Effect Modification of Chronic Kidney Disease on the Association of Circulating and Imaging Cardiac Biomarkers With Outcomes

Abstract

Background: Cardiac troponin T and brain natriuretic peptide (BNP) are elevated in >50% of dialysis patients and are associated with poor outcomes. Few data investigated these associations in earlier chronic kidney disease (CKD).

Methods and results: We studied whether CKD modified associations of elevated BNP, N-terminal-pro-BNP, high-sensitivity cardiac troponin T, coronary artery calcification, and left ventricular hypertrophy with all-cause death and cardiovascular death/events in 3218 multiethnic individuals followed for 12.5 years, and whether biomarkers added prognostic information to traditional cardiovascular risk factors in CKD. Of the cohort, 279 (9%) had CKD. There were 296 deaths and 218 cardiovascular deaths/events. Of non-CKD individuals, 7% died and 6% had cardiovascular death/event versus 32% and 30% of CKD participants, P<0.001 for both. The interaction between BNP and CKD on death was significant (P=0.01): the adjusted hazard ratio in CKD was 2.05, 95% CI (1.34, 3.14), but not significant in non-CKD, 1.04 (0.76, 1.41). CKD modified the association of high-sensitivity cardiac troponin T with cardiovascular death/event, adjusted hazard ratio 3.34 (1.56, 7.18) in CKD versus 1.65 (1.16, 2.35) in non-CKD, interaction P=0.09. There was an interaction between N-terminal-pro-BNP and CKD for death in those without prior cardiovascular disease. Addition of each biomarker to traditional risk factors improved risk prediction, except coronary artery calcification was not discriminatory for cardiovascular death/event in CKD.

Conclusions: Cardiac biomarkers, with the exception of coronary artery calcification, prognosticated outcomes in early-stage CKD as well as, if not better than, in non-CKD individuals, even after controlling for estimated glomerular filtration rate, and added to information obtained from traditional cardiovascular risk factors alone.

Keywords: N‐terminal‐pro‐brain natriuretic peptide; cardiac biomarkers; cardiovascular outcomes; chronic kidney disease; coronary artery calcium; mortality; troponin T.

Figure 1

Kaplan–Meier curves for all‐cause death with (A) BNP, (B) NT‐pro‐BNP, and (C) hs‐TnT cutoffs. P values are for log‐rank tests comparing curves within CKD and non‐CKD groups. BNP indicates brain natriuretic peptide; CKD, chronic kidney disease; hs‐TnT, high‐sensitivity troponin T; NT‐pro‐BNP, N‐terminal‐pro‐brain natriuretic peptide.

Figure 2

Kaplan–Meier curves for cardiovascular deaths or events with (A) BNP, (B) NT‐pro‐BNP, and (C) hs‐TnT cutoffs. P values are for log‐rank tests comparing curves within CKD and non‐CKD groups. BNP indicates brain natriuretic peptide; CKD, chronic kidney disease; hs‐TnT, high‐sensitivity troponin T; NT‐pro‐BNP, N‐terminal‐pro‐brain natriuretic peptide.

Figure 3

Differential prognostication of circulating biomarkers for all‐cause death in (A) non‐CKD and (B) CKD individuals; and for cardiovascular death or event in (C) non‐CKD and (D) CKD individuals. X‐axis represents Harrell's c‐statistics, and P values are for likelihood ratio tests comparing the nested models. BNP indicates brain natriuretic peptide; CKD, chronic kidney disease; hs‐TnT, high‐sensitivity troponin T; NT‐pro‐BNP, N‐terminal‐pro‐brain natriuretic peptide. *P<0.05 1 biomarker model compared with base model, including age, sex, race, diabetes mellitus, hypertension, smoking, and total and HDL cholesterol. ^† P<0.05 2 biomarker model compared to base model+BNP. ^‡ P<0.05 2 biomarker model compared to base model+NT‐pro‐BNP. ^§ P<0.05 2 biomarker model compared with base model+hs‐TnT.

Figure 4

Differential prognostication of circulating and imaging biomarkers for all‐cause death in (A) non‐CKD and (B) CKD individuals; and for cardiovascular death or event in (C) non‐CKD and (D) CKD individuals. X‐axis represents Harrell's c‐statistics, and P values are for likelihood ratio tests comparing the nested models. BNP indicates brain natriuretic peptide; CAC, coronary artery calcification; CKD, chronic kidney disease; hs‐TnT, high‐sensitivity troponin T; LVH, left ventricular hypertrophy; NT‐pro‐BNP, N‐terminal‐pro‐brain natriuretic peptide. *P<0.05 3‐biomarker model compared with base model+BNP+hs‐TnT. ^† P<0.05 4‐biomarker model compared with base model+BNP+hs‐TnT+CAC. ^‡ P<0.05 4‐biomarker model compared with base model+BNP+hs‐TnT+LVH. ^§ P<0.05 3‐biomarker model compared with base model+NT‐pro‐BNP+hs‐TnT. ^|| P<0.05 4‐biomarker model compared with base model+NT‐pro‐BNP+hs‐TnT+CAC. ^# P<0.05 4‐biomarker model compared with base model+NT‐pro‐BNP+hs‐TnT+LVH.