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Energy homeostasis and cachexia in chronic kidney disease

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Abstract

Loss of protein stores, presenting as clinical wasting, is reported to have a prevalence of 30–60% and is an important risk factor for mortality in chronic kidney disease (CKD) patients. There is debate as to whether the clinical wasting in CKD patients represents malnutrition or cachexia. Malnutrition results from inadequate intake of nutrients, despite a good appetite, and manifests as weight loss associated with adaptive metabolic responses such as decreased basic metabolic rate and preservation of lean body mass at the expense of fat mass. Furthermore, the abnormalities in malnutrition can usually be overcome simply by supplying more food or altering the composition of the diet. In contrast, cachexia is characterized by maladaptive responses such as anorexia, elevated basic metabolic rate, wasting of lean body tissue, and underutilization of fat tissue for energy. Diet supplementation and intradialytic parenteral nutrition have not been successful in reversing cachexia in CKD. The etiology of cachexia in CKD is complex and multifactorial. Two major factors causing muscle wasting in uremia are acidosis and decreased insulin responses. Inflammation secondary to cytokines may also play a significant role. The hypoalbuminemia of CKD patients is principally associated with inflammation and not changes in food intake. There is also recent evidence that hypothalamic neuropeptides may be important in the downstream signaling of cytokines in the pathogenesis of cachexia in CKD. Elevated circulating levels of cytokines, such as leptin, may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system. Further research into the molecular pathways leading to cachexia may lead to novel therapeutic therapy for this devastating and potentially fatal complication of CKD.

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References

  1. Lowrie EG, Lew NL (1990) Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458–482

    CAS  PubMed  Google Scholar 

  2. Gruppen MP, Groothoff JW, Prins M, van der Wouw P, Offringa M, Bos WJ, Davin JC, Heymans HS (2003) Cardiac disease in young adult patients with end-stage renal disease since childhood: a Dutch cohort study. Kidney Int 63:1058–1065

    PubMed  Google Scholar 

  3. Mitch WE (2002) Malnutrition: a frequent misdiagnosis for hemodialysis patients. J Clin Invest 1104:437–439

    Google Scholar 

  4. Inagaki J, Rodriguez V, Bodey GP (1974) Causes of death in cancer patients. Cancer 33:568–571

    CAS  PubMed  Google Scholar 

  5. Suttmann U, Ockenga J, Selberg O, Hoogestraat L, Deicher H, Muller MJ (1995) Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol 8:239–246

    CAS  PubMed  Google Scholar 

  6. Windsor JA, Hill GI (1988) Risk factors for postoperative pneumonia. The importance of protein depletion. Arch Surg 208:209–217

    CAS  Google Scholar 

  7. Utaka S, Avesani CM, Draibe SA, Kamimura SA, Andreoni S, Cuppari L (2005) Inflammation is associated with increased energy expenditure in patients with chronic kidney disease. Am J Clin Nutr 82:801–805

    CAS  PubMed  Google Scholar 

  8. Wang AY, Sea MM, Tang N, Sanderson JE, Lui SF, Li PK, Woo J (2004) Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients. J Am Soc Nephrol 15:3134–3143

    PubMed  Google Scholar 

  9. Tisdale MJ (2005) Molecular pathways leading to cancer cachexia. Physiology 20:340–348

    CAS  PubMed  Google Scholar 

  10. Loprinzi CL, Schaid DJ, Dose AM, Durnham NL, Jensen MD (1993) Body composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol 11:152–154

    CAS  PubMed  Google Scholar 

  11. 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

    CAS  PubMed  Google Scholar 

  12. Kaysen GA, Dubin JA, Muller HG, Rosales L, Levin NW, Mitch WE; HEMO Study Group (2004) Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int 65:1408–1415

    CAS  PubMed  Google Scholar 

  13. Wong CS, Gipson DS, Gillen DL, Emerson S, Koepsell T, Sherrard DJ, Watkins SL, Stehman-Breen C (2000) Anthropometric measures and risk of death in children with end-stage renal disease. Am J Kidney Dis 36:811–819

    CAS  PubMed  Google Scholar 

  14. Sarnak MJ, Levey AS (2000) Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 35(4 Suppl 1):S117–S131

    CAS  PubMed  Google Scholar 

  15. Kaysen G (2004) Inflammation: cause of vascular disease and malnutrition in dialysis patients. Semin Nephrol 24:431–436

    CAS  PubMed  Google Scholar 

  16. Lofberg E, Wernerman J, Anderstam B, Bergstrom J (1997) Correction of acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle. Clin Nephrol 48:230–237

    CAS  PubMed  Google Scholar 

  17. Boirie Y, Broyer M, Gagnadoux MF, Niaudet P, Bresson JL (2000) Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int 58:236–241

    CAS  PubMed  Google Scholar 

  18. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Bossola M, Muscaritoli M, Costelli P, Nanni G, Tazza L, Panocchia N, Busquets S, Argiles J, Lopez-Soriano FJ, Grieco G, Baccino FM, Rossi Fanelli F, Castagneto M, Luciani G (2002) Muscle ubiquitin m-RNA levels in patients with end-stage renal disease on maintenance hemodialysis. J Nephrol 5:527–552

    Google Scholar 

  20. Pickering WP, Price SR, Bircher G, Marinovic AC, Mitch WE, Walls J (2002) Nutrition in CAPD: serum bicarbonate and the ubiquitin-proteasome system in muscle. Kidney Int 61:1286–1292

    CAS  PubMed  Google Scholar 

  21. Mak RH, Cheung W, Cone RD, Marks DL (2006) Melanocortin signaling in uremic cachexia: basis for a novel therapeutic strategy. Nat Clin Pract Nephrol (in press)

  22. Reeds PJ, Field CR, Jahoon F (1994) Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states. J Nutr 124:906–910

    CAS  PubMed  Google Scholar 

  23. Mak RHK (1998) Insulin, branched-chain amino acids, and growth failure in uremia. Pediatr Nephrol 12:637–642

    CAS  PubMed  Google Scholar 

  24. Du J, Hu Z, Mitch WE (2005) Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions. Eur J Clin Invest 35:157–163

    CAS  PubMed  Google Scholar 

  25. Fong Y, Moldawer LL, Marano M, Wei H, Barber A, Manogue K, Tracey KJ, Kuo G, Fischman DA, Cerami A, Lowry S (1989) Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 256(3 Pt 2):R659–R665

    CAS  PubMed  Google Scholar 

  26. Plata-Salaman CR, Sonti G, Borkoski JP, Wilson CD, French-Mullen JM (1996) Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol Behav 60:867–875

    CAS  PubMed  Google Scholar 

  27. Sherry BA, Gelin J, Fong Y, Marano M, Wei H, Cerami A, Lowry SF, Lundholm KG, Moldawer LL (1989) Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J 3:1956–1962

    CAS  PubMed  Google Scholar 

  28. Matthys P, Heremans H, Opdenakker G, Billiau A (1991) Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur J Cancer 27:182–187

    CAS  PubMed  Google Scholar 

  29. Strassman G, Kambayashi T (1995) Inhibition of experimental cancer cachexia by anticytokine and anticytokine-receptor therapy. Cytokines Mol Ther 1:107–113

    Google Scholar 

  30. Kawamura I, Morishita R, Tomita N, Lacey E, Aketa M, Tsujimoto S, Manda T, Tomoi M, Kida I, Higaki J, Kaneda Y, Shimomura K, Ogihara T (1999) Intratumoral injection of oligonucleotides to the NF kappa B binding site inhibits cachexia in a mouse tumor model. Gene Ther 6:91–97

    CAS  PubMed  Google Scholar 

  31. Costelli P, Bossola M, Muscaritoli M, Grieco G, Bonelli G, Bellantone R, Doglietto GB, Baccino FM, Rossi Fanelli F (2002) Anticytokine treatment prevents the increase in activity of ATP-ubiquitin and Ca2+-dependent proteolytic systems in the muscle of tumour-bearing rats. Cytokine 19:1–5

    CAS  PubMed  Google Scholar 

  32. Mamoun AH, Soderstein P, Anderstam B, Bergstrom J (1999) Evidence of splanchnic-brain signaling in inhibition of ingestive behavior by middle molecules. J Am Soc Nephrol 10:309–314

    CAS  PubMed  Google Scholar 

  33. Espat NJ, Copeland EM, Moldwar LL (1994) Tumor necrosis factor and cachexia: a current prospective. Surg Oncol 3:255–262

    CAS  PubMed  Google Scholar 

  34. McCarthy DO (2000) Cytokines and the anorexia of infection: potential mechanism and treatments. Biol Res Nurs 1:287–298

    CAS  PubMed  Google Scholar 

  35. McCarthy DO (2000) Tumor necrosis factor alpha and interleukin-6 have differential effects on food intake and gastric emptying in fasted rats. Res Nurs Health 23:222–228

    CAS  PubMed  Google Scholar 

  36. Kalantar-Zadeh K, Glock G, McAlister CJ, Humphreys MH, Kopple JD (2004) Appetite and inflammation, nutrition, anemia and clinical outcome in hemodialysis patients. Am J Clin Nutr 80:299–307

    CAS  PubMed  Google Scholar 

  37. Diaz-Buxo JA, Lowrie EG, Lew NL, Zhang H, Lazarus JM (2000) Quality-of-life evaluation using Short Form 36: comparison in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 35:293–300

    CAS  PubMed  Google Scholar 

  38. Mingardi G (1998) Quality of life and end stage renal disease therapeutic programs. DIA-QOL Group. Dialysis quality of life. Int J Artif Organs 21:741–747

    CAS  PubMed  Google Scholar 

  39. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR (2002) Gut hormone PYY3-36 physiologically inhibits food intake. Nature 418:650–654

    CAS  PubMed  Google Scholar 

  40. Shellock FG, Riedinger MS, Fishbein MC (1986) Brown adipose tissue in cancer patients, possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol 111:82–85

    CAS  PubMed  Google Scholar 

  41. Bing C, Brown M, King P, Collins P, Tisdale MJ, Williams G (2000) Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Cancer Res 60:2405–2410

    CAS  PubMed  Google Scholar 

  42. Collins P, Bing C, McCullock P, Williams G (2002) Muscle UCP-3 mRNA levels are elevated in weight loss associated with gastrointestinal adenocarcinoma in humans. Br J Cancer 86:372–375

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Busquets S, Carbo N, Almendro V, Figueras M, Lopez-Soriano FJ, Argilles JM (2001) Hyperlipidemia: a role in regulating UCP3 gene expression in skeletal muscle during cancer cachexia. FEBS Lett 505:255–258

    CAS  PubMed  Google Scholar 

  44. Pupim LB, Flakoll PJ, Brouillette JR, Levenhagen DK, Hakim RM, Ikizler TA (2002) Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients. J Clin Invest 110:483–492

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kopple JD (1999) Therapeutic approaches to malnutrition in chronic dialysis patients: the different modalities of nutritional support. Am J Kidney Dis 33:180–185

    CAS  PubMed  Google Scholar 

  46. Wolfson M, Foulks CJ (1996) Intradialytic parenteral nutrition: a useful therapy? Nutr Clin Pract 11:5–11

    CAS  PubMed  Google Scholar 

  47. American Society for Parenteral and Enteral Nutrition Board of Directors and the Clinical Guidelines Task Force (2002) Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 26:1SA–138SA

    Google Scholar 

  48. Betts PR, McGrath G (1974) Growth patterns and dietary intake of children with chronic renal insufficiency. Br Med J 2:189–193

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Simmons JM, Wilson CJ, Potter DE, Holliday MA (1971) Relation of calorie deficiency to growth failure in children on hemodialysis and the growth response to calorie supplementation. N Engl J Med 285:653–656

    CAS  PubMed  Google Scholar 

  50. Arnold WC, Danford D, Holliday M (1983) Effect of calorie supplementation on growth in children with uremia. Kidney Int 24:205–209

    CAS  PubMed  Google Scholar 

  51. Walker S, Ledermann S, Trompeter R, Van’t Hoff W, Ridout D, Rees L (2003) Catch-up growth with normal parathyroid hormone levels in chronic renal failure. Pediatr Nephrol 18:1236–1241

    Google Scholar 

  52. Ellis EN, Yiu V, Harley F, Donaldson LA, Hand M, Warady BA, Wood EG; North American Pediatric Renal Transplant Cooperative Study (2001) The impact of supplemental feeding in young children on dialysis: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 16:404–408

    CAS  PubMed  Google Scholar 

  53. Mak RH, Cheung W, Cone RD, Marks DL (2006) Leptin and inflammation-associated cachexia in chronic kidney disease. Kidney Int 69:794–797

    CAS  PubMed  Google Scholar 

  54. Sharma K, Considine RV, Michael B, Dunn SR, Weisberg LS, Kurnik BR, Kurnik PB, O’Connor J, Sinha M, Caro JF (1997) Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patients. Kidney Int 51:1980–1985

    CAS  PubMed  Google Scholar 

  55. Daschner M, Tonshoff B, Blum WF, Englaro P, Wingen AM, Schaefer F, Wuhl E, Rascher W, Mehls O (1998) Inappropriate elevation of serum leptin levels in children with chronic renal failure. European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. J Am Soc Nephrol 9:1074–1079

    CAS  PubMed  Google Scholar 

  56. Perez-Fontan M, Cordido F, Rodriguez-Carmona A, Peteiro J, Garcia-Naveiro R, Garcia-Buela J (2004) Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal dialysis. Nephrol Dial Transplant 19:2095–2100

    CAS  PubMed  Google Scholar 

  57. Rodriguez Ayala E, Pecoits-Filho R, Heimburger 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

    CAS  PubMed  Google Scholar 

  58. Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G, Ghatei MA, Brown EA, Bloom SR, Choi P (2005) Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 16:2111–2118

    CAS  PubMed  Google Scholar 

  59. Marks DL, Ling N, Cone RD (2001) Role of central melanocortin system in cachexia. Cancer Res 61:1432–1438

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics , Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Robert H. Mak & Wai Cheung

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  1. Robert H. Mak
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  2. Wai Cheung
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Correspondence to Robert H. Mak.

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Supported by grants from the National Institute of Health R01 DK 50780 and K24 DK59574 to RHM.

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Mak, R.H., Cheung, W. Energy homeostasis and cachexia in chronic kidney disease. Pediatr Nephrol 21, 1807–1814 (2006). https://doi.org/10.1007/s00467-006-0194-3

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