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Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus

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Abstract

Aims/hypothesis

Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-d-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes.

Methods

Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP.

Results

During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042).

Conclusions/interpretation

In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic.

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Abbreviations

ACE:

Angiotensin-converting enzyme

Alb/Cr:

Urinary albumin-to-creatinine ratio

CKD:

Chronic kidney disease

Cr:

Creatinine

ESRD:

End-stage renal disease

GFR:

Glomerular filtration rate

IDI:

Integrated discrimination improvement

IQR:

Interquartile range

KIM-1:

Kidney injury molecule 1

L-FABP:

Liver fatty acid-binding protein

LOD:

Limit of detection

NAG:

N-acetyl-β-d-glucosaminidase

NGAL:

Neutrophil gelatinase-associated lipocalin

TRIBE-AKI:

Translation Research Investigating Biomarker Endpoints for Acute Kidney Injury

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Acknowledgements

We thank Abbott Laboratories for supporting the measurement of urinary NGAL and CMIC for providing control materials for our studies. Abbott Laboratories and CMIC had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank E. Cotter at University College Dublin, Dublin, Ireland for performing the urinary NGAL assays and M. J. Pencina at Duke University, Durham, NC, USA for his suggestions on how to assess the incremental value of markers added to risk prediction models. Parts of this study were presented in abstract form at the American Society of Nephrology annual meeting and scientific exposition in Atlanta, Georgia, 7–10 November 2013.

Funding

This work was supported by the Chronic Kidney Disease Biomarker Consortium funded by NIDDK U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651 and U01DK085689, and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.

Duality of interest

JVB appears as 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. KDL had reagents donated for previous biomarker studies by Abbott and CMIC. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Contribution statement

RGN, CyH, KDL, GDF, EJW, JVB and SSW designed the study with input into the study protocol from all authors. TEM, VS and JVB performed the biomarker assays. GDF, EJW, RGN, RLH, XZ and DX performed the statistical analyses. GDF, EJW, RGN and KDL drafted the manuscript and all authors assisted with revising it critically for important intellectual content. All authors contributed to the interpretation of the data and approved the final version. RGN is the guarantor of this work.

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Authors and Affiliations

  1. Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ, 85014-4972, USA

    Gudeta D. Fufaa, E. Jennifer Weil, Robert G. Nelson & Robert L. Hanson

  2. Renal Division and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joseph V. Bonventre, Venkata Sabbisetti & Sushrut S. Waikar

  3. Translational Core Laboratory (TCL), Smilow Center for Translational Research (SCTR), University of Pennsylvania, Philadelphia, PA, USA

    Theodore E. Mifflin

  4. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Xiaoming Zhang, Dawei Xie & Harold I. Feldman

  5. Division of Nephrology, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA

    Chi-yuan Hsu & Kathleen D. Liu

  6. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Harold I. Feldman

  7. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Harold I. Feldman

  8. Department of Epidemiology and Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Josef Coresh

  9. Department of Medicine, Johns Hopkins Hospital, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Josef Coresh

  10. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Ramachandran S. Vasan

  11. Division of Kidney Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Paul L. Kimmel

Authors
  1. Gudeta D. Fufaa
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  2. E. Jennifer Weil
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  3. Robert G. Nelson
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  4. Robert L. Hanson
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  5. Joseph V. Bonventre
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  6. Venkata Sabbisetti
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  7. Sushrut S. Waikar
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  8. Theodore E. Mifflin
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  9. Xiaoming Zhang
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  10. Dawei Xie
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  11. Chi-yuan Hsu
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  12. Harold I. Feldman
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  13. Josef Coresh
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  14. Ramachandran S. Vasan
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  15. Paul L. Kimmel
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  16. Kathleen D. Liu
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for the Chronic Kidney Disease Biomarkers Consortium Investigators

Corresponding author

Correspondence to Robert G. Nelson.

Additional information

Gudeta D. Fufaa and E. Jennifer Weil contributed equally to this paper.

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Fufaa, G.D., Weil, E.J., Nelson, R.G. et al. Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia 58, 188–198 (2015). https://doi.org/10.1007/s00125-014-3389-3

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