Skip to main content

Advertisement

SpringerLink
Log in

Urinary calprotectin, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin for the prediction of adverse outcome in pediatric acute kidney injury

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Early identification of patients with acute kidney injury (AKI) being at high risk for adverse outcome can influence medical treatment. This study compares urinary calprotectin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) for their performance in predicting mortality and need for renal replacement therapy (RRT) in pediatric AKI patients. Urinary biomarker concentrations were assessed prospectively in 141 subjects aged 0–18 years including 55 patients with established AKI according to pediatric Risk, Injury, Failure, Loss, and End-stage kidney disease (pRIFLE) criteria, 27 patients without AKI, and 59 healthy children. Within the AKI group, receiver operating characteristic (ROC) curve analysis revealed moderate to poor performance of calprotectin and KIM-1 in the prediction of 30-day mortality (calprotectin area under the curve (AUC) 0.55; KIM-1 AUC 0.55) and 3-month mortality (calprotectin AUC 0.61; KIM-1 AUC 0.60) and fair performance in the prediction of RRT requirement (calprotectin AUC 0.72; KIM-1 AUC 0.71). Urinary NGAL showed good performance in predicting 30-day (AUC 0.79) and 3-month (AUC 0.81) mortality and moderate performance in predicting RRT (AUC 0.61).

Conclusions: Whereas urinary calprotectin and KIM-1 can be useful for the prediction of RRT, urinary NGAL has a good diagnostic performance in predicting mortality in pediatric patients with AKI of heterogeneous etiology.

What is known:

• There is increasing evidence that urinary biomarkers like neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are valuable for the prediction of adverse outcome in adult acute kidney injury (AKI), whereas data on pediatric AKI is scarce.

What is new:

• Urinary calprotectin and KIM-1 do not predict mortality in our heterogeneous pediatric AKI cohort, but they show moderate performance in the prediction of dialysis.

• Urinary NGAL is a good predictor of mortality performing better than pRIFLE stage, eGFR, or creatinine, but it shows moderate performance in the prediction of dialysis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AKI:

acute kidney injury

AUC:

area under the curve

eCCl:

estimated creatinine clearance

HUS:

hemolytic uremic syndrome

KDIGO:

Kidney Disease: Improving Global Outcomes

KIM-1:

kidney injury molecule-1

NGAL:

neutrophil gelatinase-associated lipocalin

pRIFLE:

pediatric Risk, Injury, Failure, Loss, and End-stage kidney disease

ROC:

receiver operating characteristic

RRT:

renal replacement therapy

SCr:

serum creatinine

References

  1. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71:1028–1035

    Article  CAS  PubMed  Google Scholar 

  2. Alge JL, Arthur JM (2015) Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol 10:147–155

    Article  CAS  PubMed  Google Scholar 

  3. Bojan M, Vicca S, Lopez-Lopez V, Mogenet A, Pouard P, Falissard B, Journois D (2014) Predictive performance of urine neutrophil gelatinase-associated lipocalin for dialysis requirement and death following cardiac surgery in neonates and infants. Clin J Am Soc Nephrol 9:285–294

    Article  PubMed  Google Scholar 

  4. Chang CH, Yang CH, Yang HY, Chen TH, Lin CY, Chang SW, Chen YT, Hung CC, Fang JT, Yang CW, Chen YC (2015) Urinary biomarkers improve the diagnosis of intrinsic acute kidney injury in coronary care units. Medicine (Baltimore) 94:e1703

    Article  CAS  Google Scholar 

  5. Cruz DN, Bagshaw SM, Maisel A, Lewington A, Thadhani R, Chakravarthi R, Murray PT, Mehta RL, Chawla LS (2013) Use of biomarkers to assess prognosis and guide management of patients with acute kidney injury. Contrib Nephrol 182:45–64

    Article  PubMed  Google Scholar 

  6. Fan H, Zhao Y, Zhu JH, Song FC (2014) Urine neutrophil gelatinase-associated lipocalin in septic patients with and without acute kidney injury. Ren Fail 36:1399–1403

    Article  CAS  PubMed  Google Scholar 

  7. Fujiu K, Manabe I, Nagai R (2011) Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice. J Clin Invest 121:3425–3441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A, Rysz J (2010) The role of Toll-like receptors in renal diseases. Nat Rev Nephrol 6:224–235

    Article  CAS  PubMed  Google Scholar 

  9. Heller F, Frischmann S, Grunbaum M, Zidek W, Westhoff TH (2011) Urinary calprotectin and the distinction between prerenal and intrinsic acute kidney injury. Clin J Am Soc Nephrol 6:2347–2355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hjortrup PB, Haase N, Treschow F, Moller MH, Perner A (2015) Predictive value of NGAL for use of renal replacement therapy in patients with severe sepsis. Acta Anaesthesiol Scand 59:25–34

    Article  CAS  PubMed  Google Scholar 

  11. Jetton JG, Askenazi DJ (2012) Update on acute kidney injury in the neonate. Curr Opin Pediatr 24:191–196

    Article  CAS  PubMed  Google Scholar 

  12. Kellum JA, Lameire N, Group KAGW (2013) Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1). Crit Care 17:204

    Article  Google Scholar 

  13. Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL (2007) Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 18:904–912

    Article  CAS  PubMed  Google Scholar 

  14. Macedo E, Mehta RL (2014) Targeting recovery from acute kidney injury: incidence and prevalence of recovery. Nephron Clin Pract 127:4–9

    Article  PubMed  Google Scholar 

  15. Mishra OP, Rai AK, Srivastava P, Pandey K, Abhinay A, Prasad R, Mishra RN, Schaefer F (2017) Predictive ability of urinary biomarkers for outcome in children with acute kidney injury. Pediatr Nephrol 32:521-527

  16. Murray PT, Mehta RL, Shaw A, Ronco C, Endre Z, Kellum JA, Chawla LS, Cruz D, Ince C, Okusa MD, Workgroup A (2014) Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference. Kidney Int 85:513–521

    Article  PubMed  Google Scholar 

  17. Nickolas TL, Schmidt-Ott KM, Canetta P, Forster C, Singer E, Sise M, Elger A, Maarouf O, Sola-Del Valle DA, O'Rourke M, Sherman E, Lee P, Geara A, Imus P, Guddati A, Polland A, Rahman W, Elitok S, Malik N, Giglio J, El-Sayegh S, Devarajan P, Hebbar S, Saggi SJ, Hahn B, Kettritz R, Luft FC, Barasch J (2012) Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol 59:246–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Palazzuoli A, Ruocco G, Pellegrini M, De Gori C, Del Castillo G, Franci B, Nuti R, Ronco C (2015) Comparison of neutrophil gelatinase-associated lipocalin versus B-type natriuretic peptide and cystatin C to predict early acute kidney injury and outcome in patients with acute heart failure. Am J Cardiol 116:104–111

    Article  CAS  PubMed  Google Scholar 

  19. Ronco C (2014) Biomarkers for acute kidney injury: is NGAL ready for clinical use? Crit Care 18:680

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (2007) Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 18:407–413

    Article  CAS  PubMed  Google Scholar 

  21. Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM (2017) Biomarkers in acute kidney injury—pathophysiological basis and clinical performance. Acta Physiol (Oxf) 219:554–572

  22. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  23. Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, Kent AL (2015) Neonatal acute kidney injury. Pediatrics 136:e463–e473

    Article  PubMed  Google Scholar 

  24. Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13:1042–1049

    Article  CAS  PubMed  Google Scholar 

  25. Waikar SS, Sabbisetti VS, Bonventre JV (2010) Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate. Kidney Int 78:486–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Westhoff JH, Fichtner A, Waldherr S, Pagonas N, Seibert FS, Babel N, Tonshoff B, Bauer F, Westhoff TH (2016) Urinary biomarkers for the differentiation of prerenal and intrinsic pediatric acute kidney injury. Pediatr Nephrol 31:2353–2363

    Article  PubMed  Google Scholar 

  27. Yang HN, Boo CS, Kim MG, Jo SK, Cho WY, Kim HK (2010) Urine neutrophil gelatinase-associated lipocalin: an independent predictor of adverse outcomes in acute kidney injury. Am J Nephrol 31:501–509

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Simone Voigt for her indefatigable efforts in this study. We are indebted to all children and their parents who participated in the study.

Author information

Author notes

  1. Alexander Fichtner and Timm H. Westhoff contributed equally to this article.

Authors and Affiliations

  1. Department of Pediatrics I, University Children’s Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Jens H. Westhoff, Burkhard Tönshoff & Alexander Fichtner

  2. Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University of Bochum, Bochum, Germany

    Felix S. Seibert, Frederic Bauer & Timm H. Westhoff

  3. Department of Neonatology, University Children’s Hospital, Heidelberg, Germany

    Sina Waldherr

Authors
  1. Jens H. Westhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix S. Seibert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sina Waldherr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frederic Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Burkhard Tönshoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexander Fichtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Timm H. Westhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JHW, AF, and THW conceived and designed the experiments. JHW, SW and AF performed the experiments. JHW, AF, THW, BT, FSS, and FB analyzed the data or interpreted the results. JHW, AF, BT, and THW wrote the draft of the article. All other authors commented on the manuscript.

Corresponding author

Correspondence to Jens H. Westhoff.

Ethics declarations

Funding

The study was funded by the German Research Foundation (Research Unit FOR1368).

Conflict of interest

T.H.W. declares that patent “Assay method for intrinsic acute kidney injury” is granted. T.H.W. received speakers’ honoraria and/or research grants from Astellas, Novartis, Bristol-Myers Squibb, Pfizer, and Sanofi. All authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained by legal guardians of each patient with assent from the patient when appropriate for all individual participants included in the study.

Additional information

Communicated by Mario Bianchetti

Electronic supplementary material

Online Resource Table 1

Hosmer–Lemeshow goodness-of-fit test for biomarker calibration. (PDF 172 kb)

Online Resource Table 2

Urinary calprotectin, KIM-1, and NGAL in neonates and children stratified for pRIFLE stage. (PDF 42 kb)

Online Resource Table 3

Prognostic accuracy of urinary biomarker/urinary creatinine ratios in predicting mortality and need for RRT in pediatric AKI. (PDF 214 kb)

Online Resource Table 4

Prognostic accuracy of urinary calprotectin, KIM-1, and NGAL in predicting mortality and RRT in neonates and children. (PDF 46 kb)

Online Resource Table 5

Urinary calprotectin, KIM-1, and NGAL in the prediction of adverse outcomes in neonates classified by the neonatal-modified KDIGO definition of AKI. (PDF 39 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Westhoff, J.H., Seibert, F.S., Waldherr, S. et al. Urinary calprotectin, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin for the prediction of adverse outcome in pediatric acute kidney injury. Eur J Pediatr 176, 745–755 (2017). https://doi.org/10.1007/s00431-017-2907-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-017-2907-y

Keywords

Search

Navigation