How should plasma renin activity and aldosterone be measured and interpreted in a hypertensive patient with resistant hypertension and hypokalemia?

Measurement and Interpretation of Plasma Renin and Aldosterone in Resistant Hypertension with Hypokalemia

In a hypertensive patient with resistant hypertension and hypokalemia, you should immediately screen for primary aldosteronism using the aldosterone-to-renin ratio (ARR), as this combination represents a potentially curable cause of hypertension present in up to 20% of resistant hypertension cases, with dramatically higher cardiovascular risk than essential hypertension alone. 1

Patient Preparation Before Testing

Potassium Repletion

• Correct hypokalemia before testing by targeting serum potassium 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone production and causes false-negative results. 1, 2
• Potassium supplementation is crucial during the diagnostic workup to maintain test accuracy. 1

Medication Management

• Discontinue beta-blockers, centrally acting drugs, and diuretics when clinically feasible, as these suppress renin and cause false-positive ARR results. 1, 2
• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing. 1, 2
• Use long-acting calcium channel blockers (verapamil slow-release) and alpha-receptor antagonists (prazosin, doxazosin, hydralazine) as safe alternatives during the washout period, as they minimally interfere with ARR. 1, 2
• If medications cannot be stopped due to severe hypertension, proceed with testing and interpret results in the context of the specific medications the patient is taking. 1

Dietary Preparation

• Ensure unrestricted (liberal) salt intake before testing, as salt restriction can artificially elevate aldosterone levels. 1

Blood Collection Protocol

• Collect blood in the morning (ideally 0800-1000 hours) with the patient out of bed for at least 2 hours prior to collection. 1
• Have the patient seated for 5-15 minutes immediately before blood draw. 1
• Draw blood with the patient in a seated position. 1

Interpreting the Aldosterone-to-Renin Ratio

Positive Screening Criteria

• A positive ARR requires BOTH an ARR ≥20-30 (when aldosterone is measured in ng/dL and renin activity in ng/mL/h) AND a plasma aldosterone concentration ≥10-15 ng/dL. 1, 2
• The specificity of the ratio improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 1, 2

Common Pitfalls to Avoid

• Do not rely on hypokalemia alone for diagnosis—it is absent in approximately 50% of primary aldosteronism cases. 1
• An elevated ARR alone is not diagnostic; low renin can artificially elevate the ARR even without truly elevated aldosterone levels. 2
• ACE inhibitors and ARBs increase renin and cause false-negative ARR, while beta-blockers suppress renin and cause false-positive ARR. 1, 2

Confirmatory Testing

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

Confirmatory Test Options

• Intravenous saline suppression test: Infuse 2L of normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms the diagnosis. 1
• Oral sodium loading test: Administer high-sodium diet (>200 mEq/day) for 3 days with measurement of 24-hour urine aldosterone; urinary aldosterone >12-14 mcg/24h confirms the diagnosis. 1, 3
• Perform confirmatory testing with unrestricted salt intake and normal serum potassium levels. 1

Subtype Determination

Initial Imaging

• Obtain non-contrast CT scan of the adrenal glands to identify unilateral adenoma versus bilateral hyperplasia. 1

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. 1, 2
• Exception: AVS may be omitted in patients <40 years when imaging shows a single affected gland, as bilateral hyperplasia is rare in this population. 1

Clinical Significance and Urgency

Primary aldosteronism causes dramatically worse cardiovascular outcomes 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

Immediate Management Considerations

• Consider starting spironolactone 25-50 mg daily immediately after positive ARR screening, even before confirmatory testing is completed, as it provides significant blood pressure reduction (25/12 mmHg) when added to multidrug regimens in resistant hypertension. 1
• Monitor serum potassium within 1 week of spironolactone initiation, as hyperkalemia risk is increased in patients with diabetes, CKD, or concomitant use of ACE inhibitors/ARBs. 1

Referral Pathway

Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination and treatment planning. 1