In an adult with hypertension resistant to three or more antihypertensive agents, possibly with hypokalemia, metabolic alkalosis, or a family history of early‑onset hypertension, how should I screen for, confirm, and manage primary aldosteronism?

Primary Aldosteronism: Screening, Confirmation, and Management

Who to Screen

Screen all adults with resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic) for primary aldosteronism, as it affects 11–20% of this population and represents a potentially curable cause with dramatically higher cardiovascular risk than essential hypertension. 1, 2, 3

Additional high-risk features warranting screening include:

• Spontaneous or diuretic-induced hypokalemia (though absent in ~50% of cases) 1, 2
• Incidentally discovered adrenal mass on any imaging 1, 2
• Family history of early-onset hypertension or stroke before age 40 1, 2
• Severe hypertension (BP >180/110 mmHg) 2
• Atrial fibrillation or obstructive sleep apnea with hypertension 1

Critical Pitfall to Avoid

Never rely on the presence or absence of hypokalemia to decide whether to screen—approximately 50% of primary aldosteronism cases have normal potassium levels, and hypokalemia has low negative predictive value. 1, 2

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Initial Screening Test: Aldosterone-to-Renin Ratio (ARR)

Order simultaneous plasma aldosterone concentration and plasma renin activity to calculate the ARR. 1, 2

Patient Preparation

• Correct hypokalemia before testing (target 4.0–5.0 mEq/L), as low potassium suppresses aldosterone production and causes false-negative results 2, 4
• Encourage unrestricted (liberal) salt intake for at least 3 days before testing 1, 2
• Discontinue interfering medications when clinically feasible:
  • Stop beta-blockers, centrally acting drugs, and diuretics 2–5 days before testing (they suppress renin and cause false-positives) 2, 4, 3
  • Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing 1, 2
  • Stop ACE inhibitors and ARBs at least 2 weeks before testing (they raise renin and cause false-negatives) 2
  • Use long-acting calcium channel blockers (verapamil SR) or alpha-receptor antagonists (doxazosin, prazosin) as safe alternatives during washout 2

If medications cannot be stopped: Test on current medications and interpret results in context of known drug effects, recognizing that ACE inhibitors/ARBs may actually increase test sensitivity if renin remains suppressed despite their use. 2, 3

Blood Collection Technique

• Collect blood in the morning (0800–1000 hours) 2
• Patient should be out of bed for at least 2 hours before collection 2
• Patient should be seated for 5–15 minutes immediately before blood draw 1, 2

Positive Screening Criteria

A positive screen requires BOTH of the following:

• ARR ≥20–30 (when aldosterone measured in ng/dL and renin activity in ng/mL/h) 1, 2, 3
• Plasma aldosterone concentration ≥10–15 ng/dL 1, 2

The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 1, 2

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Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 1, 2

Pre-Test Requirements

• Unrestricted salt intake 1, 2
• Normal serum potassium levels (correct hypokalemia first) 1, 2
• Mineralocorticoid receptor antagonists withdrawn for ≥4 weeks 1, 2

Confirmatory Test Options

Choose one of the following:

1. Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis 1, 2

2. Oral sodium loading test: High-sodium diet (>200 mEq/day) for 3 days with 24-hour urine aldosterone measurement on day 3; urinary aldosterone >12–14 mcg/24h confirms diagnosis 1, 2

3. Fludrocortisone suppression test: Most sensitive confirmatory test; failure to suppress plasma aldosterone below threshold confirms diagnosis 2

Critical Consideration

If the patient is already taking spironolactone and cannot safely discontinue it due to severe hypertension, confirmatory testing cannot be reliably performed—the diagnosis cannot be definitively confirmed with standard testing. 2

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Subtype Determination: Unilateral vs. Bilateral Disease

This distinction is mandatory because it determines whether the patient is a surgical candidate (unilateral disease) or requires lifelong medical therapy (bilateral disease). 2

Step 1: Adrenal CT Imaging

• Order non-contrast CT scan of the adrenal glands as initial imaging 2
• CT findings alone are insufficient for treatment decisions—adenomas on imaging can represent hyperplasia, and false positives are common due to nodular hyperplasia 2

Step 2: Adrenal Venous Sampling (AVS)

AVS is mandatory before offering adrenalectomy to distinguish unilateral from bilateral disease, as up to 25% of patients might undergo unnecessary adrenalectomy based on CT findings alone. 2

Exception: AVS may be omitted in patients <40 years old when imaging shows a single unilateral adenoma with normal contralateral adrenal, as bilateral hyperplasia is rare in this population. 2

• AVS demonstrates lateralization when the aldosterone-to-cortisol ratio (ACR) is >4 times higher on the affected side than the contralateral side 5
• AVS remains reliable even when renin is not suppressed due to concurrent conditions like renal artery stenosis 4

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Treatment Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma)

Laparoscopic unilateral adrenalectomy is the treatment of choice for unilateral disease, improving blood pressure in virtually 100% of patients and resulting in complete cure of hypertension in approximately 50%. 1, 2

• Adrenalectomy normalizes hypokalemia, lowers blood pressure, reduces antihypertensive medication requirements, and improves cardiac and kidney function 2
• Blood pressure response to surgery has no relation to duration or severity of hypertension 6
• Even patients with prolonged and severe resistant hypertension can achieve cure 6

Bilateral Disease (Idiopathic Hyperaldosteronism)

For bilateral adrenal hyperplasia, medical therapy with mineralocorticoid receptor antagonists is the cornerstone of lifelong treatment. 1, 2

• Spironolactone is first-line treatment:

  • Start 25–50 mg daily for resistant hypertension 2
  • Titrate up to 200–400 mg daily if necessary for confirmed primary aldosteronism 2
  • Low doses (25–50 mg) are effective and minimize adverse effects 2
  • Monitor serum potassium within 1 week of initiation and regularly thereafter 2

• Eplerenone is an alternative with fewer anti-androgenic side effects but is less potent and requires twice-daily dosing 2

Hyperkalemia Risk with MRA Therapy

The risk of hyperkalemia is significantly increased in:

• Older patients 2
• Patients with diabetes 2
• Patients with chronic kidney disease 2
• Concomitant use of ACE inhibitors, ARBs, or NSAIDs 2

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Referral Pathway

Refer all patients with positive ARR screening tests or confirmed primary aldosteronism to a hypertension specialist or endocrinologist for confirmatory testing, subtype determination via adrenal venous sampling, and treatment planning. 1, 2, 4, 3

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Why Early Diagnosis Matters

Primary aldosteronism causes dramatically worse cardiovascular outcomes than essential hypertension at equivalent blood pressure levels:

• 12.1-fold increase in atrial fibrillation 2
• 6.5-fold increase in myocardial infarction 2
• 4.2-fold increase in stroke 2
• 3.7-fold increase in heart failure 2

Prompt identification and targeted treatment—either unilateral adrenalectomy or mineralocorticoid receptor antagonist therapy—can reverse aldosterone-mediated target-organ damage and mitigate this excess cardiovascular risk. 2

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Special Considerations in Resistant Hypertension

If ARR is positive in a patient with resistant hypertension, add spironolactone 25–50 mg daily immediately while awaiting confirmatory testing, as this provides significant additional BP reduction (25/12 mmHg) regardless of whether primary aldosteronism is ultimately confirmed. 2

This pragmatic approach recognizes that spironolactone benefits both true primary aldosteronism and aldosterone-sensitive hypertension. 2