Reference Intervals for Urinary Renal Injury Biomarkers KIM-1 and NGAL in Healthy Children

Abstract

Aim

The aim of this study was to establish reference intervals in healthy children for two novel urinary biomarkers of acute kidney injury, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL).

Materials & Methods

Urinary biomarkers were determined in samples from children in the UK (n = 120) and the USA (n = 171) using both Meso Scale Discovery (MSD) and Luminex-based analytical approaches.

Results

95% reference intervals for each biomarker in each cohort are presented and stratified by sex or ethnicity where necessary, and age-related variability is explored using quantile regression. We identified consistently higher NGAL concentrations in females than males (p < 0.0001), and lower KIM-1 concentrations in African–Americans than Caucasians (p = 0.02). KIM-1 demonstrated diurnal variation, with higher concentrations in the morning (p < 0.001).

Conclusion

This is the first report of reference intervals for KIM-1 and NGAL using two analytical methods in a healthy pediatric population in both UK and US-based populations.

Keywords::

• KIM-1
• nephrotoxicity
• pediatric nephrology
• proximal tubule

Acknowledgements

The authors would like to thank the UK Medicines for Children Research Network (MCRN) and Primary Care Research Network (PCRN) for their support of this study. In particular, the authors would like to thank Naomi Wallin for her contribution to recruitment and sample collection in the DERIVE cohort. We acknowledge statistical advice from Steven Lane and Laura Sutton.

Financial & competing interests disclosure

JV Bonventre is co-inventor on KIM-1 patents, which have been licensed by Partners Healthcare to a number of companies. He has received royalty income from Partners Healthcare and grant funding from Novo Nordisk. JV Bonventre or his family have received income for consulting from companies interested in biomarkers: Sekisui, Millenium, Johnson & Johnson and Novartis. M Pirmohamed is a NIHR Senior Investigator. SJ McWilliam is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant no: G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit. DJ Antoine would like to acknowledge financial support from a Royal Society International Travelling Research Fellowship and the Wellcome Trust. Urine samples used in this study and collected at Children‘s Mercy Hospitals and Clinics were part of a research study supported by NIH grant R01 058556 (JS Leeder and Yvonne Lin, co-Principal Investigators). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

JV Bonventre is co-inventor on KIM-1 patents, which have been licensed by Partners Healthcare to a number of companies. He has received royalty income from Partners Healthcare and grant funding from Novo Nordisk. JV Bonventre or his family have received income for consulting from companies interested in biomarkers: Sekisui, Millenium, Johnson & Johnson and Novartis. M Pirmohamed is a NIHR Senior Investigator. SJ McWilliam is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant no: G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit. DJ Antoine would like to acknowledge financial support from a Royal Society International Travelling Research Fellowship and the Wellcome Trust. Urine samples used in this study and collected at Children‘s Mercy Hospitals and Clinics were part of a research study supported by NIH grant R01 058556 (JS Leeder and Yvonne Lin, co-Principal Investigators). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.