Linking Chronic Kidney Disease to Incident Heart Failure and Adverse Cardiac Remodeling Through the Plasma Proteome

Background

Investigation of circulating plasma proteins may reveal insights into molecular pathways that contribute to the development of heart failure (HF) among people with chronic kidney disease.

Objectives

The authors aimed to identify circulating kidney function–related plasma proteins that are associated with the risk of incident HF.

Methods

The authors studied participants of the ongoing longitudinal Atherosclerosis Risk In Communities study. Relative plasma concentrations of 4,697 unique proteins were measured with the use of an aptamer assay (Somalogic). Each protein was tested for associations with estimated glomerular filtration rate (eGFR), log-transformed urine albumin-to-creatinine ratio (UACR), and incident HF by means of multivariable linear and Cox regression models. Protein-HF associations were validated externally in the CRIC (Chronic Renal Insufficiency Cohort) study. Two-sample mendelian randomization was used to test for potential causal associations.

Results

In fully adjusted models, 44 plasma proteins were associated with either eGFR or UACR and incident HF at two separate ARIC study visits, of which 29 were validated externally in CRIC. Most plasma proteins were associated with HF with preserved ejection fraction, but not reduced ejection fraction. A cluster within these 44 plasma proteins were associated with larger left ventricular end-diastolic volume index and left ventricular diastolic dysfunction. Mendelian randomization suggests that Golgi membrane protein 1 is causally associated with HF and eGFR.

Conclusions

This study identified 44 eGFR- and UACR-related plasma proteins that are associated with incident HF independently from demographics, risk factors, and kidney function. These results may inform future therapeutic and biomarker development for the prevention and treatment of incident HF.