What is the diagnostic approach and management for a patient with hypertension and hypokalemia?

Hypertension with Hypokalemia: Diagnostic Approach and Management

Screen immediately for primary aldosteronism using the aldosterone-to-renin ratio (ARR), as this combination represents a potentially curable cause of hypertension that carries dramatically higher cardiovascular risk than essential hypertension—including a 12-fold increase in atrial fibrillation and 6.5-fold increase in myocardial infarction. 1, 2

Who Requires Screening

Primary aldosteronism affects 5–10% of all hypertensive patients and up to 20% of those with resistant hypertension, making it the most common form of secondary hypertension. 1, 2, 3 The combination of hypertension and hypokalemia is a classic presentation, though hypokalemia is absent in approximately 50% of confirmed cases, so normal potassium does not exclude the diagnosis. 1, 2

Mandatory screening indications include: 1, 2, 3

• Spontaneous or diuretic-induced hypokalemia with hypertension
• Resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic)
• Severe hypertension (BP >180/110 mmHg)
• Adrenal incidentaloma discovered on imaging
• Family history of early-onset hypertension or stroke before age 40
• Young-onset hypertension (<30–40 years) without traditional risk factors

Initial Screening Test: Aldosterone-to-Renin Ratio (ARR)

Patient Preparation

Correct hypokalemia before testing, as low potassium suppresses aldosterone production and causes false-negative results; target serum potassium 4.0–5.0 mEq/L. 2, 4

Medication management: 1, 2

• Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks before testing—this is mandatory
• Stop beta-blockers, centrally acting drugs, and diuretics when clinically feasible, as these suppress renin and cause false-positive results
• Safe alternatives during washout: long-acting calcium channel blockers (verapamil SR) and alpha-receptor antagonists (doxazosin, prazosin, hydralazine) minimally interfere with ARR
• If medications cannot be stopped, test on current regimen and interpret results in context of known drug effects

Blood Collection Technique

Collect blood in the morning (ideally 0800–1000 hours) with the patient out of bed for at least 2 hours and seated for 5–15 minutes immediately before the blood draw. 1, 2 Ensure unrestricted (liberal) salt intake before testing. 2

Interpretation Thresholds

A positive screening test requires BOTH: 1, 2

• ARR ≥20–30 (when aldosterone is measured in ng/dL and renin activity in ng/mL/h)
• Plasma aldosterone concentration ≥10–15 ng/dL

The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations. 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, 2 The ARR alone has limited specificity due to common low-renin states from volume expansion or dietary salt. 2

Confirmatory test options: 1, 2

• Oral sodium loading test: Administer high-salt diet (>200 mEq/day) for 3 days, then measure 24-hour urine aldosterone; failure to suppress urinary aldosterone below threshold confirms diagnosis
• Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone below 5 ng/dL confirms diagnosis
• Fludrocortisone suppression test: Alternative confirmatory method

Testing must be performed with unrestricted salt intake, normal serum potassium levels, and mineralocorticoid receptor antagonists withdrawn for at least 4 weeks. 1, 2

Subtype Determination: Unilateral vs. Bilateral Disease

This distinction is mandatory because it determines whether the patient is a surgical candidate (unilateral disease) or requires lifelong medical therapy (bilateral disease). 2

Initial Imaging

Obtain non-contrast CT scan of the adrenal glands to identify unilateral adenoma versus bilateral hyperplasia. 1, 2 However, CT findings alone are insufficient for treatment decisions, as adenomas on imaging can represent hyperplasia and false positives are common due to nodular hyperplasia. 2

Adrenal Venous Sampling (AVS)

AVS is mandatory before offering adrenalectomy to distinguish unilateral from bilateral aldosterone hypersecretion, with sensitivity of 95% and specificity of 100%. 2 Up to 25% of patients might undergo unnecessary adrenalectomy based on CT findings alone. 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. 2

Treatment Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma)

Laparoscopic unilateral adrenalectomy is the treatment of choice, improving blood pressure in virtually 100% of patients and curing hypertension in approximately 30–60%. 1, 2, 3 Surgery normalizes hypokalemia in all patients and reduces cardiovascular risk. 2

The rate of cure is higher when diagnosis is made early; even after successful adrenalectomy, some patients have residual hypertension due to vascular remodeling from delayed diagnosis. 2

Bilateral Disease (Bilateral Adrenal Hyperplasia)

Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of lifelong treatment. 1, 2

Spironolactone is first-line therapy: 1, 2

• Start 25–50 mg once daily
• Titrate up to 300–400 mg once daily if necessary
• Low doses (25–50 mg) are often effective and minimize adverse effects
• Monitor serum potassium within 1 week of initiation and regularly thereafter
• Risk of hyperkalemia is increased in older patients, those with diabetes, CKD, or concomitant use of ACE inhibitors/ARBs/NSAIDs

Eplerenone is an alternative with fewer anti-androgenic side effects (gynecomastia, sexual dysfunction), but is less potent than spironolactone and requires twice-daily administration. 2

Empiric Treatment in Resistant Hypertension

For patients with resistant hypertension and positive ARR screening, add spironolactone 25–50 mg daily immediately while awaiting confirmatory testing, as this provides significant additional BP reduction of 25/12 mmHg regardless of whether primary aldosteronism is ultimately confirmed. 2 This approach is particularly effective because spironolactone benefits both true primary aldosteronism and aldosterone-sensitive hypertension. 2

Referral Recommendations

Refer all patients with confirmed primary aldosteronism to a hypertension specialist or endocrinologist for subtype determination via adrenal venous sampling and treatment planning. 1, 2

Critical Pitfalls to Avoid

• Never rely on presence or absence of hypokalemia alone to screen for primary aldosteronism, as 50% of cases have normal potassium 1, 2
• Never proceed to surgery based on CT findings alone without adrenal venous sampling (except in patients <40 years with unilateral adenoma) 2
• Never perform confirmatory testing while patient is taking mineralocorticoid receptor antagonists—these must be withdrawn for at least 4 weeks 1, 2
• Never test without correcting hypokalemia first, as this suppresses aldosterone and causes false-negative results 2
• Never assume low screening rates are acceptable—only 2–4% of eligible patients currently get screened despite the high prevalence and dramatically elevated cardiovascular risk 2

Why This Matters: Cardiovascular Risk

Primary aldosteronism causes dramatically worse outcomes than essential hypertension at equivalent blood pressure levels: 2

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

Prompt identification and targeted treatment—either surgical or medical—can reverse aldosterone-mediated target-organ damage and mitigate this excess cardiovascular risk. 2