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The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury

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Abstract

Background

Different molecular forms of urinary neutrophil gelatinase-associated lipocalin (NGAL) have recently been discovered. We aimed to explore the nature, source and discriminatory value of urinary NGAL in intensive care unit (ICU) patients.

Methods

We simultaneously measured plasma NGAL (pNGAL), urinary NGAL (uNGAL), and estimated monomeric and homodimeric uNGAL contribution using Western blotting-validated enzyme-linked immunosorbent assays [uNGALE1 and uNGALE2] and their calculated ratio in 102 patients with the systemic inflammatory response syndrome and oliguria, and/or a creatinine rise of >25 μmol/L.

Measurements and main results

Bland–Altman analysis demonstrated that, despite correlating well (r = 0.988), uNGAL and uNGALE1 were clinically distinct, lacking both accuracy and precision (bias: 266.23; 95 % CI 82.03–450.44 ng/mg creatinine; limits of agreement: −1,573.86 to 2,106.32 ng/mg creatinine). At best, urinary forms of NGAL are fair (area under the receiver operating characteristic [AUROC] ≤0.799) predictors of renal or patient outcome; most perform significantly worse. The 44 patients with a primarily monomeric source of uNGAL had higher pNGAL (118.5 ng/ml vs. 72.5 ng/ml; p < 0.001), remaining significant following Bonferroni correction.

Conclusions

uNGAL is not a useful predictor of outcome in this ICU population. uNGAL patterns may predict distinct clinical phenotypes. The nature and source of uNGAL are complex and challenge the utility of NGAL as a uniform biomarker.

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Acknowledgments

This study was supported by the Austin Hospital Intensive Care Trust Fund. The ELISA testing was funded by a grant from the Swedish Medical Research Council to Uppsala University.

Conflicts of interest

Shengyuan Xu holds patents with, and receives royalties from, Diagnostics Development. Per Venge holds patents with, and stock in, P&M Venge AB. He has received royalties from Phadia. The remaining authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Intensive Care, Austin Hospital, 145 Studley Rd, Heidelberg, Melbourne, VIC, 3084, Australia

    Neil J. Glassford, Antoine G. Schneider, Glenn M. Eastwood, Helen Young, Leah Peck & Rinaldo Bellomo

  2. Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden

    Shengyuan Xu & Per Venge

  3. Australian and New Zealand Intensive Care Research Centre and Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia

    Rinaldo Bellomo

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  1. Neil J. Glassford
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  2. Antoine G. Schneider
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  7. Per Venge
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  8. Rinaldo Bellomo
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Correspondence to Rinaldo Bellomo.

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Glossary

Glossary

NGAL:

Neutrophil gelatinase-associated lipocalin, also known as human neutrophil lipocalin [HNL]). Released from multiple tissues. Present in plasma and urine

Monomeric NGAL:

A 25-kD monomeric form of NGAL produced by both neutrophils and renal epithelium

Homodimeric NGAL:

A 45-kD homodimeric form of NGAL produced by neutrophils

Heterodimeric NGAL:

A 135-kD heterodimeric form of NGAL, covalently conjugated with gelatinase, produced by renal epithelium

pNGAL:

NGAL measured in the plasma using the triage point-of-care NGAL test (Alere)

uNGAL:

NGAL measured in the urine using the ARCHITECT platform (Abbott)

uNGALE1 :

NGAL in the urine measured by a research assay utilising monoclonal antibody clones m763/m764. Detects a proportion of all forms of NGAL in the urine

uNGALE2 :

NGAL in the urine measured by a research assay utilising monoclonal antibody clones m763/m765. Detects a fraction of homodimeric NGAL in the urine

uNGALE1:uNGALE2 ratio:

A ratio of NGAL detected in the urine by the research assays >50. Distinguishes monomeric from homodimeric NGAL with an AUROC of 0.92

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Glassford, N.J., Schneider, A.G., Xu, S. et al. The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury. Intensive Care Med 39, 1714–1724 (2013). https://doi.org/10.1007/s00134-013-3040-7

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