Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children
Jason H Greenberg, Alison G Abraham, Yunwen Xu, Jeffrey R Schelling, Harold I Feldman, Venkata S Sabbisetti, Joachim H Ix, Manasi P Jogalekar, Steven Coca, Sushrut S Waikar, Michael G Shlipak, Bradley A Warady, Ramachandran S Vasan, Paul L Kimmel, Joseph V Bonventre, Michelle Denburg, Chirag R Parikh, Susan Furth, CKD Biomarkers Consortium, CKD Biomarker consortium, Vasan S Ramachandran, Jeffrey Schelling, Michelle Denburg, Susan Furth, Bradley Warady, Joseph Bonventre, Sushrut Waikar, Venkata Sabbisetti, Josef Coresh, Morgan Grams, Casey Rebholz, Alison Abraham, Chirag Parikh, Steven Coca, Eugene Rhee, Paul L Kimmel, John W Kusek, Brad Rovin, Michael G Shlipak, Mark Sarnak, Orlando M Gutiérrez, Joachim Ix, Ruth Dubin, Tom Hostetter, Rajat Deo, Harold I Feldman, Dawei Xie, Haochang Shou, Shawn Ballard, Krista Whitehead, Heather Collins, Jason H Greenberg, Peter Ganz, Jason H Greenberg, Alison G Abraham, Yunwen Xu, Jeffrey R Schelling, Harold I Feldman, Venkata S Sabbisetti, Joachim H Ix, Manasi P Jogalekar, Steven Coca, Sushrut S Waikar, Michael G Shlipak, Bradley A Warady, Ramachandran S Vasan, Paul L Kimmel, Joseph V Bonventre, Michelle Denburg, Chirag R Parikh, Susan Furth, CKD Biomarkers Consortium, CKD Biomarker consortium, Vasan S Ramachandran, Jeffrey Schelling, Michelle Denburg, Susan Furth, Bradley Warady, Joseph Bonventre, Sushrut Waikar, Venkata Sabbisetti, Josef Coresh, Morgan Grams, Casey Rebholz, Alison Abraham, Chirag Parikh, Steven Coca, Eugene Rhee, Paul L Kimmel, John W Kusek, Brad Rovin, Michael G Shlipak, Mark Sarnak, Orlando M Gutiérrez, Joachim Ix, Ruth Dubin, Tom Hostetter, Rajat Deo, Harold I Feldman, Dawei Xie, Haochang Shou, Shawn Ballard, Krista Whitehead, Heather Collins, Jason H Greenberg, Peter Ganz
Abstract
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.
Keywords: children; chronic kidney disease; end-stage kidney disease; pediatric nephrology.
Copyright © 2021 by the American Society of Nephrology.
Figures
Source: PubMed