Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes

Maria Loredana Marcovecchio; Marco Colombo; Raymond Neil Dalton; Paul M. McKeigue; Paul Benitez-Aguirre; Fergus J. Cameron; Scott T. Chiesa; Jennifer J. Couper; Maria E. Craig; Denis Daneman; Elizabeth A. Davis; John E. Deanfield; Kim C. Donaghue; Timothy W. Jones; Farid H. Mahmud; Sally M. Marshall; Andrew Neil; Helen M. Colhoun; David B. Dunger

doi:10.1111/pedi.13095

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes

, Maria Loredana Marcovecchio (Lead / Corresponding author), Marco Colombo, Raymond Neil Dalton, Paul M. McKeigue, Paul Benitez-Aguirre, Fergus J. Cameron, Scott T. Chiesa, Jennifer J. Couper, Maria E. Craig, Denis Daneman, Elizabeth A. Davis, John E. Deanfield, Kim C. Donaghue, Timothy W. Jones, Farid H. Mahmud, Sally M. Marshall, Andrew Neil, Helen M. Colhoun, David B. Dunger

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Abstract

Objectives: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Methods: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <−3 and > 3 mL/min/1.73m²/year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource.

Results: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: −0.19 [−0.27, −0.12], P = 7.0 × 10⁻⁷; −0.18 [−0.26, −0.11], P = 5.1 × 10⁻⁶; −0.12 [−0.20, −0.05], P = 1.6 × 10⁻³), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (−0.21 [−0.28, −0.14], P = 2.3 × 10⁻⁸) and cystatin C (−0.16 [−0.22, −0.09], P = 1.6 × 10⁻⁶). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10⁻⁶), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10⁻⁴). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR.

Conclusions: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Original language	English
Pages (from-to)	1322-1332
Number of pages	11
Journal	Pediatric Diabetes
Volume	21
Issue number	7
Early online date	17 Aug 2020
DOIs	https://doi.org/10.1111/pedi.13095
Publication status	Published - Nov 2022

Keywords

adolescents
biomarkers
complications
GFR
kidney disease

ASJC Scopus subject areas

Internal Medicine
Pediatrics, Perinatology, and Child Health
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/pedi.13095Licence: CC BY-NC-ND

Final Published VersionFinal published version, 1.79 MBLicence: CC BY-NC-ND

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, Marcovecchio, M. L., Colombo, M., Dalton, R. N., McKeigue, P. M., Benitez-Aguirre, P., Cameron, F. J., Chiesa, S. T., Couper, J. J., Craig, M. E., Daneman, D., Davis, E. A., Deanfield, J. E., Donaghue, K. C., Jones, T. W., Mahmud, F. H., Marshall, S. M., Neil, A., & Colhoun, H. M., & Dunger, D. B. (2022). Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes. Pediatric Diabetes, 21(7), 1322-1332. https://doi.org/10.1111/pedi.13095

@article{1f593d7750e540fea1aee5682be26122,

title = "Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes",

abstract = "Objectives: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Methods: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <−3 and > 3 mL/min/1.73m2/year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. Results: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: −0.19 [−0.27, −0.12], P = 7.0 × 10−7; −0.18 [−0.26, −0.11], P = 5.1 × 10−6; −0.12 [−0.20, −0.05], P = 1.6 × 10−3), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (−0.21 [−0.28, −0.14], P = 2.3 × 10−8) and cystatin C (−0.16 [−0.22, −0.09], P = 1.6 × 10−6). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10−6), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10−4). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. Conclusions: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.",

keywords = "adolescents, biomarkers, complications, GFR, kidney disease",

author = "Marcovecchio, {Maria Loredana} and Marco Colombo and Dalton, {Raymond Neil} and McKeigue, {Paul M.} and Paul Benitez-Aguirre and Cameron, {Fergus J.} and Chiesa, {Scott T.} and Couper, {Jennifer J.} and Craig, {Maria E.} and Denis Daneman and Davis, {Elizabeth A.} and Deanfield, {John E.} and Donaghue, {Kim C.} and Jones, {Timothy W.} and Mahmud, {Farid H.} and Marshall, {Sally M.} and Andrew Neil and Colhoun, {Helen M.} and Dunger, {David B.} and Acerini, {Carlo L.} and Frank Ackland and Binu Anand and Tim Barrett and Virginia Birrell and Fiona Campbell and Marietta Charakida and Tim Cheetham and Chris Cooper and Ian Doughty and Atanu Dutta and Julie Edge and Alastair Gray and Julian Hamilton-Shield and Nick Mann and Loredana, {Marcovecchio M.} and H. Andrew and W. Neil and Gerry Rayman and Robinson, {Jonathon M.} and Michelle Russell-Taylor and Vengudi Sankar and Anne Smith and Nandu Thalange and Chandan Yaliwal and Fergus Cameron and Andrew Cotterill and Jennifer Couper and Maria Craig and Elizabeth Davis and Kim Donaghue and Bruce King and Charles Verge and Phil Bergman and Christine Rodda and Cheril Clarson and Jacqueline Curtis and Etienne Sochett and John Chalmers and Andrew Collier and Colin Fischbacher",

note = "Funding Information: This study was supported by funding from Juvenile Diabetes Research Foundation (Ref. 1‐SRA‐2016‐333‐M‐R). The AdDIT study was funded by Diabetes UK, Juvenile Diabetes Research Foundation, the British Heart Foundation and in Canada the JDRF‐Canadian Clinical Trial Network (CCTN), the Canadian Diabetes Association and the Heart and Stroke Foundation Canada. The SDRNT1BIO cohort was funded by Chief Scientists Office Scotland and Diabetes UK. Funding Information: This study was supported by funding from Juvenile Diabetes Research Foundation (Ref. 1-SRA-2016-333-M-R). The AdDIT study was funded by Diabetes UK, Juvenile Diabetes Research Foundation, the British Heart Foundation and in Canada the JDRF-Canadian Clinical Trial Network (CCTN), the Canadian Diabetes Association and the Heart and Stroke Foundation Canada. The SDRNT1BIO cohort was funded by Chief Scientists Office Scotland and Diabetes UK. Funding Information: H. M. C. reports grants and personal fees from Eli Lily and Company, during the conduct of the study. Grants from AstraZeneca LP, other from Novartis Pharmaceuticals, grants from Regeneron, grants from Pfizer Inc, other from Roche Pharmaceuticals, other from Sanofi Aventis, grants and personal fees from Novo Nordisk, outside the submitted work. The other coauthors do not have any duality of interest associated with their contribution to this manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.",

year = "2022",

month = nov,

doi = "10.1111/pedi.13095",

language = "English",

volume = "21",

pages = "1322--1332",

journal = "Pediatric Diabetes",

issn = "1399-543X",

publisher = "Wiley",

number = "7",

}

Marcovecchio, ML, Colombo, M, Dalton, RN, McKeigue, PM, Benitez-Aguirre, P, Cameron, FJ, Chiesa, ST, Couper, JJ, Craig, ME, Daneman, D, Davis, EA, Deanfield, JE, Donaghue, KC, Jones, TW, Mahmud, FH, Marshall, SM, Neil, A & Colhoun, HM & Dunger, DB 2022, 'Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes', Pediatric Diabetes, vol. 21, no. 7, pp. 1322-1332. https://doi.org/10.1111/pedi.13095

TY - JOUR

T1 - Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes

AU - Marcovecchio, Maria Loredana

AU - Colombo, Marco

AU - Dalton, Raymond Neil

AU - McKeigue, Paul M.

AU - Benitez-Aguirre, Paul

AU - Cameron, Fergus J.

AU - Chiesa, Scott T.

AU - Couper, Jennifer J.

AU - Craig, Maria E.

AU - Daneman, Denis

AU - Davis, Elizabeth A.

AU - Deanfield, John E.

AU - Donaghue, Kim C.

AU - Jones, Timothy W.

AU - Mahmud, Farid H.

AU - Marshall, Sally M.

AU - Neil, Andrew

AU - Colhoun, Helen M.

AU - Dunger, David B.

AU - Acerini, Carlo L.

AU - Ackland, Frank

AU - Anand, Binu

AU - Barrett, Tim

AU - Birrell, Virginia

AU - Campbell, Fiona

AU - Charakida, Marietta

AU - Cheetham, Tim

AU - Cooper, Chris

AU - Doughty, Ian

AU - Dutta, Atanu

AU - Edge, Julie

AU - Gray, Alastair

AU - Hamilton-Shield, Julian

AU - Mann, Nick

AU - Loredana , Marcovecchio M.

AU - Andrew, H.

AU - Neil, W.

AU - Rayman, Gerry

AU - Robinson, Jonathon M.

AU - Russell-Taylor, Michelle

AU - Sankar, Vengudi

AU - Smith, Anne

AU - Thalange, Nandu

AU - Yaliwal, Chandan

AU - Cameron, Fergus

AU - Cotterill, Andrew

AU - Couper, Jennifer

AU - Craig, Maria

AU - Davis, Elizabeth

AU - Donaghue, Kim

AU - King, Bruce

AU - Verge, Charles

AU - Bergman, Phil

AU - Rodda, Christine

AU - Clarson, Cheril

AU - Curtis, Jacqueline

AU - Sochett, Etienne

AU - Chalmers, John

AU - Collier, Andrew

AU - Fischbacher, Colin

N1 - Funding Information: This study was supported by funding from Juvenile Diabetes Research Foundation (Ref. 1‐SRA‐2016‐333‐M‐R). The AdDIT study was funded by Diabetes UK, Juvenile Diabetes Research Foundation, the British Heart Foundation and in Canada the JDRF‐Canadian Clinical Trial Network (CCTN), the Canadian Diabetes Association and the Heart and Stroke Foundation Canada. The SDRNT1BIO cohort was funded by Chief Scientists Office Scotland and Diabetes UK. Funding Information: This study was supported by funding from Juvenile Diabetes Research Foundation (Ref. 1-SRA-2016-333-M-R). The AdDIT study was funded by Diabetes UK, Juvenile Diabetes Research Foundation, the British Heart Foundation and in Canada the JDRF-Canadian Clinical Trial Network (CCTN), the Canadian Diabetes Association and the Heart and Stroke Foundation Canada. The SDRNT1BIO cohort was funded by Chief Scientists Office Scotland and Diabetes UK. Funding Information: H. M. C. reports grants and personal fees from Eli Lily and Company, during the conduct of the study. Grants from AstraZeneca LP, other from Novartis Pharmaceuticals, grants from Regeneron, grants from Pfizer Inc, other from Roche Pharmaceuticals, other from Sanofi Aventis, grants and personal fees from Novo Nordisk, outside the submitted work. The other coauthors do not have any duality of interest associated with their contribution to this manuscript. Publisher Copyright: © 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.

PY - 2022/11

Y1 - 2022/11

N2 - Objectives: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Methods: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <−3 and > 3 mL/min/1.73m2/year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. Results: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: −0.19 [−0.27, −0.12], P = 7.0 × 10−7; −0.18 [−0.26, −0.11], P = 5.1 × 10−6; −0.12 [−0.20, −0.05], P = 1.6 × 10−3), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (−0.21 [−0.28, −0.14], P = 2.3 × 10−8) and cystatin C (−0.16 [−0.22, −0.09], P = 1.6 × 10−6). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10−6), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10−4). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. Conclusions: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

AB - Objectives: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Methods: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <−3 and > 3 mL/min/1.73m2/year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. Results: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: −0.19 [−0.27, −0.12], P = 7.0 × 10−7; −0.18 [−0.26, −0.11], P = 5.1 × 10−6; −0.12 [−0.20, −0.05], P = 1.6 × 10−3), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (−0.21 [−0.28, −0.14], P = 2.3 × 10−8) and cystatin C (−0.16 [−0.22, −0.09], P = 1.6 × 10−6). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10−6), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10−4). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. Conclusions: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

KW - adolescents

KW - biomarkers

KW - complications

KW - GFR

KW - kidney disease

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U2 - 10.1111/pedi.13095

DO - 10.1111/pedi.13095

M3 - Article

C2 - 32783254

AN - SCOPUS:85089441364

SN - 1399-543X

VL - 21

SP - 1322

EP - 1332

JO - Pediatric Diabetes

JF - Pediatric Diabetes

IS - 7

ER -

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes

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