Leptin is secreted by adipocytes and regulates adiposity and metabolic rate by reducing food intake and increasing energy expenditure. Leptin is also a member of the IL-6 superfamily of cytokines. Experimental elevation of leptin within the physiological range produces weight loss and relative anorexia. Leptin secretion is increased by both central and systemic immunological challenge and has been proposed as a potential mediator of inflammation-induced anorexia. The mechanism of how leptin expression and secretion is enhanced during inflammation is complex, but there is evidence for mediation by both IL-1^ and TNF-a. Conversely, leptin induces production and release of IL-1^ in the brains of normal rats and the release of both IL-1P and TNF-a from mouse macrophages. Collectively, these observations suggest a complex interplay between leptin and other cytokines in the regulation of metabolism and appetite during acute and chronic illness (49).
The percentage of body fat was strongly correlated with leptin levels in these patients. However, the ratio of leptin levels to body fat is significantly greater for dialysis patients than for control subjects. Increased leptin levels are associated with markers of poor nutritional status, such as low serum albumin and high protein catabolic rate in dialysis patients. In children with CKD, leptin levels increase with declining renal function, presumably by reduced renal clearance. Leptin levels are inappropriately elevated in these children in relation to the percentage of body fat and inversely correlate with dietary nutrient intake. Thus leptin may be an important factor in the pathogenesis of anorexia and cachexia in CKD (51). Furthermore, serum leptin concentrations correlate with plasma insulin concentrations in patients with CKD independent of body fat content, suggesting that insulin resistance and hyperinsulinemia may contribute to elevated serum leptin concentrations or vice versa. The role of leptin resistance due to receptor insufficiency and saturable transport via the blood-brain barrier in limiting the potential impact of elevated leptin levels in patients with CKD is controversial and not well understood (49).
A hormonal signal involved in the short-term control of appetitie is the gastric peptide ghrelin. Levels of this appetite-stimulating hormone rise in the blood before meals (when the stomach is empty), then fall quickly after food is consumed. Ghrelin is implicated as a factor that triggers the onset of eating, participating in a meal-to-meal control system that is itself sensitive to changes in insulin and leptin levels. In this way, the size and frequency of individual meals can be adjusted so as to minimize changes in body fat content. Preliminary observations show that markedly elevated plasma ghrelin concentrations are found in advanced CKD (52,53) and correlate with body mass index, fat mass, plasma insulin, and serum leptin levels. There is no difference in plasma ghrelin between CKD patients with and without signs of wasting. Changes in plasma ghrelin concentrations over time during peritoneal dialysis treatment are associated with changes in body composition (53). Further studies are needed to examine relative changes in ghrelin versus inactive ghrelin metabolites during the course of progression of CKD and the putative associations with changes in food intake and body composition.
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