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Mechanisms of Disease: cytokine and adipokine signaling in uremic cachexia

Nature Clinical Practice Nephrology volume 2, pages 527–534 (2006)Cite this article

Abstract

Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30–60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome—more accurately described as 'cachexia'—manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-α, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.

Key Points

  • The prevalence of clinical wasting—an important risk factor for mortality—in end-stage renal disease is 30–60%

  • Cachexia in uremic patients manifests as anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins

  • The mechanisms through which acidosis and inflammation cause uremic cachexia are not well understood

  • New data indicate that circulating cytokines—levels of which are increased in end-stage renal disease—and other energy-modulating hormones might act on the hypothalamic melanocortin system in the pathogenesis of uremic cachexia

  • Antagonists of melanocortin receptors can ameliorate experimental cachexia

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Figure 1: Control of energy homeostasis by peripheral hormones and their central signaling pathways.

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Acknowledgements

This work was supported by grants, R01 DK 50780 and K24 DK 59475 to RHM and K08 DK 62207 to DLM, from the NIH.

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Authors and Affiliations

  1. Professor of Pediatrics,

    Robert H Mak, Wai Cheung & Daniel L Marks

  2. postdoctoral fellow,

    Robert H Mak, Wai Cheung & Daniel L Marks

  3. pediatric endocrinologist in the Department of Pediatrics at Oregon Health and Science University, Portland, Oregon, USA

    Robert H Mak, Wai Cheung & Daniel L Marks

  4. senior scientist at the Vollum Institute at Oregon Health and Science University,

    Roger D Cone

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Correspondence to Robert H Mak.

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Mak, R., Cheung, W., Cone, R. et al. Mechanisms of Disease: cytokine and adipokine signaling in uremic cachexia. Nat Rev Nephrol 2, 527–534 (2006). https://doi.org/10.1038/ncpneph0273

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