Pediatric Nephrology

, Volume 25, Issue 8, pp 1445–1451 | Cite as

Normal-range albuminuria does not exclude nephropathy in diabetic children

  • Jacek Zachwieja
  • Jolanta Soltysiak
  • Piotr Fichna
  • Katarzyna Lipkowska
  • Witold Stankiewicz
  • Bogda Skowronska
  • Pawel Kroll
  • Maria Lewandowska-Stachowiak
Original Article


Clinically detectable diabetic nephropathy (DN) begins with the development of microalbuminuria (MA). However, early renal dysfunction may be overlooked despite using that method. On the other hand, the gold standard in DN detection—that is, renal biopsy—is highly invasive. The aim of this study was to evaluate the level of neutrophil-gelatinase-associated lipocalin (NGAL) and interleukin (IL)-18 and their relations to albumin excretion rate (AER) in children with normal-range albuminuria, e.g. in those considered as not presenting diabetic nephropathy. The study group consisted of 22 children (age 12.7 ± 3.5 years) with type 1 diabetes mellitus (T1DM). Long-term glycemic control was assessed on hemoglobin A1c (HbA1c) levels (8.52 ± 1.78%). All patients presented normal estimated glomerular filtration rate (eGFR) (141 ± 23 ml/min/1.73 m2) and normal urinary albumin excretion (13.09 ± 7.63 mg/24 h). Fourteen healthy children served as a control group. Children with T1DM showed increased NGAL values with respect to controls—interestingly, both in serum (sNGAL) (867.43 ± 341.98 vs. 655.29 ± 196.17 ng/ml; p = 0.04) and in urine (uNGAL) (420.04 ± 374.16 vs. 156.53 ± 185.18 ng/ml, p = 0.04). IL-18 levels were not different in both groups both in serum (58.52 ± 20.11 vs. 69.79 ± 58.76 ng/ml; NS) and in urine (14.53 ± 12.74 vs. 14.60 ± 10.92 ng/ml; NS). Despite the relatively small study group, the positive correlation between sNGAL and AER was found [AER (mg/24 h) = 3.1893 + 0.01141 × sNGAL (ng/ml); r = 0.51; p = 0.014] as well as between uNGAL and AER [AER (mg/24 h) = 8.7538 + 0.01032 × uNGAL (ng/ml); r = 0.51; p = 0.016]. No relationship between sNGAL and uNGAL, and GFR and HbA1c were found. Normal-range albuminuria does not exclude diabetic nephropathy defined as increased sNGAL and uNGAL concentration. NGAL measurement can be more sensitive than MA and may become a useful tool for evaluating renal involvement in diabetic children.


Diabetic nephropathy Biomarkers NGAL IL-18 Children 



We thank Mrs. Milena Kornaszewska for her linguistic assistance and Marek Niedziela M.D., Ph.D for his kind contribution to improvement of our discussion.


  1. 1.
    Daneman D (2006) Type 1 diabetes. Lancet 367:847–858CrossRefPubMedGoogle Scholar
  2. 2.
    DIAMOND Project Group (2006) Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabet Med 23:857–866CrossRefGoogle Scholar
  3. 3.
    Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T (1983) Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25:496–501CrossRefPubMedGoogle Scholar
  4. 4.
    Ballard DJ, Humphrey LL, Melton LJ 3rd, Frohnert PP, Chu PC, O’Fallon WM, Palumbo PJ (1988) Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota. Diabetes 37:405–412CrossRefPubMedGoogle Scholar
  5. 5.
    Rossing P, Hougaard P, Borch-Johnsen K, Parving HH (1996) Predictors of mortality in insulin dependent diabetes: 10 years observational follow up study. BMJ 313:779–784PubMedGoogle Scholar
  6. 6.
    Harvey JN, Allagoa B (2004) The long-term renal and retinal outcome of childhood-onset type 1 diabetes. Diabet Med 21:26–31CrossRefPubMedGoogle Scholar
  7. 7.
    Raile K, Galler A, Hofer S, Herbst A, Dunstheimer D, Busch P, Holl RW (2007) Diabetic nephropathy in 27, 805 children, adolescents and adults with type 1 diabetes: effect of diabetes duration, HbA1c, hypertension, dyslipidemia, diabetes onset and gender. Diabetes Care 30:2523–2528CrossRefPubMedGoogle Scholar
  8. 8.
    Thomas MC, Burns WC, Cooper ME (2005) Tubular changes in early diabetic nephropathy. Adv Chronic Kidney Dis 12:177–186CrossRefPubMedGoogle Scholar
  9. 9.
    Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17:2974–2984CrossRefPubMedGoogle Scholar
  10. 10.
    Phillips AO (2003) The role of renal proximal tubular cells in diabetic nephropathy. Curr Diab Rep 3:491–496CrossRefPubMedGoogle Scholar
  11. 11.
    Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q, Dastrala S, Bennett M, Mitsnefes M, Devarajan P (2007) NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol 22:2089–2095CrossRefPubMedGoogle Scholar
  12. 12.
    Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365:1231–1238CrossRefPubMedGoogle Scholar
  13. 13.
    Trachtman H, Christen E, Cnaan A, Patrick J, Mai V, Mishra J, Jain A, Bullington N, Devarajan P, Investigators of the HUS-SYNSORB Pk Multicenter Clinical Trial (2006) Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury. Pediatr Nephrol 21:989–994CrossRefPubMedGoogle Scholar
  14. 14.
    Suzuki M, Wiers KM, Klein-Gitelman MS, Haines KA, Olson J, Onel KB, O’Neil K, Passo MH, Singer NG, Tucker L, Ying J, Devarajan P, Brunner HI (2008) Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis. Pediatr Nephrol 23:403–412CrossRefPubMedGoogle Scholar
  15. 15.
    Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N, Buemi M (2008) Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant 23:414–416CrossRefPubMedGoogle Scholar
  16. 16.
    Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432PubMedGoogle Scholar
  17. 17.
    Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, Buemi M (2008) Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis 52:595–605CrossRefPubMedGoogle Scholar
  18. 18.
    Navarro JF, Mora C (2005) Role of inflammation in diabetic complications. Nephrol Dial Transplant 20:2601–2604CrossRefPubMedGoogle Scholar
  19. 19.
    Lin J, Hu FB, Rimm EB, Rifai N, Curhan GC (2006) The association of serum lipids and inflammatory biomarkers with renal function in men with type II diabetes mellitus. Kidney Int 69:336–342CrossRefPubMedGoogle Scholar
  20. 20.
    Mühl H, Pfeilschifter J (2004) Interleukin-18 bioactivity: a novel target for immunopharmacological anti-inflammatory intervention. Eur J Pharmacol 500:63–71CrossRefPubMedGoogle Scholar
  21. 21.
    Drummond K, Mauer M, International Diabetic Nephropathy Study Group (2002) The early natural history of nephropathy in type 1 diabetes. II. Early renal structural changes in type 1 diabetes. Diabetes 51:1580–1587CrossRefPubMedGoogle Scholar
  22. 22.
    Schultz CJ, Konopelska-Bahu T, Dalton RN, Carroll TA, Stratton I, Gale EA, Neil A, Dunger DB (1999) Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Study Group. Diabetes Care 22:495–502CrossRefPubMedGoogle Scholar
  23. 23.
    Bolignano D, Lacquaniti A, Coppolino G, Donato V, Fazio MR, Nicocia G, Buemi M (2009) Neutrophil gelatinase-associated lipocalin as an early biomarker of nephropathy in diabetic patients. Kidney Blood Press Res 32:91–98CrossRefPubMedGoogle Scholar
  24. 24.
    Araki S, Haneda M, Koya D, Sugimoto T, Isshiki K, Chin-Kanasaki M, Uzu T, Kashiwagi A (2007) Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: an observational follow-up study. Diabetologia 50:867–873CrossRefPubMedGoogle Scholar
  25. 25.
    Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, Binder C, Parving HH (2004) Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 328:1105CrossRefPubMedGoogle Scholar
  26. 26.
    Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS (2003) Regression of microalbuminuria in type 1 diabetes. N Engl J Med 348:2285–2293CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  • Jacek Zachwieja
    • 1
  • Jolanta Soltysiak
    • 1
  • Piotr Fichna
    • 2
  • Katarzyna Lipkowska
    • 1
  • Witold Stankiewicz
    • 2
  • Bogda Skowronska
    • 2
  • Pawel Kroll
    • 3
  • Maria Lewandowska-Stachowiak
    • 1
  1. 1.Department of Pediatric NephrologyPoznan University of Medical SciencesPoznanPoland
  2. 2.Department of Pediatric Endocrinology and DiabetesPoznan University of Medical SciencesPoznanPoland
  3. 3.Department of Pediatric UrologyPoznan University of Medical SciencesPoznanPoland

Personalised recommendations