Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED-J Study

Abstract

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

Keywords: biomarker; cardiovascular events; chronic kidney disease; coronary artery disease; mortality; prospective cohort study.

Figure 1. Cumulative incidence of 3P‐MACE in the entire cohort (A), patients with CKD (B), and patients without CKD (C) according to the serum sFlt‐1 level at baseline.

Follow‐up results are truncated after 3 years. 3P‐MACE is defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. CKD is defined as an estimated glomerular filtration rate of <60 mL/min per 1.73 m² of body surface area. The tertiles of sFlt‐1 levels were as follows: (A) tertile 1, ≤96.59; tertile 2, 96.59<, ≤121.17; tertile 3, >121.17 pg/mL; (B) tertile 1, ≤100.00; tertile 2, 100.00<, ≤124.91; tertile 3, >124.91 pg/mL; (C) tertile 1, ≤94.45; tertile 2, 94.45<, ≤119.69; tertile 3, >119.69 pg/mL. 3P‐MACE indicates 3‐point major adverse cardiovascular events; CKD, chronic kidney disease; and sFlt‐1, soluble fms‐like tyrosine kinase 1.

Figure 2. Adjusted hazard ratios of the biomarker levels for 3P‐MACE in the entire cohort, patients with CKD, and patients without CKD.

The data were adjusted for age, sex, body mass index, hypertension, dyslipidemia, diabetes, current smoking, estimated glomerular filtration rate, the Gensini score, previous myocardial infarction, previous stroke, previous heart failure hospitalization, atrial fibrillation, anemia, antihypertensive drug use, statin use and aspirin use. CKD is defined as an estimated glomerular filtration rate of <60 mL/min per 1.73 m² of body surface area. The biomarkers are modeled as (1) continuous variables, (2) tertiles, and (3) the top tertile (ie, tertile 3 vs tertiles 1 and 2), and are natural log‐transformed for use as continuous variables. NT‐proBNP indicates N‐terminal pro‐brain natriuretic peptide; hs‐cTnI, high‐sensitivity cardiac troponin I; hs‐CRP, high‐sensitivity C‐reactive protein; NGAL, neutrophil gelatinase‐associated lipocalin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; and UACR: urine albumin to creatinine ratio. Other abbreviations used in this figure are the same as in Figure 1. The tertiles of biomarker levels and number of patients are summarized in Table S6.