Aldosterone renin ratio

Interpretation of the ARR should only be made after confirming that renin is suppressed in the setting of high endogenous aldosterone production.

Aldosterone renin ratio (ARR) in primary hyperaldosteronism

The absence of renin suppression should raise suspicion for secondary aldosteronism (not primary) and/or the use of medications that raise renin (mineralocorticoid receptor antagonists, renin inhibitors, renin-angiotensin-aldosterone system inhibitors, ENaC inhibitors, other diuretics that induce volume contraction). A limitation of the ARR is that in the presence of very low renin levels (for example, at PRA values of 0.1 ng/mL/h), the ARR may be elevated even when plasma aldosterone is also low.

PAC Plasma aldosterone concentration, ARR Aldosterone to renin ratio

Ideal testing Conditions for aldosterone renin ratio

ARR is most sensitive if samples are collected in the morning (after patients have been out of bed for at least 2 hours) and after being comfortably seated for 5 to 15 minutes

• Normal potassium levels and unrestricted dietary salt consumption
• Mineralocorticoid antagonist therapy should be held for at least 4-6weeks before testing
• A washout period of all interfering medications for patients with mild hypertension (Non-dihydropyridine calcium channel blockers, hydralazine, or alpha-blockers, can be used instead to control arterial pressure during case detection testing for primary hyperaldosteronism
• If a PRA is suppressed while on a mineralocorticoid receptor antagonist, the ARR may still be interpretable; however, in the context of an unsuppressed PRA, mineralocorticoid receptor antagonists should be discontinued for weeks-to-months until the PRA is suppressed, before the ARR is informative. If the ARR while on any medication is high, with frankly elevated PAC and suppressed PRA, the likelihood of primary aldosteronism remains very high. Remember this general rule; If renin is suppressed, the screening test is valid, irrespective of interfering medications.

Causes of a False-Positive aldosterone renin ratio

Review the regulation of aldosterone and renin release at the level of juxtaglomerular apparatus.

Causes of False-Negative aldosterone renin ratio

Confirmatory Tests (after a positive aldosterone renin ratio)

• Oral sodium loading test
• Saline infusion test
• Fludrocortisone suppression test
• Captopril challenge test

How do mineralocorticoid receptor antagonists interfere with aldosterone-renin-ratio testing?

Mineralocorticoid antagonists (eplerenone and spironolactone) occupy the mineralocorticoid receptor, thus blocking aldosterone from its receptor. This results in sodium loss and a reduction in extracellular volume. As a consequence of volume contraction, plasma renin levels increase (a feedback mechanism required to maintain blood pressure and vascular volume). A false negative aldosterone renin ratio can lead to a case of primary hyperaldosteronism being missed.

There is, however, an exception to this rule. For patients on mineralocorticoid antagonists who continue to remain hypokalemic despite treatment, it implies a suboptimal blockade of the mineralocorticoid receptors. In this setting, renin will continue to remain suppressed, and the aldosterone to renin ratio is interpretable (or valid).

What is the right approach to evaluating the aldosterone to renin ratio for patients on mineralocorticoid receptor antagonists?

Do not discontinue mineralocorticoid receptor antagonists prior to testing the ARR. If renin is suppressed, case-detection testing, confirmatory testing, and adrenal vein sampling can be done without necessarily discontinuing mineralocorticoid receptor antagonists.

On the other hand, if renin is not suppressed (normal or high), then it is recommended that these interfering medications be stopped for 4-6 weeks before repeat case-detection testing.

How do ACE inhibitors (ACEi), Angiotensin Receptor Blockers(ARBs) or direct renin inhibitors antagonists interfere with aldosterone-renin-ratio testing?

By interfering with renin receptor activation, these agents reflexively increase plasma renin levels. This can result in a falsely negative aldosterone renin ratio. Thus if the plasma renin activity is >1 ng/mL/hr, primary aldosteronism cannot be excluded without discontinuing these agents. Conversely, if the plasma renin activity is <1 ng/mL/hr despite being on these agents, this is highly suggestive of a diagnosis of primary aldosteronism.

References

John W. Funder, Robert M. Carey, Franco Mantero, M. Hassan Murad, Martin Reincke, Hirotaka Shibata, Michael Stowasser, William F. Young, Jr, The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 5, 1 May 2016, Pages 1889–1916, https://doi.org/10.1210/jc.2015-4061