Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study

Sam Hayward; Nicholas C. Chesnaye; Barnaby Hole; Ryan E Aylward; Yvette  Meuleman; Claudia Torino; Gaetana Porto; Maciej Szymczak; Christiane Drechsler; Friedo W. Dekker; Marie  Evans; Kitty J Jager; Christoph Wanner; Fergus J Caskey

doi:10.1016/j.xkme.2023.100745

Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study

Sam Hayward, Nicholas C. Chesnaye, Barnaby Hole, Ryan E Aylward, Yvette Meuleman, Claudia Torino, Gaetana Porto, Maciej Szymczak, Christiane Drechsler, Friedo W. Dekker, Marie Evans, Kitty J Jager, Christoph Wanner, Fergus J Caskey

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

RATIONALE & OBJECTIVE: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).

STUDY DESIGN: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2.

SETTING & PARTICIPANTS: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).

EXPOSURE: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.

OUTCOME: MACE.

ANALYTICAL APPROACH: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.

RESULTS: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.

LIMITATIONS: Single protein concentration measurements and limited follow-up time.

CONCLUSIONS: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies.

PLAIN-LANGUAGE SUMMARY: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

Original language	English
Article number	100745
Pages (from-to)	100745
Journal	Kidney Medicine
Volume	6
Issue number	13
Early online date	2 Nov 2023
DOIs	https://doi.org/10.1016/j.xkme.2023.100745
Publication status	Published - 1 Jan 2024

Bibliographical note

Funding Information:
Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author’s salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

Funding Information:
A list of investigators is provided in Item S1. Samantha J.L. Hayward, MBChB, Nicholas C. Chesnaye, PhD, Barnaby Hole, PhD, Ryan Aylward, MBChB, Yvette Meuleman, PhD, Claudia Torino, PhD, Gaetana Porto, MSc, Maciej Szymczak, PhD, Christiane Drechsler, PhD, Friedo W. Dekker, PhD, Marie Evans, PhD, Kitty J. Jager, PhD, Christoph Wanner, MD, and Fergus J. Caskey, MD, on behalf of the EQUAL investigators. Research idea: SJLH, BH, and FJC; data and statistical analysis: SJLH, BH, FJC, RA, and NCC; data interpretation: all authors. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author's salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The authors declare that they have no relevant financial interests. We would like to thank all the participants and health professionals participating in the EQUAL study. For a full list of EQUAL contributors, see Item S1. The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. Received February 22, 2023. Evaluated by 1 external peer reviewer, with direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form August 24, 2023.

Publisher Copyright:
© 2023 The Authors

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Hayward, S., Chesnaye, N. C., Hole, B., Aylward, R. E., Meuleman, Y., Torino, C., Porto, G., Szymczak, M., Drechsler, C., Dekker, F. W., Evans, M., Jager, K. J., Wanner, C., & Caskey, F. J. (2024). Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study. Kidney Medicine, 6(13), 100745. Article 100745. https://doi.org/10.1016/j.xkme.2023.100745

@article{5046edf9ba5e4818bb0cceda920c13da,

title = "Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study",

abstract = "RATIONALE \& OBJECTIVE: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).STUDY DESIGN: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2.SETTING \& PARTICIPANTS: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).EXPOSURE: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.OUTCOME: MACE.ANALYTICAL APPROACH: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.RESULTS: During a median follow-up of 2.9 years, 349 people (39\%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.LIMITATIONS: Single protein concentration measurements and limited follow-up time.CONCLUSIONS: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies.PLAIN-LANGUAGE SUMMARY: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.",

author = "Sam Hayward and Chesnaye, \{Nicholas C.\} and Barnaby Hole and Aylward, \{Ryan E\} and Yvette Meuleman and Claudia Torino and Gaetana Porto and Maciej Szymczak and Christiane Drechsler and Dekker, \{Friedo W.\} and Marie Evans and Jager, \{Kitty J\} and Christoph Wanner and Caskey, \{Fergus J\}",

note = "Funding Information: Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author{\textquoteright}s salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Funding Information: A list of investigators is provided in Item S1. Samantha J.L. Hayward, MBChB, Nicholas C. Chesnaye, PhD, Barnaby Hole, PhD, Ryan Aylward, MBChB, Yvette Meuleman, PhD, Claudia Torino, PhD, Gaetana Porto, MSc, Maciej Szymczak, PhD, Christiane Drechsler, PhD, Friedo W. Dekker, PhD, Marie Evans, PhD, Kitty J. Jager, PhD, Christoph Wanner, MD, and Fergus J. Caskey, MD, on behalf of the EQUAL investigators. Research idea: SJLH, BH, and FJC; data and statistical analysis: SJLH, BH, FJC, RA, and NCC; data interpretation: all authors. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author's salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The authors declare that they have no relevant financial interests. We would like to thank all the participants and health professionals participating in the EQUAL study. For a full list of EQUAL contributors, see Item S1. The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. Received February 22, 2023. Evaluated by 1 external peer reviewer, with direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form August 24, 2023. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = jan,

day = "1",

doi = "10.1016/j.xkme.2023.100745",

language = "English",

volume = "6",

pages = "100745",

journal = "Kidney Medicine",

issn = "2590-0595",

publisher = "Elsevier Inc.",

number = "13",

}

Hayward, S, Chesnaye, NC, Hole, B, Aylward, RE, Meuleman, Y, Torino, C, Porto, G, Szymczak, M, Drechsler, C, Dekker, FW, Evans, M, Jager, KJ, Wanner, C & Caskey, FJ 2024, 'Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study', Kidney Medicine, vol. 6, no. 13, 100745, pp. 100745. https://doi.org/10.1016/j.xkme.2023.100745

TY - JOUR

T1 - Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD

T2 - The European Quality (EQUAL) Study

AU - Hayward, Sam

AU - Chesnaye, Nicholas C.

AU - Hole, Barnaby

AU - Aylward, Ryan E

AU - Meuleman, Yvette

AU - Torino, Claudia

AU - Porto, Gaetana

AU - Szymczak, Maciej

AU - Drechsler, Christiane

AU - Dekker, Friedo W.

AU - Evans, Marie

AU - Jager, Kitty J

AU - Wanner, Christoph

AU - Caskey, Fergus J

N1 - Funding Information: Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author’s salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Funding Information: A list of investigators is provided in Item S1. Samantha J.L. Hayward, MBChB, Nicholas C. Chesnaye, PhD, Barnaby Hole, PhD, Ryan Aylward, MBChB, Yvette Meuleman, PhD, Claudia Torino, PhD, Gaetana Porto, MSc, Maciej Szymczak, PhD, Christiane Drechsler, PhD, Friedo W. Dekker, PhD, Marie Evans, PhD, Kitty J. Jager, PhD, Christoph Wanner, MD, and Fergus J. Caskey, MD, on behalf of the EQUAL investigators. Research idea: SJLH, BH, and FJC; data and statistical analysis: SJLH, BH, FJC, RA, and NCC; data interpretation: all authors. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Main funding was received from the European Renal Association (ERA) and contributions from the Swedish Medical Association (SLS), the Stockholm County Council ALF Medicine and Center for Innovative Research (CIMED), the Italian Society of Nephrology (SIN-Reni), the Dutch Kidney Foundation (SB 142), the Young Investigators Grant in Germany, and the National Institute for Health Research in the United Kingdom. The Medical Research Council funded the first author's salary, and specific funding for this project was obtained from Bristol Health Research Charity. Funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The authors declare that they have no relevant financial interests. We would like to thank all the participants and health professionals participating in the EQUAL study. For a full list of EQUAL contributors, see Item S1. The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. Received February 22, 2023. Evaluated by 1 external peer reviewer, with direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form August 24, 2023. Publisher Copyright: © 2023 The Authors

PY - 2024/1/1

Y1 - 2024/1/1

N2 - RATIONALE & OBJECTIVE: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).STUDY DESIGN: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2.SETTING & PARTICIPANTS: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).EXPOSURE: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.OUTCOME: MACE.ANALYTICAL APPROACH: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.RESULTS: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.LIMITATIONS: Single protein concentration measurements and limited follow-up time.CONCLUSIONS: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies.PLAIN-LANGUAGE SUMMARY: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

AB - RATIONALE & OBJECTIVE: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).STUDY DESIGN: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m2.SETTING & PARTICIPANTS: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).EXPOSURE: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.OUTCOME: MACE.ANALYTICAL APPROACH: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.RESULTS: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.LIMITATIONS: Single protein concentration measurements and limited follow-up time.CONCLUSIONS: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies.PLAIN-LANGUAGE SUMMARY: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

U2 - 10.1016/j.xkme.2023.100745

DO - 10.1016/j.xkme.2023.100745

M3 - Article (Academic Journal)

C2 - 38162538

SN - 2590-0595

VL - 6

SP - 100745

JO - Kidney Medicine

JF - Kidney Medicine

IS - 13

M1 - 100745

ER -

Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study

Abstract

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