What is aldosterone, its physiological role, and how are primary hyperaldosteronism and hypoaldosteronism diagnosed and managed?

Aldosterone: Physiology, Diagnosis, and Management

What is Aldosterone?

Aldosterone is a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex that governs volume and electrolyte homeostasis, primarily by promoting sodium retention and potassium excretion in the kidney 1, 2.

Primary Hyperaldosteronism (PA)

Clinical Significance

Primary aldosteronism is the most common endocrine cause of secondary hypertension, affecting 5-10% of all hypertensive patients, rising to 20-30% in resistant hypertension, and is associated with significantly increased cardiovascular morbidity and mortality compared to essential hypertension 3, 4, 5. The excess cardiovascular risk in PA is independent of blood pressure elevation, driven by aldosterone's direct deleterious effects on the heart, vasculature, and kidneys 3, 6.

Key clinical impacts include:

• Higher rates of left ventricular hypertrophy, heart failure, and atrial fibrillation
• Increased stroke risk
• Progressive renal impairment with proteinuria
• Poor quality of life with symptoms including chronic fatigue
• Psychiatric comorbidities (depression/anxiety in 30-70% of patients) 3, 5

Who to Screen

The 2025 Endocrine Society guideline now recommends universal screening with aldosterone-to-renin ratio (ARR) in ALL patients with hypertension 3, 7. This represents a major shift toward broader detection.

High-priority screening indications include:

• Resistant hypertension (requiring ≥3 antihypertensives)
• Severe hypertension (BP >160/100 mmHg)
• Young-onset hypertension (<40 years; 17.8% prevalence)
• Spontaneous or diuretic-induced hypokalemia
• Adrenal incidentaloma with hypertension
• Obstructive sleep apnea with hypertension (59.8% comorbidity)
• Family history of PA or early-onset hypertension
• Patients with cardiovascular events (stroke, MI, atrial fibrillation) 4, 5, 8

Diagnostic Algorithm

Step 1: Screening with ARR

Measure plasma aldosterone concentration (PAC) and direct renin concentration (DRC) or plasma renin activity (PRA) simultaneously to calculate the ARR 3, 4.

Critical medication management before testing:

• Withdraw interfering medications progressively:
  • Stop MRAs (spironolactone, eplerenone) for ≥4 weeks
  • Stop ARBs, ACE inhibitors for ≥2 weeks
  • Stop β-blockers, diuretics (including thiazides, loops, amiloride)
  • Stop NSAIDs
• Maintain blood pressure control with:
  • Alpha-1 adrenergic blockers (doxazosin, terazosin)
  • Long-acting non-dihydropyridine calcium channel blockers (verapamil, diltiazem)
  • Hydralazine 3, 4

Common pitfall: Oral contraceptives and hormone replacement therapy containing estrogen/progesterone increase PRA and aldosterone, potentially causing false-negative results. Drospirenone-containing contraceptives block the mineralocorticoid receptor and should be stopped 3.

Correct hypokalemia before testing as it suppresses aldosterone secretion and causes false-negative results 4.

Step 2: Confirmatory Testing

If PAC >20 ng/dL with suppressed renin AND spontaneous hypokalemia, NO confirmatory testing is needed—PA is confirmed 4.

For all other positive ARR screens, perform one of four confirmatory tests:

1. Intravenous saline infusion test (most commonly used)
2. Oral salt loading test
3. Fludrocortisone suppression test
4. Captopril challenge test (safest option, lower risk of hypokalemia/fluid overload) 4

Important safety consideration: All tests except captopril challenge carry risk of inducing hypokalemia, fluid overload, and worsening hypertension 4.

For borderline results: Repeat the initial test or perform a second different confirmatory test. Patients negative on both saline infusion AND captopril challenge are at low risk for unilateral disease 4.

Step 3: Subtype Classification

The goal is to distinguish unilateral from bilateral aldosterone hypersecretion to determine surgical candidacy 4.

Imaging first:

• Perform adrenal CT or MRI to identify adenomas
• Critical caveat: Not all adrenal adenomas produce aldosterone, and unilateral disease can occur without visible adenoma (40.2% of patients without CT-detected adenoma had unilateral secretion on AVS) 4

Adrenal venous sampling (AVS):

• Gold standard for distinguishing unilateral from bilateral disease
• Required before considering surgery in most patients
• Technically challenging but essential for proper subtype classification 4, 1

Modern understanding recognizes:

• Unilateral disease includes: solitary aldosterone-producing adenoma (APA), multiple nodules, micronodules, or diffuse unilateral hyperplasia
• Bilateral disease includes: bilateral hyperplasia or bilateral aldosterone-producing nodules 4

Treatment

Unilateral Disease (Surgical Candidates)

Laparoscopic unilateral adrenalectomy is the treatment of choice for unilateral aldosterone hypersecretion, offering potential cure of hyperaldosteronism and superior long-term cardiovascular outcomes compared to medical therapy 3, 9.

Preoperative optimization:

• Start mineralocorticoid receptor antagonist (MRA) to achieve BP <140/90 mmHg
• Correct potassium levels
• MRA titration supports recovery of contralateral adrenal function
• Assess for cortisol co-secretion and risk of postoperative adrenal insufficiency 9

Postoperative management:

• Primary concern is hyporeninemic hypoaldosteronism
• Down-titrate antihypertensives immediately
• Withhold MRAs
• Encourage high-sodium diet
• Weekly assessments during first month
• Structured outcome evaluation at 6-12 months using PASO criteria 9

Bilateral Disease or Non-Surgical Candidates

Lifelong treatment with mineralocorticoid receptor antagonists (spironolactone or eplerenone) is the cornerstone of medical management, combined with a low-sodium diet 3, 10.

Dosing strategy:

• Titrate MRA to maintain high-normal serum potassium without oral potassium supplements
• This ensures adequate receptor blockade
• MRAs are superior to routine antihypertensives (ACE inhibitors, ARBs) for treating low-renin hypertension 3

Critical evidence: Specific treatment with MRAs ameliorates the elevated cardiovascular risk in PA patients, providing prognostic benefit over optimal antihypertensive therapy alone 3, 10.

Patients with positive ARR screening but negative confirmatory testing (mild hyperaldosteronism) may still benefit from MRA therapy, as they have low-renin hypertension and 20% may develop overt PA over time 3, 4.

Hypoaldosteronism

Causes

Hyporeninemic hypoaldosteronism is the most common form, typically occurring in:

• Diabetic nephropathy
• Chronic kidney disease
• Following unilateral adrenalectomy for PA 9

Rare genetic causes of low aldosterone with hypertension:

• Liddle syndrome: Activating mutations in epithelial sodium channel; presents with severe early-onset hypertension, hypokalemia, metabolic alkalosis, LOW renin, LOW aldosterone; responds to amiloride or triamterene 4
• Apparent mineralocorticoid excess: 11β-hydroxysteroid dehydrogenase type 2 deficiency (or acquired from chronic licorice ingestion); cortisol activates mineralocorticoid receptor; LOW renin, LOW aldosterone 4
• Congenital adrenal hyperplasia (11β-hydroxylase or 17α-hydroxylase deficiency): Accumulation of 11-deoxycorticosterone; LOW renin, LOW aldosterone 4

Salt-wasting conditions with HIGH aldosterone:

• Bartter and Gitelman syndromes: Renal tubular defects causing salt wasting; present with hypokalemia, metabolic alkalosis, normal or LOW blood pressure, hypovolemia, HIGH renin, HIGH aldosterone 4

Clinical Presentation

Hypoaldosteronism typically manifests as:

• Hyperkalemia
• Metabolic acidosis
• Hyponatremia
• Hypotension or normal blood pressure (depending on etiology)

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Bottom line: PA is vastly underdiagnosed despite being common and causing excess cardiovascular morbidity and mortality. The 2025 guideline advocates universal screening in all hypertensive patients. Early detection enables targeted treatment—either curative surgery for unilateral disease or specific MRA therapy for bilateral disease—both of which significantly reduce cardiovascular risk beyond blood pressure control alone.