.89)

(0.81e2.90)
(0.48e2.13)
(0.16e0.56)
(0.92e2.23)
(1.38e4.70)
(0.95e3.32)

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 median 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.

No MA
Mild MA
Moderate/
severe MA
Log-Rank 35.0; p<0.0001

B
No MA
Mild MA

Moderate/
severe MA
Log-Rank 25.8; p<0.0001

Figure 3 KaplaneMeier curves depicting the cumulative proportion of survivors according to their muscle atrophy (MA)
grading among 265 incident dialysis patients (A) and 221 prevalent hemodialysis patients (B).

reproducibility, time-consumption and in some cases their

cost make them often impractical and difficult to implement in a clinical setting.15 Furthermore, while LBMI may
be influenced by the hydration status,21 MAMC may relate
to fat mass.4 In this study we demonstrate that a simple visual assessment of muscle mass relates very well to classic
markers of muscle wasting such as LBMI (as assessed both by

Table 4 Adjusted relative risk of all-cause mortality according to muscle atrophy categories in 265 incident dialysis
patients (A) and in 221 prevalent hemodialysis patients (B)
Hazard ratio

A: Incident dialysis patients

Mild muscle atrophy
1.29 (0.71e2.34) n.s.
Moderate/severe muscle
2.62 (1.34e5.13) 0.001
atrophy
Likelihood ratio (c2) Z 57.03, p < 0.0001
Adjusted for age (median), sex, inflammation (median
IL-6), diabetes mellitus, cardiovascular disease and
glomerular filtration rate (median).
B: Hemodialysis patients
Mild muscle atrophy
1.76 (1.02e3.01) 0.03
Moderate/severe muscle
3.04 (1.61e5.71) 0.0005
atrophy
Likelihood ratio (c2) Z 66.17, p < 0.0001
Adjusted for age (median), sex, inflammation (median
IL-6), diabetes mellitus, cardiovascular disease and
time on hemodialysis (median).

DEXA and anthropometrics), handgrip strength and MAMC.

IGF-1 (part of the pathway mediating growth hormone action in skeletal muscle) is being increasingly recognized as
a sensitive indicator of the muscle catabolic state and
PEW present in CKD.22,23 Thus, it is interesting that also
IGF-1 levels decreased across MA categories in our study
and contributed to increase the ORs of MA.
The present study comprised two separate cohorts, one
of incident dialysis patients and one of prevalent hemodialysis patients. MA was common, and the prevalence
similar, in both cohorts. Approximately one third of the
patients showed some sign of MA. Also of note, the
proportion of women increased with worsening MA, consistent with a previous report of an approximately 30%
increased prevalence of muscle wasting in non-Hispanic
healthy white healthy women vs. men of a similar age
range.24 The reasons for the increased prevalence of MA in
uremic women is not apparent from the present study, but
may include differences in fat distribution and/or body
composition as well as a sex-specific effect of uremia on appetite17 and food intake. Supporting this hypothesis, older
sarcopenic women (60 years) in the NHANES III study
showed increased functional disability as compared to their
male counterparts.25
As muscle loss is a common feature of many inflammatory disorders, it has been suggested that subclinical
chronic inflammation is an important component of the
pathophysiology of muscle wasting.26 Pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor (TNF), stimulate the breakdown of muscle protein.27 The close
association between muscle wasting and IL-6 in previous
studies performed in CKD patients6,28 suggests that IL-6
may be associated with muscle wasting also in patients
with advanced CKD. The present study supports such a hypothesis, as inflammation (defined by median IL-6 levels)
was, indeed, a significant determinant of MA in our cohorts.
The same association was found for CRP, in agreement with
some,29 but not all9 studies in CKD patients.
Contrary to our expectations, neither age nor diabetes
was a significant determinant of MA in the present study.
This was unanticipated, as skeletal muscle mass typically
declines with age9,30 and HD diabetic patients present increased muscle protein breakdown29 and accelerated loss
of lean body mass.31 As MA in the present study was associated with a low handgrip strength and lower circulating
IGF-1 (objective measurements of muscle wasting), it appears likely that factors such as uremia,7 dialytic procedure8,32 and inflammation11 may be more important in
determining muscle mass in this patient group.
Also of note in the present study is the association
between MA and CVD in the incident dialysis cohort. While
inflammation and malnutrition (PEW) have long been
recognized to be associated with CVD and a poor outcome
in ESRD,16 cardiac disease per se has also been shown to
contribute to muscle catabolism.33 Indeed, in non-uremic
chronic heart failure (CHF), cardiac cachexia is a serious
complication characterized by PEW and a poor prognosis.34
As CHF is common in ESRD and associated with CVD,35 it is
not surprising that CVD is also an important predictor of
MA in this population. Finally, as there should be a close
correlation between diabetes and CVD, the effect of CVD
may take away the effect of diabetes due to collinearity.

Muscle atrophy and outcome in dialysis

Some limitations of the present cross-sectional study
should be considered. First, the cross-sectional design of
our study makes causal inference impossible. Second, our
results are influenced by the different inclusion/exclusion
criteria, as well as the differing natures, of the cohorts
studied. However, this is also a strength as it allows us to
make more broadly applicable findings. Third, body weight,
skinfold thicknesses and DEXA may all be affected by fluid
retention in the ESRD setting.21 However, our findings were
consistent and also correlated with markers not influenced
by fluid status, such as handgrip strength and IGF-1.
In summary, the present study shows that a simple
subjective assessment of MA may constitute a clinically
relevant tool to predict patients mortality risk. While an
association between muscle wasting and mortality has
been already documented in CKD,12,13 also in the presence
of obesity,14 the present study is to our knowledge the first
to use such a simple and inexpensive assessment and supports the use of frequent MA and/or nutritional assessments in the clinical practice. Early detection of muscle
loss may allow the implementation of appropriate therapeutic and preventive measures such as resistance training,36 exercise maintenance,37 increasing protein intake38
or a combination of both approaches, which seems to
reverse MA39 and increase albumin fractional synthetic
rate40 in HD patients.

Acknowledgments
We would like to thank the patients and personnel involved
in the creation of these cohorts. Also, we are indebted to
our research staff at KBC (Ann Dreiman-Lif, Annika Nilsson
and Anki Emmoth) and KFC (Bjo
rn Anderstam, Monica
Ericsson and Anki Bragfors-Helin).

Sources of funding
The MIMICK cohort was supported by an unrestricted project grant from Amgen Inc. We also benefited from
Karolinska Institutet Center for Gender-based Research,
MEC (EX2006-1670), the Swedish Heart and Lung Foundation, the Swedish Medical Research Council, the Swedish
Exports Association, Martin Rinds and Westmans Foundations, an unconditional grant from Scandinavian Clinical
Nutrition AB and research grants from the ERA-EDTA.

Conflict of interest statement

B.L. is affiliated with Baxter Healthcare Inc. None of the
other authors had any conflicts of interest.

References
1. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting
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