Plasma and Urine Biomarkers of CKD: A Review of Findings in the CKiD Study

Abstract

Serum creatinine and level of proteinuria, as biomarkers of chronic kidney disease (CKD) progression, inadequately explain the variability of glomerular filtration rate decline, and are late markers of glomerular filtration rate decline. Recent studies have identified plasma and urine biomarkers at higher levels in children with CKD and also associate independently with CKD progression, even after adjustment for serum creatinine and proteinuria. These novel biomarkers represent diverse biologic pathways of tubular injury, tubular dysfunction, inflammation, and tubular health, and can be used as a liquid biopsy to better characterize CKD in children. In this review, we highlight the biomarker findings from the Chronic Kidney Disease in Children cohort, a large longitudinal study of children with CKD, and compare results with those from other pediatric CKD cohorts. The biomarkers in focus in this review include plasma kidney injury molecule-1, monocyte chemoattractant protein-1, fibroblast growth factor-23, tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase plasminogen activator receptor, and chitinase-3-like protein 1, as well as urine epidermal growth factor, α-1 microglobulin, kidney injury molecule-1, monocyte chemoattractant protein-1, and chitinase-3-like protein 1. Blood and urine biomarkers improve our ability to prognosticate CKD progression and may improve our understanding of CKD pathophysiology. Further research is required to establish how these biomarkers can be used in the clinical setting to improve the clinical management of CKD.

Keywords: Biomarker; CKD progression; chronic kidney disease; end-stage kidney disease; kidney injury; pediatrics.

Conflict of interest statement

Financial support and conflict of interest: Authors disclose no conflict of interest.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Novel plasma and urine biomarkers of CKD progression along the nephron, in the blood, kidney tubular cells, and the urinary space.[12] EGF, epidermal growth factor; FGF23, fibroblast growth factor 23; KIM-1, kidney injury molecule-1; suPAR, soluble urokinase plasminogen activator receptor; TNFR-1, TNF-α receptor type 1; TNFR-2, TNF-α receptor type 2, α−1 MG, alpha-1-microglobulin.

Figure 2:

Baseline Urine EGF, Urine KIM-1, and Plasma KIM-1 Concentrations by CKD Progression in the CKiD cohort. Urine biomarkers were indexed to urine creatinine.

Figure 3:

Adjusted hazard ratios for CKD progression according to doubling of urine biomarker levels in the CKiD study (except for EGF which is per halving) […]. α−1 MG, alpha-1-microglobulin; EGF, epidermal growth factor; KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1. The urine biomarker is indexed to urine creatinine to adjust for urine concentration.

Figure 4:

Plasma KIM-1 concentration by Etiology of Kidney Disease. Units of plasma KIM-1 is expressed in pg/ml.

Figure 5:

Risk of CKD progression in the CKiD cohort by conventional biomarkers and novel biomarker-based classification. The optimal cutoffs were determined by maximizing sensitivity and specificity: Urine Protein/Cr≥0.685 mg/mg, GFR≥60, urine EGF≥34.82 (pg/ml)/(mg/dl), and urine KIM-1≥ 18.26 (pg/ml)/(mg/dl)

Figure 6:

Adjusted hazard ratios for CKD progression according to doubling of plasma biomarker levels in the CKiD study[12]. KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; suPAR, soluble urokinase plasminogen activator receptor; TNFR-1, TNF-α receptor type 1; TNFR-2, TNF-α receptor type 2.

Figure 7:

Urine MCP-1 concentrations by etiology of kidney disease. Urine MCP-1 is indexed to urine creatinine to adjust for urine concentration. Units of urine MCP-1 indexed to urine creatinine is (pg/ml)/(mg/dl)