Related Experiment Video
Updated: Jul 6, 2025
Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL)
Samantha J L Hayward1,2, Nicholas C Chesnaye3,4, Barnaby Hole2,5
1Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
Insights
Cardiovascular disease is common in chronic kidney disease (CKD). This study identified 9 proteins associated with major adverse cardiovascular events (MACE) in older adults with CKD, with 3 showing strong predictive value for MACE.
Area of Science:
- Cardiovascular research
- Nephrology
- Biomarker discovery
Background:
- Cardiovascular disease (CVD) is the primary cause of death in patients with chronic kidney disease (CKD).
- Identifying reliable biomarkers for major adverse cardiovascular events (MACE) in CKD is crucial for risk stratification and management.
- Previous research has explored various protein biomarkers, but a comprehensive analysis in a well-defined CKD cohort is needed.
Purpose of the Study:
- To investigate the potential of 184 inflammatory and cardiovascular proteins as biomarkers for predicting MACE in older adults with severe CKD.
- To identify novel protein biomarkers associated with MACE risk in the CKD population.
Main Methods:
- The European Quality (EQUAL) study enrolled 903 participants (aged ≥65 years, eGFR ≤20 mL/min/1.73 m²) into discovery (n=611) and replication (n=292) cohorts.
- Baseline blood levels of 184 proteins were measured.
- Cox proportional hazard models were used to assess the association between protein levels and MACE, with adjustments for clinical covariates. Proteins meeting statistical significance (FDR-adjusted P<0.05) in the discovery cohort were validated in the replication cohort.
Main Results:
- During a median follow-up of 2.9 years, 39% of participants experienced a MACE.
- Forty-eight proteins were associated with MACE in the discovery cohort; 9 were replicated in the independent cohort.
- Three proteins—tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2)—maintained a significant association with MACE after comprehensive adjustments, including for traditional and CKD-specific risk factors and proteinuria.
Conclusions:
- This study identified TNC, FGF-23, and VSIG2 as robust protein biomarkers for MACE in older adults with severe CKD.
- The findings support previous associations for FGF-23 and TNC and highlight VSIG2 as a potentially novel biomarker.
- These proteins may serve as therapeutic targets or aid in risk prediction for cardiovascular events in the CKD population.
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.
Related Concept Videos
01:19Blood Studies for Cardiovascular System II: CRP, Hcy, and Cardiac Natriuretic Peptide Markers
These markers indicate stress or strain on the heart muscle:
Natriuretic Peptides (BNP)
Cardiac myocytes produce these hormones in response to ventricular stretching...
01:20Blood Studies for Cardiovascular System I: Cardiac Biomarkers
The essential diagnostic tools for detecting myocardial necrosis and monitoring individuals suspected of having acute coronary syndrome (ACS) include:
Troponins
Troponins, particularly cardiac troponins I and T, are the most precise and sensitive markers of myocardial injury. They are detectable within 4-6 hours of myocardial injury and remain...
01:17Factors Affecting Renal Clearance: Renal Impairment
One condition associated with renal failure is uremia. Uremia is characterized by impaired glomerular filtration and fluid accumulation in the body. This condition hinders the renal clearance of drugs, resulting in drug accumulation and potential...