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LETTER TO THE EDITOR |
Department of Clinical Medicine
Sapienza University
Viale dell'Universitá 37
00184 Rome
Italy
E-mail: maurizio.muscaritoli{at}uniroma1.it
Fatebenefratelli Hospital "Isola Tiberina"
Rome
Italy
Dear Sir:
We read with much interest the recent report in the Journal by Carrero et al (1), who conducted a cross-sectional study in patients undergoing hemodialysis. Many variables, including anthropometric markers, handgrip strength, and nutritional and inflammatory status, were measured and related to self-reported ratings of appetite. Of particular interest is the fact that patients with poor appetite have higher inflammatory status, as expressed by elevated C-reactive protein and interleukin-6 concentrations.
Anorexia is common in persons undergoing hemodialysis, and it contributes to malnutrition and its complications (2). The pathogenesis of this clinical condition is still controversial, and its mechanisms are currently under investigation. Many molecules, including leptin (3), have been postulated as putative contributing factors for hemodialysis-associated appetite disorders. Consistent evidence shows that plasma ghrelin concentrations are increased in advanced renal failure (4) and that those higher concentrations directly correlate with the impairment of kidney function, which suggests that reduced renal excretion of ghrelin is the main causative factor of ghrelin's increase in plasma (4). The potential effects of excess ghrelin in chronic kidney disease is still a matter of discussion.
There is convincing evidence that patients with end-stage renal disease (ESRD) who are undergoing maintenance hemodialysis have inappropriately high plasma ghrelin concentrations (4, 5). Ghrelin is secreted mainly by the stomach, and 2 major molecular forms are found in plasma: acylated ghrelin, with a n-octanoylated serine residue in position 3, and des-acyl ghrelin. Other minor forms are also present in plasma, and they have apparently marginal biological functions. The n-octanoyl modification of ghrelin—ie, n-octanoyl's role as an endogenous ligand—appears to be essential to growth hormone (GH)–releasing activity for the GH secretagogue receptor (GHS-R) (6).
The administration of acylated ghrelin induces gains in body weight and fat mass via increased food intake and decreased fat oxidation for energy expenditure (7). In contrast, des-acyl ghrelin, which accounts for >90% of total circulating ghrelin, could bind to GHS-R or other receptors, for which n-octanoyl ligand is not necessary. Thus, des-acyl ghrelin could play an important role in the control of the desire to eat and in adipogenesis via mechanisms independent of the GH pathway—mechanisms that are more likely controlled by a specific central neuronal network that is also modulated by leptin (6).
In patients with chronic renal failure, glomerular filtration rate has been shown to be inversely correlated with plasma des-acyl ghrelin concentrations, whereas no relation was found with acylated ghrelin (4). Des-acyl ghrelin does not act through the GHS-1a receptor, but it is not yet clear whether it may influence appetite in humans, because the orexigenic effect could be independent of the GH secretory pathway and could, instead, be mediated by other receptors (7). Indeed, in a recent experimental study, it was shown that des-acyl ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying and that this effect is mediated within the hypothalamus (8). In addition, peripherally administered des-acyl ghrelin decreases food intake and disrupts the motor activity of the antrum in freely moving, conscious, fasted rats via direct activation of brain receptors after the des-acyl ghrelin crosses the blood-brain barrier, but there is no activation of vagal afferent pathways. In the brain, a selective corticotropin-releasing factor 2 receptor is involved in this action (9).
We recently conducted a study in ESRD patients to investigate whether increased des-acyl ghrelin concentrations may be implicated in the pathogenesis of hemodialysis-related anorexia (10). Our study confirmed that persons undergoing hemodialysis have significantly higher des-acyl ghrelin concentrations than do healthy subjects. Furthermore, des-acyl ghrelin concentrations are significantly higher in anorexic than in nonanorexic persons undergoing hemodialysis. Indeed, calorie intakes and fat-free mass were significantly lower in anorexic than in nonanorexic persons undergoing hemodialysis. It is interesting that the prevalence of reduced appetite was similar in the patients in our study (41%) and in those in the study of Carrero et al (44%), despite the different tools the 2 studies used to assess anorexia. These figures confirm that, in persons undergoing hemodialysis, the decrease in appetite is a clinically relevant feature that may significantly affect quality of life and outcome (2).
The hypothesis that increased des-acyl ghrelin may contribute to the development of hemodialysis-related anorexia represents another advancement in the understanding of the mechanisms underlying appetite disorders in ESRD, and it may set the stage for the development of more effective preventive and therapeutic interventions.
ACKNOWLEDGMENTS
None of the authors had a personal or financial conflict of interest.
REFERENCES
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