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NDT Advance Access originally published online on April 16, 2007
Nephrology Dialysis Transplantation 2007 22(9):2554-2562; doi:10.1093/ndt/gfm204
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Insulin resistance and muscle wasting in non-diabetic end-stage renal disease patients

Seoung Woo Lee1,3, Geun Ho Park1,3, Seung Won Lee1,3, Joon Ho Song1,3, Kee Chun Hong2,3 and Moon-Jae Kim1,3

1Division of Nephrology and Hypertension, Department of Internal Medicine, 2Department of Surgery and 3Kidney Disease Research Group, Inha University College of Medicine, Inchon, Korea

Correspondence and offprint requests to: Moon-Jae Kim, MD, Kidney Center, Inha University Hospital, 7-206, 3-Ga, Sinhung-Dong, Jung-Gu, Inchon city, Korea. E-mail: nhkimj{at}inha.ac.kr



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Background. Insulin resistance (IR) is prevalent in uraemia. Recent experimental studies suggested IR to be a central mechanism for uraemic malnutrition. However, it is not known whether IR is related to muscle wasting in non-diabetic end-stage renal disease (ESRD) patients.

Methods. We cross-sectionally assessed IR and muscle wasting in 21 non-diabetic ESRD patients who admitted for the initiation of dialysis. For the assessment of muscle wasting, lean body mass was measured (LBMm) by dual energy X-ray absorptiometry and compared with the estimated LBM (LBMe) from the prediction equation derived from healthy controls using the ratio of LBMm/LBMe. For measurement of IR, the homoeostasis model (HOMA-IR) was used. In addition, among patients who chose continuous ambulatory peritoneal dialysis, muscle was sampled during catheter insertion from the rectus abdominis to measure 14-kDa actin fragments, a marker of muscle protein degradation.

Results. Patients with a low LBMm/LBMe ratio (<1.00) showed higher HOMA-IR and fat mass (FM) (% body weight) and lower LBM (% body weight) than those with a high LBMm/LBMe ratio (≥1.00). LBMm/LBMe ratio was negatively correlated with HOMA-IR, regardless of obesity. By multiple regression analysis, HOMA-IR was an independent factor affecting LBMm/LBMe ratio. Furthermore, in the muscle samples, patients with high HOMA-IR had lower LBMm/LBMe ratios and stronger bands for the 14-kDa actin fragments than did patients with low HOMA-IR.

Conclusion. These results suggest that IR seems to be associated with muscle wasting in non-diabetic ESRD patients.

Keywords: end-stage renal disease; insulin resistance; malnutrition; muscle atrophy



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
Patients with chronic kidney disease (CKD) have varying degrees of lean body mass (LBM) loss [1]. Consequently, uraemic malnutrition is prevalent at the initiation of dialysis in end-stage renal disease (ESRD) patients [2]. LBM loss in uraemia has been attributed to inadequate dietary intake [3,4]; however, a high-protein diet is associated with a low efficiency of protein utilization in rats with CKD, indicating that simply raising dietary protein may be deleterious or ineffective [5]. Evidence suggests that other complications of CKD are the principal cause of muscle protein losses [6].

Among several uraemia-associated factors that can initiate muscle protein catabolism, an impaired insulin signalling pathway or insulin resistance (IR) seems to play a central role in the loss of LBM in uraemia [7]. Indeed, the insulin/insulin-like growth factor-1 (IGF-1) signalling pathway modulates muscle mass [8]. The IGF-1/PI3K/Akt pathway also prevents the upregulation of muscle atrophy genes encoding ubiquitin ligases [9].

IR is prevalent in uraemia [10] and is already present in patients with incipient renal disease [11] and has inevitably been mentioned as a potential cause for the increase in protein catabolism [12–14]. However, because few studies have focused on whether IR is related to muscle wasting or LBM loss in CKD patients, our goal was to examine the relationship between IR and LBM at the time of initiation of dialysis in non-diabetic ESRD patients.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Subjects
ESRD subjects
From March 2004 to August 2005, non-diabetic ESRD patients who were admitted to Inha University Hospital (IUH), Inchon, Korea, for the initiation of dialysis were included in the study. Most patients were on antihypertensive medications including angiotensin converting enzyme inhibitors (14) or angiotensin II receptor antagonists (3), as well as other commonly used drugs in CKD, such as phosphate and potassium binders (calcium polystyrene sulphonate) and diuretics. No one was administered recombinant human erythropoietin (EPO) because EPO was expensive and was not reimbursed by medical insurance in pre-dialysis CKD patients. An iron supplement was not routinely administered. Most patients were educated to eat a low protein diet (0.6–0.75 g/kg/day). Exclusion criteria were current acute illness (including infectious disease), diabetic nephropathy, serum C-reactive protein (CRP) of >0.30 mg/dl, medical history of cardiovascular disease (cardiac, cerebral, or peripheral vascular disease), cancer, or refusal to participate in the study.

The protocol was in accordance with the Declaration of Helsinki, and all ESRD patients gave informed written consent before participating in the study. This study was approved by the ethical board of IUH.

Control subjects
A total of 2940 healthy adults were selected for this study from 3781 people visiting the Health Promotion Center (HPC), IUH, from March 2003 to February 2004. The exclusion criteria were as follows: age <18 years, serum creatinine >1.4 mg/dl, positive urine protein, subjects who complained of oedema, those with an amputation or who had diabetes mellitus, congestive heart failure, chronic liver disease, or those subjects who did not allow bioelectrical impedance analysis (BIA) to be performed.

Design
On admission for ESRD, patient's, body weight (BW) and height (Ht) were measured. Body mass index (BMI) was calculated as kg/m2. In the case of oedema, oedema-free BW was used. Glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease (MDRD) equation [15]. Subjective global assessment (SGA) was also performed. On hospital day 2, blood was drawn after overnight fasting for IR measurement and other assays (BUN, creatinine, total cholesterol, albumin, total CO2, and prealbumin), and dual energy X-ray absorptiometry (DEXA) was performed for the measurement of LBM (LBMm).

Then, dialysis was started by either continuous ambulatory peritoneal dialysis (CAPD) catheter insertion or internal jugular catheterization. In the case of CAPD, the catheter was inserted under local anaesthesia. During the procedure, a piece of rectus abdominis muscle was obtained, immediately frozen in liquid nitrogen and stored at –80°C until the measurements of 14-kDa actin fragments. In the case of severe uraemic symptoms and signs (generalized oedema, dyspnoea, pulmonary oedema, serum total CO2 ≤10 mEq/l, K+ ≥7.0 mEq/l, BUN ≥200.0 mg/dl, and serum creatinine ≥20.0 mg/dl), emergency haemodialysis (HD) was done on hospital days 2 and 3, and the procedures for maintenance dialysis and DEXA were postponed until hospital day 4 or 5 to control uraemia and oedema.

The ratio of LBMm/the estimated LBM (LBMe) was used as an index of LBM loss. Arbitrarily, LBMm/LBMe ratio of <1.00 was considered as LBM loss and that of ≥1.00 as LBM maintenance. This was a cross-sectional study, performed in a single centre. Thus, we used indirect assessment of LBM loss by comparing the patient's measured LBM to the LBMe. LBMe was derived from healthy control data. This approach has been used by other researchers [16,17].

Blood sampling and assays
Whole blood was used for haematocrit, plasma was used for glucose and insulin measurements and serum was used for the other biochemical assays. Glucose was measured using a glucose oxidase method, and insulin was measured by immunoradiometric assay (IRMA) (RIABEAD II, Special Reference Laboratory, Tokyo, Japan). Total cholesterol was measured enzymatically, and serum prealbumin was measured using a nephelometry method. Other assays employed standard methods.

The homoeostasis model (HOMA) was used for the assessment of IR with the following formula [18]:

HOMA-IR (mmol/l x µU/ml) = Fasting plasma glucose (mmol/l) x Fasting plasma insulin (µU/ml)/22.5.

DEXA
In non-diabetic ESRD patients, DEXA was used for the measurement of LBM. A whole body scan was performed using a fan beam model QDR-4500A (Hologic, Inc., Waltham, MA, USA) to determine body composition. The scan time was 3 min and the radiation dose approximately 2 µSv per scan. The precision error of DEXA is 425 g for both fat and LBM (LBMDEXA). The coefficients of variation for DEXA measurements are 0.7% for LBMDEXA [19]. DEXA is a reliable, non-invasive method to assess the three main components of body composition in ESRD patients [20]. However, DEXA-based LBM may be overestimated in the commonly overhydrated ESRD patients, because it represents the sum of the muscle mass, water content and bone mass [21]. Thus, DEXA was performed when the patients were in an oedema-free state, as much as possible.

SGA
SGA included six subjective assessments, three based on the patient's history of weight loss, incidence of anorexia and incidence of vomiting, and three based on the physician's grading of muscle wasting, presence of oedema and loss of subcutaneous fat [22]. Each patient was classified as normal, mildly, moderately or severely malnutrition, respectively.

Measurement of the 14-kDa actin fragments from muscle
The 14-kDa actin fragments were detected using previously described methods with slight modifications [23]. Briefly, a 30 mg muscle sample was homogenized on ice for 5 min using a Dounce homogenizer in 900 µl grinding buffer consisting of phosphate buffered saline (PBS) with protease inhibitors (Sigma-Aldrich, St. Louis, MO, USA). About 100 µl of the mixture was centrifuged at 3000 x g at 4°C for 5 min, and the supernatant was discarded. The pellet was mixed with 100 µL of 2x Laemmli sample buffer and mixed well before boiling for 20 min and then centrifuged at 16 000 x g for 5 min at room temperature. About 15–20 µl of supernatant was separated on a 15% SDS-PAGE gel at 100 V. Proteins were transferred to a PDVF membrane (Millipore, Billerica, MA, USA) and then the membrane was blocked using 5% milk/PBS for 1 h and incubated with anti-actin antibody (Sigma-Aldrich, St. Louis, MO, USA) in 5% milk/PBS overnight at 4°C at a dilution of 1 : 500. Membranes were washed 3x with PBS/0.1% Tween-20. As a secondary antibody, horseradish peroxidase-conjugated anti-rabbit IgG (Amersham Biosciences Corp., Piscataway, New Jersey, USA) was used at a dilution of 1 : 2000 at room temperature for 1 h. ECL western blotting detection (Amersham Biosciences Corp., Piscataway, New Jersey, USA) was used. To compare the amount of muscle protein loaded, the amount of the full length 42 kDa actin band was compared among the samples. This served as the control for determining unequal amounts of loading when comparing the density of the 14 kDa actin fragment.

LBM assessment in healthy controls
LBM (LBMBIA) in control subjects was measured by segmental multifrequency BIA (Inbody 3.0, Biospace Co., Seoul, Korea). The accuracy of this method in the measurement of body composition was validated on healthy subjects [24]. The principle and procedure of this method have been described previously [24,25]. Briefly, after >9 h of fasting, the subjects reported to the HPC at 9 a.m. Ht (nearest 0.1 cm) and BW (nearest 0.1 kg) were measured using a linear height scale and an electronic weight scale, respectively. BIA was performed by a well-trained nursing staff. When the subject was standing on the sole electrodes and gripping the hand electrodes, the microprocessor was switched on and the impedance analyser began measuring the segmental resistance of the right arm, left arm, trunk, right leg, and left leg at four frequencies (5, 50, 250 and 500 kHz). The mean values of two sets of BIA measurements were used for analysis. The repeat measured coefficient of variation for LBM was 0.29%, and the day-to-day coefficient of variation was 1.18%. The adjusted R2 and root mean square error between LBMDEXA and LBMBIA were 0.92 and 2.8 kg [24].

Statistical analysis
The data were expressed as mean ± SD. In ESRD patients, differences in parameters between groups were analysed using the Mann–Whitney U test because the number in each group was small. Spearman's correlation coefficient (r) was used to find the relationship between two variables when appropriate. Multiple linear regression analysis was performed to determine the independent factors for LBMm/LBMe ratio.

In control subjects, multiple linear regression analysis was performed to develop the equation predicting LBMBIA with the following variables: Ht, BW and sex. Of the 2940 control subjects, 2222 were used as a reference set and the remaining 718 as the validation set. To assess the agreement, a Bland–Altman plot using the means and differences between LBMBIA and LBMe was used [26]. To quantify the degrees of bias, we compared the correlation coefficients of the respective differences and means. All tests were two-sided, and a P value <0.05 was considered statistically significant. The statistical software package SPSS version 12.0 (Chicago, IL, USA) was used for all analyses, and graphs.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Characteristics of ESRD patients
A total of 36 non-diabetic ESRD patients were admitted during the study period. Of these, 15 patients were excluded from the study for the following reasons: serum CRP >0.30 mg/dl (4); infusion of dextrose fluid before blood sampling (4); DEXA not performed (2); and refusal to participate (5). Finally, 21 patients were included in this study. Their demographic and laboratory data are shown in Table 1. Nine patients were male (42.9%). Mean age was 51 ± 18 years, Ht was 159.7 ± 9.4 cm, BW was 59.4 ± 10.2 kg, LBMDEXA was 44.6 ± 8.5 kg, FM was 12.2 ± 6.3 kg, LBMe was 44.7 ± 8.6 kg and LBMm/LBMe ratio was 1.00 ± 0.09, and BMI was 23.3 ± 3.4 kg/m2. The causes of ESRD were chronic glomerulonephritis in 10 cases (47.6%), hypertensive nephropathy in nine (42.9%), biopsy-proven focal segmental glomerulosclerosis in one (4.75%) and unknown in one (4.75%). Estimated GFR by MDRD equation was 4.78 ± 1.38 (range 2.63–7.66) ml/min/1.73 m2.


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  		Table 1. Characteristics of non-diabetic ESRD patients

 
According to subjective global assessment (SGA), 12 (57.1%) were normal, 7 (33.3%) were mildly-to-moderately malnourished, and 2 (9.5%) were severely malnourished. Due to small numbers of severely malnourished patients, mildly-to-moderately malnourished patients and severely malnourished patients were combined into malnourished group. Non-obese patients (BMI < 25 kg/m2) were 15 (71.4%) and obese patients (BMI ≥ 25 kg/m2) were 6 (28.6%).

Relationship between LBM loss and IR in ESRD patients
LBM loss group showed significantly higher plasma insulin concentrations (19.1 ± 5.1 vs 8.5 ± 4.9 mU/l, P < 0.001), HOMA-IR (4.8 ± 1.4 vs 2.0 ± 1.3, P < 0.001), FM/LBM (0.38 ± 0.15 vs 0.20 ± 0.13, P = 0.016) and FM (%BW) (26.0 ± 7.8 vs 15.5 ± 8.3%, P = 0.016) and lower LBM (%BW) (71.4 ± 7.6 vs 81.3 ± 7.9%, P = 0.013) than LBM maintenance group (Table 2). However, there were no differences in BW, BUN, serum creatinine, total CO2 concentration, serum albumin, or prealbumin between the two groups. On the contrary, more malnourished patients seemed to be in the LBM maintenance group than in the LBM loss group (20.0 vs 63.6%, P = 0.08) (Table 2) and normal patients tended to have a higher HOMA-IR than malnourished patients (3.86 ± 1.75 vs 2.62 ± 2.05, P = 0.129) without statistical significance.


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  		Table 2. Comparison of variables according to the LBMm/LBMe ratio

 
The LBMm/LBMe ratio was significantly correlated with plasma insulin (r = –0.82, P < 0.001), glucose (r = –0.51, P = 0.018), HOMA-IR (r = –0.83, P < 0.001), FM/LBM ratio (r = –0.61, P = 0.004) and FM (%BW) (r = –0.61, P = 0.004) (Table 3). HOMA-IR showed significant positive correlation with FM/LBM ratio (r = 0.699, P < 0.001). Negative correlation between LBMm/LBMe ratio and HOMA-IR was still present in obese (r = –0.829, P = 0.042) and non-obese patients (r = –0.807, P < 0.001) (Figure 1). There were no correlations between LBMm/LBMe ratio and serologic nutritional markers or C-reactive protein. By multiple linear regression analysis, plasma insulin concentration was an independent variable for the LBMm/LBMe ratio (Table 4). If plasma insulin and glucose concentrations were removed, HOMA-IR was an independent variable for the LBMm/LBMe ratio.


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  		Table 3. Correlation of LBMm/LBMe ratio with other variables

 

Figure 1
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  		Fig. 1. Correlation between HOMA-IR and LBMm/LBMe ratio in obese and non-obese patients. HOMA-IR, homoeostasis model for assessment of insulin resistance; LBMm/LBMe ratio, lean body mass by dual energy X-ray absorptiometry/lean body mass by LBMe equation. Spearman's correlation coefficient was –0.829 (P = 0.004) in obese patients and –0.807 (P < 0.001) in non-obese patients.

 

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  		Table 4. Multiple linear regression analysis for LBMm/LBMe ratio

 
Of 21 patients, 8 started HD and 13 chose CAPD. Among the 13 patients who did CAPD, four refused to perform muscle biopsy. Thus, nine muscle samples were available. Among nine samples, western blot data of three samples were discarded due to unequal loading. Western blots indicated that patients with high HOMA-IR had lower LBMm/LBMe ratios and more 14 kDa actin fragments than those with low HOMA-IR (Figure 2).


Figure 2
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  		Fig. 2. Western blot for detecting 14-kDa actin fragments in six patients who performed CAPD.

 
Development of an equation predicting LBM in control subjects
In the reference set of 2222 controls, the male-to-female ratio was 1.2 : 1. For the men (n = 1226), age was 47 ± 11 years, BW was 68.7 ± 9.7 kg, Ht was 169.4 ± 6.0 cm, fat mass (FM) was 13.9 ± 4.6 kg and LBMBIA was 54.8 ± 6.5 kg. For the women in the reference set (n = 996), age was 47 ± 11 years, BW was 57.4 ± 8.4 kg, Ht was 156.8 ± 7.9 cm, FM was 16.6 ± 5.4 kg and LBMBIA was 40.8 ± 4.3 kg. The equations were developed by linear regression analysis (Table 5); LBMe = –9.451 + 1.284 x BW – 170.709 x BW2/Ht2 + 4.498 x Sex (m = 1, f = 0). The adjusted R2 was 0.953.


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  		Table 5. Prediction equation of LBM in control subjects

 
In the validation set of 718 subjects, male was 403 and female was 315, the mean age was 47 ± 11 years, the mean BW was 63.6 ± 10.5 kg, the mean Ht was 163.7 ± 8.6 cm and the mean LBMBIA was 48.6 ± 8.7 kg. In both men and women, there were no differences among our identified LBMBIA and that predicted by LBMe (54.7 ± 6.5 vs 54.6 ± 5.7 kg in male, 40.9 ± 4.3 vs 40.8 ± 4.4 kg in female). On the Bland–Altman plot, Pearson's correlation coefficients between means and differences was –0.145 (P < 0.001).



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
The novel finding of this study is the association of IR with LBM loss in non-diabetic ESRD patients. This finding is supported by the following evidence: (i) patients with a low LBMm/LBMe ratio had higher HOMA-IR than those with a high LBMm/LBMe ratio; (ii) HOMA-IR was independently associated with LBMm/LBMe ratio, regardless of FM.; and (iii) in the muscle samples, patients with a high HOMA-IR showed lower LBMm/LBMe ratio and stronger band for 14 kDa actin fragments than those with low HOMA-IR.

Recent experimental studies have emphasized the central role of impaired insulin/IGF-1 signalling pathways or IR on muscle wasting. Activation of the ubiquitin–proteasome system is the final common step of muscle atrophy occurring in many catabolic conditions, including uraemia [27]. However, the process of muscle protein breakdown requires more than activation of this system; additional proteolytic enzymes are needed [28]. Among several candidates, caspase 3, a final player in the apoptotic pathway, cleaves actomyosin into its constituent proteins, which are then degraded by the ubiquitin–proteasome system [29]. Of note, impairment of the insulin/IGF-1 pathway triggers activation of caspase 3. In cell and animal studies, caspase 3 activation occurred when insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3 kinase (PI3K) activity was suppressed by insulin deprivation or resistance [30]. It is also known that IGF-1 induces muscle hypertrophy by stimulating the PI3K-Akt pathway and suppressing the ubiquitin–proteasome system [31,32]. Thus, muscle loss appears to result from suppression of the insulin/IGF-1 pathway, activation of caspase 3 and its fragmentation of muscle proteins, and subsequent activation of the ubiquitin–proteasome system.

IR has already been identified at the early stage of CKD, increasing its degree linearly with the decline in renal function [11,33], and both HD and CAPD improved IR [34]. These data suggest that the degree of IR is highest at ESRD just before the initiation of dialysis and, at this stage with maximal degree of IR, the relationship between IR and LBM loss may be clearer than the mild-to-moderate stage of CKD. Thus, we included the patients who were admitted to the hospital for the initiation of dialysis. Our results confirm that IR is associated with muscle wasting and this relationship was independent of FM in non-diabetic ESRD patients. We found a significant negative relationship between IR and the index of LBM loss in the patient's whole body and this relationship was still significantly present in both non-obese and obese patients. Multiple regression analysis also showed that IR was independently associated with the index of LBM loss. Additionally, in muscle, patients with high IR had lower LBMm/LBMe ratio and more actin fragmentation than patients with low IR. As noted above, caspase 3 activity results in characteristic 14-kDa actin fragments [29]; thus, the detection of these 14-kDa actin fragments indicates the suppression of the IRS-1-associated PI3K pathway by IR. In spite of similar BW and age, LBM loss group (LBMm/LBMe ratio <1.00) showed higher FM (%BW) and lower LBM (%BW) than LBM maintenance group (LBMm/LBMe ratio ≥1.00), suggesting the replacement of muscle mass by FM.

Several studies also suggest the importance of impairment of the insulin/IGF-1 pathway or IR in muscle wasting in uraemia. Insulin reduced proteolysis and leucine oxidation, and insulin given with amino acids increased net protein synthesis in both pre-HD and HD patients [35]. Injection of recombinant human IGF-1 induced a strong and sustained anabolic effect in malnourished CAPD and HD patients [36,37]. Pupim et al. showed that diabetic ESRD patients showed greater loss of LBM than non-diabetic ESRD patients during 1-year follow-up after initiation of dialysis [38,39]. They also showed that type 2 diabetic ESRD patients had more muscle protein breakdown than non-diabetics. Though they did not measure IR, these results suggested that IR might be one of the causes. Recently, Siew et al. [40] showed that IR was associated with skeletal muscle protein breakdown in non-diabetic HD patients.

In this study, there were no correlations between LBM loss and serologic nutritional parameters. It is possible that our findings may be attributable to the relatively small number of severely malnourished CKD subjects in the group. However, biochemical nutritional markers such as serum albumin, prealbumin, creatinine and cholesterol are often abnormal late in the course of a deteriorating nutritional state and are considered insensitive to change in nutritional status [41]. Additionally, serum albumin concentration in another study was not correlated with LBM in pre-dialysis CKD patients [42].

However, surprisingly, more malnourished patients tended to be more in the LBM maintenance group and normal patients tended to have higher HOMA-IR than malnourished patients. This finding does not mean that muscle wasting is not associated with IR because negative correlation was still present between LBMm/LBMe ratio and HOMA-IR in both obese and non-obese patients.

One possible explanation is that LBM is not solely responsible for IR. FM is also an important factor for IR. Importance of both LBM and FM is also shown by the study of Chevalier et al. [43] in aging, another example of IR. They suggested that, although muscle mass is reduced with aging, this reduction did not fully explain the lower response to insulin and increased relative adiposity combined with lower LBM, both changes in body composition intrinsic to the aging process, explained a large part of the lesser sensitivity of protein metabolism to insulin.

Another possible explanation is that weight loss caused by severe uraemia might reduce IR. Obesity is another example of IR state [44,45] and weight loss resulted in the improvement of insulin sensitivity [46]. In malnourished patients, both LBM and FM were reduced. Thus, loss of FM might contribute to the improvement of insulin sensitivity in these ESRD patients.

The results of this study must be considered with the following drawbacks. First, this study is a cross-sectional study. Thus, the assessment of LBM loss was estimated by the index. Second, BIA was used for the development of the LBM equation in control subjects. Therefore, in spite of high agreement between LBMDEXA and LBMBIA in healthy adults, there may be some differences in the measurement of LBM between BIA and DEXA. Third, our LBM equation should be used with caution, especially in case of abnormal body figures (e.g. amputee, hemiplegia, etc) and different races. Besides, in CKD patients, oedema should be controlled before the measurement of LBM. Furthermore, these equations still showed the tendency to underestimate LBM when LBM increased. Nevertheless, this equation seems to give a rough knowledge about the muscle wasting in patients. Fourth, the glucose clamp method has been the standard for assessing IR. However, in this study, we used HOMA-IR. HOMA is easy to perform and results using HOMA are consistent with the results of the glucose clamp technique [47]; thus, this index can be applied to subjects with CKD [48]. Fifth, we regarded a CRP level of >0.30 mg/dl as indicating the presence of inflammation. In one study, CRP levels of >0.10 mg/dl were identified as the best cut-off points for the predictor of mortality in ESRD patients [49]. However, we could not find any relationship between CRP levels and LBM loss or IR. Sixth, the small number of ESRD subjects in this study should be noted. The error or selection bias may be larger in smaller numbers than in larger number of subjects. The number of cases must substantially exceed the number of independent variables we are using in multiple regression analysis. The absolute minimum is that we have 5x as many cases as independent variables [50]. Though the number of subjects meets the minimum requirement in this study, the small number of subjects should be taken into account when a reader reads this article.

In conclusion, our data suggest that, at least in part, IR seems to be associated with muscle wasting in non-diabetic ESRD patients. Further prospective study is needed to prove the relationship between IR and muscle wasting.



   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
This study was supported by 2004 INHA UNIVERSITY Research Grant (# 31588). This study was registered at The Cochrane Renal Group Registry (ID # CRG110500019). The abstract of this study was presented at the 38th annual meeting of ASN, Philadelphia, USA.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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Received for publication: 24.12.05
Accepted in revised form: 15. 3.07


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