GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD

Abstract

Rationale & objective: Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.

Study design: Observational cohort study.

Setting & participants: Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).

Exposures: Circulating GDF-15, Gal-3, and sST2 measured at baseline.

Outcomes: Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.

Analytic approach: Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.

Results: Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m². Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.

Limitations: Event rates for heart failure and atherosclerotic CVD were low.

Conclusions: Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.

Keywords: CKD; Growth differentiation factor 15 (GDF-15); acute ischemic stroke; acute myocardial infarction (AMI); atherosclerotic CVD; cardiac biomarker; cardiovascular disease (CVD); galectin 3 (Gal-3); heart failure (HF); mortality; soluble ST2 (sST2).