How should plasma renin activity and aldosterone concentrations be interpreted when evaluating an adult with hypertension, hypokalemia, or an adrenal mass?

Interpretation of Plasma Renin Activity and Aldosterone Levels

The aldosterone-to-renin ratio (ARR) is the key screening test, with a positive result defined as ARR ≥20-30 (when aldosterone is in ng/dL and renin activity in ng/mL/h) AND plasma aldosterone concentration ≥10-15 ng/dL, requiring confirmatory testing before proceeding to treatment decisions. 1

Patient Preparation Before Testing

Critical preparation steps directly impact test accuracy:

• Ensure potassium repletion to serum levels of 4.0-5.0 mEq/L before testing, as hypokalemia suppresses aldosterone production and causes false-negative results 1, 2
• Discontinue interfering medications when clinically feasible: 1
  • Stop beta-blockers, centrally acting drugs, and diuretics (these suppress renin and cause false-positive ARR) 1
  • Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing 1
  • ACE inhibitors and ARBs increase renin and lower ARR, potentially causing false-negatives 1
• Use safe alternatives during washout: long-acting calcium channel blockers and alpha-receptor antagonists minimally interfere with ARR 1
• If medications cannot be stopped, interpret results in the context of the specific drugs the patient is taking 1

Blood Collection Technique

Proper timing and positioning are essential:

• Collect blood in the morning (ideally 0800-1000 hours) after the patient has been out of bed for 2 hours 1
• Patient should be seated for 5-15 minutes immediately before blood draw 1
• Ensure unrestricted salt intake before testing 1

Interpreting the Results

Screening Test Interpretation

The ARR threshold and aldosterone level must both be met:

• ARR ≥20-30 (when aldosterone is measured in ng/dL and plasma renin activity in ng/mL/h) indicates a positive screen 1
• Plasma aldosterone concentration must be ≥10-15 ng/dL in addition to the elevated ratio 1
• Specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations 1

Alternative renin measurement: If direct renin concentration (DRC) is used instead of plasma renin activity, an ARR threshold of ≥150 pmol/ng may indicate primary aldosteronism 3, 4

Pattern Recognition

High aldosterone + Low renin + Elevated ARR = Primary aldosteronism pattern:

• This indicates autonomous aldosterone production independent of the renin-angiotensin system 2
• Approximately 50% of cases are unilateral (aldosterone-producing adenoma), 50% are bilateral adrenal hyperplasia 2
• Hypokalemia is absent in approximately 50% of primary aldosteronism cases, so normal potassium does not exclude the diagnosis 1

Low aldosterone + Low renin = Consider other causes:

• Volume expansion from other causes
• Chronic kidney disease
• Medications affecting the renin-angiotensin-aldosterone system

High aldosterone + High renin = Secondary aldosteronism:

• Renovascular hypertension
• Renin-secreting tumor
• Diuretic use
• Volume depletion

Mandatory Next Steps After Positive Screening

A positive ARR is only a screening test and requires confirmation:

• Confirmatory testing is mandatory to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading 1
• Options for confirmatory testing: 1
  • Intravenous saline suppression test (2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis) 1
  • Oral sodium loading test with 24-hour urine aldosterone measurement 1
  • Fludrocortisone suppression test 1
• Testing conditions: unrestricted salt intake and normal serum potassium levels 1

Subtype Determination

After biochemical confirmation, determine if disease is unilateral or bilateral:

• Initial imaging: non-contrast CT scan of adrenal glands 1
• Adrenal venous sampling (AVS) is mandatory before offering adrenalectomy, as up to 25% of patients might undergo unnecessary surgery based on CT findings alone 1
• Exception: AVS may be omitted in patients <40 years with imaging showing only one affected gland, as bilateral hyperplasia is rare in this population 1

Clinical Context for Testing

Screen these high-risk populations:

• Resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic) – prevalence up to 20% 1
• Severe hypertension (BP >180/110 mmHg) 1
• Spontaneous or diuretic-induced hypokalemia 1
• Adrenal incidentaloma discovered on imaging 1
• Family history of early-onset hypertension or stroke at age <40 years 1

Common Pitfalls to Avoid

• Never rely on presence or absence of hypokalemia alone – it is absent in 50% of cases 1
• Never proceed to surgery based on CT findings alone – AVS is required for lateralization 1
• Never perform confirmatory testing while patient is on spironolactone – requires 4-week washout 1
• Never test without correcting hypokalemia first – causes false-negative results 1, 2
• Never interpret ARR without checking absolute aldosterone level – both criteria must be met 1

Why This Matters

Primary aldosteronism carries dramatically higher cardiovascular risk than essential hypertension at equivalent blood pressure levels: 1

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

Early diagnosis and treatment (unilateral adrenalectomy for unilateral disease or mineralocorticoid receptor antagonists for bilateral disease) can reverse aldosterone-mediated target-organ damage and reduce this excess cardiovascular risk 1, 2