In a 25‑year‑old male on an angiotensin‑receptor blocker, does a plasma renin activity of ~600 units and aldosterone level of ~135 units indicate primary or secondary hyperaldosteronism?

Secondary Hyperaldosteronism

In this 25-year-old male on an ARB with renin ~600 units and aldosterone ~135 units, these findings indicate secondary hyperaldosteronism, not primary aldosteronism. The markedly elevated renin in the setting of ARB therapy excludes primary aldosteronism, where renin should be suppressed despite medication effects.

Key Diagnostic Reasoning

The elevated renin is the critical distinguishing feature. In primary aldosteronism, autonomous aldosterone production suppresses plasma renin activity, and this suppression persists even when patients are taking medications like ARBs that would normally stimulate renin 1, 2. When renin remains suppressed (<1.0 ng/mL/hr) despite ARB therapy, it strongly suggests autonomous aldosterone production 2.

Why This Is Secondary Hyperaldosteronism

• ARBs dramatically increase renin levels by blocking the negative feedback loop of the renin-angiotensin-aldosterone system, and a renin of ~600 units represents an appropriate physiologic response to ARB therapy 3.

• The aldosterone-to-renin ratio (ARR) is the screening test for primary aldosteronism, not absolute aldosterone levels alone 1, 2. With renin at 600 and aldosterone at 135, the ARR would be approximately 0.23 (if using ng/dL per ng/mL/hr units), which is far below the diagnostic threshold of ≥20-30 for primary aldosteronism 2.

• In true primary aldosteronism, renin remains suppressed (<0.5-1.0 ng/mL/hr) even on ARBs because the autonomous aldosterone production causes volume expansion that overrides medication effects 1, 2. Some patients with severe hypertensive kidney damage from longstanding primary aldosteronism can develop "escape" of renin from suppression, but this occurs only with advanced renal arteriolosclerosis and elevated creatinine 4.

Clinical Context and Next Steps

Medication Effects on Testing

• ARBs cause false-negative ARR results by raising renin levels, which lowers the ratio and can mask primary aldosteronism 2, 3. Irbesartan specifically causes a 43% decrease in ARR and produces false-negative results in up to 23.5% of primary aldosteronism cases 3.

• If clinical suspicion for primary aldosteronism remains high (resistant hypertension, spontaneous hypokalemia, adrenal incidentaloma, family history of early-onset hypertension or stroke <40 years), the ARB should be withdrawn for at least 2 weeks before retesting 2.

• Safe alternative antihypertensives during washout include long-acting calcium channel blockers (verapamil slow-release, amlodipine) and alpha-receptor antagonists (doxazosin, prazosin), which minimally interfere with ARR 2, 3.

When to Screen for Primary Aldosteronism in Young Patients

This 25-year-old should be screened for primary aldosteronism if any of the following are present 1, 2:

• Resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic)
• Spontaneous or substantial diuretic-induced hypokalemia (though 50% of primary aldosteronism cases have normal potassium) 1, 2
• Incidentally discovered adrenal mass on imaging 1, 2
• Family history of early-onset hypertension or stroke at age <40 years in first-degree relatives 1, 2
• Severe hypertension (BP >180/110 mmHg) 2

Proper Testing Protocol

If screening is warranted, follow this algorithm 2:

1. Discontinue ARB for ≥2 weeks and switch to non-interfering agents (calcium channel blockers, alpha-blockers) 2
2. Ensure potassium repletion to 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone and causes false-negatives 2
3. Collect blood in the morning (0800-1000 hours) after patient has been out of bed for 2 hours and seated for 5-15 minutes 2
4. Measure simultaneous plasma aldosterone concentration and plasma renin activity to calculate ARR 1, 2
5. Positive screen requires ARR ≥20-30 AND plasma aldosterone ≥10-15 ng/dL 1, 2
6. All positive screens require confirmatory testing (IV saline suppression test or oral sodium loading with 24-hour urine aldosterone) to demonstrate autonomous aldosterone secretion 1, 2

Common Pitfalls to Avoid

• Do not rely on hypokalemia as a screening trigger—it is absent in approximately 50% of primary aldosteronism cases 1, 2.

• Do not interpret ARR while patient is on ARBs, ACE inhibitors, beta-blockers, or diuretics without understanding the directional effects on the ratio 2, 3. Beta-blockers suppress renin and cause false-positive ARR, while ARBs/ACE inhibitors raise renin and cause false-negative ARR 2, 3.

• Do not proceed to adrenalectomy based on CT imaging alone—adrenal venous sampling is mandatory to distinguish unilateral from bilateral disease, as up to 25% of patients would undergo unnecessary surgery based on CT findings 2.

Why Early Diagnosis Matters

Primary aldosteronism carries dramatically higher cardiovascular risk than essential hypertension at equivalent blood pressure levels 2:

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

These excess risks are reversible with appropriate treatment—either unilateral adrenalectomy for unilateral disease (cures hypertension in ~50% and improves BP in virtually 100%) or mineralocorticoid receptor antagonist therapy for bilateral disease 2, 5.