Pediatric Nephrology

, Volume 22, Issue 10, pp 1751–1756 | Cite as

Hyperinsulinemia in pediatric patients with chronic kidney disease: the role of tumor necrosis factor-α

Original Article


We sought to determine the prevalence of hyperinsulinemia and insulin resistance in pediatric patients with chronic kidney disease (CKD) stages 2–4. Data were collected on 43 subjects, aged 6–21 years with mean glomerular filtration rate (GFR) = 47 ml/min per 1.73 m2 body surface area. Patients were grouped by body mass index (BMI) as either non-lean (>85th percentile) or lean (≤85th percentile). Fourteen (33%) subjects had hyperinsulinemia, and seven (16%) had elevated homeostasis model assessment of insulin resistance (HOMA-IR). Non-lean subjects had a higher serum insulin level (21.0 μU/ml vs 13.4 μU/ml, P < 0.0001) and HOMA-IR (4.9 vs 3.2, P < 0.001) than lean subjects had. The prevalence of hyperinsulinemia was higher in non-lean patients (40%) than in lean patients (29%) but was not statistically significant. High HOMA-IR was present in six (40%) non-lean subjects and in one lean subject (P < 0.001). Correlation analysis demonstrated that serum insulin level was significantly associated with BMI, leptin and tumor necrosis factor (TNF)-α. Stepwise regression determined that increased BMI (P = 0.003) and TNF-α (P = 0.01) independently predicted higher insulin level in the whole cohort. Separate analysis for lean subjects showed no significant associations between serum insulin level and BMI; TNF-α was the only independent predictor of serum insulin (β = 1.11, P = 0.01). We conclude that hyperinsulinemia and insulin resistance are frequent in pediatric CKD. In lean patients inflammation appears to be an important determinant of serum insulin level.


TNF-α Children Pediatric Chronic kidney disease Hyperinsulinemia Insulin resistance 





chronic kidney disease


glomerular filtration rate


tumor necrosis factor-α


high-sensitivity C-reactive protein




body mass index


systolic blood pressure


diastolic blood pressure


homeostasis model assessment of insulin resistance


nuclear factor κB


insulin receptor substrate-1


  1. 1.
    Sechi LA, Catena C, Zingaro L, Melis A, De Marchi S (2002) Abnormalities of glucose metabolism in patients with early renal failure. Diabetes 51:1226–1232PubMedCrossRefGoogle Scholar
  2. 2.
    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 ESRD. J Am Soc Nephrol 13:1894–2000PubMedCrossRefGoogle Scholar
  3. 3.
    Knight EL, Rimm EB, Pai JK, Rexrode KM, Cannuscio CC, Manson JE, Stampfer MJ, Curhan GC (2004) Kidney dysfunction, inflammation and coronary events: a prospective study. J Am Soc Nephrol 15:1897–1903PubMedCrossRefGoogle Scholar
  4. 4.
    Chen J, Muntner P, Hamm LL, Fonseca V, Batuman V, Whelton PK, He J (2003) Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 14:469–77PubMedCrossRefGoogle Scholar
  5. 5.
    Mak RH (1995) Insulin secretion and growth failure in uremia. Pediatr Res 38:378–383Google Scholar
  6. 6.
    El-Bishti M, Counahan R, Jarrett RJ (1977) Hyperlipidemia in children on regular hemodialysis. Arch Dis Child 15:932–936Google Scholar
  7. 7.
    Parra A, Lopez-Uriarte A, Argote RM, Garcia G, Ledon S, Santos D (1979) Effect of hemodialysis on glucose tolerance in children with chronic renal failure. Arch Invest Med (Mex) 10:39–52Google Scholar
  8. 8.
    Buyan N, Bideci A, Ozkaya O, Ortac E, Bakkaloglu S, Gonen S, Peru H, Soylemezoglu O, Cinaz P (2006) Leptin and resistin levels and their relationships with glucose metabolism in children with chronic renal insufficiency and undergoing dialysis. Nephrology 11:192–196PubMedCrossRefGoogle Scholar
  9. 9.
    Shishido S, Sato H, Asanuma H, Shindo M, Hataya H, Ishikura K, Hamasaki Y, Goto M, Ikeda M, Honda M (2006) Unexpectedly high prevalence of pretransplant abnormal glucose tolerance in pediatric kidney transplant recipients. Pediatr Transplant 10:1–4CrossRefGoogle Scholar
  10. 10.
    Haffner D, Nissel R, Wuhl E, Schaefer F, Bettendorf M, Tonshoff B, Mehls O (1998) Metabolic effects of long-term growth hormone treatment in prepubertal children with chronic renal failure and after kidney transplantation. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. Pediatr Res 43:209–215PubMedCrossRefGoogle Scholar
  11. 11.
    Stake G, Monclair T (1991) A single plasma sample method for estimation of the glomerular filtration rate in infants and children using iohexol: establishment of a body weight-related formula for the distribution volume of iohexol. Scand J Clin Lab Invest 51:335–342PubMedGoogle Scholar
  12. 12.
    Schwartz GJ, Gauthier B (1985) A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 106:522–526PubMedCrossRefGoogle Scholar
  13. 13.
    Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374PubMedCrossRefGoogle Scholar
  14. 14.
    Lee JM, Okumura MJ, Davis MM, Herman WH, Gurney JG (2006) Prevalence and determinants of insulin resistance among US adolescents: a population-based study. Diabetes Care 29:2427–2432PubMedCrossRefGoogle Scholar
  15. 15.
    Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD (2003) Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int 63:793–808PubMedCrossRefGoogle Scholar
  16. 16.
    Santoro A, Mancini E (2002) Cardiac effects of chronic inflammation in dialysis patients. Nephrol Dial Transplant 17 [Suppl 8]:10–15PubMedCrossRefGoogle Scholar
  17. 17.
    Churchill DN, Taylor W, Keshaviah PR (1996) Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. CANUSA Peritoneal Dialysis Study Group. J Am Soc Nephrol 7:198–207Google Scholar
  18. 18.
    Kaysen GA (2006) Association between inflammation and malnutrition as risk factors of cardiovascular disease. Blood Purif 25:51–55CrossRefGoogle Scholar
  19. 19.
    Kaysen GA (2001) The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 12:1549–1557PubMedGoogle Scholar
  20. 20.
    Steinvenkel P, Ketteler M, Johnson RJ (2005) IL-10, IL-6, and TNF-α: central factors in the altered cytokine network of uremia—the good, the bad, the ugly. Kidney Int 67:1216–1223CrossRefGoogle Scholar
  21. 21.
    Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J (2004) Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 65:1009–1016PubMedCrossRefGoogle Scholar
  22. 22.
    Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA (1994) Plasma levels of IL-1β, TNF-α and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45:890–896PubMedCrossRefGoogle Scholar
  23. 23.
    Witko-Sarsat V, Friedlander M, Nguyen Khoa T, Capeillere-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drueke T, Descamps-Latscha B (1998) Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161:2524–2532PubMedGoogle Scholar
  24. 24.
    Ceballos-Picot I, Witko-Sarsat V, Berad-Boudia M, Nguyen AT, Thévenin M, Jaudon MC, Zingraff J, Verger C, Jungers P, Descamps-Latscha B (1996) Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Rad Biol Med 21:845–853PubMedCrossRefGoogle Scholar
  25. 25.
    Guarnieri G, Antonione R, Biolo G (2003) Mechanisms of malnutrition in uremia. J Ren Nutr 13:153–157PubMedCrossRefGoogle Scholar
  26. 26.
    Reid MB, Li YP (2001) Tumor necrosis factor-α and muscle wasting: a cellular perspective. Respir Res 2:269–272PubMedCrossRefGoogle Scholar
  27. 27.
    Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr (2000) NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289:2363–2366PubMedCrossRefGoogle Scholar
  28. 28.
    Li YP, Reid MB (2000) NF-κB mediates the protein loss induced by TNF-α in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 279:R1165–R1170PubMedGoogle Scholar
  29. 29.
    Li Y, Schwartz RJ, Waddell ID, Holloway BR, Reid MB (1998) Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated KF-κB activation in response to tumor necrosis factor α. FASEB J 12:871–880PubMedGoogle Scholar
  30. 30.
    Sen CK, Khanna S, Reznick AZ, Roy S, Packer L (1997) Glutathione regulation of tumor necrosis factor α-induced NF-κB activation in skeletal muscle-derived L6 cells. Biochem Biophys Res Com 237:645–649PubMedCrossRefGoogle Scholar
  31. 31.
    Buck M, Chojkier M (1996) Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 15:1753–1765PubMedGoogle Scholar
  32. 32.
    Brenner DA, Buck M, Feitelberg SP, Chojkier M (1990) Tumor necrosis factor-α inhibits albumin gene expression in a murine model of cachexia. J Clin Invest 85:248–255PubMedGoogle Scholar
  33. 33.
    Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) Reduced tyrosine kinase activity of insulin receptor in obesity-diabetes: central role of tumor necrosis factor-α. J Clin Invest 94:1543–1549PubMedCrossRefGoogle Scholar
  34. 34.
    Cheung AT, Ree D, Kolls JK, Feselier J, Coy DH, Breyer-Ash M (1998) An in vivo model for elucidation of the mechanism of tumor necrosis facto- α (TNF-α) induced insulin resistance: evidence for differential regulation of insulin signalling by TNF-α. Endocrinology 139:4928–4935PubMedCrossRefGoogle Scholar
  35. 35.
    Breder CD, Hazuka C, Ghayur T, Klug C, Huginin M, Yasuda K, Teng M, Saper CB (1994) Regional induction of tumor necrosis factor α expression in the mouse brain after systemic lipopolysaccharide administration. Proc Natl Acad Sci USA 91:11393–11397PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2007

Authors and Affiliations

  1. 1.Division of Nephrology and HypertensionCincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations