TY - JOUR
T1 - Urine biomarkers of kidney tubule health, injury, and inflammation are associated with progression of CKD in children
AU - Greenberg, Jason H.
AU - Abraham, Alison G.
AU - Xu, Yunwen
AU - Schelling, Jeffrey R.
AU - Feldman, Harold I.
AU - Sabbisetti, Venkata S.
AU - Ix, Joachim H.
AU - Jogalekar, Manasi P.
AU - Coca, Steven
AU - Waikar, Sushrut S.
AU - Shlipak, Michael G.
AU - Warady, Bradley A.
AU - Vasan, Ramachandran S.
AU - Kimmel, Paul L.
AU - Bonventre, Joseph V.
AU - Denburg, Michelle
AU - Parikh, Chirag R.
AU - Furth, Susan
N1 - Funding Information:
This research was supported by NIH career development grant K08DK110536 (to J. Greenberg). This research was also supported by the CKD Biomarkers Consortium (NIDDK grants U01 DK085689, U01 DK102730, U01 DK103225, U01 DK085660) to J. Bonventre, S. Coca, H. Feldman, S. Furth, J. Ix, M. Jogalekar, C. Parikh, V. Sabbisetti, J. Schelling, M. Shlipak, R. Vasan, S. Waikar, and Y. Xu. C. Parikh is supported by NIH grants K24DK090203, R01HL085757, U01DK082185, and P30DK079310-07 O’Brien Center Grant. J. Bonventre is supported by NIH grants R37DK039773 and R01DKD072381. S. Furth is supported by the NIH K24DK078737 and U01DK66174. The CKiD study is funded by the NIDDK, with additional funding from the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116).
Funding Information:
Interventions (spouse); reports receiving research funding from Mallinck-rodt; reports being a scientific advisor or member of the National Kidney Foundation Delaware Valley Medical Advisory Board and Trisalus Life Sciences Scientific Advisory Board (spouse); and reports other interests/relationships with the American Society of Pediatric Nephrology Research and Program Committees, and National Kidney Foundation Pediatric Education Planning Committee. M. Shlipak reports consultancy agreements with Cricket Health, Intercept Pharmaceuticals, University of Washington Cardiovascular Health Study, University of North Carolina at Chapel Hill, and Veterans Medical Research Foundation; reports having an ownership interest in Transplant and Immunology Diagnostics; reports receiving research funding from Bayer Pharmaceuticals; reports receiving honoraria from University of California at Irvine; reports being a scientific advisor or member of the American Journal of Kidney Disease, Circulation, Journal of the American Society of Nephrology, TAI Diagnostics; and reports other interests/relationships as a Board Member of Northern California Institute for Research and Education. P. Kimmel reports other interests/relationships as Co-Editor of Chronic Renal Disease Academic Press, Co-Editor of Psychosocial Aspects of Chronic Kidney Disease; and reports receiving Academic Press Royalties. S. Coca reports consultancy agreements with Akebia, Bayer, Boehringer Ingelheim, Congestive Heart Failure Solutions, Quark, RenalytixAI, Relypsa, and Takeda; reports having an ownership interest in pulseData and RenalytixAI; reports receiving research funding from inRegen and RenalytixAI; reports patents and inventions with Renaly-tixAI; reports being a scientific advisor or member of RenalytixAI; and reports other interests/relationships as Associate Editor for Kidney360, Editorial Board CJASN, JASN, and Kidney International. S. Waikar reports consultancy agreements with Allena, BioMarin, Consumer Value Stores, GlaxoSmithKline, Johnson & Johnson, Mallinckrodt, Mass Medical International, Metro Biotechnology, Oxidien, Pfizer, Regeneron, Roth Capital Partners, Sironax, Strataca/3ive, Venbio, and Wolters Kluwer; reports receiving research funding from Vertex; reports being a scientific advisor or member with Kantum (scientific advisory board); and other interests/relationships as an expert witness for litigation related to the General Electric product Omniscan, expert witness for litigation related to Fresenius product Granu-flo, expert witness for litigation involving cisplatin toxicity, expert witness for litigation related to Gilead product tenofovir, and expert witness for litigation related to DaVita lab testing. V. Ramachandran reports consultancy agreements with NIDDK. V. Sabbisetti reports patents and inventions via patents on plasma Kim-1. All remaining authors have nothing to disclose.
Publisher Copyright:
© 2021 by the American Society of Nephrology.
PY - 2021/10
Y1 - 2021/10
N2 - 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 a-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 a-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 a-1 microglobulin concentrations were each associated with CKD progression in children.
AB - 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 a-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 a-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 a-1 microglobulin concentrations were each associated with CKD progression in children.
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U2 - 10.1681/ASN.2021010094
DO - 10.1681/ASN.2021010094
M3 - Article
C2 - 34544821
AN - SCOPUS:85116515937
VL - 32
SP - 2664
EP - 2677
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 10
ER -