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

Abstract

Rationale & ObjectiveCardiovascular 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 (MACE). Study DesignEQUAL is an observational cohort study which enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 ml/min/1.73m2. Setting & ParticipantsRecruited participants were split into Discovery (n=611) and Replication cohorts (n=292). ExposureOne hundred and eighty four blood protein levels measured at the baseline visit, each protein was analysed individually. OutcomeMACE. Analytical ApproachCox proportional hazard models adjusted for age, sex, eGFR, previous MACE and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values <0.05 in the Discovery cohort were tested in the Replication cohort. Sensitivity analyses were performed, adjusting for traditional risk factors, CKD-specific risk factors and level of proteinuria, and with atherosclerotic and non-atherosclerotic MACE segregated. ResultsDuring 2.9 years median follow-up, 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 non-atherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with non-atherosclerotic MACE. LimitationsSingle protein concentration measurements and limited follow up time. ConclusionsOur 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.