Clinical nutrition
Malnutrition Is an Unusual Cause of Decreased Muscle Mass in Chronic Kidney Disease

https://doi.org/10.1053/j.jrn.2006.10.010Get rights and content

Patients with chronic kidney disease (CKD), including those who are treated with hemodialysis, frequently develop hypoalbuminemia and a decrease in body weight. These abnormalities are usually attributed to malnutrition, but true malnutrition (ie, a disorder due to an abnormal diet) is rarely the mechanism causing decreased protein stores. Hypoalbuminemia is closely related to evidence of inflammation, and a decrease in muscle mass is caused by activation of muscle protein breakdown. In uremic rodents and patients, the initial step in the loss of muscle protein is activation of caspase-3, which cleaves the complex structure of muscle to provide substrates for the ubiquitin–proteasome pathway (UPP). The activity of caspase-3 can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of a muscle biopsy specimen. Abnormalities in cell signaling activate caspase-3 and the UPP; a key abnormality is decreased activity in the phosphatidylinositol-3-kinase/Akt pathway, leading to activation of caspase-3 and a specific E3 ubiquitin conjugating enzyme, atrogin-1/MAFbx. Inflammatory cytokines also represent a potential cell signaling abnormality that activates muscle protein breakdown, possibly because cytokines activate the E3 ubiquigin conjugating enzyme, MuRF1. An understanding of these pathways could help the clinician to identify therapeutic targets for preventing loss of muscle protein.

Section snippets

Chronic Kidney Disease and Muscle Protein Loss

In uremic patients, malnutrition is frequently cited as the cause of lost protein stores, but several lines of evidence indicate that malnutrition is rarely the cause of this problem.8 First, malnutrition is defined as a disorder that is caused by an inadequate or abnormal diet. However, the mechanism that most often causes a loss of muscle mass in CKD is the activation of pathways that break down intracellular proteins. Second, hypoalbuminemia is most closely linked to the presence of

Caspase-3 and Muscle Proteolysis

The breakdown of muscle protein begins with breakdown of the complex structure of muscle to produce substrates that are degraded in the UPP.16 In cultured muscle cells and muscle of rodents or patients with catabolic disorders, we identified caspase-3 as the enzyme that performs this initial cleavage. In atrophying muscles, caspase-3 activity can be detected because it leaves a characteristic “footprint” of its action, a 14-kDa fragment of actin in the insoluble fraction of a muscle biopsy.6, 16

Cellular Signals That Activate Muscle Protein Degradation

Insulin and IGF-I suppress protein degradation when they activate the PI3K/Akt pathway.6, 22 Part of the evidence that decreased PI3K/Akt signaling in muscle activates protein degradation involves activation of the E3 enzymes, atrogin-1/MAFbx and MuRF1.3 In this case, the expression of atrogin-1 involves upregulation of forkhead transcription factors (FoxO) because decreased Akt activation does not phosphorylate FoxO, and it migrates into the nucleus to enhance transcription of the

Conclusions and Future Directions

CKD can decrease protein stores because complications may arise from loss of kidney function, which activates the breakdown of protein stores. Muscle atrophy in uremia begins with complications such as metabolic acidosis and insulin resistance, both of which decrease the activities of PI3K and Akt in muscle. This leads to activation of proteolytic enzymes. These proteolytic enzymes include activated caspase-3 and the specific E3, ubiquitin-conjugating enzymes, atrogin-1/MAFbx and MuRF1. These

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      In view of the complexity of the assessment and the need for an objective and reliable one, we developed a quantitative method, the Integrative Clinical Nutrition Dialysis Score (ICNDS), evaluating the nutritional status of HD patients. We have used a scoring system that is based on a series of objective measurements, each previously shown to correlate with nutrition status and clinical outcome: albumin,25-33 creatinine,34-37 urea,38 and cholesterol,39-42 routinely taken each month before starting a dialysis session. Three other parameters embedded in ICNDS are routinely taken every 3 months: delivered dose of dialysis (Kt/V),43-45 C-reactive protein (CRP),46-49 and end dialysis dry weight change.50-52

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      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.

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    Copyright © 2007 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.