How do diuretics affect the aldosterone-to-renin ratio?

Diuretics' Effects on Aldosterone-to-Renin Ratio

Diuretics significantly interfere with the aldosterone-to-renin ratio (ARR) testing and should be discontinued at least 6 weeks before testing to avoid false negative results in the diagnosis of primary aldosteronism. 1

Mechanism of Interference

Different classes of diuretics affect the ARR in distinct ways:

Loop and Thiazide Diuretics

• Stimulate renin secretion through volume depletion
• Lower the ARR by increasing renin more than aldosterone
• Can cause false negative results when screening for primary aldosteronism
• Effect is most pronounced within the first 3 days of administration 2

Aldosterone Antagonists (Spironolactone, Eplerenone)

• Cause significant elevation of renin levels
• In patients with primary aldosteronism treated with spironolactone, renin escapes suppression and can reach very high levels 3
• This leads to a marked decrease in the ARR and potential false negative results
• Eplerenone produces sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion 4

Clinical Implications

For Primary Aldosteronism Screening

• The ARR is the recommended screening test for primary aldosteronism 2
• Two approaches exist for patients already on antihypertensive medications:
  1. Conduct ARR testing without changing medications, but interpret results in context of the specific medications
  2. Discontinue interfering medications before testing (preferred when feasible) 2

Medication Management Before ARR Testing

• Diuretics should be discontinued at least 6 weeks before testing 1
• If medications cannot be stopped, substitute with non-interfering agents:
  • Verapamil slow-release (non-dihydropyridine calcium channel blocker)
  • Alpha-blockers (prazosin or doxazosin) 1
• Long-acting calcium channel blockers have minimal effect on ARR 2, 3

Impact of Different Antihypertensives on ARR

• Beta-blockers: Suppress renin, potentially causing false positive ARR results 3, 5
• ACE inhibitors and ARBs: Decrease aldosterone levels and increase renin, potentially causing false negative results (especially ARBs) 5
• Calcium channel blockers (non-dihydropyridine): Minimal effect on ARR 3

Special Considerations

When Diuretics Cannot Be Discontinued

• Recent evidence suggests that even when mineralocorticoid receptor antagonists cannot be stopped for safety reasons (severe hypokalemia or hypertension), the accuracy of ARR testing is only marginally impacted, particularly in florid primary aldosteronism 2

Other Factors Affecting ARR

• Hypokalemia should be corrected before testing as it suppresses aldosterone production 1
• Liberal salt diet should be encouraged before testing 1
• Blood collection should be done midmorning from seated patients following 2-4 hours of upright posture 1
• Female sex and oral contraceptives containing drospirenone can affect the ratio 1

Practical Recommendations

1. When possible, discontinue diuretics 6 weeks before ARR testing
2. If diuretics cannot be stopped, document this and interpret results cautiously
3. Consider using non-interfering antihypertensives during the washout period
4. Repeat the ARR at least once before proceeding to confirmatory testing
5. Correct hypokalemia before testing
6. Consider using adrenal venous sampling to confirm diagnosis in ambiguous cases 6

Remember that the ARR is a screening test only, and positive results should be followed by confirmatory testing such as fludrocortisone suppression test or 24-hour urine collection for aldosterone 6.