Primary Aldosteronism

Recommendation 1

In all individuals with hypertension, we suggest screening for primary aldosteronism (PA) (2 | ⊕⊕OO).

Technical remarks:

• This is a conditional recommendation, with implementation depending on contextual factors such as available resources, local expertise, and healthcare system capacity, which may affect feasibility and prioritization.
• This recommendation emphasizes care that is informed and guided by screening, with a positive screening result serving as the critical first step in the care process for individuals with PA.
• PA screening includes measurement of serum/plasma aldosterone concentration and plasma renin (concentration or activity) with determination of the aldosterone to renin ratio (ARR). Potassium is also assessed—not for screening itself—but to aid in the accurate interpretation of aldosterone (refer to Question 3).

Recommendation 2

In individuals with hypertension and primary aldosteronism (PA), we suggest PA-specific therapy (medical or surgical) (2 | ⊕⊕OO).

Technical remarks:

• In individuals with lateralizing PA who are not surgical candidates or do not desire surgery and in individuals with bilateral PA, medical treatment with mineralocorticoid receptor antagonists (MRAs) should be considered preferable over nonspecific antihypertensive therapy.
• In individuals with lateralizing PA who are surgical candidates and desire surgery, unilateral adrenalectomy should be considered preferable over nonspecific antihypertensive therapy.

Recommendation 3

In individuals with hypertension, we suggest primary aldosteronism (PA) screening with serum/plasma aldosterone concentration and plasma renin (concentration or activity) (2 | ⊕⊕OO).

Technical remarks:

• Screen for PA by measuring serum/plasma aldosterone and plasma renin (concentration or activity) in the morning with individuals seated and avoiding dietary sodium restriction during the few days prior to screening. Potassium should be measured alongside renin and aldosterone—not for screening itself but to aid in the accurate interpretation of aldosterone—as low potassium may lead to a falsely low aldosterone.
• If screening results are negative and the patient has hypokalemia, potassium should be corrected to within the laboratory reference range and screening should be repeated.
• Manage interfering medications depending on individual safety and feasibility. The Guideline Development Panel outlined both minimal withdrawal and no-withdrawal strategies of interfering medications before screening (Tables 6 and 7, Fig. 1).
• A positive screen meets both of the following conditions in most circumstances:
  • Renin is low/suppressed (hallmark of diagnosis) and aldosterone is inappropriately high relative to renin: indicative of PA if plasma renin activity (PRA) is ≤1 ng/mL/h or direct renin concentration (DRC) is ≤8.2 mU/L AND serum/plasma aldosterone concentration is ≥10 ng/dL (≥277 pmol/L) when measured by immunoassay or ≥7.5 ng/dL (≥208 pmol/L) when measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS). 
  • Elevated aldosterone to renin ratio (ARR): indicative of PA if the aldosterone [ng/dL] to PRA [ng/mL/h] ratio is >20 or aldosterone [pmol/L] to DRC [mU/L] ratio is >70 when aldosterone is measured by immunoassay; the ARR indicative of PA is about 25% lower when aldosterone is measured by LC-MS/MS). (see Fig. 1 and Table 5 for ARR cut points for differing assays and units).
• The aldosterone, renin, and ARR values above are provided for guidance. However, as with many diagnostic tests based on continuous variables, the sensitivity and specificity depend on the selected threshold. Aldosterone and renin levels are further influenced by individual variability, local laboratory assays, and other factors. Where possible, clinicians should rely on local laboratory cut points, as assays may vary. No cut point is perfect—each carries a trade-off between false positives and false negatives. Therefore, results should be interpreted within the context of the patient’s pretest probability for PA, along with potential interfering medications and conditions.
• If the individual’s initial screen is negative and factors are present that could have led to a false negative result (eg, hypokalemia or medications), the test should be repeated on a different day, preferably after correcting hypokalemia (where present) and withdrawing interfering medications if safe and feasible (for 4 weeks for mineralocorticoid receptor antagonists [MRAs], epithelial sodium-channel [ENaC] inhibitors [eg, amiloride, triamterene], and other diuretics; and 2 weeks for angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]), which raise renin or lower aldosterone. For the most accurate determination of potassium, measure plasma potassium in blood collected slowly with a syringe and needle (preferably not using a vacuum-sealed blood collection tube to minimize the risk of spuriously raising potassium). During collection, avoid fist clenching, wait at least 5 seconds after tourniquet release (if used) to achieve insertion of needle, and ensure separation of plasma from cells within 30 minutes of collection.
• If the individual's initial screen is negative and the pretest probability of PA is moderate to high (e.g., hypokalemia and/or resistant hypertension) or renin is suppressed with aldosterone of 5 to 10 ng/dL (138 to 277 pmol/L) by immunoassay, the test should be repeated on a different day.
• If the individual’s initial screen is positive, but they are receiving medications (e.g., β-adrenergic blockers and centrally acting α2-agonists [e.g. clonidine, α-methyldopa]) that can lower renin and thereby cause false-positive results, the test should be repeated after withdrawing those medications for 2 weeks if it is safe and feasible. Consider potential false positives induced by β-adrenergic blockers when aldosterone is 10-15 ng/dL (277-416 pmol/L) by immunoassay or 7.5-10 ng/dL (208-277 pmol/L) by LC-MS/MS; if aldosterone is above these concentrations, PA is likely despite being on β-adrenergic blockers.
• If screening hypertensive patients with chronic kidney disease, renin decreases proportionately to nephron loss, except in cases where there is renal ischemia from renal artery stenosis where renin will be elevated. Aldosterone can also be elevated in chronic kidney disease, leading to overall increases in false positive testing.
• If all initial screening is negative, consider re-screening in the future if a patient develops:
  • Unexplained worsening of hypertension or resistant hypertension
  • New spontaneous or diuretic-induced hypokalemia
  • Atrial fibrillation in the absence of structural heart disease or hyperthyroidism

Recommendation 4

In individuals who screen positive for PA, we suggest aldosterone-suppression testing in situations when screening results suggest an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy. (2 | ⊕OOO)

Technical remarks:

Situations in which aldosterone-suppression testing may be helpful include:

• In individuals with an intermediate probability of having lateralizing PA who are willing and able to undergo surgical adrenalectomy (see Figure 2).

Situations in which aldosterone-suppression testing is not required prior to initiating PA-specific therapy include (Figure 2):

• In individuals with resistant hypertension or hypertension with hypokalemia and overt biochemical evidence of renin-independent aldosterone production (PRA <0.2 ng/mL/h or DRC <2 mU/L and plasma aldosterone concentration >15 ng/dL [>416 pmol/L] via LC-MS/MS assay or >20 ng/dL [>554 pmol/L] via immunoassay), aldosterone-suppression testing is not recommended due to the risk of false-negative results, which may exceed the risk of false-positive screening results.
• Individuals unwilling or unable to pursue adrenal venous sampling and adrenalectomy can be empirically treated with MRAs based on screening results, without aldosterone-suppression testing. Aldosterone-suppression testing may still provide value in some cases for further documenting the diagnosis.
• Aldosterone-suppression testing is unnecessary in individuals from families with germline mutations associated with familial hyperaldosteronism. Genetic screening is recommended for all first-degree relatives of individuals with familial hyperaldosteronism and for individuals with young-onset PA (<20 years) to enable early diagnosis and treatment.
• Aldosterone-suppression testing can also be avoided if the likelihood of lateralizing PA is so low that pursuing a formal diagnosis of PA is not justifiable (e.g., normokalaemia + plasma/serum aldosterone <~11ng/dL [<∼305 pmol/L] [immunoassay] or <~8 ng/dL [<∼222 pmol/L] [LC-MS/MS]).

Recommendation 5

In individuals with PA, we suggest medical therapy or surgical therapy with the choice of therapy based on lateralization of aldosterone hypersecretion and candidacy for surgery. (2 | ⊕OOO)

Technical remarks:

• Surgical therapy by total unilateral adrenalectomy, usually by the laparoscopic approach, is mainly offered to individuals with lateralizing PA who choose to pursue the surgical option (Figure 2).
• Lifelong medical therapy, that includes an MRA, is usually offered to individuals with bilateral PA or lateralization status unknown (refer to Question 6 for definition of lateralization) and to those who are not surgical candidates or who decline the surgical option (Figure 2).
• Individuals with mild PA typically have bilateral disease and may bypass adrenal venous sampling (AVS), proceeding directly to medical management, as outlined in the diagnostic algorithm (Figure 2).
• Individuals with multiple comorbidities who may not be good surgical candidates may also proceed directly to medical therapy (Figure 2).

Recommendation 6

In individuals with PA considering surgery, we suggest adrenal lateralization with CT scanning and AVS prior to deciding the treatment approach (medical or surgical). (2 | ⊕⊕OO)

Technical remarks:

• Individuals with PA who desire and are candidates for adrenalectomy should undergo AVS in order to reliably differentiate lateralizing from bilateral forms.
• A potential exception is when the diagnosis of unilateral aldosterone-producing adenoma (APA) is so likely that AVS could be considered unnecessary (e.g., individual age <35 years with marked PA with hypokalemia and a >1.0-cm unilateral adrenal adenoma on computed tomography [CT] scanning).

Recommendation 7

In individuals with PA receiving PA-specific medical therapy whose hypertension is not controlled and renin is suppressed, we suggest increasing PA-specific medical therapy to raise renin. (2 | ⊕OOO).

Technical remarks:

• This recommendation applies to individuals with PA receiving aldosterone-directed medical therapy whose BP remains high. Uncertainty remains as to whether titrating aldosterone-directed medical therapy to raise renin when BP is controlled is efficacious.
• The panel does not specify a renin level to target, but rather advises titration of aldosterone-directed medical therapy to a rise in renin from pretreatment baseline.

Recommendation 8

In individuals with PA and adrenal adenoma, we suggest a dexamethasone-suppression test. (2 | ⊕OOO)

Technical remarks:

• A dexamethasone-suppression test should be performed, and a positive test should prompt further evaluation for Cushing syndrome as detailed in the Endocrine Society Clinical Practice Guidelines.
• For the 1-mg overnight dexamethasone-suppression test, 1-mg dexamethasone is taken orally at 23:00 to 24:00 with serum cortisol measured at 08:00 to 09:00 the next morning. A serum cortisol >1.8 μg/dl (50 nmol/L) suggests autonomous cortisol secretion (ACS).
• For individuals with mild ACS, measuring plasma metanephrine during AVS may help lateralize both aldosterone and cortisol secretion although further research is needed. It will also be important to measure early morning cortisol following adrenal surgery and prepare for a period of possible glucocorticoid insufficiency.

Recommendation 9

In individuals with PA receiving PA-specific medical therapy, we suggest spironolactone over other MRAs due to its low cost and widespread availability. (2 | ⊕OOO)

Technical remarks:

• The recommendation is driven by the availability and low cost of spironolactone vs. other MRAs; however, all MRAs, when titrated to equivalent potencies, are anticipated to have similar efficacy in treating PA. MRAs with greater MR specificity and fewer androgen/progesterone receptor-mediated side effects may be preferred.
• When initiating an MRA, consider hypertension severity for dosing and potential discontinuation of other antihypertensive medications (see Figure 3).
• Monitor potassium, renal function, renin (concentration or activity), and BP response during follow-up to guide MRA dose titration.

Recommendation 10

For individuals with PA receiving PA-specific medical therapy, we suggest using MRAs rather than ENaC inhibitors (amiloride, triamterene).  (2 | ⊕OOO)

Technical remark:

• The recommendation (Figure 3) does not apply to clinical conditions in which spironolactone is contraindicated (e.g., hyperkalemia, advanced renal impairment, or pregnancy) or if a non-spironolactone MRA were indicated for other non-PA indications (e.g., heart failure).