Aldosterone and Renin

Aldosterone is the main mineralocorticoid, made in the adrenal zona glomerulosa, which promotes renal sodium retention and potassium loss. Its secretion is controlled by angiotensin II (through renin), potassium and, to a lesser degree, ACTH.

Renin is an enzyme released by the juxtaglomerular cells in response to low renal perfusion, low sodium and sympathetic activation, which converts angiotensinogen into angiotensin I. Plasma renin is measured as direct renin concentration (mIU/L or ng/L) or as plasma renin activity (ng/mL per hour of angiotensin I generation), and aldosterone by immunoassay or mass spectrometry (pmol/L or ng/dL).

The aldosterone to renin ratio (ARR) is the screening test for primary aldosteronism, the commonest cause of secondary hypertension. Renin and aldosterone are also used to find the cause of hypokalaemia, hyperkalaemia, hyponatraemia, adrenal insufficiency and salt wasting.

Primary aldosteronism is present in 5 to 10% of unselected hypertensive patients, up to 20% of those with resistant hypertension, and a larger share of those with hypokalaemia or a family history. It is under diagnosed (fewer than 2% of those at risk are tested), and it carries more cardiovascular damage than other forms of hypertension at the same pressure.

Indications. Resistant hypertension (three drugs including a diuretic), hypertension with hypokalaemia, hypertension with an adrenal incidentaloma, hypertension with sleep apnoea, onset of hypertension before age 40 or a family history of early stroke, atrial fibrillation or stroke in young patients, unexplained hypokalaemia or hyperkalaemia, suspected adrenal insufficiency, and suspected salt losing states.

Specimen. Sampled in the morning, at least 2 hours after rising and after 5 to 15 minutes seated. Potassium should be corrected to 4 mmol/L or more, with unrestricted dietary salt. Collect into EDTA or serum, at room temperature, since cold storage activates prorenin and gives false high renin (this applies to direct renin). Transport at room temperature and separate promptly.

Ranges are assay specific and posture specific. Conversion: aldosterone ng/dL multiplied by 27.7 gives pmol/L.

Aldosterone. Seated morning: about 100 to 800 pmol/L (4 to 31 ng/dL), higher with salt depletion. Raised: primary aldosteronism, secondary hyperaldosteronism (heart failure, cirrhosis, nephrotic syndrome, renal artery stenosis, diuretics), pregnancy, and Bartter and Gitelman syndromes. Lowered: adrenal insufficiency, hyporeninaemic hypoaldosteronism (diabetes, kidney disease, NSAIDs), congenital adrenal hyperplasia (some types), and mineralocorticoid excess other than aldosterone.

Renin (direct renin concentration or plasma renin activity).

Raised:

• salt depletion
• hypovolaemia
• diuretics
• heart failure
• cirrhosis
• renal artery stenosis
• adrenal insufficiency
• reninoma
• Bartter and Gitelman syndromes
• ACE inhibitors and angiotensin receptor blockers

Suppressed:

• primary aldosteronism
• Liddle syndrome
• apparent mineralocorticoid excess
• Cushing syndrome
• congenital adrenal hyperplasia (11-beta-hydroxylase and 17-alpha-hydroxylase deficiency)
• liquorice ingestion
• beta blockers
• clonidine
• NSAIDs
• older age and people of African ancestry (low renin hypertension)

Aldosterone to renin ratio. A positive screen needs:

• Aldosterone over about 300 pmol/L (over 10 ng/dL) with suppressed renin (under 5 mIU/L for direct renin, or plasma renin activity under 1 ng/mL per hour), and a ratio over 70 pmol/L per mIU/L (over 30 ng/dL per ng/mL per hour). Cut offs are assay specific.
• Aldosterone can be low normal with undetectable renin in a patient on interfering drugs.

Confirmatory tests. In a positive screen, confirmatory testing shows autonomous aldosterone secretion: saline infusion (2 litres of saline over 4 hours, aldosterone remaining over 140 pmol/L, or 5 ng/dL, confirms), captopril challenge, oral salt loading with 24-hour urine aldosterone over 33 nmol/day, or fludrocortisone suppression. Confirmation may be unnecessary when there is spontaneous hypokalaemia, undetectable renin and aldosterone over 550 pmol/L.

Subtype testing. CT or MRI adrenal imaging, then adrenal vein sampling (with cortisol correction) in patients considering surgery, to distinguish unilateral adenoma (about 30 to 40%, curable by adrenalectomy) from bilateral hyperplasia (treated with a mineralocorticoid receptor antagonist). Genetic testing is used in early onset disease (familial hyperaldosteronism types I to IV).

Pattern table.

• High aldosterone, low renin: primary aldosteronism.
• High aldosterone, high renin: secondary hyperaldosteronism (volume depletion, heart failure, cirrhosis, renal artery stenosis, diuretics, Bartter and Gitelman syndromes).
• Low aldosterone, high renin: adrenal insufficiency, 21-hydroxylase deficiency, drugs (heparin, ACE inhibitors).
• Low aldosterone, low renin: hyporeninaemic hypoaldosteronism, apparent mineralocorticoid excess, Liddle syndrome, Cushing syndrome, 11-beta-hydroxylase deficiency, liquorice excess, exogenous mineralocorticoids.
• Normal results do not exclude primary aldosteronism when interfering drugs are present.

Drug effects on the ARR.

• Drugs that can cause false negatives (they raise renin and lower the ratio): mineralocorticoid receptor antagonists, ACE inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers and diuretics.
• Drugs that can cause false positives (they suppress renin and raise the ratio): beta blockers, clonidine and NSAIDs.
• Hypokalaemia suppresses aldosterone and can mask the diagnosis.
• Mineralocorticoid receptor antagonists are withdrawn for 4 to 6 weeks before testing where safe. If renin remains suppressed on treatment, the ratio is still valid.
• Alpha blockers, verapamil and hydralazine have little effect and bridge antihypertensive therapy during withdrawal.

Primary aldosteronism features. Hypertension, hypokalaemia (only in about 30%), mild hypernatraemia, metabolic alkalosis, atrial fibrillation, left ventricular hypertrophy, albuminuria, and adrenal adenoma on imaging.

Hyperkalaemia. Low aldosterone with high renin points to adrenal insufficiency, low aldosterone with low renin to hyporeninaemic hypoaldosteronism (type 4 renal tubular acidosis), and high aldosterone with hyperkalaemia to aldosterone resistance (pseudohypoaldosteronism).

Critical values and findings needing immediate action.

• Potassium under 2.5 mmol/L with ECG change, weakness or paralysis, and suppressed renin.
• Hypertension with severe hypokalaemia and a suspected adrenal tumour.
• Hyperkalaemia over 6.5 mmol/L with low aldosterone and high renin (adrenal crisis).
• Hypertension in pregnancy with suppressed renin and hypokalaemia.

Interferences and pitfalls.

• Posture, time of day and salt intake alter results, so conditions are standardised.
• Hypokalaemia lowers aldosterone, and potassium is corrected before testing.
• Cold storage falsely raises direct renin (cryoactivation of prorenin) and leads to false negative ratios.
• Oral contraceptives and pregnancy raise angiotensinogen and renin and may reduce the ratio.
• Kidney failure and older age alter the ratio.
• Assay methods differ in ranges and cut offs, and the ratio units (pmol/L per mIU/L, ng/dL per ng/mL per hour) are not interchangeable.
• A low aldosterone with high renin on heparin therapy is a drug effect.
• A single normal ARR does not exclude primary aldosteronism when pre-test probability is high, and repeat testing off interfering drugs is done.

Special groups.

• Neonates and infants: renin and aldosterone are high at birth, and salt wasting adrenal hyperplasia presents in the first weeks.
• Children: hypertension with hypokalaemia suggests a monogenic cause.
• Pregnancy: both renin and aldosterone rise, and the ratio is difficult to interpret.
• Older adults: renin falls with age, and lower cut offs are used for renin.
• People of African ancestry: low renin hypertension is frequent, and the ratio can be raised without primary aldosteronism.
• Regions: access to adrenal vein sampling is limited in many settings.

Follow up tests. Potassium and sodium, bicarbonate, urinary potassium, saline infusion or captopril confirmatory test, adrenal CT, adrenal vein sampling, cortisol and dexamethasone suppressible aldosterone studies, genetic testing for familial hyperaldosteronism, echocardiography, urine albumin to creatinine ratio, ECG, sleep study, and renal artery imaging in secondary hyperaldosteronism.