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.
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.
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).
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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Urinary albumin-to-creatinine ratio
Chronic kidney disease
End-stage renal disease
Glomerular filtration rate
Integrated discrimination improvement
Kidney injury molecule 1
Liver fatty acid-binding protein
Limit of detection
Neutrophil gelatinase-associated lipocalin
Translation Research Investigating Biomarker Endpoints for Acute Kidney Injury
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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.
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.
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.
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