Home Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants
Article
Licensed
Unlicensed Requires Authentication

Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants

  • Alexandra J.M. Zwiers , Saskia N. de Wildt , Yolanda B. de Rijke , Sten P. Willemsen , Najma S. Abdullahi , Dick Tibboel and Karlien Cransberg EMAIL logo
Published/Copyright: February 7, 2015
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 53 Issue 8

Abstract

Background: Reliable reference intervals for two novel urinary biomarkers of renal injury, neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) are lacking for infants. Therefore, the aim of our study was to establish reference intervals for urinary NGAL and KIM-1 absolute concentrations as well as normalized to urinary creatinine in young infants categorized in small age intervals.

Methods: From June 2010 to March 2014, serum and urine samples of 106 basically healthy infants (born between 37 and 42 weeks of gestation) aged 1 day to 1 year were collected. Blood samples were assayed for serum creatinine levels to confirm a healthy renal status. Urine samples were assayed for creatinine, uNGAL (ng/mL) and uKIM-1 (ng/mL).

Results: Two thirds of the study cohort were boys. uNGAL concentrations declined with increasing age (likelihood ratio test, p=0.001). Also, uNGAL concentrations were higher in girls (50th centile uNGAL was 27.1 ng/mL) than boys (50th centile uNGAL was 14.3 ng/mL) (two tailed Wald test, p<0.001) NGAL concentrations were not related to ethnicity. uKIM-1 concentrations were extremely low in almost all 106 subjects [median uKIM-1 was 0.08 (IQR 0.08–0.08) ng/mL] and not related with age, gender or ethnicity (all p>0.05).

Conclusions: Our data uniquely provide uNGAL and uKIM-1 reference intervals for the first year of life. Notably, only uNGAL levels decreased with increasing age and were higher in girls. These reference intervals enable future studies to evaluate the performance of both biomarkers in detecting early kidney tubular injury, particularly in the setting of critical care.

Keywords: kidney injury molecule-1 (KIM-1); neutrophil gelatinase-associated lipocalin (NGAL); pediatrics; reference intervals; serum creatinine; urinary biomarkers
Corresponding author: Karlien Cransberg, Department of Pediatric Nephrology, Erasmus Medical Center-Sophia Children’s Hospital, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands, Phone: +31 10 7040704, Fax: +31 10 7036288, E-mail:

Acknowledgments

The analytical assistance of Barry Koelewijn was greatly appreciated. The authors are grateful to Ko Hagoort for editorial assistance. The authors also gratefully acknowledge the research assistance provided by Joke Dunk (research nurse).

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: This study was supported by a grant from the Sophia Foundation for Scientific Research (633).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Basu RK, Devarajan P, Wong H, Wheeler DS. An update and review of acute kidney injury in pediatrics. Pediatr Crit Care Med 2011;12:339–47.10.1097/PCC.0b013e3181fe2e0bSearch in Google Scholar

2. Andreoli SP. Acute kidney injury in children. Pediatr Nephrol 2009;24:253–63.10.1007/s00467-008-1074-9Search in Google Scholar

3. Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatr Nephrol 2007;22:1839–48.10.1007/s00467-006-0358-1Search in Google Scholar

4. Arant BS, Jr. Postnatal development of renal function during the first year of life. Pediatr Nephrol 1987;1:308–13.10.1007/BF00849229Search in Google Scholar

5. Drukker A, Guignard JP. Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 2002;14:175–82.10.1097/00008480-200204000-00006Search in Google Scholar

6. Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 2009;24:265–74.10.1007/s00467-008-1060-2Search in Google Scholar

7. Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993;268:10425–32.10.1016/S0021-9258(18)82217-7Search in Google Scholar

8. Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482:298–307.10.1016/S0167-4838(00)00163-1Search in Google Scholar

9. Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, et al. Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int 2009;75:285–94.10.1038/ki.2008.499Search in Google Scholar PubMed

10. Devarajan P. Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med 2010;4:265–80.10.2217/bmm.10.12Search in Google Scholar PubMed PubMed Central

11. Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007;18:407–13.10.1681/ASN.2006080882Search in Google Scholar

12. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231–8.10.1016/S0140-6736(05)74811-XSearch in Google Scholar

13. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002;62:237–44.10.1046/j.1523-1755.2002.00433.xSearch in Google Scholar PubMed

14. Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV. Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem 2002;277:39739–48.10.1074/jbc.M200562200Search in Google Scholar PubMed

15. Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan P, et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008;73:863–9.10.1038/sj.ki.5002715Search in Google Scholar PubMed PubMed Central

16. Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011;57:1752–61.10.1016/j.jacc.2010.11.051Search in Google Scholar PubMed PubMed Central

17. Krawczeski CD, Goldstein SL, Woo JG, Wang Y, Piyaphanee N, Ma Q, et al. Temporal relationship and predictive value of urinary acute kidney injury biomarkers after pediatric cardiopulmonary bypass. J Am Coll Cardiol 2011;58:2301–9.10.1016/j.jacc.2011.08.017Search in Google Scholar PubMed PubMed Central

18. Edelstein CL. Biomarkers of acute kidney injury. Adv Chronic Kidney Dis 2008;15:222–34.10.1053/j.ackd.2008.04.003Search in Google Scholar PubMed PubMed Central

19. McWilliam SJ, Antoine DJ, Sabbisetti V, Pearce RE, Jorgensen AL, Lin Y, et al. Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children. Biomark Med 2014;8:1189–97.10.2217/bmm.14.36Search in Google Scholar PubMed PubMed Central

20. Pennemans V, Rigo JM, Faes C, Reynders C, Penders J, Swennen Q. Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue? Clin Chem Lab Med 2013;51:1795–802.10.1515/cclm-2013-0157Search in Google Scholar PubMed

21. Rybi-Szuminska A, Wasilewska A, Litwin M, Kulaga Z, Szuminski M. Paediatric normative data for urine NGAL/creatinine ratio. Acta Paediatr 2013;102:e269–72.10.1111/apa.12200Search in Google Scholar PubMed

22. Cangemi G, Storti S, Cantinotti M, Fortunato A, Emdin M, Bruschettini M, et al. Reference values for urinary neutrophil gelatinase-associated lipocalin (NGAL) in pediatric age measured with a fully automated chemiluminescent platform. Clin Chem Lab Med 2013;51:1101–5.10.1515/cclm-2012-0540Search in Google Scholar PubMed

23. Cullen MR, Murray PT, Fitzgibbon MC. Establishment of a reference interval for urinary neutrophil gelatinase-associated lipocalin. Ann Clin Biochem 2012;49:190–3.10.1258/acb.2011.011105Search in Google Scholar PubMed

24. Madsen MG, Norregaard R, Palmfeldt J, Olsen LH, Frokiaer J, Jorgensen TM. Urinary NGAL, cystatin C, beta2-microglobulin, and osteopontin significance in hydronephrotic children. Pediatr Nephrol 2012;27:2099–106.10.1007/s00467-012-2217-6Search in Google Scholar PubMed

25. Wasilewska A, Taranta-Janusz K, Debek W, Zoch-Zwierz W, Kuroczycka-Saniutycz E. KIM-1 and NGAL: new markers of obstructive nephropathy. Pediatr Nephrol 2011;26:579–86.10.1007/s00467-011-1773-5Search in Google Scholar PubMed PubMed Central

26. Delanaye P, Rozet E, Krzesinski JM, Cavalier E. Urinary NGAL measurement: biological variation and ratio to creatinine. Clin Chim Acta. 2011;412:390.10.1016/j.cca.2010.10.011Search in Google Scholar PubMed

27. Wasilewska A, Zoch-Zwierz W, Taranta-Janusz K, Michaluk-Skutnik J. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity? Pediatr Nephrol 2010;25:889–97.10.1007/s00467-009-1397-1Search in Google Scholar PubMed

28. Bolignano D, Coppolino G, Aloisi C, Romeo A, Nicocia G, Buemi M. Effect of a single intravenous immunoglobulin infusion on neutrophil gelatinase-associated lipocalin levels in proteinuric patients with normal renal function. J Investig Med 2008;56:997–1003.10.2310/JIM.0b013e31818e7e95Search in Google Scholar PubMed

29. Fahmy N, Sener A, Sabbisetti V, Nott L, Lang RM, Welk BK, et al. Urinary expression of novel tissue markers of kidney injury after ureteroscopy, shockwave lithotripsy, and in normal healthy controls. J Endourol 2013;27:1455–62.10.1089/end.2013.0188Search in Google Scholar PubMed PubMed Central

30. Chaturvedi S, Farmer T, Kapke GF. Assay validation for KIM-1: human urinary renal dysfunction biomarker. Int J Biol Sci 2009;5:128–34.10.7150/ijbs.5.128Search in Google Scholar PubMed PubMed Central

31. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009–2010. JAMA 2012;307:693–703.10.1001/jama.2012.101Search in Google Scholar PubMed PubMed Central

32. Lepage N, Huang SH, Nieuwenhuys E, Filler G. Pediatric reference intervals for immunoglobulin G and its subclasses with Siemens immunonephelometric assays. Clin Biochem 2010;43:694–6.10.1016/j.clinbiochem.2010.02.003Search in Google Scholar PubMed

33. Boer DP, de Rijke YB, Hop WC, Cransberg K, Dorresteijn EM. Reference values for serum creatinine in children younger than 1 year of age. Pediatr Nephrol 2010;25:2107–13.10.1007/s00467-010-1533-ySearch in Google Scholar PubMed PubMed Central

34. Rigby RA, Stasinopoulos DM. Generalized additive models for location, scale and shape. Appl Statist 2005;54:507–54.Search in Google Scholar

35. Akaike H. Information theory as an extension of the maximum likelihood principle. In: Petrov BN, Csáki F, editors. Budapest: Akadémiai Kiado, 1973.Search in Google Scholar

36. Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG. Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem 2005;280:7875–82.10.1074/jbc.M413192200Search in Google Scholar PubMed

37. Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis 2008;52:595–605.10.1053/j.ajkd.2008.01.020Search in Google Scholar PubMed

38. Askenazi DJ, Koralkar R, Levitan EB, Goldstein SL, Devarajan P, Khandrika S, et al. Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants. Pediatr Res 2011;70:302–6.10.1203/PDR.0b013e3182275164Search in Google Scholar PubMed PubMed Central

39. Huynh TK, Bateman DA, Parravicini E, Lorenz JM, Nemerofsky SL, Sise ME, et al. Reference values of urinary neutrophil gelatinase-associated lipocalin in very low birth weight infants. Pediatr Res 2009;66:528–32.10.1203/PDR.0b013e3181baa3ddSearch in Google Scholar PubMed PubMed Central

40. Ralib AM, Pickering JW, Shaw GM, Devarajan P, Edelstein CL, Bonventre JV, et al. Test characteristics of urinary biomarkers depend on quantitation method in acute kidney injury. J Am Soc Nephrol 2012;23:322–33.10.1681/ASN.2011040325Search in Google Scholar PubMed PubMed Central

41. Goldstein SL. Urinary kidney injury biomarkers and urine creatinine normalization: a false premise or not? Kidney Int 2010;78:433–5.10.1038/ki.2010.200Search in Google Scholar PubMed

42. Filler G, Huang SH, Yasin A. The usefulness of cystatin C and related formulae in pediatrics. Clin Chem Lab Med 2012;50:2081–91.10.1515/cclm-2012-0257Search in Google Scholar PubMed

Received: 2014-10-18
Accepted: 2014-12-19
Published Online: 2015-2-7
Published in Print: 2015-7-1

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Once upon a time: a tale of ISO 15189 accreditation
  4. A new integrated tool for assessing and monitoring test comparability and stability
  5. Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests
  6. Reviews
  7. Thromboembolic risk in hematological malignancies
  8. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population
  9. Opinion Paper
  10. Permissible limits for uncertainty of measurement in laboratory medicine
  11. EFLM Position Paper
  12. Flexible scope for ISO 15189 accreditation: a guidance prepared by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO)
  13. Genetics and Molecular Diagnostics
  14. Evaluation of a low-cost procedure for sampling, long-term storage, and extraction of RNA from blood for qPCR analyses
  15. Application of real-time PCR of sex-independent insertion-deletion polymorphisms to determine fetal sex using cell-free fetal DNA from maternal plasma
  16. General Clinical Chemistry and Laboratory Medicine
  17. The Empower project – a new way of assessing and monitoring test comparability and stability
  18. Comparison of four automated serum vitamin B12 assays
  19. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points
  20. INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison
  21. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods
  22. Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine
  23. Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients
  24. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome
  25. Reference Values and Biological Variations
  26. Relevance of EDTA carryover during blood collection
  27. Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants
  28. Cardiovascular Diseases
  29. NT-proBNP levels and their relationship with systemic ventricular impairment in adult patients with transposition of the great arteries long after Mustard or Senning procedure
  30. Letters to the Editors
  31. Troponin T measured with highly sensitive assay (hsTnT) on admission does not reflect infarct size in ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention
  32. Analytical challenges related to the use of biomarker ratios for the biological diagnosis of Alzheimer’s disease
  33. Serum brain injury biomarkers as predictors of mortality after severe aneurysmal subarachnoid hemorrhage: preliminary results
  34. Tumor markers assay by the Lumipulse G
  35. Real-world costs of laboratory tests for non-small cell lung cancer
  36. Impact of stopping vitamin K antagonist therapy on concentrations of dephospho-uncarboxylated Matrix Gla protein
  37. Practicability of fetal scalp blood sampling during labor using microtubes and a point-of-care (POC) lactate testing device: difficulty assessment, sampling time and failure rates
  38. Establishing objective analytical quality requirements in the IgE specific assay: a message in a bottle
  39. Bacteria on a peripheral blood smear as presenting sign of overwhelming post-splenectomy infection in a patient with secondary acute myeloid leukemia
https://doi.org/10.1515/cclm-2014-1020
Keywords for this article
kidney injury molecule-1 (KIM-1); neutrophil gelatinase-associated lipocalin (NGAL); pediatrics; reference intervals; serum creatinine; urinary biomarkers

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Once upon a time: a tale of ISO 15189 accreditation
  4. A new integrated tool for assessing and monitoring test comparability and stability
  5. Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests
  6. Reviews
  7. Thromboembolic risk in hematological malignancies
  8. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population
  9. Opinion Paper
  10. Permissible limits for uncertainty of measurement in laboratory medicine
  11. EFLM Position Paper
  12. Flexible scope for ISO 15189 accreditation: a guidance prepared by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO)
  13. Genetics and Molecular Diagnostics
  14. Evaluation of a low-cost procedure for sampling, long-term storage, and extraction of RNA from blood for qPCR analyses
  15. Application of real-time PCR of sex-independent insertion-deletion polymorphisms to determine fetal sex using cell-free fetal DNA from maternal plasma
  16. General Clinical Chemistry and Laboratory Medicine
  17. The Empower project – a new way of assessing and monitoring test comparability and stability
  18. Comparison of four automated serum vitamin B12 assays
  19. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points
  20. INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison
  21. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods
  22. Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine
  23. Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients
  24. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome
  25. Reference Values and Biological Variations
  26. Relevance of EDTA carryover during blood collection
  27. Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants
  28. Cardiovascular Diseases
  29. NT-proBNP levels and their relationship with systemic ventricular impairment in adult patients with transposition of the great arteries long after Mustard or Senning procedure
  30. Letters to the Editors
  31. Troponin T measured with highly sensitive assay (hsTnT) on admission does not reflect infarct size in ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention
  32. Analytical challenges related to the use of biomarker ratios for the biological diagnosis of Alzheimer’s disease
  33. Serum brain injury biomarkers as predictors of mortality after severe aneurysmal subarachnoid hemorrhage: preliminary results
  34. Tumor markers assay by the Lumipulse G
  35. Real-world costs of laboratory tests for non-small cell lung cancer
  36. Impact of stopping vitamin K antagonist therapy on concentrations of dephospho-uncarboxylated Matrix Gla protein
  37. Practicability of fetal scalp blood sampling during labor using microtubes and a point-of-care (POC) lactate testing device: difficulty assessment, sampling time and failure rates
  38. Establishing objective analytical quality requirements in the IgE specific assay: a message in a bottle
  39. Bacteria on a peripheral blood smear as presenting sign of overwhelming post-splenectomy infection in a patient with secondary acute myeloid leukemia
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 5.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2014-1020/html
Scroll to top button