Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
available at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/clnu
ORIGINAL ARTICLE
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
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
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)
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
560
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,
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.
561
Hangrip strength
% of age-matched controls
P<0.0001 in
both cohorts
% of age-matched controls
P<0.0001 in
both cohorts
No muscle
atrophy
Mild muscle
atrophy
Discussion
Moderate/severe
muscle atrophy
Figure 2 Handgrip strength and mid-arm muscle circumference across muscle atrophy categories in 265 incident dialysis
patients and in 221 prevalent hemodialysis patients.
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
Hemodialysis patientsb
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
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).
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
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.
References
1. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting
in acute and chronic kidney disease. Kidney Int 2008;73:391e8.
2. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD.
Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis 2003;42:
864e81.
563
3. Qureshi AR, Alvestrand A, Danielsson A, et al. Factors predicting malnutrition in hemodialysis patients: a cross-sectional
study. Kidney Int 1998;53:773e82.
4. Heimburger O, Qureshi AR, Blaner WS, Berglund L,
Stenvinkel P. Hand-grip muscle strength, lean body mass, and
plasma proteins as markers of nutritional status in patients
with chronic renal failure close to start of dialysis therapy.
Am J Kidney Dis 2000;36:1213e25.
5. Kaysen GA. Diabetes, a cause of progressive sarcopenia in dialysis patients? Kidney Int 2005;68:2396e7.
6. Kaizu Y, Ohkawa S, Odamaki M, Ikegaya N, Hibi I, Miyaji K,
Kumagai H. Association between inflammatory mediators and
muscle mass in long-term hemodialysis patients. Am J Kidney
Dis 2003;42:295e302.
7. Du J, Hu Z, Mitch WE. Molecular mechanisms activating muscle
protein degradation in chronic kidney disease and other catabolic conditions. Eur J Clin Invest 2005;35:157e63.
8. Ikizler TA, Pupim LB, Brouillette JR, et al. Hemodialysis stimulates muscle and whole body protein loss and alters substrate
oxidation. Am J Physiol 2002;282:E107e16.
9. Foley RN, Wang C, Ishani A, Collins AJ, Murray AM. Kidney function and sarcopenia in the United States general population:
NHANES III. Am J Nephrol 2007;27:279e86.
10. Mak RH, Cheung W. Cachexia in chronic kidney disease: role of
inflammation and neuropeptide signaling. Curr Opin Nephro
Hypertens 2007;16:27e31.
11. Mitch WE. Malnutrition is an unusual cause of decreased muscle
mass in chronic kidney disease. J Ren Nutr 2007;17:66e9.
12. Desmeules S, Levesque R, Jaussent I, Leray-Moragues H,
Chalabi L, Canaud B. Creatinine index and lean body mass
are excellent predictors of long-term survival in haemodiafiltration patients. Nephrol Dial Transplant 2004;19:1182e9.
13. Dong J, Li YJ, Lu XH, Gan HP, Zuo L, Wang HY. Correlations of
lean body mass with nutritional indicators and mortality in
patients on peritoneal dialysis. Kidney Int 2008;73:334e40.
14. Honda H, Qureshi AR, Axelsson J, et al. Obese sarcopenia in patients with end-stage renal disease is associated with inflammation and increased mortality. Am J Clin Nutr 2007;86:
633e8.
15. Workeneh BT, Rondon-Berrios H, Zhang L, et al. Development
of a diagnostic method for detecting increased muscle protein
degradation in patients with catabolic conditions. J Am Soc
Nephrol 2006;17:3233e9.
16. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association
between malnutrition, inflammation, and atherosclerosis in
chronic renal failure. Kidney Int 1999;55:1899e911.
17. Carrero JJ, Qureshi AR, Axelsson J, et al. Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite. Am J Clin Nutr 2007;85:695e701.
18. Durnin JV, Womersley J. Body fat assessed from total body
density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J
Nutr 1974;32:77e97.
19. Kyle UG, Schutz Y, Dupertuis YM, Pichard C. Body composition
interpretation. Contributions of the fat-free mass index and
the body fat mass index. Nutrition 2003;19:597e604.
20. Detsky AS, McLaughlin JR, Baker JP, et al. What is subjective
global assessment of nutritional status? J Parenter Enter Nutr
1987;11:8e13.
21. Nielsen PK, Ladefoged J, Olgaard K. Lean body mass by Dual
Energy X-ray Absorptiometry (DEXA) and by urine and dialysate
creatinine recovery in CAPD and pre-dialysis patients
compared to normal subjects. Adv Periton Dial 1994;10:
99e103.
22. Axelsson J, Qureshi AR, Divino-Filho JC, et al. Are insulin-like
growth factor and its binding proteins 1 and 3 clinically useful
as markers of malnutrition, sarcopenia and inflammation in
end-stage renal disease? Eur J Clin Nutr 2006;60:718e26.
564
23. Mak RH, Rotwein P. Myostatin and insulin-like growth factors in
uremic sarcopenia: the yin and yang in muscle mass regulation.
Kidney Int 2006;70:410e2.
24. Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology
of sarcopenia among the elderly in New Mexico. Am J Epidemiol 1998;147:755e63.
25. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle
mass (sarcopenia) in older persons is associated with functional
impairment and physical disability. J Am Geriatr Soc 2002;50:
889e96.
26. Roubenoff R. Catabolism of aging: is it an inflammatory process? Curr Opin Clin Nutr Metab Care 2003;6:295e9.
27. Goodman MN. Interleukin-6 induces skeletal muscle protein
breakdown in rats. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology
and Medicine 1994;205:182e5 (New York, NY).
28. Castaneda-Sceppa C, Sarnak MJ, Wang X, et al. Role of adipose
tissue in determining muscle mass in patients with chronic kidney disease. J Ren Nutr 2007;17:314e22.
29. Pupim LB, Flakoll PJ, Majchrzak KM, Aftab Guy DL,
Stenvinkel P, Ikizler TA. Increased muscle protein breakdown
in chronic hemodialysis patients with type 2 diabetes mellitus.
Kidney Int 2005;68:1857e65.
30. Janssen I, Heymsfield SB, Baumgartner RN, Ross R. Estimation
of skeletal muscle mass by bioelectrical impedance analysis.
J Appl Physiol 2000;89:465e71.
31. Pupim LB, Heimburger O, Qureshi AR, Ikizler TA, Stenvinkel P.
Accelerated lean body mass loss in incident chronic dialysis patients with diabetes mellitus. Kidney Int 2005;68:2368e74.
32. McIntyre CW, Selby NM, Sigrist M, Pearce LE, Mercer TH,
Naish PF. Patients receiving maintenance dialysis have more
33.
34.
35.
36.
37.
38.
39.
40.