NDT Advance Access originally published online on September 22, 2007
Nephrology Dialysis Transplantation 2007 22(12):3673-3674; doi:10.1093/ndt/gfm505
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Does desacyl ghrelin contribute to uraemic anorexia?
Email: maubosso{at}tin.it
Sir,
A study investigating the possible role of desacyl ghrelin in uraemic anorexia was published recently in the American Journal of Nephrology [1]. This study by Muscaritoli et al. shows that desacyl ghrelin levels were significantly higher in anorexic than in non-anorexic haemodialysis patients, suggesting that desacyl ghrelin may be involved in the pathogenesis of uraemic anorexia.
However, this study raises the question of how desacyl ghrelin may induce anorexia in haemodialysis patients. Indeed, there is strong evidence that desacyl ghrelin, like ghrelin, functions as orexigenic peptides in the hypothalamus [2]. Very recently, in an elegant experimental study, Toshinai et al. [2] demonstrated that intracerebroventricular administration of desacyl ghrelin to rats or mice fed ad libitum significantly stimulated feeding during the light phase [2]. In addition, neither intraperitoneal nor intracerebroventricular administration of desacyl ghrelin to fasting mice suppressed fasting. Toshinai et al. also showed that the intracerebroventricular administration of desacyl ghrelin induces the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons, and increased locomotor activity, suggesting that that desacyl ghrelin may increase wakefulness and locomotor activity for food seeking by stimultating orexin neurons. Finally, the study of Toshinai et al. documented the fact that central administration of desacyl ghrelin to GHS-R-deficient mice stimulates feeding, suggesting that desacyl acts on a target protein that is specific for desacyl ghrelin and independent of the GSH-R.
In contrast with these results are those of the study by Asakawa et al. [3], which suggest that desacyl ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. Indeed, in the study by Asakawa et al., the administration of desacyl ghrelin into the third central ventricle reduced food intake in food-deprived mice but not in non-food-deprived ones [3].
To further support the hypotheses that acylated and desacyl ghrelin play different roles in the regulation of food intake, Muscaritoli et al. cited the study of Aguilera et al. [4], demonstrating that acylated ghrelin is lower in anorexic than in non-anorexic uraemic patients undergoing peritoneal dialysis. Indeed, also in this field, data are conflicting [4,5]. Chang et al. [5] have determined the profile of plasma ghrelin levels over 24 h in non-diabetic haemodialysis patients, showing a unique diurnal change without an obvious plasma ghrelin rise before each meal nor a rapid fall after eating. They also found that the average level of plasma ghrelin in haemodialysis patients was one-fifth higher than in the healthy control group at most sampling times during the day, except between 10 p.m. and 2 a.m. According to the authors of the study, these observations suggest that there is a resistance to ghrelin action in end-stage renal disease patients, either peripheral or central or both. The detection of high plasma ghrelin levels in haemodialysis patients is in contrast to the strong tendency of these patients to be anorexic [5]. Recently, we measured the circulating levels of ghrelin in 51 haemodialysis patients in our laboratory, without detecting statistically significant differences between patients with very poor, poor, fair, good or very good appetite (personal communication).
The pathogenesis of anorexia in haemodialysis patients is essentially unknown. It has been proposed that uraemic toxins as middle molecules, inflammation, altered amino acid pattern, hormones (e.g. leptin and ghrelin) and neuropeptides (e.g. neuropeptide Y) are involved [6].
However, the studies of recent years have suggested that the simple and mechanical transmission of results obtained in experimental studies cannot be applied directly in humans and in clinical practice [7–9]. As an example, against the evidence of experimental studies [10], we demonstrated in the laboratory of the Department of Surgery of our University that serum leptin does not play a major pathogenetic role in anorexia of haemodialysis patients [8], suggesting that a state of relative leptin resistance may occur in patients with end-stage renal disease [9].
The pathogenesis of anorexia in uraemic patients remains an enigma, although it continues to have detrimental effects on nutritional status, quality of life and survival.
Servizio Emodialisi, Istituto di
Clinica Chirurgica
Università cattolica del sacro Cuore
Roma, Italia
Notes
See http://www.oxfordjournals.org/our_journals/ndtplus/
References
- Muscaritoli M, Molfino A, Chiappini MG, et al. Anorexia in hemodialysis patients: the possibile role of des-acyl ghrelin. Am J Nephrol (2007) 27:360–365.[CrossRef][Web of Science][Medline]
- Toshinai K, Yamaguchi H, Sun Y, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology (2006) 147:2306–2314.
[Abstract/Free Full Text] - Asakawa A, Inui A, Fujimiya M, et al. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut (2005) 54:18–24.
[Abstract/Free Full Text] - Aguilera A, Cirugeda A, Amair R, et al. Ghrelin plasma levels and appetite in peritoneal dialysis patients. Adv perit Dial (2004) 20:194–199.[Medline]
- Chang CC, Hung CH, Yen CS, et al. The relationship of plasma ghrelin level to energy regulation, feeling and left ventricular function in non-diabetic hemodialysis patients. Nephrol Dial Transplant (2005) 20:2172–2177.
[Abstract/Free Full Text] - Bossola M, Tazza L, Giungi S, Luciani G. Anorexia in hemodialysis patients: an update. Kidney Int (2006) 70:417–422.[Web of Science][Medline]
- Wiecek A. How does leptin contribute to uraemic cachexia? Nephrol Dial Transplant (2005) 20:2620–2622.
[Free Full Text] - Bossola M, Muscaritoli M, Valenza V, et al. Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Practice (2004) 97:c76–c82.[CrossRef]
- Bossola M. Does leptin conribute to uraemic cachexia? Nephrol Dial Transplant (2006) 21:1125–1126.
[Free Full Text] - Cheung W, Yu PX, Little BM, et al. Role of leptin and melanocortin signalling in uremia-associated cachexia. J Clin Invest (2005) 115:1659–1665.[CrossRef][Web of Science][Medline]
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