What is the diagnosis and treatment approach for patients with suspected disorders of plasma renin and aldosterone?

Diagnosis and Management of Plasma Renin and Aldosterone Disorders

Screen high-risk hypertensive patients using the aldosterone-to-renin ratio (ARR), confirm positive results with saline suppression or oral salt loading, determine lateralization with adrenal venous sampling, and treat unilateral disease surgically while managing bilateral disease with spironolactone.

Who Should Be Screened

Screen the following patient populations for primary aldosteronism using ARR testing 1:

• Resistant hypertension (blood pressure uncontrolled on 3 medications including a diuretic) 1
• Severe hypertension (BP >180/110 mmHg) 1
• Hypokalemia (spontaneous or diuretic-induced) 1
• Adrenal incidentaloma with hypertension 1
• Family history of early-onset hypertension or stroke before age 40 1

Primary aldosteronism affects up to 20% of patients with resistant hypertension, making screening essential in this population 1.

Patient Preparation for ARR Testing

Medication Management

Discontinue interfering medications when clinically safe 1:

• Stop at least 2-4 weeks before testing: Beta-blockers, centrally acting antihypertensives (clonidine), and diuretics 1, 2
• Withdraw at least 4 weeks before: Mineralocorticoid receptor antagonists (spironolactone, eplerenone) 1
• Safe alternatives to use: Long-acting calcium channel blockers and alpha-receptor antagonists minimally interfere with ARR 1, 2

If medications cannot be stopped, interpret results in the context of the specific drugs being taken 1. Beta-blockers can cause false-positive ARRs by suppressing renin 3, while ACE inhibitors and ARBs can cause false-negative results 3.

Metabolic and Timing Requirements

• Correct hypokalemia before testing, as low potassium suppresses aldosterone production 1
• Ensure unrestricted salt intake and normal serum potassium levels 1
• Collect blood in the morning after the patient has been out of bed for 2 hours and seated for 5-15 minutes immediately before collection 1

Interpreting the ARR Screening Test

Diagnostic Thresholds

A positive ARR requires BOTH criteria 1, 2:

• ARR ≥30 (when aldosterone measured in ng/dL and renin activity in ng/mL/h) 1
• Plasma aldosterone concentration ≥10-15 ng/dL 1, 2

The specificity improves if a minimum plasma renin activity of 0.5 ng/mL/h is used in calculations 1, 2.

Alternative Renin Measurement

Direct renin concentration (DRC) can replace plasma renin activity (PRA), with excellent correlation between methods (r=0.98) 4. When using DRC, the threshold for a positive test is ARR >150 pmol/ng 4. DRC assays are faster, simpler, and more reproducible than PRA 5, and may reduce false-positive rates in treated patients 5.

Common Causes of Low Renin Beyond Primary Aldosteronism

Low renin with an elevated ARR does not automatically confirm primary aldosteronism 2:

• Low-renin essential hypertension (particularly common in Black patients) 2
• Chronic kidney disease with reduced renin production 2
• Cushing syndrome (presents with hypertension, hypokalemia, and suppressed renin) 2
• Excessive sodium intake or volume expansion 2

Confirmatory Testing

All positive ARR screening tests require confirmatory testing to demonstrate autonomous aldosterone production 1, 2.

Confirmatory Test Options

Choose one of the following 1:

• Intravenous saline suppression test: Infuse 2 liters of normal saline over 4 hours; failure to suppress aldosterone below 5-10 ng/dL confirms primary aldosteronism 1
• Oral sodium loading test: Administer high-sodium diet (>200 mEq/day) for 3 days with 24-hour urine collection; aldosterone >12 mcg/24h with urinary sodium >200 mEq/24h confirms diagnosis 1

Perform confirmatory testing with unrestricted salt intake and normal serum potassium levels 1, 2.

Subtype Determination

Initial Imaging

Obtain non-contrast CT scan of the adrenal glands after biochemical confirmation to assess for unilateral adenoma versus bilateral hyperplasia 1.

Adrenal Venous Sampling (AVS)

Perform AVS before offering adrenalectomy to distinguish unilateral from bilateral disease 1. This is critical because up to 25% of patients would undergo unnecessary adrenalectomy based on CT findings alone 1, 2. Small adrenal lesions like myolipomas are typically non-functional and rarely associated with hormone production 6.

Treatment Based on Subtype

Unilateral Disease (Aldosterone-Producing Adenoma)

Laparoscopic unilateral adrenalectomy is the treatment of choice 1, 7:

• Improves blood pressure in virtually 100% of patients 1
• Achieves complete cure of hypertension in approximately 50% 1
• Resolves hypokalemia and reduces cardiovascular and kidney damage 2

Spironolactone 100-400 mg daily can be used for short-term preoperative treatment 7.

Bilateral Disease (Idiopathic Hyperaldosteronism)

Medical therapy with mineralocorticoid receptor antagonists is the cornerstone of treatment 1, 2:

• First-line: Spironolactone 25-100 mg daily initially, titrated up to 400 mg daily for long-term maintenance 1, 7
• Alternative: Eplerenone when anti-androgenic side effects (gynecomastia, sexual dysfunction) occur with spironolactone 1, 2

For patients unsuitable for surgery with unilateral disease, spironolactone can be used as long-term maintenance therapy at the lowest effective dose 7.

Critical Pitfalls to Avoid

• Do not rely on hypokalemia as a screening criterion—it is absent in the majority of primary aldosteronism cases 1, 2
• Do not skip confirmatory testing after a positive ARR, as false positives are common 1
• Do not proceed to surgery without AVS unless the patient has clear unilateral disease on imaging with compelling biochemical features 1, 2
• Do not interpret ARR in isolation—always ensure aldosterone is absolutely elevated (≥10-15 ng/dL), not just the ratio 1, 2