Raas

Clinical relevance to anaesthesia & critical care

RAAS is a key compensatory system in hypotension/haemorrhage/anaesthesia-induced vasodilation: maintains perfusion pressure and ECF volume via vasoconstriction and sodium retention.
- Blunted by ACE inhibitors/ARBs/aliskiren → risk of refractory vasoplegia under GA/neuraxial anaesthesia.
- Exaggerated in heart failure/cirrhosis/nephrotic syndrome → sodium/water retention, oedema, hyponatraemia (often dilutional).
Renal haemodynamics: angiotensin II preferentially constricts efferent arteriole → helps preserve GFR when renal perfusion pressure falls, at the expense of reduced renal blood flow and increased filtration fraction.
- ACEi/ARB can precipitate AKI in bilateral renal artery stenosis, solitary kidney with stenosis, severe hypovolaemia, or advanced CKD with low perfusion pressure.
Electrolytes/acid–base: aldosterone increases K+ and H+ secretion in the distal nephron → hypokalaemic metabolic alkalosis when excessive.
- ACEi/ARB, K+-sparing diuretics, adrenal insufficiency → hyperkalaemia ± metabolic acidosis.
Vasopressor choice in ACEi/ARB-related hypotension: vasopressin (V1) often effective; noradrenaline may be less responsive in profound RAAS blockade.
- RAAS blockade reduces angiotensin II-mediated tone; exogenous angiotensin II (where available) can be used in refractory vasodilatory shock.

Perioperative considerations (high-yield)

ACEi/ARB continuation vs withholding: practice varies; key concept is increased risk of intraoperative hypotension/vasoplegia if continued, especially with neuraxial anaesthesia, major surgery, hypovolaemia.
- If withheld: aim to optimise BP/volume status; restart when haemodynamically stable and euvolaemic.
Diuretics and RAAS: loop/thiazide diuretics increase renin via volume depletion and increased distal NaCl delivery; can potentiate RAAS activation.
- Spironolactone/eplerenone block aldosterone effects → hyperkalaemia risk, especially with ACEi/ARB/CKD.

Core components and sequence

Renin (enzyme) released from juxtaglomerular (JG) cells → cleaves angiotensinogen (liver) to angiotensin I.
- Renin release is the rate-limiting step for RAAS activation.
ACE (mainly pulmonary and endothelial) converts angiotensin I → angiotensin II; also degrades bradykinin.
- ACE inhibitors reduce angiotensin II and increase bradykinin → cough/angioedema.
Angiotensin II acts predominantly at AT1 receptors (vasoconstriction, aldosterone release, sodium retention, sympathetic facilitation).
- AT2 receptor effects are less prominent in adults; often counter-regulatory (vasodilation/anti-proliferative).
Aldosterone (zona glomerulosa) acts on principal cells in late distal tubule/collecting duct → ↑ ENaC and Na+/K+ ATPase → Na+ reabsorption, K+ secretion; also increases H+ secretion via α-intercalated cells.
- Net effect: ↑ ECF volume, ↑ BP; tendency to hypokalaemia and metabolic alkalosis if excessive.

Stimuli for renin release (JG apparatus)

Reduced afferent arteriolar pressure (intrarenal baroreceptor) → ↑ renin.
Reduced NaCl delivery to macula densa (e.g., low GFR, loop diuretics) → prostaglandin/NO-mediated ↑ renin.
Increased renal sympathetic activity (β1 receptors on JG cells) → ↑ renin.
- Explains renin rise in stress, haemorrhage, anaesthesia-induced hypotension with sympathetic activation.
Negative feedback: angiotensin II inhibits renin release (short-loop feedback).

Major actions of angiotensin II (AT1)

Vascular: potent systemic vasoconstrictor → ↑ SVR and arterial pressure; constricts renal efferent arteriole > afferent.
- Maintains glomerular capillary pressure and GFR when renal perfusion falls; reduces renal blood flow.
Adrenal: stimulates aldosterone secretion (zona glomerulosa).
Renal tubule: increases proximal tubular Na+ reabsorption (via Na+/H+ exchanger) → Na+ and water retention; contributes to metabolic alkalosis tendency.
CNS/endocrine: stimulates thirst and ADH release; resets baroreflex to tolerate higher BP.
Sympathetic: facilitates noradrenaline release and reduces reuptake; increases sympathetic tone.
Remodelling: promotes myocardial and vascular hypertrophy/fibrosis (chronic activation).

Aldosterone physiology (key renal mechanisms)

Site: late distal convoluted tubule and cortical collecting duct principal cells (and α-intercalated cells).
Mechanism: intracellular mineralocorticoid receptor → gene transcription → ↑ ENaC, ↑ Na+/K+ ATPase; increases ROMK activity → K+ secretion.
- Slower onset (hours) compared with angiotensin II vasoconstriction (minutes).
Acid–base: increases H+ secretion (α-intercalated cells) → metabolic alkalosis with excess; acidosis with deficiency.
Determinants of K+ secretion: aldosterone level, distal Na+ delivery, tubular flow rate.
- Loop/thiazide diuretics increase distal Na+ delivery/flow → increase K+ loss (especially with high aldosterone).

Integration with other systems

ADH: RAAS increases ADH and thirst; ADH primarily controls water balance (osmolality), RAAS primarily controls sodium balance (ECF volume).
ANP/BNP: released with atrial/ventricular stretch → oppose RAAS (vasodilation, natriuresis, inhibit renin and aldosterone).
Prostaglandins: support afferent vasodilation and renin release; NSAIDs can reduce renin and renal perfusion, worsening AKI risk when combined with ACEi/ARB and diuretics.
- Mechanism: NSAIDs constrict afferent (↓ prostaglandins), ACEi/ARB dilate efferent, diuretics reduce volume → fall in glomerular pressure and GFR.

Pharmacology links (high-yield)

ACE inhibitors (e.g., ramipril): ↓ Ang II, ↑ bradykinin → vasodilation; adverse: cough, angioedema, hyperkalaemia, AKI in renal artery stenosis.
ARBs (e.g., losartan): block AT1 receptor; no bradykinin accumulation → less cough/angioedema (but not zero).
Direct renin inhibitor (aliskiren): reduces Ang I/II; similar risks (hyperkalaemia, hypotension, renal dysfunction).
Mineralocorticoid receptor antagonists (spironolactone/eplerenone): reduce Na+ retention and remodelling; adverse: hyperkalaemia; spironolactone anti-androgen effects (gynaecomastia).

Describe the renin–angiotensin–aldosterone system and its physiological role.

Aim: outline the cascade, triggers, and main effects on BP, GFR and sodium balance.

Renin from JG cells cleaves angiotensinogen → angiotensin I; ACE converts to angiotensin II; angiotensin II stimulates aldosterone release and causes vasoconstriction.
Triggers for renin: ↓ afferent pressure, ↓ macula densa NaCl, ↑ renal sympathetic (β1).
Ang II: ↑ SVR, efferent constriction to preserve GFR, ↑ proximal Na+ reabsorption, ↑ ADH/thirst, sympathetic facilitation.
Aldosterone: ↑ ENaC/Na-K ATPase in principal cells → Na+ retention; ↑ K+ and H+ secretion → hypokalaemic alkalosis if excessive.

What are the stimuli for renin release? How does the macula densa regulate renin?

Common FRCA viva: expect the triad and a brief mechanism for macula densa signalling.

↓ Renal perfusion pressure sensed at afferent arteriole (intrarenal baroreceptor) → ↑ renin.
↓ NaCl delivery to macula densa (often due to ↓ GFR) → mediators (NO/prostaglandins) stimulate JG renin release.
↑ Sympathetic activity (β1 on JG cells) → ↑ renin.
Negative feedback: Ang II suppresses renin (short-loop).

Explain how angiotensin II affects renal blood flow and GFR, particularly in hypovolaemia.

Key concept: efferent constriction maintains glomerular pressure and filtration fraction.

Ang II constricts renal arterioles, with a greater effect on the efferent arteriole than the afferent → maintains/increases glomerular capillary hydrostatic pressure.
This helps preserve GFR when renal perfusion pressure falls (e.g., haemorrhage), but reduces renal blood flow and increases filtration fraction.
If RAAS is blocked (ACEi/ARB), the efferent arteriole dilates → fall in glomerular pressure → fall in GFR, especially in renal artery stenosis or hypovolaemia.

A patient on an ACE inhibitor becomes profoundly hypotensive at induction. Explain the physiology and outline management principles.

Classic FRCA scenario: link ACEi to loss of Ang II tone and reduced response to catecholamines.

ACE inhibition reduces Ang II-mediated vasoconstriction and aldosterone-mediated volume retention; anaesthetic-induced vasodilation may then cause marked hypotension.
Catecholamine responsiveness may be reduced because RAAS normally supports vascular tone and sympathetic facilitation.
Management: exclude hypovolaemia/bleeding; give IV fluid boluses; use vasopressors (noradrenaline) and consider vasopressin early in refractory vasoplegia.
If available/appropriate in ICU: consider exogenous angiotensin II for refractory vasodilatory shock.

Describe the actions of aldosterone on the nephron and its effects on potassium and acid–base balance.

Expect site + transporters + net effects.

Acts on principal cells in late distal tubule/cortical collecting duct: ↑ ENaC and ↑ Na+/K+ ATPase → ↑ Na+ reabsorption and lumen-negative potential.
Increases K+ secretion via ROMK (enhanced by high distal Na+ delivery and tubular flow) → hypokalaemia when excessive.
Increases H+ secretion in α-intercalated cells → metabolic alkalosis when excessive; deficiency tends to hyperkalaemia and metabolic acidosis.

How do ANP/BNP interact with the RAAS?

Often asked as counter-regulatory hormones in volume overload states.

ANP/BNP are released with cardiac stretch and promote natriuresis and vasodilation.
They inhibit renin release and reduce aldosterone secretion → oppose RAAS-mediated sodium retention.

Explain why ACE inhibitors/ARBs can precipitate acute kidney injury in renal artery stenosis.

This is a common written/viva physiology question: focus on glomerular capillary pressure dependence on efferent tone.

Renal artery stenosis reduces perfusion pressure at the afferent arteriole → kidney relies on Ang II-mediated efferent constriction to maintain glomerular pressure and GFR.
ACEi/ARB remove efferent constriction → fall in glomerular capillary hydrostatic pressure → fall in GFR → rise in creatinine/AKI.
Risk is highest in bilateral stenosis or stenosis to a solitary functioning kidney, and in hypovolaemia/diuretic use.

What is meant by the 'triple whammy' causing renal impairment? Explain the physiology.

Frequently examined in perioperative medicine/renal physiology integration.

Combination: NSAID + ACEi/ARB + diuretic.
NSAIDs inhibit prostaglandins → afferent vasoconstriction (↓ renal blood flow).
ACEi/ARB cause efferent vasodilation → reduced glomerular pressure.
Diuretics reduce effective circulating volume → further reduces renal perfusion; net effect: marked fall in GFR and risk of AKI.

Compare the roles of RAAS and ADH in homeostasis.

Examiners often want a clear distinction: sodium/volume vs water/osmolality, with overlap.

RAAS primarily regulates sodium balance and ECF volume (and therefore arterial pressure).
ADH primarily regulates water balance and plasma osmolality via V2-mediated aquaporin insertion in collecting ducts.
RAAS can increase ADH and thirst; both systems interact in hypovolaemia.

A patient has Conn’s syndrome. Predict renin, aldosterone, potassium and acid–base status, and explain.

Primary hyperaldosteronism pattern is a classic physiology question.

Aldosterone: high (autonomous secretion).
Renin: low due to ECF expansion and negative feedback from raised BP/Ang II suppression.
Potassium: low (renal K+ wasting).
Acid–base: metabolic alkalosis (↑ H+ secretion).

In heart failure, why can RAAS activation be maladaptive despite low effective circulating volume?

Important concept: perceived underfilling drives RAAS, worsening congestion and remodelling.

Reduced cardiac output leads to reduced renal perfusion and perceived underfilling → renin release and RAAS activation.
Ang II and aldosterone cause vasoconstriction and sodium/water retention → increased preload and congestion, raising filling pressures and oedema.
Chronic Ang II/aldosterone promote myocardial fibrosis and adverse remodelling; RAAS blockade improves outcomes.