In a 25‑year‑old with severe episodic hypertension, plasma renin activity 600 units and aldosterone 135 units while on an angiotensin‑II receptor blocker (ARB) for three months, what is the next step in evaluation and management?

Evaluation of Elevated Renin and Aldosterone in a Patient on ARB Therapy

Interpretation of Laboratory Values

The markedly elevated renin (600 units) with elevated aldosterone (135 units) in a patient taking an ARB for 3 months indicates an appropriate physiologic response to renin-angiotensin system blockade, NOT primary aldosteronism. 1

Why These Values Are Expected on ARB Therapy

• ARBs block the angiotensin II type 1 receptor, removing negative feedback on renin secretion and causing a compensatory rise in plasma renin activity—often to levels 2–10 times baseline 2, 3
• The elevated aldosterone despite ARB therapy reflects the markedly increased renin driving aldosterone production through alternative pathways (angiotensin II type 2 receptors, direct renin effects) 2, 4
• The aldosterone-to-renin ratio (ARR) in this case is approximately 0.23 (135÷600), which is far below the screening threshold of 30 and effectively rules out primary aldosteronism 1

Drug Effects on the Renin-Angiotensin-Aldosterone System

• ARBs and ACE inhibitors cause the most profound increases in plasma renin activity (often 200–600% above baseline) while producing only modest decreases in aldosterone 2, 4
• Beta-blockers suppress renin by 30–70%, artificially elevating the ARR and causing false-positive screening results for primary aldosteronism 2, 3, 4
• Calcium channel blockers have minimal effect on renin or aldosterone and can be continued during screening 2, 4

Recommended Next Steps

1. Discontinue the ARB Before Screening

• Withdraw the ARB for at least 4 weeks before measuring aldosterone and renin to obtain interpretable values 1
• During the washout period, substitute a calcium channel blocker (amlodipine 5–10 mg daily) and/or an alpha-blocker (doxazosin 2–8 mg daily) to maintain blood pressure control 1, 2
• Ensure the patient maintains unrestricted salt intake and normal serum potassium during the washout period 1

2. Repeat Screening After Medication Adjustment

• Measure a morning (0800–1000 hours) paired plasma aldosterone concentration and plasma renin activity after the 4-week washout 1, 5
• An ARR >30 with plasma aldosterone ≥10 ng/dL (or ≥15 ng/dL depending on the assay) warrants confirmatory testing 1
• If the repeat ARR remains <30, primary aldosteronism is effectively excluded 1

3. Consider Alternative Causes of Severe Episodic Hypertension

• Screen for pheochromocytoma with 24-hour urine metanephrines or plasma free metanephrines, as episodic severe hypertension in a young patient raises this possibility 1
• Evaluate for renovascular hypertension with renal artery duplex ultrasound or CT/MR angiography if clinical suspicion exists 1
• Assess for obstructive sleep apnea, which is common in resistant hypertension and causes episodic blood pressure elevations 1

4. Optimize Blood Pressure Control During Evaluation

• Continue the ARB or substitute with a calcium channel blocker plus an alpha-blocker to achieve target blood pressure <130/80 mmHg 1
• Add a thiazide-like diuretic (chlorthalidone 12.5–25 mg daily) if blood pressure remains uncontrolled on dual therapy 1
• Reinforce lifestyle modifications: sodium restriction <2 g/day, weight loss if BMI ≥25 kg/m², regular aerobic exercise, and alcohol limitation 1

Critical Pitfalls to Avoid

• Do not interpret aldosterone and renin values while the patient is taking an ARB, ACE inhibitor, or beta-blocker—these medications profoundly alter the renin-angiotensin-aldosterone axis and render screening results uninterpretable 1, 2, 4
• Do not assume primary aldosteronism based on elevated absolute aldosterone levels alone—the diagnosis requires demonstration of autonomous aldosterone secretion with suppressed renin (ARR >30) 1, 5
• Do not abruptly discontinue antihypertensive therapy without substituting alternative agents—severe rebound hypertension can occur, particularly in young patients with episodic severe elevations 1
• Do not delay evaluation for pheochromocytoma if episodic symptoms (headache, palpitations, diaphoresis) accompany the hypertensive episodes, as this diagnosis requires urgent exclusion 1