Renin–Angiotensin–Aldosterone System (RAAS)
Under normal physiology, renin release is stimulated in a low-volume, low-salt state by:
- Low renal perfusion pressure
- Increased renal sympathetic nervous activity
- Low sodium concentration sensed by the macula densa
Renin then cleaves angiotensinogen to angiotensin I, which in turn is cleaved by angiotensin-converting enzyme (ACE) to angiotensin II.
- Angiotensin II — has two functions: it is a potent vasoconstrictor (in the kidney it constricts both efferent and afferent arterioles, with a stronger effect on the efferent), and it triggers the release of aldosterone.
- Aldosterone — produced by the zona glomerulosa of the adrenal gland. Production is stimulated by three factors: angiotensin II (most potent stimulator), elevated serum potassium and decreased serum sodium, and ACTH (much less potent); it is inhibited by atrial natriuretic peptide. The zona glomerulosa is the only region of the adrenal cortex that does not atrophy on pituitary failure. Aldosterone increases sodium reabsorption and potassium secretion in the distal nephron, and the increased sodium reabsorption raises total body volume.
Classification
Primary hyperaldosteronism — aldosterone secretion is independent of the RAAS, and renin levels are suppressed.
- Can lead to hypokalemia, hypomagnesemia, alkalosis, fluid depletion or retention, refractory hypertension, cardiac dysfunction, and arrhythmias.
- Hypernatremia does not occur, because sodium reabsorption is accompanied by water uptake, thereby maintaining isotonicity.
- Most patients are normokalemic — although hypokalemia is classically described as a common finding, only 9–37% of newly diagnosed patients are hypokalemic.
- Hypertension secondary to hyperaldosteronism carries an increased risk of end-organ damage compared with essential hypertension.
Causes of primary hyperaldosteronism (8):
| Cause | Frequency | Notes |
|---|---|---|
| Bilateral (idiopathic) hyperplasia | 60% | Less severe hypertension and less likely to be hypokalemic than aldosterone-producing adenomas |
| Aldosterone-producing adrenal adenoma | 35% | |
| Unilateral adrenal hyperplasia | 2% | |
| Aldosterone-producing adrenal cortical carcinoma | <1% | |
| Ectopic aldosterone-producing tumour | <1% | |
| Familial hyperaldosteronism type I | <1% | Aldosterone production is mediated by ACTH |
| Familial hyperaldosteronism type II | <1% | |
| Familial hyperaldosteronism type III | <1% |
Secondary hyperaldosteronism — elevated renin levels drive the increased aldosterone secretion. Causes of elevated renin (4): renal artery stenosis, hypovolemia (e.g. cirrhosis, heart failure), juxtaglomerular cell tumour, and fibromuscular dysplasia.
Primary Hyperaldosteronism — Diagnosis and Evaluation
Indications for screening (9)
- Unexplained hypokalemia (spontaneous or diuretic-induced)
- Hypertension with hypokalemia
- Adrenal incidentaloma with hypertension
- Resistant hypertension (3 or more oral agents with poor control)
- Early-onset hypertension (<20 years) or stroke (<50 years)
- Severe hypertension (≥160/≥110)
- Whenever considering secondary causes of hypertension (e.g. pheochromocytoma or renovascular disease)
- Evidence of target-organ damage disproportionate to the degree of hypertension
- Hypertension with a family history of primary aldosteronism
Primary hyperaldosteronism may be unmasked by diuretic-induced hypokalemia. The diagnosis is confirmed if 24-hour urinary aldosterone remains elevated after sodium loading (see below); after confirmation, a CT scan localizes the tumour.
Labs
- Aldosterone-to-renin ratio (ARR) — the screening test for primary hyperaldosteronism. Measure a morning (8–10 AM) plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An ARR > 20 (some suggest > 30) with a concomitant aldosterone concentration > 15 ng/mL indicates hyperaldosteronism; standard thresholds have not been established, owing to laboratory variability.
- Before screening, hypokalemia should be corrected and all contraindicated medications discontinued. Patients can continue most antihypertensives, but potassium-sparing diuretics (amiloride, triamterene) and especially mineralocorticoid receptor blockers (spironolactone, eplerenone) alter the RAAS and affect results — stop these approximately 6 weeks before testing.
- 50–70% of patients with a positive screen are diagnosed with primary aldosteronism after confirmatory testing. Most confirmatory tests assess suppression of aldosterone after sodium loading — loading decreases plasma renin and aldosterone production in patients without autonomous aldosterone secretion. The oral sodium loading test gives a high-sodium diet for 3 days, followed by 24-hour urine measurement of aldosterone, sodium, and creatinine.
Imaging
- Cross-sectional abdominal imaging should be performed in all patients with primary aldosteronism who are potential surgical candidates.
- Aldosterone-producing adenomas appear as a unilateral, low-density, non-enhancing lesion of < 10 Hounsfield units.
- Lateralization cannot be based on CT alone. Patients with confirmed primary aldosteronism should undergo adrenal vein sampling to establish lateralization when adrenalectomy is being considered. Exceptions: patients <40 years with a clear unilateral adenoma and a normal contralateral gland on imaging, and patients suspected of having an ACC.
Genetic screening
Given the rarity of familial primary hyperaldosteronism, genetic screening should not be performed in all patients. Consider it in patients with a family history of primary aldosteronism, early age of onset (<20 years), or a family history of cerebrovascular accidents at a young age.
Management
The role of surgery depends on the cause.
- Surgically correctable causes (4): aldosterone-producing adrenal adenoma, unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumour, and aldosterone-producing adrenal cortical carcinoma. In patients with confirmed lateralizing aldosterone secretion, adrenalectomy should be considered. Given the small size of aldosterone-producing adenomas, most patients are candidates for laparoscopic adrenalectomy; an open procedure may be recommended when aldosterone hypersecretion is associated with an ACC.
- Not correctable by surgery (4): bilateral adrenal hyperplasia and familial hyperaldosteronism types I, II, and III. Treat medically with mineralocorticoid receptor antagonists (spironolactone, eplerenone) — also indicated for patients who are not surgical candidates.
Self-Test
1. What is the most potent stimulator of aldosterone secretion, and what are the other stimulators? Angiotensin II is the most potent; the others are ACTH and elevated serum potassium.
2. How are the causes of hyperaldosteronism categorized, and what lab test differentiates them? Primary vs secondary, differentiated by the plasma aldosterone-to-renin ratio.
3. List 8 causes of primary hyperaldosteronism. Bilateral hyperplasia, aldosterone-producing adrenal adenoma, unilateral adrenal hyperplasia, aldosterone-producing ACC, ectopic aldosterone-producing tumour, and familial hyperaldosteronism types I, II, and III.
4. List 9 indications for primary aldosteronism screening. Unexplained hypokalemia, hypertension with hypokalemia, adrenal incidentaloma with hypertension, resistant hypertension, early-onset hypertension (<20 years) or stroke (<50 years), severe hypertension (≥160/≥110), when considering secondary causes of hypertension, target-organ damage disproportionate to the hypertension, and hypertension with a family history of primary aldosteronism.
5. Which medications should be held prior to testing for hyperaldosteronism? Potassium-sparing diuretics (amiloride, triamterene) and mineralocorticoid receptor blockers (spironolactone, eplerenone), stopped ~6 weeks before testing; hypokalemia should also be corrected first.
6. What are the surgically correctable and non-correctable subtypes of hyperaldosteronism? Surgically correctable: aldosterone-producing adrenal adenoma, unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumour, aldosterone-producing adrenal cortical carcinoma. Not correctable by surgery: bilateral adrenal hyperplasia and familial hyperaldosteronism types I, II, and III.
7. What laboratory test is recommended to rule out primary hyperaldosteronism? The plasma aldosterone-to-renin ratio (ARR).
8. How is laterality of primary hyperaldosteronism established, and when should this not be performed? By adrenal vein sampling (lateralization cannot be established on imaging alone). It can be omitted in patients <40 years with a clear unilateral adenoma and a normal contralateral gland, or in patients suspected of having an ACC.
9. What are the medical treatments for the non-surgically-correctable subtypes? Mineralocorticoid receptor antagonists such as spironolactone and eplerenone.