Neutrophil Gelatinase-Associated Lipocalin: A Biomarker for Early Diagnosis of Urinary Tract Infections in Infants

  • Grażyna Krzemień
  • Małgorzata Pańczyk-Tomaszewska
  • Dominika Adamczuk
  • Iwona Kotuła
  • Urszula Demkow
  • Agnieszka Szmigielska
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1047)


Early diagnosis of urinary tract infection (UTI) is challenging in infants due to unspecific symptoms, difficulty in urine collection and possible contamination. The aim of this study was to assesses the usefulness of serum and urine neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL, respectively) in the diagnosis of febrile and non-febrile UTI in infants. This prospective observational study enrolled 66 infants with the first episode of UTI and 18 healthy controls. At the time of enrollment, sNGAL, uNGAL, urinalysis, urine culture, white blood cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), and serum creatinine (sCr) were assessed. We found that, on average, both sNGAL and uNGAL levels were significantly higher in febrile UTI, compared to non-febrile UTI and controls. In turn, the mean sNGAL level, but not uNGAL, was significantly higher in the non-febrile UTI group compared to controls. sNGAL positively correlated with WBC, CRP, ESR and PCT, and uNGAL with CRP and leukocyturia. The receiver operating curves (ROC) demonstrate that the optimum cut-off of 76.2 ng/ml for sNGAL (sensitivity 92.9%, specificity 94.4%, and the area under the curve (AUC) of 0.98) and of 42.2 ng/ml for uNGAL (sensitivity 73.8%, specificity 72.2%, and AUC of 0.76) for diagnosing febrile UTI and 39.0 ng/ml for sNGAL (sensitivity 83.3%, specificity 55.6%, and AUC of 0.70) for diagnosing non-febrile UTI. In conclusion, serum NGAL is an excellent marker for the early diagnosis of febrile UTI, with sensitivity and specificity higher than those of urine NGAL. Diagnostic sensitivity of serum NGAL is smaller in non-febrile infants suffering from UTI, and urine NGAL is not useful for this purpose at all.


Biomarkers Children Lipocalin Neutrophils Receiver operating curve Urinanalysis Urine culture Urinary tract infection 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.


  1. AAP (2011) American Academy of Pediatrics. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary Tract Infection: Clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 128:595–610Google Scholar
  2. Arambašić J, Mandić S, Debeliak Ž, Mandić D, Horvat V, Šerić V (2016) Differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinase-associated lipocalin (uNGAL). Clin Chem Lab Med 54(10):55–61PubMedGoogle Scholar
  3. Bennett MR, Nehus E, Haffner C, Ma Q, Devarajan P (2015) Pediatric reference ranges for acute kidney injury biomarkers. Pediatr Nephrol 30:677–685CrossRefGoogle Scholar
  4. Cullen MR, Murray PT, Fitzgibbon MC (2012) Estabilishment of a reference interval for urinary neutrophil gelainase-associated lipocalin. Ann Clin Biochem 49:190–193CrossRefGoogle Scholar
  5. Decavele AS, Dhondt L, De Buyzere ML, Delanghe JR (2011) Increased urinary neutrophil gelainase associated lipocalin in urinary tract infections and leukocyturia. Clin Chem Lab Med 49(6):999–1003CrossRefGoogle Scholar
  6. Etoubleau C, Reveret M, Brouet D, Badier L, Brosset P, Fourcade L, Bahans C, Garnier F, Blanc P, Guigonis V (2009) Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures. J Pediatr 154:803–806CrossRefGoogle Scholar
  7. Filho LT, Grande AJ, Colonetti T, Colonetti T, Della ÉSP, da Rosa MI (2017) Accuracy of neutropfil gelatinase-associated lipocalin for acute kidney injury diagnosis in children: systematic review and meta-analysis. Pediatr Nephrol.
  8. Forster CS, Johnson K, Patel V, Wax R, Rodig N, Barasch J, Bachur R, Lee R (2017) Urinary NGAL deficiency in recurrent urinary tract infections. Pediatr Nephrol 32:1077–1080CrossRefGoogle Scholar
  9. Ghasemi K, Esteghamati M, Borzoo S, Parvaneh E, Borzoo S (2016) Predictive accuracy of urinary neutrophil gelatinase associated lipocalin (NGAL) for renal parenchymal involvement in children with acute pyelonephritis. Electron Physician 8:1911–1917CrossRefGoogle Scholar
  10. Hatipoglu S, Sevketoglu E, Gedikbasi A, Ylmaz A, Kiyak A, Mulazimoglu M, Aydogan G, Ozpacaci T (2011) Urinary MMP-9/NGAL complex in children with acute cystitis. Pediatr Nephrol 26:1263–1268CrossRefGoogle Scholar
  11. Ichino M, Kuroyanagi Y, Kusaka M, Mori T, Ishikawa K, Shiroki R, Kurahashi H, Hoshinaga K (2009) Increased urinary neutrophil gelatinase associated lipocalin levels in a rat model of upper urinary tract infection. J Urol 181(5):2326–2331CrossRefGoogle Scholar
  12. Kim BH, Yu N, Kim HR, Yun KW, Lim IS, Kim TH, Lee M-K (2014) Evaluation of the optimal neutrophil gelatinase-associated lipocalin value as a screening biomarker for urinary tract infections in children. Ann Lab Med 34:354–359CrossRefGoogle Scholar
  13. Kim BK, Yim HE, Yoo KH (2017) Plasma neutrophil gelatinase-associated lipocalin: a marker of acute pyelonephritis in children. Pediatr Nephrol 32:477–484CrossRefGoogle Scholar
  14. Krzemień G, Szmigielska A, Artemiuk I, Roszkowska-Blaim M (2014) False positive urine cultures in children under two years of age – own research. Dev Period Med 18(2):172–177Google Scholar
  15. Lee H-E, Lee SH, Baek M, Choi H, Park K (2013) Urinary measurement of neutrophil gelatinase associated lipocalin and kidney injury molecule-1 helps diagnose acute pyelonephritis in a preclinical model. J Biomarkers 2013:6CrossRefGoogle Scholar
  16. Lee H-E, Kim DK, Kang HK, Park K (2015) The diagnosis of febrile urinary tract infection in children may be facilitated by urinary biomarkers. Pediatr Nephrol 30:123–130CrossRefGoogle Scholar
  17. McWilliam SJ, Antoine DJ, Sabbisetti V, Pearce RE, Jorgensen AL, Lin Y, Leeder JS, Bonventre JV, Smyth RL, Primohamed M (2014) Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children. Biomark Med 8:1189–1197CrossRefGoogle Scholar
  18. Nasioudis D, Witkin SS (2015) Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections. Med Microbiol Immunol 204:471–479CrossRefGoogle Scholar
  19. Nickavar A, Safaeian B, Valavi E, Moradpour F (2016) Validity of neutrophil gelatinase associated lipocaline as a biomarker for diagnosis of children with acute pyelonephritis. Pediatr Urol 13(5):2860–2863Google Scholar
  20. Petrovic S, Bogavac-Stanojevic N, Peco-Antic A, Ivanisevic I, Kotur-Stevuljevic J, Paripovic D, Sopic M, Jelic-Ivanovic Z (2013) Clinical application neutrophil-associated lipocalin and kidney injury molecule-1 as indicators of inflammation persistence and acute kidney injury in children with urinary tract infection. Biomed Res Int 2013:947157PubMedPubMedCentralGoogle Scholar
  21. Rafiei A, Mohammadjafari H, Bazi S, Mirabi AM (2015) Urinary neutrophil gelatinase-associated lipocalin (NGAL) might be an independent marker for anticipating scar formation in children with acute pyelonephritis. J Renal Inj Prev 4:39–44PubMedPubMedCentralGoogle Scholar
  22. Readorn JM, Carstairs KL, Rudinsky SL, Simon LV, Riffenburgh RH, Tanen AD (2009) Urinalysis is not reliable to detect a urinary tract infection in febrile infants presenting to the ED. Am J Emerg Med 27:930–932CrossRefGoogle Scholar
  23. Salleeh H, McGillivray D, Martin M, Patel H (2010) Duration of fever affects the likelihood of positive bag urinalysis or catheter culture in young children. J Pediatr 156:629–633CrossRefGoogle Scholar
  24. Seo WH, Nam SW, Lee EH, Je B-K, Yim HE, Choi BM (2014) A rapid plasma neutrophil gelatinase-associted lipocalin assay for diagnosis of acute pyelonephritis in infants with acute febrile urinary tract infections: a preliminary study. Eur J Pediatr 173:229–232CrossRefGoogle Scholar
  25. Sim JH, Yim HE, Choi BM, Lee JH, Yoo KH (2015) Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infection. Pediatr Res 78:48–55CrossRefGoogle Scholar
  26. Singer E, Marko L, Paragas N, Barasch N, Dragun D, Müller DN, Budde K, Schmidt-Ott KM (2013) Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta Physiol 207(4):663–672CrossRefGoogle Scholar
  27. Stein R, Dogan HS, Hoebeke P, Kočvara R, Nijman RJM, Radmayr C, Tekgül S, European Association of Urology, European Society for Pediatric Urology (2015) Urinary tract infection in children: EAU/ESPU guidelines. Eur Urol 67:546–558CrossRefGoogle Scholar
  28. Szmigielska A, Krzemień G (2017) Sterile leukocyturia – difficult diagnostic problem in children. Dev Period Med 21(2):108–112Google Scholar
  29. Tullus K (2011) Difficulties in diagnosing urinary tract infections in small children. Pediatr Nephrol 26:1923–1926CrossRefGoogle Scholar
  30. Urbschat A, Obermüller PP, Reissig M, Hadji P, Hofmann R, Geiger H, Gauer S (2014) Upper and lower urinary tract infections can be detected early but not be descriminated by urinary NGAL in adults. Int Urol Nephrol 46:2243–2249CrossRefGoogle Scholar
  31. Waikar SS, Sabbisetti VS, Bonventre JV (2010) Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate. Kidney Int 78(5):486–496CrossRefGoogle Scholar
  32. Yim HE, Yim H, Bae ES, Woo SU, Yoo KH (2014) Predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections. Pediatr Nephrol 29:2181–2189CrossRefGoogle Scholar
  33. Ylmaz A, Sevketoglu E, Gedikbasi A, Karyagar S, Kiyak A, Mulazimoglu M, Aydogan G, Ozpacaci T, Hatipoglu S (2009) Early prediction of urinary tract infection with urinary neutrophil gelatinase associated lipocalin. Pediatr Nephrol 24:2387–2392CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG  2017

Authors and Affiliations

  • Grażyna Krzemień
    • 1
  • Małgorzata Pańczyk-Tomaszewska
    • 1
  • Dominika Adamczuk
    • 1
  • Iwona Kotuła
    • 2
  • Urszula Demkow
    • 2
  • Agnieszka Szmigielska
    • 1
  1. 1.Department of Pediatrics and NephrologyWarsaw Medical UniversityWarsawPoland
  2. 2.Department of Laboratory Diagnostics and Clinical Immunology of Developmental AgeWarsaw Medical UniversityWarsawPoland

Personalised recommendations