Association between blood biomarkers and adverse cardiovascular and kidney outcomes

Project Abstract Kidney Disease is prevalent in people with hypertension and is associated with adverse cardiovascular (CV) outcomes. Knowledge regarding circulating biomarkers for early detection of which patients with hypertension are at future risk for decline in glomerular filtration rate (eGFR) and adverse heart outcomes is limited. Evidence from clinical trials clearly demonstrated that effective blood pressure (BP) lowering treatment ameliorates the harmful effects of uncontrolled hypertension on adverse kidney and heart outcomes; yet, it remains unclear in which individuals intensive BP lowering will result in further GFR decline, and guidelines regarding BP target in people with hypertension, with and without baseline diabetes mellitus or chronic kidney disease, are controversial. In our previous NIH-funded research, using data from BioLINCC in people with heart failure (HF) with preserved ejection fraction, we found a subset of 6 circulating proteins (CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3), higher baseline levels of which were associated with adverse kidney outcomes (increase in urine albumin-to-creatinine ratio (UACR) and decline in eGFR), and also associated with a composite event of CV death, heart failure hospitalization, and aborted cardiac arrest. Our overarching hypothesis is that these proteins are also associated with decline in eGFR and increase in UACR in people with hypertension prior to the development of left ventricular hypertrophy or heart failure. We further hypothesize that intensive BP control will ameliorate the association of these biomarkers with adverse CV and kidney outcomes. We plan to obtain specimens from the Systolic Blood Pressure Intervention Trial (SPRINT), a study population with hypertension without diabetes mellitus, and the Action to Control Cardiovascular Risk in Diabetes (ACCORD), a study population with hypertension and diabetes, available in BioLINCC and use the Olink proteomics platform to measure these 6 proteins. Our other biomarkers of interest, serum creatinine and UACR, are available in the database. We will use these data to (Aim 1) determine whether higher baseline levels of a subset of prespecified blood biomarkers, CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3, are associated with a CV composite of non-fatal MI, stroke, CV death, congestive HF, or unstable angina in people with hypertension but without LVH or HF; and identify whether intensive BP lowering ameliorates the association; and (Aim 2) determine whether higher baseline levels of blood biomarkers, CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3, are associated with (a) eGFR decline and (b) increase in UACR from baseline to 3 years in people with hypertension but without LVH or HF; and identify whether intensive BP lowering ameliorates this association. We will also explore whether diabetes will modify the association of these biomarkers with the CV and kidney outcomes in people with hypertension. These biomarkers will be useful in early understanding of which people with hypertension are at increased risk of kidney function decline and adverse CV events. Moreover, identifying such biomarkers will pave the way for future studies to better understand kidney disease pathogenesis in the setting of hypertension.