Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children

• Published in: Journal of the American Society of Nephrology 2020-05, Vol.31 (5), p.1067-1077
• Main 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
• Format: Article
• Language: English
• Subjects: Adolescent; Biomarkers; Chemokine CCL2 - blood; Child; Chitinase-3-Like Protein 1 - blood; Clinical Research; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1 - blood; Humans; Inflammation - blood; Kidney Tubules - metabolism; Kidney Tubules - pathology; Male; Proportional Hazards Models; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I - blood; Receptors, Tumor Necrosis Factor, Type II - blood; Receptors, Urokinase Plasminogen Activator - blood; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - pathology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2019070723

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. 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 m 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. Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m ), 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. Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.