A balancing act: protein-energy wasting in chronic kidney disease.

PROTEIN ENERGY WASTING and its extreme form, cachexia, is common among patients with chronic kidney disease (CKD). This maladaptive metabolic state is fueled by inflammation and is characterized by anorexia, increased energy expenditure, ineffective utilization of nutrients, and augmented protein catabolism leading to loss of lean body mass. At the core of the regulation of energy balance is the complex and tightly regulated system of proopiomelanocortin (POMC) neurons, a panel of endogenous neuropeptides, and their receptors as described in Fig. 1. Peripheral signals regarding energy stores are received and processed by two distinct subtypes of neurons with opposing actions that are located in the arcuate nucleus (ARC) of the hypothalamus. One group of arcuate neurons express POMC, which is cleaved into biologically active peptides including melanocortins, which act through a family of melanocortin receptors (MC1R through MC5R) in mediating anorectic and catabolic responses. The second group of neurons expresses the orexigenic peptide neuropeptide Y (NPY) and agouti-related peptide (AgRP), an endogenous antagonist of MC3R and MC4R. Thus the gain and loss of body weight are determined by the balance between these two opposing regulatory systems. It appears that the adaptive metabolic, immune, and behavioral response to maintain protein-energy homeostasis during acute disease processes goes awry in chronic disease states such as CKD. Chronic unregulated systemic inflammation seems to be central to this dysregulated response. Besides promoting muscle protein breakdown, cytokines also act on neural circuits in the hypothalamus and the brainstem and modulate energy homeostasis, hormone secretion, and autonomic function. Preliminary evidence indicates that hypothalamic sensitivity to the actions of melanocortins is accentuated in the presence of inflammation (6). Recently, activation of nuclear factorB (NFB) in hypothalamic POMC neurons was shown to be an important molecular mechanism for infection-associated cachexia (7). Given the elevated circulating level of endotoxin in patients with kidney disease (8), it is tempting to speculate that this could be a potential mechanism for the persistent anorexigenic/cachexic activity of the central melanocortin system observed in uremic cachexia. The gain and loss of body weight, however, are only partly explained by the anorective/orexigenic effects resulting from the interactions of -melanocortin-stimulating hormone and AgRP/NPY. Muscle wasting in CKD could also be due to increased muscle proteolysis and decreased myogenesis. Breakdown of muscle occurs when the ubiquitin proteasome system is activated through E3 ligases, which can be controlled by forkhead transcription factors (FoxOs). Blocking FoxO1 Address for reprint requests and other correspondence: D. Raj, Div. of Renal Diseases and Hypertension MFA-George Washington Univ. School of Medicine, 2150 Pennsylvania Ave. NW, Washington, DC 20037 (e-mail: [email protected]).