Genes & Nutrition

, Volume 8, Issue 6, pp 611–621

Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients

  • Richa Sharma
  • Suraksha Agrawal
  • Anita Saxena
  • Manmohan Pandey
  • R. K. Sharma
Research Paper


Malnutrition inflammation syndrome (MIS) is common among ESRD patients. In the present study, we have investigated the association of genetic markers associated with appetite and energy regulation with malnutrition inflammation syndrome among end-stage renal disease (ESRD) patients. Two hundred and fifty-seven patients on maintenance hemodialysis and 200 normal healthy controls were included in the study. Nutritional assessment was done by subjective global assessment scores (SGA). Genotyping of leptin-2548 G/A (rs7799039), ghrelin Leu72Met (rs696217-408 C/A), Arg51Gln (rs34911341-346 G/A) and uncoupling protein 2 (UCP2) 45 bp insertion deletion was done using PCR–RFLP. Levels of leptin and acyl ghrelin were assessed using ELISA. Leptin-2548 AA genotype was associated with twofold higher risk of disease susceptibility while UCP2 insertion–deletion heterozygotes showed protective effect. Ghrelin Gln51Gln and Met72Met genotype were associated with 3.4- and 2.5-fold higher disease susceptibility. The Met72 and Gln51 allele showed 3.3- and 2.1-fold higher susceptibility to malnutrition in severe SGA group. Further, the levels of acyl ghrelin were significantly less in severe category of malnutrition and in poor appetite group. On combined analysis, the group 2 (presence of 3–4 risk alleles) showed 1.5- and twofold higher susceptibility to disease and malnutrition, respectively. On docking analysis, it was observed that higher receptor binding energy was associated with the mutant form of ghrelin (Gln51). Moderate and severe SGA were associated with 2.2- and 4.1-fold higher death hazard. Our study suggests that ghrelin may be major marker contributing to susceptibility to MIS among ESRD patients.


End-stage renal disease Malnutrition inflammation syndrome Leptin Ghrelin UCP2 

Supplementary material

12263_2013_353_MOESM1_ESM.docx (37 kb)
Supplementary material 1 (DOCX 37 kb)


  1. (1996) Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. Canada-USA (CANUSA) Peritoneal Dialysis Study Group. J Am Soc Nephrol 198–207Google Scholar
  2. Atamer A, Alisir Ecder S, Akkus Z, Kocyigit Y, Atamer Y, Ilhan N, Ecder T (2008) Relationship between leptin, insulin resistance, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with chronic kidney disease. J Int Med Res 36:522–528CrossRefPubMedGoogle Scholar
  3. Auwerx J, Staels B (1998) Leptin. Lancet 351:737–742. doi:10.1016/S0140-6736(97)06348-4 CrossRefPubMedGoogle Scholar
  4. Avesani CM, Kamimura MA, Utaka S, Pecoits-Filho R, Nordfors L, Stenvinkel P, Lindholm B, Draibe SA, Cuppari L (2008) Is UCP2 gene polymorphism associated with decreased resting energy expenditure in nondialyzed chronic kidney disease patients? J Ren Nutr 18:489–494. doi:10.1053/j.jrn.2008.08.009 CrossRefPubMedGoogle Scholar
  5. Bartella V, Cascio S, Fiorio E, Auriemma A, Russo A, Surmacz E (2008) Insulin-dependent leptin expression in breast cancer cells. Cancer Res 68:4919–4927. doi:10.1158/0008-5472.CAN-08-0642 CrossRefPubMedGoogle Scholar
  6. Blumenkrantz MJ, Kopple JD, Gutman RA, Chan YK, Barbour GL, Roberts C, Shen FH, Gandhi VC, Tucker CT, Curtis FK, Coburn JW (1980) Methods for assessing nutritional status of patients with renal failure. Am J Clin Nutr 33:1567–1585PubMedGoogle Scholar
  7. Bossola M, Giungi S, Luciani G, Tazza L (2009) Appetite in chronic hemodialysis patients: a longitudinal study. J Ren Nutr 19:372–379. doi:10.1053/j.jrn.2009.01.015 CrossRefPubMedGoogle Scholar
  8. Caliskan Y, Yelken B, Gorgulu N, Ozkok A, Yazici H, Telci A, Turkmen A, Yildiz A, Sever MS (2012) Comparison of markers of appetite and inflammation between hemodialysis patients with and without failed renal transplants. J Ren Nutr 22:258–267. doi:10.1053/j.jrn.2011.07.005 CrossRefPubMedGoogle Scholar
  9. 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. doi:10.1038/ki.2010.487 CrossRefPubMedGoogle Scholar
  10. Carrero JJ, Stenvinkel P, Cuppari L, Ikizler TA, Kalantar-Zadeh K, Kaysen G, Mitch WE, Price SR, Wanner C, Wang AY, Ter Wee P, Franch HA (2013) Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the international society of renal nutrition and metabolism (ISRNM). J Ren Nutr 23:77–90. doi:10.1053/j.jrn.2013.01.001 CrossRefPubMedGoogle Scholar
  11. Cassell PG, Neverova M, Janmohamed S, Uwakwe N, Qureshi A, McCarthy MI, Saker PJ, Albon L, Kopelman P, Noonan K, Easlick J, Ramachandran A, Snehalatha C, Pecqueur C, Ricquier D, Warden C, Hitman GA (1999) An uncoupling protein 2 gene variant is associated with a raised body mass index but not type II diabetes. Diabetologia 42:688–692. doi:10.1007/s001250051216 CrossRefPubMedGoogle Scholar
  12. Cheung WW, Mak RH (2010) Ghrelin in chronic kidney disease. Int J Pept 2010. doi:10.1155/2010/567343
  13. Cheung WW, Paik KH, Mak RH (2010) Inflammation and cachexia in chronic kidney disease. Pediatr Nephrol 25:711–724. doi:10.1007/s00467-009-1427-z CrossRefPubMedGoogle Scholar
  14. Chou CC, Bai CH, Tsai SC, Wu MS (2010) Low serum acylated ghrelin levels are associated with the development of cardiovascular disease in hemodialysis patients. Intern Med 49:2057–2064CrossRefPubMedGoogle Scholar
  15. 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. doi:10.1210/en.2007-1046 CrossRefPubMedGoogle Scholar
  16. Gama-Axelsson T, Lindholm B, Barany P, Heimburger O, Stenvinkel P, Qureshi AR (2013) Self-rated appetite as a predictor of mortality in patients with stage 5 chronic kidney disease. J Ren Nutr 23:106–113. doi:10.1053/j.jrn.2012.04.009 CrossRefPubMedGoogle Scholar
  17. Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 97:2152–2157. doi:10.1172/JCI118653 CrossRefPubMedGoogle Scholar
  18. Jequier E, Tappy L (1999) Regulation of body weight in humans. Physiol Rev 79:451–480PubMedGoogle Scholar
  19. Julienne CM, Dumas JF, Goupille C, Pinault M, Berri C, Collin A, Tesseraud S, Couet C, Servais S (2012) Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency. J Cachexia Sarcopenia Muscle. doi:10.1007/s13539-012-0071-9
  20. Mak RH, Cheung WW, Zhan JY, Shen Q, Foster BJ (2012) Cachexia and protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol 27:173–181. doi:10.1007/s00467-011-1765-5 CrossRefPubMedGoogle Scholar
  21. Mitch WE (2002) Malnutrition: a frequent misdiagnosis for hemodialysis patients. J Clin Invest 110:437–439. doi:10.1172/JCI16494 PubMedGoogle Scholar
  22. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K (2001) Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 104:2034–2038CrossRefPubMedGoogle Scholar
  23. Nordfors L, Lonnqvist F, Heimburger O, Danielsson A, Schalling M, Stenvinkel P (1998) Low leptin gene expression and hyperleptinemia in chronic renal failure. Kidney Int 54:1267–1275. doi:10.1046/j.1523-1755.1998.00088.x CrossRefPubMedGoogle Scholar
  24. Nordfors L, Heimburger O, Lonnqvist F, Lindholm B, Helmrich J, Schalling M, Stenvinkel P (2000) Fat tissue accumulation during peritoneal dialysis is associated with a polymorphism in uncoupling protein 2. Kidney Int 57:1713–1719. doi:10.1046/j.1523-1755.2000.00016.x CrossRefPubMedGoogle Scholar
  25. Okpechi IG, Rayner BL, van der Merwe L, Mayosi BM, Adeyemo A, Tiffin N, Ramesar R (2010) Genetic variation at selected SNPs in the leptin gene and association of alleles with markers of kidney disease in a Xhosa population of South Africa. PLoS ONE 5:e9086. doi:10.1371/journal.pone.0009086 CrossRefPubMedGoogle Scholar
  26. Oner-Iyidogan Y, Gurdol F, Kocak H, Oner P, Cetinalp-Demircan P, Caliskan Y, Kocak T, Turkmen A (2011) Appetite-regulating hormones in chronic kidney disease patients. J Ren Nutr 21:316–321. doi:10.1053/j.jrn.2010.07.005 CrossRefPubMedGoogle Scholar
  27. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107:499–511CrossRefPubMedGoogle Scholar
  28. Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S, Ricquier D, Bouillaud F, Miroux B (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem 276:8705–8712. doi:10.1074/jbc.M006938200 CrossRefPubMedGoogle Scholar
  29. Pedersen SB, Nyholm B, Kristensen K, Nielsen MF, Schmitz O, Richelsen B (2005) Increased adiposity and reduced adipose tissue mRNA expression of uncoupling protein-2 in first-degree relatives of type 2 diabetic patients: evidence for insulin stimulation of UCP-2 and UCP-3 gene expression in adipose tissue. Diabetes Obes Metab 7:98–105. doi:10.1111/j.1463-1326.2005.00365.x CrossRefPubMedGoogle Scholar
  30. 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. doi:10.1093/ndt/gfh313 CrossRefPubMedGoogle Scholar
  31. Poykko S, Ukkola O, Kauma H, Savolainen MJ, Kesaniemi YA (2003) Ghrelin Arg51Gln mutation is a risk factor for type 2 diabetes and hypertension in a random sample of middle-aged subjects. Diabetologia 46:455–458. doi:10.1007/s00125-003-1058-z PubMedGoogle Scholar
  32. Sali A, Potterton L, Yuan F, van Vlijmen H, Karplus M (1995) Evaluation of comparative protein modeling by MODELLER. Proteins 23:318–326. doi:10.1002/prot.340230306 CrossRefPubMedGoogle Scholar
  33. Scholze A, Rattensperger D, Zidek W, Tepel M (2007) Low serum leptin predicts mortality in patients with chronic kidney disease stage 5. Obesity (Silver Spring) 15:1617–1622. doi:10.1038/oby.2007.191 CrossRefGoogle Scholar
  34. Schrauwen P, Hesselink M (2002) UCP2 and UCP3 in muscle controlling body metabolism. J Exp Biol 205:2275–2285PubMedGoogle Scholar
  35. Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR (2005) Variants in the ghrelin gene are associated with metabolic syndrome in the old order Amish. J Clin Endocrinol Metab 90:6672–6677. doi:10.1210/jc.2005-0549 CrossRefPubMedGoogle Scholar
  36. Tracey KJ, Lowry SF, Cerami A (1988) Cachetin/TNF-alpha in septic shock and septic adult respiratory distress syndrome. Am Rev Respir Dis 138:1377–1379CrossRefPubMedGoogle Scholar
  37. Ukkola O, Kesaniemi YA (2003) Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. J Intern Med 254:391–394CrossRefPubMedGoogle Scholar
  38. Walder K, Norman RA, Hanson RL, Schrauwen P, Neverova M, Jenkinson CP, Easlick J, Warden CH, Pecqueur C, Raimbault S, Ricquier D, Silver MH, Shuldiner AR, Solanes G, Lowell BB, Chung WK, Leibel RL, Pratley R, Ravussin E (1998) Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. Hum Mol Genet 7:1431–1435CrossRefPubMedGoogle Scholar
  39. Wang X, Axelsson J, Nordfors L, Qureshi AR, Avesani C, Barany P, Schalling M, Heimburger O, Lindholm B, Stenvinkel P (2007) Changes in fat mass after initiation of maintenance dialysis is influenced by the uncoupling protein 2 exon 8 insertion/deletion polymorphism. Nephrol Dial Transplant 22:196–202. doi:10.1093/ndt/gfl504 CrossRefPubMedGoogle Scholar
  40. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992CrossRefPubMedGoogle Scholar
  41. Wu R, Dong W, Cui X, Zhou M, Simms HH, Ravikumar TS, Wang P (2007) Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Ann Surg 245:480–486. doi:10.1097/01.sla.0000251614.42290 CrossRefPubMedGoogle Scholar
  42. 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. doi:10.1681/ASN.2005010039 CrossRefPubMedGoogle Scholar
  43. 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 13:2748–2752CrossRefPubMedGoogle Scholar
  44. Young GA, Woodrow G, Kendall S, Oldroyd B, Turney JH, Brownjohn AM, Smith MA (1997) Increased plasma leptin/fat ratio in patients with chronic renal failure: a cause of malnutrition? Nephrol Dial Transplant 12:2318–2323CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Richa Sharma
    • 1
  • Suraksha Agrawal
    • 2
  • Anita Saxena
    • 1
  • Manmohan Pandey
    • 3
  • R. K. Sharma
    • 1
  1. 1.Department of NephrologySanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS)LucknowIndia
  2. 2.Department of Medical GeneticsSGPGIMSLucknowIndia
  3. 3.School of Telemedicine and Biomedical InformaticsSGPGIMSLucknowIndia

Personalised recommendations