Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children
Authors: Greenberg Jason H. , Abraham Alison G. , Xu Yunwen , Schelling Jeffrey R. , Feldman Harold I. , Sabbisetti Venkata S. , Gonzalez Mariana Cardenas , Coca Steven , Schrauben Sarah J. , Waikar Sushrut S. , Ramachandran Vasan S. , Shlipak Michael G. , Warady Bradley , Kimmel Paul L. , Bonventre Joseph V. , Denburg Michelle , Parikh Chirag R. , Furth Susan ,   on behalf of the CKD Biomarkers Consortium
Published: March 2020

Significance Statement
Identifying novel biomarkers of kidney function decline in children may have clinical value and help elucidate the biologic mechanisms of CKD progression. In the CKiD prospective cohort study, the authors evaluated 651 children with CKD and measured biomarkers in plasma collected 5 months after enrollment. After multivariable adjustment, risk of CKD progression was significantly higher among children with concentrations of a biomarker of tubular injury (KIM-1) or either of two biomarkers of inflammation (TNF receptor–1 [TNFR-1] and TNFR-2) in the highest quartile compared with those with concentrations in the lowest quartile for the respective biomarker. Use of plasma KIM-1, TNFR-1, and TNFR-2 as biomarkers of ongoing tubular damage and inflammation may identify children at increased risk of CKD progression.

Background
After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline.

Methods
We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30–90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD.

Results
Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly.

Conclusions
Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.