Introduction

Primary aldosteronism is a strong candidate for one of the most underdiagnosed and consequential disorders in internal medicine. It is common, clinically important, and treatable, yet most affected patients are never screened. The missed opportunity is substantial: many patients labeled as having “essential hypertension” actually have autonomous aldosterone excess that can be treated with targeted medical therapy or, in selected unilateral cases, potentially curative adrenalectomy.

The older teaching was simple but misleading. Primary aldosteronism was described as severe hypertension with hypokalemia, often caused by a unilateral adrenal adenoma. That phenotype exists, but it represents only part of the spectrum. Most patients with primary aldosteronism are normokalemic, and many have biochemical disease that is less dramatic than the classic Conn syndrome presentation. Reliance on hypokalemia as a trigger for screening misses many cases.

The 2025 Endocrine Society guideline marks a major shift. It suggests screening all individuals with hypertension by measuring aldosterone and renin and interpreting the aldosterone-to-renin ratio, rather than restricting case detection to classic high-risk groups alone. The guideline also emphasizes that potassium should be checked to aid interpretation, as hypokalemia can suppress aldosterone secretion and provide false reassurance.

This change reflects a broader conceptual shift: primary aldosteronism is not merely a secondary cause of rare hypertension. It is a common, modifiable driver of cardiovascular and renal risk.

Why Primary Aldosteronism Is Missed

Primary aldosteronism remains underdiagnosed for several reasons.

First, clinicians still associate the diagnosis with hypokalemia. This is the most persistent misconception. Hypokalemia occurs in only a minority of affected patients, so normal potassium cannot exclude the disorder. The 2025 Endocrine Society guideline explicitly notes that relying on hypokalemia alone would miss many cases.

Second, many clinicians believe testing requires stopping nearly all antihypertensive therapy. While medication effects matter, screening can often proceed with minimal or no withdrawal strategies when medication changes are unsafe or impractical. Borderline or discordant results can be repeated under more optimized conditions.

Third, the interpretation of aldosterone and renin is more nuanced than reading a single lab value. A high aldosterone-to-renin ratio can be misleading if aldosterone is not actually elevated. Conversely, suppressed renin despite medications that should raise renin is highly suspicious.

Fourth, the diagnostic pathway can seem complicated. Screening, confirmatory testing, adrenal imaging, adrenal venous sampling, surgical referral, and long-term medical monitoring may involve multiple clinicians. Without a clear pathway, abnormal screens may not lead to a definitive diagnosis or treatment.

Finally, hypertension care is often focused on achieving blood pressure targets rather than identifying the mechanism. This approach may control numbers but miss aldosterone-mediated cardiovascular, renal, and metabolic injury.

Epidemiology and Clinical Importance

Primary aldosteronism is the most common endocrine cause of hypertension and one of the most common forms of secondary hypertension. Prevalence varies by population and diagnostic method, but studies consistently show that primary aldosteronism is far more common than historically believed. It is found in a meaningful proportion of general hypertensive patients and in a substantially higher proportion of those with resistant hypertension.

The clinical importance extends beyond blood pressure. Compared with patients who have primary hypertension and similar blood pressure levels, patients with primary aldosteronism have higher rates of atrial fibrillation, stroke, coronary disease, left ventricular hypertrophy, kidney disease, and mortality. The excess risk is thought to reflect direct effects of aldosterone on the heart, vasculature, kidneys, and metabolic tissues.

This is why disease-specific therapy matters. Treating primary aldosteronism as ordinary hypertension may lower blood pressure, but it may not adequately address mineralocorticoid receptor activation. In medically treated primary aldosteronism, observational data suggest that persistent renin suppression during mineralocorticoid receptor antagonist therapy may identify patients with incomplete blockade and residual cardiometabolic risk.

Pathophysiology

Primary aldosteronism results from autonomous aldosterone production that is at least partly independent of the renin-angiotensin system. Excess aldosterone promotes sodium retention, intravascular volume expansion, potassium wasting, hydrogen ion loss, and suppression of renin.

However, the disease is not simply a volume-expanded hypertension state. Aldosterone acts directly through mineralocorticoid receptors in the heart, kidney, vasculature, brain, and immune system. These effects promote inflammation, oxidative stress, fibrosis, endothelial dysfunction, arterial stiffness, albuminuria, and myocardial remodeling.

The two major clinical subtypes are:

1. Unilateral primary aldosteronism is often due to an aldosterone-producing adenoma or unilateral hyperplasia.
2. Bilateral primary aldosteronism, often called bilateral adrenal hyperplasia, although the pathologic substrate can be more complex.

Somatic mutations in genes involved in ion channels and calcium signaling, including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others, have improved understanding of aldosterone-producing lesions. These discoveries help explain autonomous aldosterone production and may eventually refine imaging, subtyping, and targeted therapy.

Clinical Presentation

Hypertension

Hypertension is the central clinical feature. It may be mild, moderate, severe, or resistant. Resistant hypertension remains a high-yield phenotype, but primary aldosteronism can also be present in patients whose blood pressure is controlled on one or two medications.

Normal potassium is common

Normal potassium does not exclude primary aldosteronism. Hypokalemia, when present, increases suspicion, but it is not required. Hypokalemia may be spontaneous or diuretic-induced and can cause fatigue, weakness, cramps, polyuria, or, rarely, periodic paralysis.

Cardiovascular clues

Clinical clues may include:

• Atrial fibrillation at a younger age than expected.
• Left ventricular hypertrophy disproportionate to blood pressure history.
• Resistant hypertension.
• Stroke or transient ischemic attack at a young age.
• Sleep apnea with difficult-to-control hypertension.
• Family history of early-onset hypertension or stroke.

Kidney and metabolic clues

Patients may have albuminuria, reduced estimated glomerular filtration rate, nephrolithiasis due to hypercalciuria, impaired glucose metabolism, or an increased risk of cardiometabolic events.

Who Should Be Screened?

2016 high-risk screening model

The 2016 Endocrine Society guideline recommended case detection in high-risk groups, including patients with resistant hypertension, sustained blood pressure above 150/100 mm Hg, controlled blood pressure requiring four or more medications, hypertension with spontaneous or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, hypertension with sleep apnea, hypertension with family history of early-onset hypertension or stroke before age 40, and hypertensive first-degree relatives of patients with primary aldosteronism.

2025 broader screening model

The 2025 Endocrine Society guideline recommends screening all individuals with hypertension for aldosterone and renin levels and interpreting the aldosterone-to-renin ratio. This recommendation reflects the high prevalence of normokalemic disease, the limitations of selective case detection, and the relative feasibility of aldosterone and renin testing.

Practical implementation

Although broad screening is now suggested, health systems may need a phased implementation strategy. The highest-yield groups should be prioritized immediately:

High-yield group	Why screening matters
Resistant hypertension	High prevalence and high treatment impact
Hypertension with hypokalemia	Classic high-probability phenotype
Hypertension controlled on four or more drugs	Suggests severe or resistant physiology
Hypertension with adrenal incidentaloma	Possible unilateral source
Early-onset hypertension	Raises suspicion for secondary forms
Hypertension with sleep apnea	Frequent coexistence and high cardiometabolic risk
Family history of early stroke or early hypertension	May indicate familial or severe phenotype
Atrial fibrillation with hypertension	Aldosterone excess promotes atrial remodeling

A practical message for clinicians is to start with high-yield groups now, but build systems that make aldosterone-renin screening routine in hypertension care.

Screening Test: Aldosterone, Renin, and ARR

The aldosterone-to-renin ratio is the most widely used screening method, but the ratio should not be interpreted in isolation.

A convincing positive screen generally includes:

1. Suppressed renin.
2. Aldosterone is inappropriately high relative to renin.
3. Elevated aldosterone-to-renin ratio using assay-specific cut points.

The 2025 guideline provides technical criteria for interpretation. It notes that a positive screen generally requires low or suppressed renin, inappropriately high aldosterone, and an elevated ARR, while also emphasizing local assay variability and the need to interpret results in the clinical context.

Why the ratio alone can mislead

If renin is extremely low, the ARR can be high even when aldosterone is not meaningfully elevated. That pattern may not represent clinically important primary aldosteronism. Conversely, a patient taking medications that raise renin may have a falsely low ARR despite true disease.

Therefore, clinicians should always inspect:

• Aldosterone concentration.
• Renin concentration or plasma renin activity.
• ARR.
• Potassium level.
• Sodium intake status.
• Medication effects.
• Pretest probability.

Test Preparation and Medication Effects

Medication washout improves diagnostic accuracy, but it is not always safe or necessary for initial screening. Overly rigid washout requirements can become a barrier to diagnosis.

Key preparation principles

• Measure aldosterone and renin in the morning when feasible.
• Obtain the sample with the patient seated, in accordance with local protocol.
• Avoid dietary sodium restriction before testing.
• Correct hypokalemia before testing when possible, because low potassium can suppress aldosterone and produce a false-negative result.
• Review medications and interpret results accordingly.

Medication effects

Medication class	Possible effect on screening
Mineralocorticoid receptor antagonists	Can raise renin and lower ARR, risking false negatives
ENaC inhibitors such as amiloride	Can interfere with interpretation
ACE inhibitors and ARBs	Often raises renin and may lower ARR
Diuretics	Often raises renin and may lower ARR
Beta-blockers	Suppresses renin and may raise ARR, causing false positives
Central alpha-2 agonists	Suppresses renin and may raise ARR
Dihydropyridine calcium channel blockers	May raise renin modestly and lower ARR
Verapamil, hydralazine, alpha blockers	Often used as lower-interference options

If renin remains suppressed despite ACE inhibitors, ARBs, or diuretics, primary aldosteronism becomes more suspicious because those drugs would usually raise renin. If results are borderline, repeat testing under more controlled medication conditions may be appropriate.

Confirmatory Testing

Confirmatory testing is often used after a positive screen to demonstrate autonomous aldosterone production. Common options include:

• Saline infusion test.
• Oral sodium loading test.
• Captopril challenge test.
• Fludrocortisone suppression test.

Each has advantages and limitations. The saline infusion test is widely used but may be inappropriate in patients with severe uncontrolled hypertension, heart failure, advanced kidney disease, or marked volume sensitivity. Oral sodium loading requires careful urine collection and monitoring. Fludrocortisone suppression is labor-intensive but rigorous. Captopril challenge is easier but may be less definitive in some settings.

When confirmatory testing may be bypassed

Confirmatory testing may not be necessary in a classic, high-probability phenotype. The 2016 guideline suggested that confirmatory testing may be omitted in patients with spontaneous hypokalemia, undetectable renin, and plasma aldosterone concentration above 20 ng/dL.

The 2025 guideline also supports more individualized pathways, including proceeding toward subtype evaluation when screening results indicate a high probability of lateralizing disease.

Subtype Classification

Once primary aldosteronism is diagnosed, the next question is whether aldosterone excess is unilateral or bilateral.

Adrenal CT

Adrenal CT is generally performed after biochemical diagnosis to exclude adrenocortical carcinoma, identify adrenal anatomy, and guide planning. However, CT cannot reliably determine whether the disease is unilateral or bilateral. Nonfunctioning adrenal nodules are common, especially with age, and small aldosterone-producing lesions can be missed.

Adrenal venous sampling

Adrenal venous sampling is the usual gold standard for determining lateralization before adrenalectomy. It measures aldosterone production from each adrenal gland while correcting for cortisol to confirm successful sampling.

The 2016 guideline recommended adrenal CT for all patients with confirmed primary aldosteronism and adrenal venous sampling by an experienced radiologist to establish or exclude unilateral disease before surgery.

Exception to AVS

An exception may be considered in selected younger patients, often younger than 35 years, with spontaneous hypokalemia, marked aldosterone excess, and a clear unilateral adrenal adenoma with a normal contralateral gland. Practice varies, and many centers still prefer AVS when feasible.

Treatment

Treatment depends on whether the disease is unilateral, bilateral, or not fully subtyped.

Unilateral disease: adrenalectomy

Laparoscopic adrenalectomy is preferred for appropriate surgical candidates with lateralizing primary aldosteronism. Surgery can correct aldosterone excess, normalize potassium, reduce medication burden, and improve cardiovascular risk markers.

Clinical expectations must be realistic. Biochemical cure is common after adrenalectomy, but complete blood pressure cure is variable. Most patients benefit clinically, but many still require some antihypertensive therapy after surgery. Younger age and female sex were associated with more favorable clinical outcomes in the PASO cohort.

Factors associated with better blood pressure control include:

• Younger age.
• Shorter duration of hypertension.
• Fewer preoperative antihypertensive medications.
• Lower body mass index.
• Female sex in some cohorts.
• Absence of advanced vascular remodeling.
• Preserved kidney function.

Bilateral disease or nonsurgical patients: medical therapy

Mineralocorticoid receptor antagonists are the foundation of medical therapy. Spironolactone is often preferred because of cost, availability, and potency. Eplerenone is more selective and causes fewer sex hormone-related adverse effects, but it is typically less potent and may require twice daily dosing.

The 2025 guideline recommends mineralocorticoid receptor antagonists over ENaC inhibitors and favors spironolactone over other MRAs because of its lower cost and greater availability. It also states that more selective MRAs may be preferred in some situations.

Spironolactone

Spironolactone is effective but can cause:

• Hyperkalemia.
• Decline in kidney function.
• Gynecomastia.
• Breast tenderness.
• Menstrual irregularities.
• Reduced libido or erectile dysfunction in some patients.

Dosing often begins at a low dose and is titrated based on blood pressure, potassium, kidney function, tolerability, and renin response.

Eplerenone

Eplerenone is useful when spironolactone causes intolerable endocrine side effects. It is less likely to cause gynecomastia or menstrual side effects, but it may require higher or twice-daily dosing.

Amiloride

Amiloride can be used when MRAs are not tolerated, but it blocks epithelial sodium channels rather than the mineralocorticoid receptor. It may improve blood pressure and potassium levels, but it is generally not considered equivalent to MRA therapy in blocking aldosterone-mediated tissue effects.

Renin-Guided Medical Therapy

Traditional treatment targets include blood pressure control and potassium normalization. Increasingly, clinicians also consider whether renin remains suppressed during MRA therapy.

Persistent renin suppression may indicate incomplete blockade of mineralocorticoid receptor activity. Observational data suggest that medically treated primary aldosteronism patients whose renin rises with MRA therapy may have lower residual cardiometabolic risk than those whose renin remains suppressed.

A practical approach is:

• Treat blood pressure to guideline targets.
• Normalize potassium.
• Monitor kidney function.
• Titrate MRA therapy as tolerated.
• Consider renin response as a marker of adequate blockade, especially if blood pressure remains uncontrolled and renin remains suppressed.

Dose escalation must be limited by hyperkalemia, kidney function, hypotension, and patient tolerability.

Monitoring

After adrenalectomy

Postoperative monitoring includes:

• Blood pressure.
• Serum potassium.
• Kidney function.
• Aldosterone and renin assessment.
• Medication reduction is safe when it is.
• Evaluation for adrenal insufficiency if clinically suspected, especially if cortisol co-secretion was present.

During medical therapy

Monitoring includes:

• Blood pressure and home readings.
• Serum potassium.
• Creatinine and estimated glomerular filtration rate.
• Renin is used for titration.
• Aldosterone is clinically useful.
• Side effects and adherence.

Monitoring is especially important in patients with chronic kidney disease, diabetes, older age, or concurrent ACE inhibitor or ARB therapy.

Cardiovascular and Renal Outcomes

Primary aldosteronism causes target-organ damage beyond ordinary hypertension. Aldosterone excess promotes left ventricular hypertrophy, myocardial fibrosis, atrial remodeling, endothelial dysfunction, albuminuria, and kidney injury.

Compared with blood pressure-matched primary hypertension, primary aldosteronism is associated with a higher risk of:

• Atrial fibrillation.
• Stroke.
• Coronary artery disease.
• Heart failure.
• Left ventricular hypertrophy.
• Chronic kidney disease.
• Albuminuria.
• Mortality.

This risk profile explains why diagnosis matters even when blood pressure can be controlled with nonspecific antihypertensives. The goal is not simply to reduce blood pressure. The goal is to block or remove aldosterone excess.

Implementation in Internal Medicine Practice

A practical internal medicine workflow can reduce missed diagnoses.

Step 1: Identify candidates

Under the 2025 guideline, all hypertensive patients are candidates for screening for aldosterone and renin. If full implementation is not yet feasible, prioritize resistant hypertension, hypokalemia, adrenal incidentaloma, early-onset hypertension, sleep apnea with hypertension, atrial fibrillation with hypertension, and family history of early stroke or hypertension.

Step 2: Order the right labs

Order:

• Plasma or serum aldosterone.
• Plasma renin activity or direct renin concentration.
• Serum potassium.
• Basic metabolic panel.

Use local lab cut points because assays differ.

Step 3: Interpret the pattern

Look for:

• Suppressed renin.
• Inappropriately elevated aldosterone.
• Elevated ARR.
• Compatible clinical phenotype.

Do not interpret ARR without separately assessing aldosterone and renin.

Step 4: Manage medication issues

Do not abandon screening simply because medication washout is difficult. Interpret results in the context of medications. Repeat testing under optimized conditions if the first result is equivocal.

Step 5: Refer appropriately

Refer to endocrinology or a hypertension specialist when screening is positive, results are ambiguous, or subtype classification is needed. Refer to endocrine surgery only after biochemical diagnosis and appropriate lateralization evaluation.

Common Diagnostic Mistakes

Mistake	Why it matters
Waiting for hypokalemia	Most patients are normokalemic
Ordering aldosterone without renin	Cannot determine autonomy
Interpreting ARR without aldosterone level	Low renin alone can inflate the ratio
Assuming CT laterality equals functional laterality	Incidentalomas are common
Skipping AVS before surgery in most patients	Risk of removing the wrong adrenal or missing bilateral disease
Treating with standard antihypertensives only	May leave aldosterone-mediated risk untreated
Stopping all BP medications unsafely before testing	Can create avoidable harm
Failing to repeat equivocal tests	False positives and false negatives occur
Not monitoring potassium and renal function after MRA	Hyperkalemia and changes in kidney function can occur
Declaring surgery a failure because BP meds remain needed	Biochemical cure and medication reduction still matter

Future Directions

Research on primary aldosteronism is moving toward earlier detection, better subtyping, and more targeted therapy.

Promising areas include:

• Broader screening models in primary care.
• Electronic health record prompts for aldosterone-renin testing.
• Noninvasive functional imaging such as metomidate PET.
• Better biomarkers for subtype prediction.
• Aldosterone synthase inhibitors.
• More selective mineralocorticoid receptor antagonists.
• Renin-guided treatment strategies.
• Long-term outcomes comparing surgery, MRA therapy, and nonspecific hypertension treatment.

Finerenone is important in diabetic kidney disease and cardiorenal risk reduction, but it is not established as standard therapy for primary aldosteronism. Future drugs that directly inhibit aldosterone synthesis or more selectively block mineralocorticoid receptor pathways may change treatment options.

 

Frequently Asked Questions

How common is primary aldosteronism?

Primary aldosteronism is found in a meaningful proportion of patients with hypertension and is especially common in resistant hypertension. Prevalence estimates vary by population and diagnostic criteria, but it is much more common than historically taught.

Can primary aldosteronism be present with normal potassium?

Yes. Most patients have normal potassium. Hypokalemia increases suspicion but is not required for diagnosis.

What is the best screening test?

Screening uses paired aldosterone and renin measurements with interpretation of the aldosterone-to-renin ratio. Clinicians should inspect aldosterone and renin separately, not just the ratio.

Do all antihypertensive medications need to be stopped before screening?

No. Medication effects matter, but testing can often proceed with minimal or no medication withdrawal when washout is unsafe or impractical. Equivocal results can be repeated under optimized conditions.

Why is renin important?

Suppressed renin is the hallmark of autonomous aldosterone physiology. Aldosterone that is inappropriately high despite suppressed renin suggests primary aldosteronism.

Is an adrenal CT enough to decide on surgery?

Usually no. CT can show adrenal anatomy, but it cannot reliably prove which adrenal gland is overproducing aldosterone. AVS is usually needed before adrenalectomy.

Can surgery cure primary aldosteronism?

Surgery can biochemically cure unilateral disease in many patients. Complete blood pressure control is variable, but most patients have improved blood pressure control or reduced medication needs.

What if the disease is bilateral?

Bilateral disease is treated medically, usually with spironolactone or eplerenone.

Should all patients with hypertension be screened?

The 2025 Endocrine Society guideline suggests screening all individuals with hypertension using aldosterone and renin. In practice, systems may prioritize high-yield groups while building capacity for broader screening.

References

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