Proteomic Assessment of the Risk of Secondary Cardiovascular Events among Individuals with CKD

Abstract

Key Points:

1. Machine learning and large-scale proteomics led to a 16-protein secondary cardiovascular risk model in patients with CKD.

2. Hepatic fibrosis and liver X receptor activation represented biologic pathways that link kidney disease and risk of secondary cardiovascular events.

3. An understanding of the circulating proteins associated with secondary cardiovascular events may help to identify novel therapeutic targets.

Background: Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have CKD. We sought to develop a proteomic risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease.

Methods: We measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities (ARIC) Cohort. All had non–dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared with clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis.

Results: A 16-protein risk model was superior to the Framingham Risk Score for secondary events, including a modified score that included eGFR. In CRIC, the annualized area under the receiver operating characteristic curve (area under the curve) within 1–5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis.

Conclusions: The proteomic risk model for secondary cardiovascular events outperformed clinical models on the basis of traditional risk factors and eGFR.