What is the best approach to manage a patient with resistant hypertension, considering an aldosterone (aldosterone) renin ratio and potential addition of an aldosterone antagonist like spironolactone?

Aldosterone Renin Ratio in Resistant Hypertension

Screen all patients with resistant hypertension using the aldosterone-to-renin ratio (ARR), and if positive (ARR ≥30 with aldosterone ≥10 ng/dL), add spironolactone 25-50 mg daily while awaiting confirmatory testing, as this provides significant blood pressure reduction regardless of whether primary aldosteronism is ultimately confirmed. 1, 2

Who Should Be Screened

Screen for primary aldosteronism in patients with: 2

• Resistant hypertension (BP uncontrolled on 3+ medications including a diuretic)
• Severe hypertension (BP >180/110 mmHg) 1
• Spontaneous or diuretic-induced hypokalemia
• Incidentally discovered adrenal mass
• Family history of early-onset hypertension or stroke at age <40 years

Primary aldosteronism is present in up to 20% of patients with resistant hypertension, making screening essential in this population. 1, 2

Patient Preparation for ARR Testing

Medication Management

• Stop beta-blockers, centrally acting drugs, and diuretics when clinically feasible, as these suppress renin and cause false-positive results 2
• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) at least 4 weeks before testing 2
• Use long-acting calcium channel blockers (verapamil) and alpha-receptor antagonists (doxazosin, prazosin) as alternatives during testing, as they minimally interfere with ARR 2
• If medications cannot be stopped, proceed with testing and interpret results in context of the specific medications 2

Metabolic Preparation

• Ensure potassium repletion before testing (target 4.0-5.0 mEq/L), as hypokalemia suppresses aldosterone production and causes false-negative results 2
• Encourage unrestricted (liberal) salt intake before testing 2

Blood Collection Technique

• Collect blood in the morning (0800-1000 hours) 2
• Patient should be out of bed for 2 hours prior to collection 2
• Patient should be seated for 5-15 minutes immediately before blood draw 2

Interpreting the ARR Test

Positive Screening Criteria

A positive screening test requires BOTH of the following: 1, 2

• ARR ≥30 (when aldosterone measured in ng/dL and renin activity in ng/mL/h)
• Plasma aldosterone concentration ≥10-15 ng/dL

The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 2

Common Pitfall to Avoid

Do not rely on hypokalemia as a screening trigger—it is absent in 50% of primary aldosteronism cases. 2 Normal potassium does not exclude the diagnosis. 3

Immediate Management After Positive ARR

Add Spironolactone Empirically

Start spironolactone 25-50 mg daily immediately after positive ARR screening, even before confirmatory testing is completed. 1 This approach is supported by:

• Spironolactone provides significant additional BP reduction of 25/12 mmHg when added to multidrug regimens in resistant hypertension 1, 4
• The BP response occurs regardless of whether formal primary aldosteronism is confirmed, suggesting benefit in both true primary aldosteronism and aldosterone-sensitive hypertension 1, 4
• Low doses (25-50 mg daily) are effective and minimize adverse effects 1
• The response is similar in both African American and white patients 1

Monitoring Requirements

• Monitor serum potassium within 1 week of initiation and regularly thereafter 5
• Monitor serum creatinine, especially in patients with reduced eGFR or those taking ACE inhibitors/ARBs 5
• Risk of hyperkalemia is increased in older patients, those with diabetes, CKD, or concomitant use of ACE inhibitors/ARBs/NSAIDs 1, 5

Dosing Considerations by Renal Function

• eGFR >50 mL/min/1.73 m²: Start 25 mg once daily, may increase to 50 mg daily 5
• eGFR 30-50 mL/min/1.73 m²: Consider starting 25 mg every other day due to hyperkalemia risk 5

Confirmatory Testing (Parallel to Treatment)

While spironolactone is initiated, proceed with confirmatory testing to demonstrate autonomous aldosterone secretion: 2

Options for Confirmatory Testing

1. Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis 2
2. Oral sodium loading test: Measure 24-hour urine aldosterone after 3 days of high salt intake; aldosterone >12 μg/24h with urinary sodium >200 mEq/24h confirms diagnosis 2, 4

Testing Conditions

• Perform with unrestricted salt intake 2
• Ensure normal serum potassium levels 2
• Mineralocorticoid receptor antagonists must be withdrawn 4 weeks before confirmatory testing (temporarily stop spironolactone if already started) 2

Subtype Determination

When to Pursue Imaging

After biochemical confirmation of primary aldosteronism, obtain non-contrast CT scan of adrenal glands to assess for unilateral adenoma versus bilateral hyperplasia. 2

Critical Decision Point: Adrenal Venous Sampling

Do not proceed to surgery based on CT findings alone. 2 Adrenal venous sampling (AVS) is mandatory before offering adrenalectomy, as up to 25% of patients might undergo unnecessary surgery based on CT alone. 2

Exception: AVS may be omitted in patients <40 years with imaging showing a single affected gland, as bilateral hyperplasia is rare in this population. 2

Long-Term Treatment Strategy

For Unilateral Disease (Confirmed by AVS)

Laparoscopic unilateral adrenalectomy is the treatment of choice, improving BP in virtually 100% of patients and curing hypertension in approximately 50%. 2 Surgery also normalizes hypokalemia and improves cardiac and kidney function. 2

For Bilateral Disease or Non-Surgical Candidates

Continue spironolactone as lifelong therapy: 2, 5

• Start with 50-100 mg once daily 2
• Titrate up to 300-400 mg once daily if necessary 2
• Eplerenone is an alternative for patients who develop gynecomastia or breast tenderness with spironolactone 2

Expected Adverse Effects

• Gynecomastia occurs in approximately 9% of male patients at mean dose of 26 mg daily, with dose-dependent risk 5
• Onset varies from 1-2 months to over a year; usually reversible 5
• Hyperkalemia risk necessitates ongoing monitoring 5

Clinical Nuance: ARR Does Not Predict Response

The baseline ARR, plasma aldosterone level, or plasma renin activity do NOT predict the magnitude of BP response to spironolactone. 1 This finding from the American Heart Association guideline is critical: even patients without confirmed primary aldosteronism benefit substantially from spironolactone in resistant hypertension, suggesting a broader role for mineralocorticoid receptor blockade beyond classical primary aldosteronism. 1, 4

This supports the strategy of empiric spironolactone use in resistant hypertension while diagnostic workup proceeds, rather than withholding treatment pending complete evaluation.