In a young adult with resistant hypertension despite two antihypertensive medications, which test is most appropriate: 24‑hour urine cortisol, renin‑aldosterone ratio, plasma fractionated metanephrines, or urinary fractionated metanephrine?

Renin-Aldosterone Ratio Testing for Resistant Hypertension

In a young adult with resistant hypertension on two antihypertensive medications, the renin-aldosterone ratio (option B) is the most appropriate initial screening test, as primary aldosteronism is present in up to 20% of patients with resistant hypertension and represents a potentially curable cause with dramatically higher cardiovascular risk than essential hypertension. 1

Why Screen for Primary Aldosteronism First

Primary aldosteronism should be the priority in this clinical scenario for several compelling reasons:

• Prevalence: Up to 20% of patients with resistant hypertension have primary aldosteronism, making it the most common secondary cause in this population 1, 2
• Cardiovascular risk: Compared to essential hypertension at equivalent blood pressure levels, primary aldosteronism carries a 3.7-fold increase in heart failure, 4.2-fold increase in stroke, 6.5-fold increase in myocardial infarction, and 12.1-fold increase in atrial fibrillation 1
• Treatability: This is a potentially curable condition—unilateral disease can be surgically cured with laparoscopic adrenalectomy, achieving blood pressure improvement in virtually 100% of patients and complete cure in approximately 50% 1

The Aldosterone-Renin Ratio (ARR) as Screening Test

Test Characteristics and Interpretation

• Positive screening criteria: ARR ≥20-30 (when aldosterone is measured in ng/dL and renin activity in ng/mL/h) AND plasma aldosterone concentration ≥10-15 ng/dL 1
• Improved specificity: Use a minimum plasma renin activity of 0.5 ng/mL/h in calculations to enhance test specificity 1
• Diagnostic accuracy: The ARR provides fair to good diagnostic accuracy with sensitivity of 73-87% and specificity of 74-75%, with areas under ROC curves ranging from 0.80-0.85 3

Patient Preparation for Testing

Medication management (ideally, but not mandatory):

• Discontinue beta-blockers, centrally acting drugs, and diuretics when clinically feasible, as these suppress renin and cause false-positive results 1
• Long-acting calcium channel blockers and alpha-receptor antagonists can be used as alternatives, as they minimally interfere with ARR 1
• Critical: Mineralocorticoid receptor antagonists must be withdrawn at least 4 weeks before testing 1
• Practical approach: If medications cannot be safely stopped, testing can proceed with interpretation in the context of current medications 1, 3

Metabolic preparation:

• Ensure potassium repletion (target 4.0-5.0 mEq/L) before testing, as hypokalemia suppresses aldosterone production and causes false-negative results 1
• Unrestricted salt intake is recommended 1

Blood collection technique:

• Collect in the morning (ideally 0800-1000 hours) 1
• Patient should be out of bed for 2 hours prior to collection 1
• Patient seated for 5-15 minutes immediately before blood draw 1

Common Pitfalls to Avoid

• Do not rely on hypokalemia: Approximately 50% of primary aldosteronism cases have normal potassium levels 1, 2
• Do not skip confirmatory testing: A positive ARR requires confirmation with additional testing (intravenous saline suppression test or oral sodium loading with 24-hour urine aldosterone) to demonstrate autonomous aldosterone secretion 1
• Do not proceed to surgery based on CT alone: Adrenal venous sampling is mandatory before offering adrenalectomy, as up to 25% of patients might undergo unnecessary surgery based on CT findings alone 1

Why Not the Other Options

Option A (24-hour urine cortisol): While Cushing syndrome can present with hypertension and hypokalemia, it is far less common than primary aldosteronism in resistant hypertension and typically presents with additional features (central obesity, striae, proximal muscle weakness, moon facies) 4

Options C & D (Plasma or urinary fractionated metanephrines): Pheochromocytoma screening is appropriate when patients have paroxysmal hypertension, headaches, palpitations, and diaphoresis—not the typical presentation of resistant hypertension 1. Primary aldosteronism is approximately 10-20 times more common than pheochromocytoma in resistant hypertension populations 1, 2

Next Steps After Positive Screening

If ARR is positive (≥20-30 with aldosterone ≥10-15 ng/dL):

1. Confirmatory testing is mandatory to demonstrate autonomous aldosterone secretion 1

   • Intravenous saline suppression test (2L normal saline over 4 hours; failure to suppress aldosterone below 5 ng/dL confirms diagnosis) 1
   • Oral sodium loading test with 24-hour urine aldosterone measurement 1

2. Subtype determination after biochemical confirmation 1:

   • Non-contrast CT scan of adrenal glands as initial imaging 1
   • Adrenal venous sampling to distinguish unilateral from bilateral disease (mandatory before surgery, except in patients <40 years with unilateral adenoma on imaging) 1

3. Referral to hypertension specialist or endocrinologist for subtype determination and treatment planning 1

Treatment Implications

• Unilateral disease: Laparoscopic unilateral adrenalectomy is the treatment of choice 1
• Bilateral disease: Medical therapy with mineralocorticoid receptor antagonists (spironolactone 50-100 mg daily, titrated up to 300-400 mg if needed) is the cornerstone of lifelong treatment 1
• Immediate benefit: Even while awaiting confirmatory testing, adding spironolactone 25-50 mg daily provides significant blood pressure reduction (25/12 mmHg) in resistant hypertension, regardless of whether primary aldosteronism is ultimately confirmed 1