Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children
Authors: Greenberg Jason H. , Abraham Alison G. , Xu Yunwen , Schelling Jeffrey R. , Feldman Harold I. , Sabbisetti Venkata S. , Ix Joachim H. , Jogalekar Manasi P. , Coca Steven , Waikar Sushrut S. , Shlipak Michael G. , Warady Bradley A. , Vasan Ramachandran S. , Kimmel Paul L. , Bonventre Joseph V. , Denburg Michelle , Parikh Chirag R. , Furth Susan ,   on behalf of the CKD Biomarkers Consortium
Published: September 2021

Significance Statement
Measuring urine biomarkers provides an opportunity to assess kidney tubular health, tubular injury, and inflammation from the filtrate that passes through the tubular lumen. As such, urine biomarkers such as EGF, α-1 microglobulin, KIM-1, MCP-1, and YKL-40 might provide insights into CKD pathophysiology and improve risk prediction of CKD progression in children. In this prospective cohort study of 665 children with CKD, children in the lowest quartile of urine EGF (versus the highest quartile) or those in the highest quartile of urine KIM-1, MCP-1, or α-1 microglobulin concentrations (versus the respective lowest quartiles) were at a significantly higher risk of CKD progression, even after multivariable adjustment. The addition of the five urine biomarkers to a clinical model significantly improved discrimination and reclassification for CKD progression.

Background
Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression.

Methods
We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30–90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4–7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period.

Results
Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression.

Conclusions
After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.