The Associations of Blood Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin with Progression from CKD to ESRD

Abstract

Background and objectives: Elevated levels of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are associated with negative outcomes in CKD. Our study aimed to explore the prognostic accuracy of blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for progression to ESRD, major adverse cardiovascular events, and death in a large cohort of adult patients with all-cause nondialysis-dependent CKD stages 3-5. We considered whether these factors improve prediction in relation to traditional biomarkers and clinical parameters.

Design, setting, participants, & measurements: Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were measured on baseline plasma samples from 1982 patients who were recruited to the Chronic Renal Insufficiency Standards Implementation Study between the start of June of 2002 and the start of June of 2013. Associations with study end points were assessed using Cox regression models, receiver operator characteristic curve analyses, and reclassification statistics.

Results: Over a median follow-up of 29.5 months (interquartile range, 14.9-53.5), 21.6% of patients progressed to ESRD, 27% died, and 6.6% suffered a major adverse cardiovascular event. Higher blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were independently associated with a greater risk for ESRD (hazard ratio, 1.25; 95% confidence interval, 1.10 to 1.43; P<0.001 and hazard ratio, 1.35; 95% confidence interval, 1.14 to 1.59; P≤0.001, respectively, per 1 SD higher biomarker concentration). There was no association with risk for cardiovascular events or death. The addition of biomarkers to our baseline risk model of traditional clinical characteristics and laboratory parameters did not significantly improve model discrimination or risk reclassification.

Conclusions: In patients with moderate to severe CKD, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin blood levels are independent risk factors for progression to ESRD. Additional studies are needed to establish the utility and cost-effectiveness of these novel biomarkers in the clinical setting.

Keywords: Acute-Phase Proteins; Adult; Biomarkers; KIM-1; Kidney Failure, Chronic; LCN2 protein, human; Lipocalins; NGAL; Proto-Oncogene Proteins; ROC Curve; biomarkers; clinical outcomes; follow-up studies; humans; renal dialysis; renal insufficiency, chronic; risk factors; risk prediction.

Figure 1.

(A) Receiver operator characteristic (ROC) curve for progression to ESRD for baseline multivariate model and biomarkers models showing minimal improvement in model discrimination following the addition of the KIM-1 and NGAL. (B) ROC curves for progression stratified for CKD stage. AUC, area under the curve; KIM-1, either kidney injury molecule-1; NGAL, neutrophil gelatinase–associated lipocalin.

Figure 2.

Receiver operator characteristic (ROC) curves showing effect of substituting proteinuria in the multivariate risk model for either kidney injury molecule-1 (KIM-1) and neutrophil gelatinase–associated lipocalin (NGAL) in turn or both biomarkers together in our whole study population and according to stage of CKD. Receiver operator characteristic (ROC) curves demonstrating a fall in model discrimination when kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are substituted for eGFR and no change in discrimination when they are substituted for proteinuria in the multivariate risk model. (A) All CKD stages (B) CKD stage 3 (C) CKD stage 4 (D) CKD stage 5. AUC, area under the curve.