Notes · Physiology · 5 October 2026

Renin-Angiotensin-Aldosterone System (RAAS)

Definition

• The Renin‑Angiotensin‑Aldosterone System (RAAS) is a hormonal cascade that regulates arterial pressure, extracellular fluid volume, and electrolyte balance.
• It is initiated by renin release from juxtaglomerular (JG) cells of the kidney in response to decreased renal perfusion, decreased sodium chloride delivery to the macula densa, or sympathetic stimulation.
• Renin cleaves angiotensinogen (produced by the liver) to angiotensin I, which is converted by angiotensin‑converting enzyme (ACE) mainly in the pulmonary capillaries to angiotensin II.
• Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion from the adrenal zona glomerulosa, leading to sodium and water retention.
• The system also modulates antidiuretic hormone (ADH) release, sympathetic tone, and cardiac remodeling.

Epidemiology

• Dysregulation of RAAS contributes to ~30–40 % of hypertension cases worldwide.
• In the Indian population, prevalence of primary hyperaldosteronism (PA) is estimated at 5–10 % among hypertensives, higher in those with resistant hypertension or hypokalemia.
• ACE‑I and ARB use is common in diabetic nephropathy, heart failure, and post‑myocardial infarction, reflecting RAAS’s role in cardiovascular morbidity.
• Genetic polymorphisms in ACE, AGT, and AT1R genes show variable frequencies across ethnic groups, influencing susceptibility to hypertension and cardiovascular disease.

Aetiology

• Physiological triggers:
  • Decreased renal perfusion pressure (e.g., renal artery stenosis).
  • Reduced sodium chloride delivery to the macula densa (e.g., low‑salt diet, diuretics).
  • Sympathetic nervous system activation (e.g., stress, catecholamine surge).
• Pathological conditions:
  • Primary hyperaldosteronism (Conn’s syndrome).
  • Secondary hyperaldosteronism (renal artery stenosis, heart failure, cirrhosis).
  • ACE gene insertion/deletion polymorphism.
  • Angiotensinogen gene mutations (e.g., AGT M235T).
• Pharmacological influences:
  • ACE inhibitors, ARBs, diuretics, and beta‑blockers modulate RAAS activity.
  • NSAIDs inhibit prostaglandin‑mediated renin release, potentially reducing RAAS activation.

Pathophysiology

1. Renin release
   • JG cells sense low perfusion or sodium via baroreceptors and macula densa sensors.
   • Sympathetic α1‑adrenergic stimulation increases renin secretion.
2. Angiotensinogen → Angiotensin I
   • Renin cleaves the 20‑kDa angiotensinogen to 10‑kDa angiotensin I.
3. Angiotensin I → Angiotensin II
   • ACE (predominantly in lung endothelium) removes two residues to form the 8‑kDa angiotensin II.
   • ACE2 converts angiotensin II to angiotensin‑(1‑7), a vasodilatory counter‑regulatory peptide.
4. Angiotensin II actions
   • Vasoconstriction via AT1 receptors on vascular smooth muscle.
   • Aldosterone secretion from adrenal cortex → ↑Na⁺/H₂O reabsorption, ↑K⁺ excretion.
   • ADH release from posterior pituitary → water retention.
   • Sympathetic tone augmentation and cardiac remodeling (fibrosis, hypertrophy).
5. Feedback inhibition
   • Elevated BP and sodium load suppress renin release.
   • Aldosterone antagonism (e.g., spironolactone) reduces sodium retention, lowering BP.

Clinical Features

• Hypertension: sustained elevation of systolic/diastolic BP, often resistant to standard therapy.
• Hypokalemia: muscle weakness, cramps, arrhythmias, especially in PA.
• Metabolic alkalosis: due to increased bicarbonate reabsorption.
• Edema: peripheral or pulmonary in severe volume overload.
• Cardiovascular sequelae: left ventricular hypertrophy, ischemic heart disease, heart failure.
• Renal impairment: progressive chronic kidney disease (CKD) from sustained glomerular hypertension.
• Endocrine manifestations: menstrual irregularities, infertility in PA; hyperpigmentation in hyperaldosteronism with adrenal hyperplasia.

Investigations

Screening algorithm (Indian guideline 2024):

1. Measure PAC, SRA, ARR.
2. If ARR >20 and PAC >15 ng/dL, confirm with 24‑h urinary aldosterone.
3. Imaging (CT adrenal) if PA confirmed.
4. Evaluate for secondary causes (renal artery stenosis, heart failure).

Management (2024 Indian Guidelines)

• Lifestyle: low‑salt diet (<5 g/day), weight loss, exercise, alcohol moderation.
• Pharmacologic:
  • ACE inhibitors (e.g., lisinopril 10–40 mg) or ARBs (e.g., losartan 50–100 mg) as first‑line in hypertension with CKD or diabetes.
  • Spironolactone (25–50 mg) for PA; monitor potassium, renal function.
  • Eplerenone preferred in patients with hyperkalemia risk.
  • Beta‑blockers (e.g., metoprolol) for sympathetic‑driven RAAS activation.
  • Mineralocorticoid receptor antagonists (MRA) for heart failure with reduced EF.
• Surgical: adrenalectomy for unilateral aldosterone‑producing adenoma.
• Endovascular: percutaneous transluminal angioplasty for renal artery stenosis.
• Monitoring: BP, serum potassium, creatinine every 4–6 weeks initially, then every 3–6 months.
• Target: BP <130/80 mmHg in CKD, <140/90 mmHg in general hypertensives.
• Adjunct: ACE2 activators and neprilysin inhibitors (sacubitril/valsartan) are emerging but not yet standard for RAAS modulation alone.

Complications

• Cardiovascular: myocardial infarction, stroke, heart failure, arrhythmias.
• Renal: progressive CKD, end‑stage renal disease.
• Metabolic: hypokalemia‑induced muscle weakness, arrhythmias, metabolic alkalosis.
• Endocrine: adrenal hyperplasia, Cushingoid features with long‑term MRA use.
• Nephrogenic diabetes insipidus: rare with high aldosterone.
• Drug‑induced: hyperkalemia with ACEI/ARB/MRA, angioedema with ACEI.

High‑Yield Exam Points

• ARR >20 with PAC >15 ng/dL is highly suggestive of primary hyperaldosteronism.
• ACE2 converts angiotensin II to angiotensin‑(1‑7), providing vasodilatory, anti‑fibrotic effects.
• Renin release is inhibited by increased sodium chloride delivery to the macula densa (feedback).
• Spironolactone is a competitive antagonist at mineralocorticoid receptors; eplerenone has fewer endocrine side effects.
• ACE inhibitors reduce angiotensin II and increase bradykinin, leading to cough and angioedema.
• ARBs block AT1 receptors, sparing bradykinin metabolism.
• Renal artery stenosis presents with refractory hypertension and worsening renal function; duplex Doppler is first‑line imaging.
• Hypokalemia in PA is due to increased Na⁺ reabsorption and K⁺ secretion in the distal nephron.
• ACE gene I/D polymorphism: D allele associated with higher ACE levels and hypertension risk.

Practice Questions

1. A 45‑year‑old man with resistant hypertension has serum PAC 28 ng/dL and plasma renin activity 0.4 ng/mL/h. What is the most appropriate next step?
   Answer: C – Perform a 24‑hour urinary aldosterone test to confirm primary hyperaldosteronism.

2. Which of the following is a major adverse effect of ACE inhibitors?
   Answer: A – Angioedema due to bradykinin accumulation.

3. In primary hyperaldosteronism, the most common electrolyte abnormality is:
   Answer: B – Hypokalemia from increased distal sodium reabsorption and potassium excretion.

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