Background and objective

Muscle atrophy in end-stage renal disease (ESRD) may be due to the activation of apoptotic and proteolytic pathways. We hypothesized that activation of caspase-3 in the skeletal muscle mediates apoptosis and proteolysis during haemodialysis (HD).

Materials and methods

Eight ESRD patients were studied before (pre-HD) and during HD and the findings were compared with those from six healthy volunteers. Protein kinetics was determined by primed constant infusion of L-(ring (13)C(6) ) Phenylalanine.

Results

Caspase-3 activity in the skeletal muscle was higher in ESRD patients pre-HD than in controls (24966·0 ± 4023·9 vs. 15293·3 ± 2120·0 units, P<0·01) and increased further during HD (end-HD) (37666·6 ± 4208·3 units) (P<0·001). Actin fragments (14 kDa) generated by caspase-3 mediated cleavage of actomyosin was higher in the skeletal muscle pre-HD (68%) and during HD (164%) compared with controls. The abundance of ubiquitinized carboxy-terminal actin fragment was also significantly increased during HD. Skeletal muscle biopsies obtained at the end of HD exhibited augmented apoptosis, which was higher than that observed in pre-HD and control samples (P<0·001). IL-6 content in the soluble fraction of the muscle skeletal muscle was increased significantly during HD. Protein kinetic studies showed that catabolism was higher in ESRD patients during HD compared with pre-HD and control subjects. Muscle protein catabolism was positively associated with caspase-3 activity and skeletal muscle IL-6 content.

Conclusion

Muscle atrophy in ESRD may be due to IL-6 induced activation of caspase-3 resulting in apoptosis as well as muscle proteolysis during HD.

Objective

Lipopolysaccharide or endotoxin constitutes most part of the outer portion of the cell wall in the gram-negative bacteria. Subclinical endotoxemia could contribute to increased inflammation and mortality in hemodialysis (HD) patients. Endotoxin level and clinical effect are determined by its soluble receptor sCD14 and high-density lipoprotein. We examine the hypothesis that endotoxin level correlates with mortality.

Methods

In this cohort study, endotoxin levels were measured in 306 long-term HD patients who were then followed up for a maximum of 42 months. Soluble CD14 and cytokines levels were also measured.

Results

The mean (±SD) endotoxin level was 2.31 ± 3.10 EU/mL (minimum: 0.26 EU/mL, maximum: 22.94 EU/mL, interquartile range: 1.33 EU/mL, median: 1.27 EU/mL). Endotoxin correlated with C-reactive protein (r = 0.11, P < .04). On multivariate logistic regression analysis, high body mass index and low high-density lipoprotein (HDL) cholesterol levels were associated with higher endotoxemia (endotoxin below or above of median). In multivariate Cox regression analysis adjusted for case-mix and nutritional/inflammatory confounders, endotoxin levels in the third quartile versus first quartile were associated with a trend toward increased hazard ratio for death (hazard ratio: 1.83, 95% confidence interval: 0.93 to 3.6, P = .08).

Conclusions

In this HD cohort, we found associations between endotoxemia and C-reactive protein, body composition, and HDL. Moderately high endotoxin levels tended to correlate with increased mortality than the highest circulating endotoxin level. Additional studies are required to assess the effect of endotoxemia on mortality in dialysis population.