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Mechanisms by Which Inflammation May Promote Protein Energy Wasting

Inflammation is a condition encountered not only in the majority of chronic kidney disease (CKD) patients but also in other chronic disease states in which loss of muscle mass is a common complication, such as cancer, congestive heart failure, chronic pulmonary disease, AIDS, and aging. Because circulating inflammatory markers are strong predictors of outcome in CKD, they are logical therapeutic targets for interventions. Indeed, animal studies show that infusion of TNF, IL-1 and IL-6 leads to muscle protein breakdown and muscle atrophy (1). As cross-sectional clinical studies in CKD show strong associations between inflammatory biomarkers and surrogate markers of muscle wasting (2), the renal community needs prospective studies to prove the hypothesis that persistent inflammation leads to protein energy wasting (PEW). Several mechanisms exist by which persistent inflammation may promote PEW (Fig. 1). Both animal and human studies have shown that inflammation contributes to anorexia. In HD patients, levels of proinflammatory cytokines, such as IL-6 and TNF, have been reported to progressively increase as appetite scores worsened. As the immune system subjugates the brain, inflammation may also indirectly contribute to low nutrient intake via depression and psychosocial disorders. Persistent inflammation may also contribute to PEW by stimulation of resting energy expenditure. Actually, next to the brain and muscles, the immune system is the third major energy consumer in the body. The fourth mechanism by which proinflammatory cytokines, such as IL-6 and TNF, may contribute to catabolism are direct effects via stimulation of ubiquitin-proteasome and NF-jB pathways. Moreover, inflammation may have indirect catabolic effects via insulin and myostatin. Finally, inflammation may promote catabolism via suppression and⁄ or resistance to anabolic hormones, such as growth hormone (GH), insulin-growth factor (IGF-1), and testosterone. In the uremic milieu, increased muscle breakdown may not be compensated for by a corresponding increase in anabolic pathways.