Aldosterone: Which Tests to Order Alongside (Complete Lab Panel Guide)

What Is Aldosterone and Why Does It Matter?

Aldosterone is a mineralocorticoid hormone secreted by the zona glomerulosa of the adrenal cortex. Its primary job is sodium retention and potassium excretion in the distal nephron, which directly controls blood pressure and extracellular fluid volume. When aldosterone production is autonomous, not suppressed by a high-salt diet or volume expansion, blood pressure rises, potassium falls, and cardiovascular risk climbs 1.

Why Isolated Aldosterone Values Are Misleading

A serum aldosterone of 20 ng/dL means something very different depending on whether plasma renin is suppressed at 0.1 ng/mL/hr or elevated at 5.0 ng/mL/hr. In the first scenario the ARR is 200, strongly suggesting primary aldosteronism. In the second the elevated renin explains the elevated aldosterone, pointing instead to secondary aldosteronism from renal artery stenosis or volume depletion 2.

Testing aldosterone without renin is like checking a TSH without ever ordering free T4. The ratio carries the diagnostic weight.

Physiological Drivers of Aldosterone Secretion

Three stimuli drive aldosterone release: angiotensin II (the dominant driver), hyperkalemia, and ACTH (a minor, short-lived stimulus). The renin-angiotensin-aldosterone system (RAAS) forms the feedback loop that makes the ARR interpretable. When renin is high, elevated aldosterone is expected and physiological. When renin is suppressed and aldosterone is still high, the production is autonomous 3.

The Core Paired Test: Aldosterone-to-Renin Ratio (ARR)

The ARR is the single most important paired test. The Endocrine Society's 2016 guideline states that the ARR "is the most reliable screening test for primary aldosteronism" and should be the first-line biochemical screen in all patients meeting criteria 4.

How to Calculate the ARR

• Using PRA: ARR = serum aldosterone (ng/dL) divided by PRA (ng/mL/hr). A ratio >30, combined with an aldosterone >15 ng/dL, is the widely cited threshold 4.
• Using DRC: When laboratories report direct renin concentration in mU/L rather than PRA, the threshold shifts. An ARR >3.7 ng/dL per mU/L is commonly used, though labs vary 5.

Sensitivity and Specificity of ARR Screening

A 2020 meta-analysis published in the Journal of Hypertension (N=6,745 patients across 21 studies) reported ARR sensitivity of 85% and specificity of 70% for confirming primary aldosteronism via subsequent confirmatory testing 6. Sensitivity climbs when the aldosterone absolute value threshold is also applied.

Factors That Distort the ARR

Certain conditions and drugs inflate or suppress the ratio independent of true primary aldosteronism 7:

| Factor | Effect on Aldosterone | Effect on Renin | Net Effect on ARR | |---|---|---|---| | Beta-blockers | Slight decrease | Marked suppression | False elevation | | ACE inhibitors / ARBs | Decrease | Marked increase | False decrease | | Spironolactone / eplerenone | Increase (reflex) | Increase | Unreliable, hold 4 to 6 weeks | | NSAIDs | Decrease | Decrease | Variable | | Oral contraceptives (estrogen) | Increase | Suppress (PRA) | False elevation | | Potassium depletion | Suppress aldosterone | Raise renin | False decrease |

Correcting hypokalemia to ≥3.5 mEq/L before drawing the panel is mandatory. Hypokalemia itself blunts aldosterone secretion from an adenoma, making autonomous production harder to detect 4.

Complete Paired Lab Panel for Aldosterone Workup

Beyond the ARR, a clinically actionable aldosterone workup requires several supporting labs. Each one answers a specific question the ARR alone cannot 8.

Serum Potassium

Hypokalemia is present in only 9 to 37% of confirmed primary aldosteronism cases, so a normal potassium does not rule out the diagnosis 9. Still, potassium must be measured to:

1. Correct deficits before testing (to avoid false-negative ARR).
2. Assess cardiovascular risk. Potassium below 3.0 mEq/L from autonomous aldosteronism is associated with QT prolongation and arrhythmia risk 10.
3. Monitor treatment response, potassium normalizing on spironolactone confirms mineralocorticoid excess was driving the loss.

Serum Sodium

Sodium is usually high-normal or mildly elevated in primary aldosteronism due to sodium retention. Hyponatremia alongside suppressed renin should prompt consideration of other adrenal disorders, including 11-beta-hydroxylase deficiency or apparent mineralocorticoid excess syndrome 11.

Serum Creatinine and eGFR

Aldosterone-excess states cause glomerular hyperfiltration. Paradoxically, when primary aldosteronism is treated surgically or medically, creatinine sometimes rises modestly as the hyperfiltration resolves. Baseline creatinine documents kidney function before treatment and helps interpret post-treatment changes 12.

24-Hour Urine Aldosterone (Confirmatory)

Serum aldosterone fluctuates over the day. A 24-hour urine collection integrates aldosterone excretion across the full day and is the standard confirmatory test after a positive ARR screen, particularly during a high-sodium diet of ≥200 mEq/day for 3 days (oral sodium loading) 4.

A value >12 mcg/day during high-sodium loading confirms autonomous aldosterone production. Simultaneous urine sodium ≥200 mEq/day verifies adequate sodium intake during collection, validating the result 13.

Plasma Cortisol and ACTH (When Indicated)

If the clinical picture suggests co-secretion (Cushing syndrome with hypertension and hypokalemia), adding 8 AM cortisol, 24-hour urine free cortisol, and plasma ACTH is appropriate. Glucocorticoid-remediable aldosteronism (GRA), a rare inherited form, shows ACTH-driven aldosterone secretion and responds completely to low-dose dexamethasone suppression 14.

Magnesium

Often overlooked. Chronic aldosterone excess promotes renal magnesium wasting alongside potassium. Hypomagnesemia compounds the arrhythmia risk from hypokalemia and impairs potassium repletion. Checking magnesium at baseline is particularly useful in patients with serum potassium below 3.2 mEq/L 15.

Who Should Be Screened: Endocrine Society Criteria

The Endocrine Society guideline specifies eight clinical settings that warrant ARR screening 4:

1. Sustained blood pressure >150/100 mmHg on three separate occasions.
2. Hypertension resistant to three conventional drugs including a diuretic.
3. Hypertension controlled on four or more drugs.
4. Hypertension with spontaneous or diuretic-induced hypokalemia.
5. Hypertension with adrenal incidentaloma.
6. Hypertension with sleep apnea.
7. Hypertension with a first-degree relative diagnosed with primary aldosteronism.
8. All patients with hypertension and early-onset stroke (<40 years).

The American Association of Clinical Endocrinology (AACE) 2022 hypertension guidelines similarly recommend aldosterone and renin testing in any patient with resistant or difficult-to-control hypertension 16.

Normal Aldosterone Range and What Shifts It

Reference Ranges by Posture and Collection Method

Reference ranges differ by posture, time of day, dietary sodium intake, and assay platform 17:

| Condition | Serum Aldosterone (ng/dL) | |---|---| | Supine (fasted, morning) | 1 to 16 ng/dL | | Upright (after 2 hours) | 7 to 30 ng/dL | | Low-sodium diet (<50 mEq/day) | Up to 3× above baseline | | High-sodium diet (>200 mEq/day) | Suppressed below 5 ng/dL in normals | | 24-hour urine (normal Na diet) | 2 to 16 mcg/day |

Most clinical laboratories report upright, morning values as the reference standard. Always confirm the posture condition on the requisition.

Pregnancy and Age Effects

Aldosterone rises 2 to 3x above non-pregnant levels by the third trimester due to elevated estrogen and progesterone stimulating renin and thus angiotensin II. In healthy pregnancy, blood pressure does not rise because progesterone antagonizes mineralocorticoid receptors 18.

Children and adolescents have higher normal ranges per unit body surface area than adults. Aldosterone also declines modestly with age as renin falls, making the ARR less sensitive in elderly patients on beta-blockers 19.

What High Aldosterone Means

Primary Aldosteronism (Autonomous Production)

Primary aldosteronism (PA) is the most common correctable cause of secondary hypertension, affecting approximately 5 to 10% of all hypertensive adults and up to 20% of those with resistant hypertension 20. The PAPY Study (N=1,125 consecutive hypertensive referrals) confirmed PA in 11.2% using ARR-based screening followed by confirmatory testing 21.

Causes of PA include:

• Bilateral adrenal hyperplasia (BAH): Accounts for 60 to 70% of PA cases. Treated medically with mineralocorticoid receptor antagonists (MRAs).
• Aldosterone-producing adenoma (APA): Accounts for 30 to 40%. Unilateral adrenalectomy is curative in 35 to 60% of cases 22.
• Familial hyperaldosteronism types I, IV: Rare inherited forms including GRA (FH-I), requiring genetic testing 14.

Secondary Aldosteronism

Here renin is high rather than suppressed. Common causes include renal artery stenosis, congestive heart failure, cirrhosis with ascites, and nephrotic syndrome. The clinical response is appropriate RAAS activation, not autonomous adrenal secretion 23.

Cardiovascular Consequences of Undiagnosed PA

Beyond blood pressure, excess aldosterone causes direct cardiac and vascular injury independent of hypertension. The PAPY Study found PA patients had a 4-fold higher rate of atrial fibrillation and a 12-fold higher rate of stroke compared to blood-pressure-matched essential hypertension controls 21. Early detection and treatment with spironolactone or surgery reverses much of this excess risk 24.

What Low Aldosterone Means

Adrenal Insufficiency and Hypoaldosteronism

Low aldosterone with high renin indicates the adrenal gland is failing to respond normally. Causes include:

• Primary adrenal insufficiency (Addison disease): Cortisol and aldosterone are both low. Plasma ACTH is markedly elevated. Patients present with hypotension, hyperkalemia, and hyponatremia 25.
• Hyporeninemic hypoaldosteronism (Type IV renal tubular acidosis): Renin is also low, seen most often in patients with diabetic nephropathy or NSAIDs use. Hyperkalemia is present despite preserved renal function. Adding plasma renin to aldosterone clarifies this pattern 26.
• Isolated aldosterone synthase deficiency: Rare genetic condition causing salt-wasting and hyperkalemia in infancy 27.

Drug-Induced Hypoaldosteronism

ACE inhibitors, ARBs, heparin (even low-molecular-weight formulations), and direct renin inhibitors (aliskiren) can all suppress aldosterone enough to cause clinical hyperkalemia, particularly in patients with CKD or diabetes. A baseline aldosterone and renin panel helps attribute hyperkalemia to drug effect versus intrinsic adrenal dysfunction 28.

How to Raise Aldosterone (When It Is Pathologically Low)

Fludrocortisone Replacement

Fludrocortisone (Florinef) 0.05 to 0.2 mg/day is the standard replacement for primary adrenal insufficiency and isolated hypoaldosteronism. The Endocrine Society recommends monitoring serum potassium, sodium, and blood pressure every 3 to 6 months during dose titration 29.

Sodium and Fluid Management

Before fludrocortisone is initiated or during tapering, generous sodium intake (2 to 4 g above typical dietary intake) can partially compensate for aldosterone deficiency by increasing the distal sodium delivery that aldosterone would otherwise reabsorb. Patients with Addison disease are counseled to increase salt intake during heat, exercise, or illness 29.

Licorice-Avoidance Note

Glycyrrhizin in licorice root inhibits 11-beta-hydroxysteroid dehydrogenase type 2, producing an aldosterone-excess phenotype even when aldosterone is low. Patients taking fludrocortisone must avoid licorice-containing supplements and herbal preparations 30.

How to Lower Aldosterone (When It Is Pathologically High)

Mineralocorticoid Receptor Antagonists

Spironolactone 25 to 100 mg/day is first-line for bilateral adrenal hyperplasia. The PATHWAY-2 trial (N=335, resistant hypertension) showed spironolactone reduced systolic BP by 8.70 mmHg more than placebo (P<0.001), making it the most effective fourth-line antihypertensive agent tested 31.

Eplerenone 25 to 100 mg/day is a selective MRA with fewer anti-androgenic side effects, preferred in men experiencing gynecomastia on spironolactone 32.

Surgical Adrenalectomy for APA

Unilateral laparoscopic adrenalectomy for confirmed APA achieves biochemical cure (ARR normalization) in nearly 100% of patients and complete hypertension cure (off all antihypertensives) in 35 to 60%, with blood pressure improvement in an additional 35% 33. Adrenal vein sampling (AVS) must confirm unilateral lateralization before surgery because CT imaging alone misclassifies laterality in approximately 37% of PA patients 34.

Dietary Sodium Restriction

High sodium intake stimulates renin suppression and thus amplifies the relative excess of autonomous aldosterone production. Limiting sodium to <2 g/day partially blunts the effect and potentiates the blood pressure response to MRAs 35.

Pre-Analytical Considerations: Getting the Draw Right

The following draw protocol reflects the Endocrine Society 2016 guideline recommendations combined with HealthRX clinical operations experience across aldosterone panel orders 4:

Step 1: Drug holidays (4 to 6 weeks before the draw) Hold spironolactone, eplerenone, amiloride, triamterene, and drospirenone-containing contraceptives for 4 to 6 weeks. Hold licorice preparations for 2 weeks. Beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers can remain on board but must be documented because they shift the ARR 4.

Step 2: Correct hypokalemia Potassium must be ≥3.5 mEq/L at draw. Oral supplementation with potassium chloride 40 to 80 mEq/day for 7 to 14 days typically suffices. Avoid potassium-sparing diuretics during repletion (they alter the renin reading) 36.

Step 3: Morning draw, upright posture Patient should be awake and ambulatory for at least 2 hours before the draw and seated for 5 to 15 minutes at the chair. Draw between 8 to 10 AM. Avoid strenuous exercise the morning of the draw 4.

Step 4: Sample handling Aldosterone is stable at room temperature for up to 8 hours. PRA samples require chilling on ice and rapid centrifugation. Confirm your laboratory's specific handling requirements before collection, PRA degradation at room temperature falsely elevates the ARR 37.

Step 5: Interpret ARR in context If the ARR is positive (>30) but absolute aldosterone is <15 ng/dL, results are equivocal. Repeat the panel under ideal conditions before moving to confirmatory testing 4.

Confirmatory Testing After a Positive ARR Screen

A positive ARR is a screen, not a diagnosis. At least one of the following four confirmatory tests is required before labeling a patient with primary aldosteronism 4:

Oral Sodium Loading Test

Patient consumes >200 mEq sodium/day for 3 days (approximately 5.8 g NaCl supplementation on top of usual diet). On day 3, collect a 24-hour urine for aldosterone, sodium, and creatinine. Urine aldosterone >12 mcg/day confirms PA 4. This test requires caution in patients with severe hypertension or heart failure.

IV Saline Infusion Test

2 liters of 0.9% saline infused over 4 hours in the morning, with the patient supine. Post-infusion serum aldosterone >10 ng/dL confirms PA; a level <5 ng/dL excludes it. The 5 to 10 ng/dL zone is indeterminate 38.

Fludrocortisone Suppression Test

Fludrocortisone 0.1 mg every 6 hours for 4 days, combined with sodium chloride tablets and potassium supplementation. Upright aldosterone >6 ng/dL at day 4 with suppressed PRA confirms PA. This test requires inpatient or close outpatient monitoring due to BP and potassium risks 39.

Captopril Challenge Test

Captopril 25 to 50 mg orally, with aldosterone and renin drawn at 1 to 2 hours post-dose. In normal patients, captopril suppresses aldosterone to <15 ng/dL. Failure to suppress confirms autonomous secretion. Sensitivity is lower than the saline infusion test, making it preferred mainly when saline loading is contraindicated 40.

Subtype Classification: Adrenal CT and Adrenal Vein Sampling

Once PA is biochemically confirmed, subtype classification determines treatment. CT adrenal imaging is the first step. An adrenal adenoma >1 cm on one side with a normal contralateral gland raises suspicion for APA, but CT alone should not determine surgical candidacy 4.

Adrenal vein sampling (AVS) remains the gold-standard procedure for lateralization. A lateralization index (aldosterone-to-cortisol ratio on the dominant side divided by the ratio on the non-dominant side) >4 with adequate cannulation (cortisol selectivity index >3) confirms unilateral disease 41. AVS is recommended in all patients with confirmed PA who are surgical candidates, regardless of CT findings 4.

The SPARTACUS trial (N=184) compared CT-guided treatment versus AVS-guided treatment and found no significant difference in blood pressure outcomes at 1 year 42, generating debate. Subsequent analyses and the Endocrine Society still recommend AVS at experienced centers because CT misclassification can lead to incorrect surgery on the wrong adrenal gland 4.