Skip to main content
SpringerLink
Log in

Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury in neonates with perinatal asphyxia: a systematic review and meta-analysis

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

Abstract

There is growing evidence that neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker of acute kidney injury. The objective of this meta-analysis is to determine the accuracy of serum and urinary NGAL in the detection of acute kidney injury in neonates with perinatal asphyxia. Medline (1966–2018), Scopus (2004–2018), EMBASE (1980–2018), Clinicaltrials.gov (2008–2018), and Google Scholar (2004–2018) databases, along with the reference lists of the electronically retrieved articles, were systematically searched. Eleven studies were included, with a total number of 652 neonates. The summary sensitivity of serum NGAL was 0.818 (95% CI [0.668, 0.909]), the specificity 0.870 (95% CI [0.754, 0.936]), and the area under the curve 0.912. Regarding urinary NGAL, pooled sensitivity was calculated at 0.897 (95% CI [0.829, 0.940]), specificity at 0.729 (95% CI [0.561, 0.850]), and area under the curve at 0.899.

Conclusion: Serum and urinary NGAL represent candidate biomarkers with high performance in the prediction of acute kidney injury in newborns with perinatal asphyxia. Before NGAL can be widely used in clinical practice, future large prospective studies are needed to define the optimal cutoffs and accurately determine which levels are suggestive of post-asphyxial acute kidney injury.

What is Known:

• Acute kidney injury is a major cause of morbidity and mortality in perinatal asphyxia.

• Current markers are insufficient in predicting post-asphyxial acute kidney injury.

What is New:

• Area under the curve for serum and urinary neutrophil gelatinase-associated lipocalin is 0.818 and 0.899, respectively.

• Neutrophil gelatinase-associated lipocalin is a useful marker for detecting asphyxiated neonates at risk of developing acute kidney injury.

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

Similar content being viewed by others

Abbreviations

95% CI:

95% confidence intervals

AKI:

Acute kidney injury

AKIN:

Acute Kidney Injury Network

AUC:

Area under the curve

DOR:

Diagnostic odds ratio

ESS:

Effective sample size

GFR:

Glomerular filtration rate

KDIGO:

Kidney Disease: Improving Global Outcomes

LR:

Likelihood ratio

NGAL:

Neutrophil gelatinase-associated lipocalin

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

ROBINS:

Risk Of Bias In Non-randomized Studies

SROC:

Summary receiver operating characteristic

References

  1. Abdelhady S, Gawad ERA, Haie OMA, Mansour AI (2016) Usefulness of serum and urinary neutrophil gelatinase-associated lipocalin in detecting acute kidney injury in asphyxiated neonates. Int J Med Health Sci 5(4):230–236

    CAS  Google Scholar 

  2. Askenazi D (2012) Are we ready for the clinical use of novel acute kidney injury biomarkers? Pediatr Nephrol 27(9):1423–1425. https://doi.org/10.1007/s00467-012-2185-x

    Article  PubMed  Google Scholar 

  3. Askenazi DJ, Ambalavanan N, Goldstein SL (2009) Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 24(2):265–274. https://doi.org/10.1007/s00467-008-1060-2

    Article  PubMed  PubMed Central  Google Scholar 

  4. Baumert M, Surmiak P, Więcek A, Walencka Z (2017) Serum NGAL and copeptin levels as predictors of acute kidney injury in asphyxiated neonates. Clin Exp Nephrol 21(4):658–664. https://doi.org/10.1007/s10157-016-1320-6

    Article  PubMed  CAS  Google Scholar 

  5. Caraguel CGB, Vanderstichel R (2013) The two-step Fagan’s nomogram: ad hoc interpretation of a diagnostic test result without calculation. Evidence Based Medicine 18(4):25–128. https://doi.org/10.1136/eb-2013-101243

    Article  Google Scholar 

  6. Chandrashekar C, Venkatkrishnan A (2016) Clinical utility of serum neutrophil gelatinase associated lipocalin (NGAL) as an early marker of acute kidney injury in asphyxiated neonates. Journal of Nepal Paediatric Society 36(2):121. https://doi.org/10.3126/jnps.v36i2.14985

    Article  Google Scholar 

  7. Clerico A, Galli C, Fortunato A, Ronco C (2012) Neutrophil gelatinase-associated lipocalin (NGAL) as biomarker of acute kidney injury: a review of the laboratory characteristics and clinical evidences. Clin Chem Lab Med 50(9):1505–1517. https://doi.org/10.1515/cclm-2011-0814

    Article  PubMed  CAS  Google Scholar 

  8. Deeks JJ, Macaskill P, Irwig L (2005) The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 58(9):882–893. https://doi.org/10.1016/j.jclinepi.2005.01.016

    Article  PubMed  Google Scholar 

  9. Dinnes J, Mallett S, Hopewell S, Roderick PJ, Deeks JJ (2016) The Moses-Littenberg meta-analytical method generates systematic differences in test accuracy compared to hierarchical meta-analytical models. J Clin Epidemiol 80:77–87. https://doi.org/10.1016/j.jclinepi.2016.07.011

    Article  PubMed  PubMed Central  Google Scholar 

  10. Doebler P, Münster W, Holling H (2015) Meta-analysis of diagnostic accuracy with mada. https://cran.r-project.org/web/packages/mada/vignettes/mada.pdf

  11. Dong L, Ma Q, Bennett M, Devarajan P (2017) Urinary biomarkers of cell cycle arrest are delayed predictors of acute kidney injury after pediatric cardiopulmonary bypass. Pediatr Nephrol 32(12):2351–2360. https://doi.org/10.1007/s00467-017-3748-7

    Article  PubMed  PubMed Central  Google Scholar 

  12. Durkan AM, Alexander RT (2011) Acute kidney injury post neonatal asphyxia. J Pediatr 158(2):e29–e33. https://doi.org/10.1016/j.jpeds.2010.11.010

    Article  PubMed  Google Scholar 

  13. El Raggal N, Khafagy SM, Mahmoud NH, El Beltagy S (2013) Serum neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury in asphyxiated neonates. Indian Pediatr 50(5):459–462

    Article  PubMed  Google Scholar 

  14. El-Salam MA, Zaher MM, Mohamed RAE-S et al (2014) Comparison of some urinary biomarkers of acute kidney injury in term new born with and without asphyxia. Clinical Medicine and Diagnostics 4(2):23–28. https://doi.org/10.5923/j.cmd.20140402.02

    Article  Google Scholar 

  15. Eslami Z, Shajari A, Kheirandish M, Heidary A (2009) Theophylline for prevention of kidney dysfunction in neonates with severe asphyxia. Iran J Kidney Dis 3(4):222–226

    PubMed  Google Scholar 

  16. Essajee F, Were F, Admani B (2015) Urine neutrophil gelatinase-associated lipocalin in asphyxiated neonates: a prospective cohort study. Pediatr Nephrol 30(7):1189–1196. https://doi.org/10.1007/s00467-014-3035-9

    Article  PubMed  Google Scholar 

  17. Fiala M, Baumert M, Surmiak P, Walencka Z, Sodowska P (2016) Umbilical markers of perinatal hypoxia. Ginekol Pol 87(3):200–204

    Article  PubMed  Google Scholar 

  18. Filho LT, Grande AJ, Colonetti T, Della ÉSP, da Rosa MI (2017) Accuracy of neutrophil gelatinase-associated lipocalin for acute kidney injury diagnosis in children: systematic review and meta-analysis. Pediatr Nephrol 32(10):1979–1988. https://doi.org/10.1007/s00467-017-3704-6

    Article  PubMed  Google Scholar 

  19. Firmani ND, Yuniati T, Rachmadi D (2015) The differences of urinary neutrophil gelatinase-associated lipocalin (NGAL) levels between asphyxiated and non-asphyxiated neonates. Open J Pediatr 5(3):185–189. https://doi.org/10.4236/ojped.2015.53028

    Article  CAS  Google Scholar 

  20. Forster CS, Devarajan P (2017) Neutrophil gelatinase-associated lipocalin: utility in urologic conditions. Pediatr Nephrol 32(3):377–381. https://doi.org/10.1007/s00467-016-3540-0

    Article  PubMed  Google Scholar 

  21. Jenik AG, Cernadas JMC, Gorenstein A et al (2000) A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatics 105(4):E45

    CAS  Google Scholar 

  22. Jiang L, Cui H (2015) Could blood neutrophil gelatinase-associated lipocalin (NGAL) be a diagnostic marker for acute kidney injury in neonates? A systemic review and meta-analysis. Clin Lab 61(12):1815–1820

    PubMed  CAS  Google Scholar 

  23. Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical practice 120(4):c179–c184. https://doi.org/10.1159/000339789

    Article  PubMed  Google Scholar 

  24. Kisiel A, Roszkowska-Blaim M, Pańczyk-Tomaszewska M, Stelmaszczyk-Emmel A, Górska E, Borszewska-Kornacka M (2017) Effect of perinatal risk factors on neutrophil gelatinase-associated lipocalin (NGAL) level in umbilical and peripheral blood in neonates. Central European Journal of Immunology 3(3):274–280. https://doi.org/10.5114/ceji.2017.70970

    Article  Google Scholar 

  25. Kriplani DS, Sethna CB, Leisman DE, Schneider JB (2016) Acute kidney injury in neonates in the PICU. Pediatr Crit Care Med 17(4):e159–e164. https://doi.org/10.1097/PCC.0000000000000668

    Article  PubMed  Google Scholar 

  26. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10):e1–e34. https://doi.org/10.1016/j.jclinepi.2009.06.006

    Article  PubMed  Google Scholar 

  27. McGuire W (2007) Perinatal asphyxia. BMJ Clin Evid 2007:0320

    PubMed  PubMed Central  Google Scholar 

  28. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A, Acute Kidney Injury Network (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11(2):R31. https://doi.org/10.1186/cc5713

    Article  PubMed  PubMed Central  Google Scholar 

  29. Merrikhi AR, Ghaemi S, Gheissari A, Shokrani M, Madihi Y, Mousavinasab F (2012) Effects of aminophyllinein preventing renal failure in premature neonates with asphyxia in Isfahan-Iran. JPMA J Pak Med Assoc 62:S48–S51

    PubMed  CAS  Google Scholar 

  30. Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P (2004) Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 15(12):3073–3082. https://doi.org/10.1097/01.ASN.0000145013.44578.45

    Article  PubMed  Google Scholar 

  31. Oncel MY, Canpolat FE, Arayici S, Alyamac Dizdar E, Uras N, Oguz SS (2016) Urinary markers of acute kidney injury in newborns with perinatal asphyxia. Ren Fail 38(6):882–888. https://doi.org/10.3109/0886022X.2016.1165070

    Article  PubMed  CAS  Google Scholar 

  32. Osswald H, Gleiter C, Mühlbauer B (1995) Therapeutic use of theophylline to antagonize renal effects of adenosine. Clin Nephrol 43:S33–S37

    PubMed  Google Scholar 

  33. Pejović B, Erić-Marinković J, Pejović M, Kotur-Stevuljević J, Peco-Antić A (2015) Detection of acute kidney injury in premature asphyxiated neonates by serum neutrophil gelatinase-associated lipocalin (sNGAL)—sensitivity and specificity of a potential new biomarker. Biochem Medica 25(3):450–459. https://doi.org/10.11613/BM.2015.046

    Article  Google Scholar 

  34. Raina A, Pandita A, Harish R, Yachha M, Jamwal A (2016) Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatr 105(10):e448–e451. https://doi.org/10.1111/apa.13469

    Article  PubMed  CAS  Google Scholar 

  35. Reitsma JB, Glas AS, Rutjes AWS, Scholten RJPM, Bossuyt PM, Zwinderman AH (2005) Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 58(10):982–990. https://doi.org/10.1016/j.jclinepi.2005.02.022

    Article  PubMed  Google Scholar 

  36. Rutter CM, Gatsonis CA (2001) A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med 20(19):2865–2884

    Article  PubMed  CAS  Google Scholar 

  37. Saleh NY, Abo El Fotoh WMM, El-Hawy MA (2017) Serum neutrophil gelatinase–associated lipocalin. Pediatr Crit Care Med 18(6):e245–e252. https://doi.org/10.1097/PCC.0000000000001186

    Article  PubMed  Google Scholar 

  38. Sarafidis K, Tsepkentzi E, Agakidou E, Diamanti E, Taparkou A, Soubasi V, Papachristou F, Drossou V (2012) Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 27(9):1575–1582. https://doi.org/10.1007/s00467-012-2162-4

    Article  PubMed  Google Scholar 

  39. Sarkar S, Askenazi DJ, Jordan BK, Bhagat I, Bapuraj JR, Dechert RE, Selewski DT (2014) Relationship between acute kidney injury and brain MRI findings in asphyxiated newborns after therapeutic hypothermia. Pediatr Res 75(3):431–435. https://doi.org/10.1038/pr.2013.230

    Article  PubMed  Google Scholar 

  40. Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, Kent AL (2015) Neonatal acute kidney injury. Pediatrics 136(2):e463–e473. https://doi.org/10.1542/peds.2014-3819

    Article  PubMed  Google Scholar 

  41. Song Y, Sun S, Yu Y et al (2017) Diagnostic value of neutrophil gelatinase-associated lipocalin for renal injury in asphyxiated preterm infants. Exp Ther Med 13(4):1245–1248. https://doi.org/10.3892/etm.2017.4107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sterne JA, Hernán MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919. https://doi.org/10.1136/BMJ.I4919

    Article  PubMed  PubMed Central  Google Scholar 

  43. Suchojad A, Tarko A, Smertka M, Majcherczyk M, Brzozowska A, Wroblewska J, Maruniak-Chudek I (2015) Factors limiting usefulness of serum and urinary NGAL as a marker of acute kidney injury in preterm newborns. Ren Fail 37(3):439–445. https://doi.org/10.3109/0886022X.2014.996109

    Article  PubMed  CAS  Google Scholar 

  44. Surmiak P, Baumert M, Fiala M, Sypniewska K, Walencka Z, Łukomska A, Karcz K (2014) Umbilical cord blood NGAL concentration as an early marker of perinatal asphyxia in neonates. Ginekol Pol 85(6):424–427

    Article  PubMed  Google Scholar 

  45. Sweetman DU (2017) Neonatal acute kidney injury—severity and recovery prediction and the role of serum and urinary biomarkers. Early Hum Dev 105:57–61. https://doi.org/10.1016/j.earlhumdev.2016.12.006

    Article  PubMed  CAS  Google Scholar 

  46. Sweetman DU, Onwuneme C, Watson WR, O'Neill A, Murphy JFA, Molloy EJ (2016) Renal function and novel urinary biomarkers in infants with neonatal encephalopathy. Acta Paediatr 105(11):e513–e519. https://doi.org/10.1111/apa.13555

    Article  PubMed  CAS  Google Scholar 

  47. Tanigasalam V, Bhat V, Adhisivam B, Sridhar MG (2015) Does therapeutic hypothermia reduce acute kidney injury among term neonates with perinatal asphyxia?—a randomized controlled trial. J Matern Fetal Neonatal Med 29(15):2545–2548. https://doi.org/10.3109/14767058.2015.1094785

    Article  PubMed  CAS  Google Scholar 

  48. Tanigasalam V, Bhat BV, Adhisivam B, Sridhar MG, Harichandrakumar KT (2016) Predicting severity of acute kidney injury in term neonates with perinatal asphyxia using urinary neutrophil gelatinase associated lipocalin. The Indian Journal of Pediatrics 83(12–13):1374–1378. https://doi.org/10.1007/s12098-016-2178-z

    Article  PubMed  Google Scholar 

  49. Tanzil WL, Wilar R, Mantik MFJ et al (2017) Comparison of urine neutrophil gelatinase-associated lipocalin to serum creatinine to assess kidney function in neonatal asphyxia. Paediatr Indones 56(6):356. https://doi.org/10.14238/pi56.6.2016.356-9

    Article  Google Scholar 

  50. Treiber M, Gorenjak M, Pecovnik Balon B (2014) Serum cystatin-C as a marker of acute kidney injury in the newborn after perinatal hypoxia/asphyxia. Ther Apher Dial 18(1):57–67. https://doi.org/10.1111/1744-9987.12054

    Article  PubMed  CAS  Google Scholar 

  51. Valdimarsson S, Jodal U, Barregård L, Hansson S (2017) Urine neutrophil gelatinase-associated lipocalin and other biomarkers in infants with urinary tract infection and in febrile controls. Pediatr Nephrol 32(11):2079–2087. https://doi.org/10.1007/s00467-017-3709-1

    Article  PubMed  Google Scholar 

  52. Wang K, Duan C, Wu J et al (2016) Predictive value of neutrophil gelatinase-associated lipocalin for contrast-induced acute kidney injury after cardiac catheterization: a meta-analysis. Can J Cardiol 32(8):1033.e19–1033.e29. https://doi.org/10.1016/j.cjca.2015.09.011

    Article  Google Scholar 

  53. Whiting PF, Rutjes AWS, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM, QUADAS-2 Group (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536. https://doi.org/10.7326/0003-4819-155-8-201110180-00009

    Article  PubMed  Google Scholar 

  54. Zhang A, Cai Y, Wang P-F, Qu JN, Luo ZC, Chen XD, Huang B, Liu Y, Huang WQ, Wu J, Yin YH (2016) Diagnosis and prognosis of neutrophil gelatinase-associated lipocalin for acute kidney injury with sepsis: a systematic review and meta-analysis. Crit Care 20:41. https://doi.org/10.1186/s13054-016-1212-x

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, 15Β, Ag. Thoma str., 115 27, Athens, Greece

    Ioannis Bellos, Georgia Fitrou, Despina N. Perrea & Vasilios Pergialiotis

  2. First Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Georgios Daskalakis

Authors
  1. Ioannis Bellos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgia Fitrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georgios Daskalakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Despina N. Perrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vasilios Pergialiotis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ioannis Bellos conceived the idea and designed the analysis.

Georgia Fitrou performed the literature search and tabulated the data.

Georgios Daskalakis performed the statistical analysis and wrote the manuscript.

Despina N. Perrea performed the quality assessment and the sensitivity analysis.

Vasilios Pergialiotis contributed to the quality assessment and revised the manuscript.

Corresponding author

Correspondence to Ioannis Bellos.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

The present systematic review and meta-analysis is based on aggregated data that were retrieved from studies already retrieved. We did not collect individual patient data and did not have direct contact with patients included.

Additional information

Communicated by Patrick Van Reempts

Electronic supplementary material

Supplemental Table 1

Methodological characteristics of the included studies. (DOCX 20 kb)

Supplemental Table 2

Patients’ characteristics of the included studies. (DOCX 16 kb)

Supplemental Table 3

Outcomes of ROBINS-I evaluation. The overall risk of bias was evaluated as moderate. (DOCX 18 kb)

Supplemental Table 4

Results of the qualitative synthesis. NGAL levels were significantly higher in asphyxiated newborns with acute kidney injury. (DOCX 23 kb)

Supplemental Table 5

Outcomes of the leave-one-out analysis. No single study affected significantly the overall results. (DOCX 14 kb)

Supplemental Figure 1

Forest plots for sensitivity and specificity of serum and urinary NGAL. (PNG 265 kb)

Supplemental Figure 2

Deeks’ funnel plot. No evidence of publication bias is present (p-value >0.05). (PNG 37 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bellos, I., Fitrou, G., Daskalakis, G. et al. Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury in neonates with perinatal asphyxia: a systematic review and meta-analysis. Eur J Pediatr 177, 1425–1434 (2018). https://doi.org/10.1007/s00431-018-3221-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-018-3221-z

Keywords

Search

Navigation