Skip to main content

Advertisement

SpringerLink
Log in

Ghrelin and cachexia in chronic kidney disease

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding–regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

AgRP:

Agouti-related protein

CKD:

Chronic kidney disease

GH:

Growth hormone

GOAT:

Ghrelin O-acyltransferase

IGF-1:

Insulin-like growth factor 1

MC4R:

Melanocortin-4 receptor

α-MSH:

α-Melanocyte stimulating hormone

NPY:

Neuropeptide Y

POMC:

Pro-opiomelanocortin

PPAR:

Peroxisome proliferator-activated receptor

References

  1. Deboer MD, Marks DL (2006) Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab 2:459–466

    Article  PubMed  CAS  Google Scholar 

  2. Mak RH, Cheung W (2006) Energy homeostasis and cachexia in chronic kidney disease. Pediatr Nephrol 21:1807–1814

    Article  PubMed  Google Scholar 

  3. Deboer MD, Zhu X, Levasseur PR, Inui A, Hu Z, Han G, Mitch WE, Taylor JE, Halem HA, Dong JZ, Datta R, Culler MD, Marks DL (2008) Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 149:827–835

    Article  PubMed  CAS  Google Scholar 

  4. Deboer MD (2007) Melanocortin interventions in cachexia: how soon from bench to bedside? Curr Opin Clin Nutr Metab Care 10:457–462

    Article  PubMed  CAS  Google Scholar 

  5. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    Article  PubMed  CAS  Google Scholar 

  6. Sun Y (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 101:4679–4684

    Article  PubMed  CAS  Google Scholar 

  7. Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K (2011) Wasting in chronic kidney disease. J Cachex Sarcopenia Muscle 2:9–25

    Article  Google Scholar 

  8. Nass RM, Gaylinn BD, Rogol AD, Thorner MO (2010) Ghrelin and growth hormone: story in reverse. Proc Natl Acad Sci USA 107:8501–8502

    Article  PubMed  CAS  Google Scholar 

  9. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    Article  PubMed  CAS  Google Scholar 

  10. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schürmann A, Joost HG, Jandacek RJ, Hale JE, Heiman ML, Tschöp MH (2009) GOAT links dietary lipids with the endocrine control of energy balance. Nat Med 15:741–745

    Article  PubMed  CAS  Google Scholar 

  11. Akamizu T, Takaya K, Irako T, Hosoda H, Teramukai S, Matsuyama A, Tada H, Miura K, Shimizu A, Fukushima M, Yokode M, Tanaka K, Kangawa K (2004) Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol 150:447–455

    Article  PubMed  CAS  Google Scholar 

  12. Hosoda H, Kojima M, Matsuo H, Kangawa K (2000) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279:909–913

    Article  PubMed  CAS  Google Scholar 

  13. Asakawa A, Inui A, Fujimiya M, Sakamaki R, Shinfuku N, Ueta Y, Meguid MM, Kasuga M (2005) Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut 54:18–24

    Article  PubMed  CAS  Google Scholar 

  14. Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, Ueno N, Fujimiya M (2005) Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 129:8–25

    Article  PubMed  CAS  Google Scholar 

  15. Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2:551–560

    Article  PubMed  CAS  Google Scholar 

  16. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48:23–29

    Article  PubMed  CAS  Google Scholar 

  17. Laviano A, Inui A, Marks DL, Meguid MM, Pichard C, Rossi Fanelli F, Seelaender M (2008) Neural control of the anorexia-cachexia syndrome. Am J Physiol Endocrinol Metab 295:E1000–E1008

    Article  PubMed  CAS  Google Scholar 

  18. Wardlaw SL (2011) Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol 660:213–219

    Article  PubMed  CAS  Google Scholar 

  19. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578

    Article  PubMed  CAS  Google Scholar 

  20. Büscher AK, Büscher R, Hauffa BP, Hoyer PF (2010) Alterations in appetite-regulating hormones influence protein-energy wasting in pediatric patients with chronic kidney disease. Pediatr Nephrol 25:2295–2301

    Article  PubMed  Google Scholar 

  21. Bergström J (1995) Why are dialysis patients malnourished? Am J Kidney Dis 26:229–241

    Article  PubMed  Google Scholar 

  22. Mitch WE (1998) Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. Am J Clin Nutr 67:359–366

    PubMed  CAS  Google Scholar 

  23. Heimbürger O, Lönnqvist F, Danielsson A, Nordenström J, Stenvinkel P (1997) Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 8:1423–1430

    PubMed  Google Scholar 

  24. Shinohara K, Shoji T, Emoto M, Tahara H, Koyama H, Ishimura E, Miki T, Tabata T, Nishizawa Y (2002) Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 13:1894–1900

    Article  PubMed  Google Scholar 

  25. Siew ED, Pupim LB, Majchrzak KM, Shintani A, Flakoll PJ, Ikizler TA (2007) Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients. Kidney Int 71:146–152

    Article  PubMed  CAS  Google Scholar 

  26. Bailey JL, Zheng B, Hu Z, Price SR, Mitch WE (2006) Chronic kidney disease causes defects in signaling through the insulin receptor substrate/ phosphatidylinositol 3-kinase/ Akt pathway: implications for muscle atrophy. J Am Soc Nephrol 17:1388–1394

    Article  PubMed  CAS  Google Scholar 

  27. Mitch WE, Goldberg AL (1996) Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 335:1897–1905

    Article  PubMed  CAS  Google Scholar 

  28. Mitch WE (2002) Malnutrition: a frequent misdiagnosis for hemodialysis patients. J Clin Invest 110:437–439

    PubMed  CAS  Google Scholar 

  29. Goodman MN (1991) Tumor necrosis factor induces skeletal muscle protein breakdown in rats. Am J Physiol 260:E727–E730

    PubMed  CAS  Google Scholar 

  30. Du J, Wang X, Miereles C, Bailey JL, Debigare R, Zheng B, Price SR, Mitch WE (2004) Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest 113:115–123

    PubMed  CAS  Google Scholar 

  31. Lee SW, Dai G, Hu Z, Wang X, Du J, Mitch WE (2004) Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. J Am Soc Nephrol 15:1537–1545

    Article  PubMed  CAS  Google Scholar 

  32. Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH (2005) Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115:1659–1665

    Article  PubMed  CAS  Google Scholar 

  33. Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, Cattin L, Biolo G, Zanetti M, Guarnieri G (2005) Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab 288:E228–E235

    Article  PubMed  CAS  Google Scholar 

  34. Barazzoni R, Zanetti M, Cattin MR, Visintin L, Vinci P, Cattin L, Stebel M, Guarnieri G (2007) Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats. Obesity (Silver Spring) 15:2614–2623

    Article  CAS  Google Scholar 

  35. Barazzoni R, Zhu X, Deboer M, Datta R, Culler MD, Zanetti M, Guarnieri G, Marks DL (2010) Combined effects of ghrelin and higher food intake enhance skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rats with chronic kidney disease. Kidney Int 77:23–28

    Article  PubMed  CAS  Google Scholar 

  36. Barazzoni R, Zanetti M, Ferreira C, Vinci P, Pirulli A, Mucci M, Dore F, Fonda M, Ciocchi B, Cattin L, Guarnieri G (2007) Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab 92:3935–3940

    Article  PubMed  CAS  Google Scholar 

  37. Barazzoni R, Zanetti M, Stulle M, Mucci MP, Pirulli A, Dore F, Panzetta G, Vasile A, Biolo G, Guarnieri G (2008) Higher total ghrelin levels are associated with higher insulin-mediated glucose disposal in non-diabetic maintenance hemodialysis patients. Clin Nutr 27:142–149

    Article  PubMed  CAS  Google Scholar 

  38. Carrero JJ, Nakashima A, Qureshi AR, Lindholm B, Heimburger O, Barany P, Stenvinkel P (2011) Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients. Kidney Int 79:749–756

    Article  PubMed  CAS  Google Scholar 

  39. Yoshimoto A, Mori K, Sugawara A, Mukoyama M, Yahata K, Suganami T, Takaya K, Hosoda H, Kojima M, Kangawa K, Nakao K (2002) Plasma ghrelin and desacyl ghrelin concentrations in renal failure. J Am Soc Nephrol 13:2748–2752

    Article  PubMed  CAS  Google Scholar 

  40. Naufel MF, Bordon M, de Aquino TM, Ribeiro EB, de Abreu Carvalhaes JT (2010) Plasma levels of acylated and total ghrelin in pediatric patients with chronic kidney disease. Pediatr Nephrol 25:2477–2482

    Article  PubMed  Google Scholar 

  41. Arbeiter AK, Büscher R, Petersenn S, Hauffa BP, Mann K, Hoyer PF (2008) Ghrelin and other appetite-regulating hormones in paediatric patients with chronic renal failure during dialysis and following kidney transplantation. Nephrol Dial Transplant 24:643–646

    Article  PubMed  Google Scholar 

  42. Iglesias P, Díez JJ, Fernández-Reyes MJ, Codoceo R, Alvarez-Fidalgo P, Bajo MA, Aguilera A, Selgas R (2005) Serum ghrelin concentrations in patients with chronic renal failure undergoing dialysis. Clin Endocrinol (Oxf) 64:68–73

    Article  Google Scholar 

  43. Jarkovská Z, Hodková M, Sazamová M, Rosická M, Dusilová-Sulková S, Marek J, Justová V, Lacinová Z, Haluzík M, Haas T, Krsek M (2005) Plasma levels of active and total ghrelin in renal failure: a relationship with GH/IGF-I axis. Growth Horm IGF Res 15:369–376

    Article  PubMed  Google Scholar 

  44. Rodriguez Ayala E, Pecoits-Filho R, Heimbürger O, Lindholm B, Nordfors L, Stenvinkel P (2004) Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study. Nephrol Dial Transplant 19:421–426

    Article  PubMed  CAS  Google Scholar 

  45. Pérez-Fontán M, Cordido F, Rodríguez-Carmona A, García-Naveiro R, Isidro ML, Villaverde P, García-Buela J (2005) Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure. Kidney Int 68:2877–2885

    Article  PubMed  Google Scholar 

  46. Mak RH, Cheung WW (2011) Is ghrelin a biomarker for mortality in end-stage renal disease? Kidney Int 79:697–699

    Article  PubMed  CAS  Google Scholar 

  47. DeBoer MD (2008) Emergence of ghrelin as a treatment for cachexia syndromes. Nutrition 24:806–814

    Article  PubMed  CAS  Google Scholar 

  48. Ashby DR, Ford HE, Wynne KJ, Wren AM, Murphy KG, Busbridge M, Brown EA, Taube DH, Ghatei MA, Tam FW, Bloom SR, Choi P (2009) Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int 76:199–206

    Article  PubMed  CAS  Google Scholar 

  49. Venables G, Hunne B, Bron R, Cho HJ, Brock JA, Furness JB (2011) Ghrelin receptors are expressed by distal tubules of the mouse kidney. Cell Tissue Res 346:135–139

    Article  PubMed  CAS  Google Scholar 

  50. Kemp BA, Howell NL, Gray JT, Keller SR, Nass RM, Padia SH (2011) Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats. Hypertension 57:633–639

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Hajime Suzuki, Akihiro Asakawa, Haruka Amitani & Akio Inui

  2. Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan

    Hajime Suzuki & Norifumi Nakamura

Authors
  1. Hajime Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihiro Asakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haruka Amitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norifumi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akio Inui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akio Inui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suzuki, H., Asakawa, A., Amitani, H. et al. Ghrelin and cachexia in chronic kidney disease. Pediatr Nephrol 28, 521–526 (2013). https://doi.org/10.1007/s00467-012-2241-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-012-2241-6

Keywords

Search

Navigation