Supplemental Table S7. Hyperaldosteronism: Screening and diagnosis
Screening
i. Plasma aldosterone and plasma renin activity or renin mass/concentration (see ii below for conversion factors) should be collected as follows:
  1. In the morning after the patient has been ambulatory (sitting, standing, or walking) for at least 2 hours.
  2. Patients should be seated for 5-15 minutes prior to the blood draw.
  3. Hypokalemia should be corrected and sodium intake should be liberalized.
  4. Agents that markedly affect the results of testing (aldosterone antagonists, potassium sparing and wasting diuretics) should be withdrawn at least 4-6 weeks prior.
  5. If the results are not diagnostic, and if hypertension can be controlled with medications less likely to affect testing (slow-release verapamil, hydralazine, prazosin, doxazosin, and terazosin), repeat testing two weeks after withdrawing the following medications that can interfere with test accuracy: beta-blockers, centrally acting alpha-2 agonists, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, directly acting renin inhibitors, dihydropyridine calcium channel blockers
  6. False positive results may occur with direct renin mass/concentration if the patient is a woman using an oral contraceptive pill. If possible, oral contraception should be discontinued for 1 month prior to testing, or alternately, plasma renin activity should be measured instead.
ii. The aldosterone to renin ratio is the preferred screening test for primary aldosteronism. Traditionally this was based on measuring aldosterone by radioimmunoassay and renin activity. Currently most laboratories use automated chemiluminescent assays for aldosterone and renin mass. Interpretation of a positive screening test is dependent upon the local laboratory method for renin measurement but assumes standard reporting of aldosterone in pmol/L. Optimal screening cut-offs remain undefined. Suggested cut-offs are below:
Renin method used Aldosterone-torenin ratio: higher sensitivity, lower specificity Aldosterone-torenin ratio: lower sensitivity, higher specificity
Plasma renin activity (ng/ml/h) 555 750
Direct renin concentration (mIU/L) 60 91
Direct renin concentration (ng/L) 100 144
Confirmatory Testing
iii. If one of the following criteria is met, autonomous hypersecretion of aldosterone is confirmed (interfering drugs should continue to be held, as outlined above):
  1. Saline loading tests (perform either):
    1. Administer two litres of normal saline intravenously over 4h with the patient in a recumbent position. This test is contraindicated in the presence of severe, uncontrolled hypertension or congestive heart failure. Primary hyperaldosteronism is defined as a post-infusion plasma aldosterone >280 pmol/L. If <140 pmol/L, primary hyperaldosteronism is unlikely. Values in between are considered indeterminate;
    2. Administer >200 mmol/day of oral sodium (i.e., equivalent to >5 g/day of sodium; >12 g/day of sodium chloride; or >2 tsp/day of salt) for three days, with primary aldosteronism defined as a 24-hr urinary aldosterone >33 nmol/d (measured from the morning of day 3 to the morning of day 4). If <28 nmol/day, primary aldosteronism is unlikely.
  2. A plasma aldosterone to PRA ratio greater than 1400 pmol/L/ng/ml/hr (or 270 pmol/L/ng/L), with a plasma aldosterone greater than 440 pmol/L.
  3. Captopril suppression test: Administer 25-50 mg captopril orally after the patient has been sitting or standing for 1 hour. While seated, renin and plasma aldosterone levels should be measured at time zero and 1 to 2 hours after ingestion. Primary aldosteronism is unlikely if plasma aldosterone is suppressed by >30% following captopril ingestion. In primary aldosteronism, plasma aldosterone remains elevated, while renin remains suppressed.
Subtype Classification
iv. Differentiating potential causes of confirmed primary aldosteronism (unilateral vs bilateral secretion):
  1. CT scanning (or MRI) can help localize the presence of adrenal lesion(s). If imaging demonstrates an adrenal lesion/adenoma, it may be non-functional. Therefore, if surgery to remove a suspected unilateral source of primary aldosteronism is planned, selective adrenal venous sampling should be considered first (to verify that abnormally appearing adrenal gland is the source of hypersecretion).
  2. For patients with established primary hyperaldosteronism, negative imaging studies, and in whom surgery is an option, selective adrenal venous sampling should be considered to differentiate unilateral from bilateral overproduction of aldosterone.
  3. Adrenal venous sampling should be conducted in centers with experience in performing this diagnostic technique.
  4. We suggest selective genetic testing for glucocorticoid remediable aldosteronism in patients with confirmed primary aldosteronism and either:
    1. A family history of primary aldosteronism or stroke at young age (≤40 years); or
    2. onset of hypertension ≤20y and negative imaging
Treatment
v. Treatment is informed by subtype classification (unilateral vs. bilateral secretion):
  1. Surgery with ipsilateral adrenalectomy should be considered for unilateral forms of hypersecretion (e.g., aldosterone-producing adenonas). Patients should be followed closely after surgery as a significant proportion may remain hypertensive.
  2. Mineralocorticoid receptor antagonists (particularly spironolactone in low to moderate doses) are quite effective for those with bilateral disease (e.g., idiopathic/bilateral adrenal hyperplasia). Monitoring of potassium and creatinine are required, especially if combined with angiotensin receptor blockers or angiotensin converting enzyme inhibitors.
  3. Mineralocorticoid receptor antagonists should be considered for individuals who are not surgical candidates or for those who refuse surgery (even with confirmed unilateral hypersecretion). Blood pressure lowering responses to other antihypertensives (e.g., angiotensin receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers) are often only modest-to-moderate.