Kidney function may rapidly decline in adults with hypertension and renin-independent aldosterone production, reveals a study. Furthermore, those with higher aldosterone-to-renin ratio (ARR) levels are at increased risk of kidney failure and major adverse cardiovascular events (MACE).
“Although clinical practice guidelines recommend distinct thresholds for diagnosing primary aldosteronism, our findings underscore that the risk for kidney and cardiovascular outcomes in adults with hypertension manifests as a continuous gradient that parallels the magnitude of renin-independent aldosterone production,” the researchers said.
In this study, the researchers used linked Danish health registries with complete laboratory test results from January 2017 to November 2024. Adults with hypertension selected by clinicians for aldosterone and renin testing were included. Cox regression and restricted cubic spline models were used, adjusting for age, sex, index year, comorbidities, and comedications. Median follow-up was 3.6 years.
A total of 12,650 adults with hypertension were included, of whom 1,840 (15 percent) had an ARR of 27.7 to <70 pmol/mIU, 480 (4 percent) 70 to <138.7 pmol/mIU, and 310 (2 percent) ≥138.7 pmol/mIU. [J Am Coll Cardiol 2026;87:2846-2860]
In cubic spline models, higher ARR, higher aldosterone, and lower renin levels correlated with a higher risk of rapid kidney function decline (estimated glomerular filtration rate [eGFR] ≥5 mL/min/1.73 m2 per year), kidney failure or ≥40-percent eGFR decline, and MACE.
“Risk of kidney function decline outcomes varied across combinations of aldosterone and renin levels, with higher risk observed in individuals with elevated aldosterone in the context of low renin,” the researchers said.
Similar trends were noted in analyses using predefined ARR levels. The adjusted hazard ratios (aHRs) for rapid kidney decline were 1.27 (95 percent confidence interval [CI], 1.17‒1.38) for ARR 27.7‒70.0 pmol/mIU, 1.98 (95 percent CI, 1.75‒2.25) for ARR 70.0‒138.7 pmol/mIU, and 2.66 (95 percent CI, 2.31‒3.08) for ARR >138.7 pmol/mIU.
The aHRs for kidney failure or ≥40-percent eGFR decline and for MACE were not increased at ARR 27.7‒70.0 pmol/mIU but elevated at higher ARR levels.
“Even below classic thresholds for primary aldosteronism, renin-independent aldosterone production may identify patients at increased risk of progressive kidney disease in a dose-dependent manner,” the researchers said.
“Finally, ARR-tested patients represent a high-risk clinical subset; results should be interpreted in this context,” they added.
Mechanisms
The observed associations may be explained by several pathophysiologic mechanisms. For instance, activation of the mineralocorticoid receptor enables the aldosterone to exert direct adverse effects of cardiovascular and renal tissues that go beyond blood pressure regulation. [J Am Heart Assoc 2024;13:e030142]
“Experimental and clinical studies have implicated the activation of mineralocorticoid receptor by aldosterone in renal fibrosis, glomerular hypertrophy, vascular inflammation, oxidative stress, and endothelial dysfunction, all of which contribute to progressive kidney damage as well as the development of atherosclerosis and cardiovascular damage,” the researchers said. [Hypertension 2022;79:1984-1993; J Am Heart Assoc 2024;13:e030142]