Circulating renin concentration is differentially associated with blood pressure, target-organ damage and mortality in a large population cohort

Background

The renin–angiotensin–aldosterone system (RAAS) is central to contemporary cardiovascular prevention. However, the population-level pathophysiological relevance of circulating renin—particularly in cohorts sufficiently powered for hard outcomes—remains insufficiently characterised.

Purpose

To examine associations of plasma renin with blood pressure, vascular, renal and cardiac target-organ damage, and long-term mortality in a large population cohort of the UK Biobank.

Methods

Plasma renin was quantified using a proximity extension assay. Associations with systolic and diastolic blood pressure were analysed using linear mixed-effects spline models. Markers of hypertension-mediated organ damage included pulse wave velocity (PWV), urinary albumin-to-creatinine ratio (UACR), cardiac magnetic resonance–derived metrics, and brain white matter hyperintensity volume; N-terminal pro–B-type natriuretic peptide and cardiac troponin I were evaluated as additional circulating biomarkers. All-cause and cardiovascular mortality were examined using cause-specific Cox models with renin splines and sequential adjustment. Mediation analyses applied a counterfactual framework to test organ damage mediation of renin–mortality associations.

Results

Among 48,739 participants, renin was strongly associated with systolic and diastolic blood pressure across all adjustment stages (fully adjusted p<0.0001). In fully adjusted models (n=30,648), predicted systolic blood pressure differed by ~15 mmHg between the 5th and 95th renin percentiles, with lower renin associated with higher blood pressure.

For structural phenotypes, lower renin concentrations were associated with higher PWV, greater left ventricular wall thickness and mass (all fully adjusted p<0.0001), and higher brain white matter hyperintensity volume (p=0.002), mirroring blood pressure patterns. In contrast, UACR showed a non-linear association with elevations at both low and high renin levels (p<0.0001).

Over a median follow-up of 15.3 years, 6,714 all-cause and 1,470 cardiovascular deaths occurred. Higher renin concentrations were strongly associated with increased all-cause mortality in a non-linear pattern (fully adjusted overall p<0.0001), with similar findings for cardiovascular mortality. Mediation analyses demonstrated that most of the renin–mortality association was not explained by standard target-organ damage markers; only kidney function and heart rate showed measurable mediation of mortality.

Conclusion

Circulating renin exhibits distinct phenotypic patterns: low renin associates with blood pressure–mediated hypertensive organ damage, whereas higher renin relates to renal injury and increased mortality. The majority of the renin–mortality association is not accounted for by conventional hypertension-mediated organ damage pathways, suggesting additional renal or neurohumoral mechanisms and independent prognostic relevance.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.