Jason H Greenberg1,2, Alison G Abraham3, Yunwen Xu3, Jeffrey R Schelling4, Harold I Feldman5, Venkata S Sabbisetti6, Mariana Cardenas Gonzalez6, Steven Coca7, Sarah J Schrauben5, Sushrut S Waikar6, Vasan S Ramachandran8, Michael G Shlipak9, Bradley Warady10, Paul L Kimmel11, Joseph V Bonventre6, Michelle Denburg12, Chirag R Parikh13, Susan Furth12. 1. Department of Pediatrics, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut jason.greenberg@yale.edu. 2. Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut. 3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 4. Division of Nephrology, Department of Internal Medicine, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio. 5. Department of Medicine, Clinical Center for Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 6. Department of Internal Medicine, Section of Nephrology, Brigham and Women's Hospital, Boston, Massachusetts. 7. Department of Internal Medicine, Section of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York. 8. Departments of Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts. 9. Department of Medicine, University of California, San Francisco, California. 10. Division of Nephrology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri. 11. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 12. Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 13. Department of Internal Medicine, Section of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Abstract
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.
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.
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