NephrologyTier 2Topic

Process of hormonal regulation - renin-angiotensin system (RAS)

Overview

The body's volume and perfusion-pressure defence system - and the single most drugged pathway in medicine

Angiotensinogen (liver) --renin--> Angiotensin I --ACE (pulmonary endothelium)--> Angiotensin II --aldosterone synthase--> Aldosterone
Renin (from juxtaglomerular cells) is the rate-limiting step
ACE also degrades bradykinin - hence ACEi cough and angioedema; ARBs do not do this

ACE2 -> angiotensin-(1-7) -> Mas receptor: vasodilatation, anti-fibrotic, anti-proliferative - opposes angiotensin II
Natriuretic peptides (ANP, BNP) oppose the whole system; neprilysin degrades them - the ARNI target

RAS blockade is first-line in hypertension, heart failure, diabetic and proteinuric CKD, and post-MI
ACEi cough in ~10-20% (higher in East Asian populations); angioedema ~0.1-0.7%, ~3-5x more common in patients of African ancestry
Hyperkalaemia is the commonest reason RAS blockade is under-dosed or stopped

1. Renal baroreceptor - dec afferent arteriolar stretch (dec perfusion pressure) -> inc renin
2. Tubuloglomerular feedback at the macula densa - senses NaCl delivery in the early distal tubule
- High GFR -> rapid flow -> more NaCl reaches the macula densa -> dec renin, and afferent constriction
- Low GFR -> more proximal reabsorption -> less NaCl at the macula densa -> inc renin, and afferent dilatation
- *This is the loop that SGLT2 inhibitors exploit*: blocking proximal Na reabsorption increases distal NaCl delivery -> afferent constriction -> dec hyperfiltration
3. Sympathetic beta-1 stimulation of juxtaglomerular cells -> inc renin
- Why beta blockers suppress renin - and why they cause a false-positive aldosterone:renin ratio

Vasoconstriction - systemic, and preferentially the EFFERENT arteriole -> maintains GFR when perfusion falls
inc aldosterone (adrenal zona glomerulosa)
inc proximal tubular Na+/H+ exchange -> Na and bicarbonate reabsorption
inc ADH release and thirst (hypothalamus)
inc sympathetic outflow
Growth and fibrosis: cardiac hypertrophy, vascular remodelling, renal interstitial fibrosis (TGF-beta)

*The efferent effect is the whole story for renal drugs*: blocking it drops intraglomerular pressure -> less proteinuria and slower CKD progression, at the price of a fall in eGFR

Plasma renin activity (or direct renin concentration) and plasma aldosterone
Aldosterone-to-renin ratio (ARR) - the screening test for primary aldosteronism

Renin	Aldosterone	Diagnosis
dec	inc	Primary aldosteronism
inc	inc	Secondary hyperaldosteronism - renal artery stenosis, renin-secreting tumour, diuretics, heart failure, cirrhosis, Bartter/Gitelman
dec	dec	Apparent mineralocorticoid excess, Liddle syndrome, exogenous mineralocorticoid, CAH
inc	dec	Adrenal insufficiency, hyporeninaemic states excluded

Beta blockers cause FALSE POSITIVES - they suppress renin more than aldosterone, so the ratio rises
ACEi, ARBs, diuretics and MRAs cause FALSE NEGATIVES - they raise renin
Withdraw interfering drugs where clinically safe (MRAs for 4-6 weeks, others 2 weeks); verapamil, prazosin, hydralazine and moxonidine are ARR-neutral substitutes
Correct hypokalaemia first (hypokalaemia suppresses aldosterone and causes false negatives)

Class	Target	Notes
ACE inhibitor	ACE	Cough and angioedema (bradykinin); first-line in CKD, HF, post-MI
ARB	AT1 receptor	No cough; use if ACEi-intolerant
ARNI (sacubitril/valsartan)	Neprilysin + AT1	HFrEF; *36 h washout from an ACEi - angioedema*
MRA (spironolactone, eplerenone)	Mineralocorticoid receptor	Heart failure, resistant hypertension, primary aldosteronism
Non-steroidal MRA (finerenone)	Mineralocorticoid receptor	Diabetic CKD; less hyperkalaemia, no gynaecomastia
Direct renin inhibitor (aliskiren)	Renin	Largely abandoned - no added benefit, more harm in combination
Beta blocker	Renin release	Indirect suppression

Never combine an ACEi with an ARB (or either with aliskiren) - more hyperkalaemia and AKI, no benefit
Expect a creatinine rise of up to 30% on starting - this is haemodynamic and predicts long-term benefit. A rise >30% or a K+ >5.5 warrants investigation, not automatic cessation
A large creatinine rise suggests bilateral renal artery stenosis, volume depletion, or concurrent NSAID use
Check UEC 1-2 weeks after starting or up-titrating
Contraindicated in pregnancy - fetal renal dysgenesis, oligohydramnios, skull hypoplasia
Withhold in acute illness with volume depletion (sick-day rules) and restart on recovery

Renal artery stenosis - dec perfusion -> inc renin -> hypertension; ACEi precipitates AKI if bilateral or in a single kidney
Heart failure and cirrhosis - reduced effective circulating volume -> chronic RAS activation -> Na retention and fibrosis
Primary aldosteronism - autonomous aldosterone with suppressed renin

Hypertension (essential, renovascular, primary aldosteronism)
Heart failure - RAS activation is adaptive acutely, destructive chronically
CKD and proteinuria - the efferent mechanism
Cirrhosis with ascites; hepatorenal syndrome
Bartter and Gitelman syndromes - hyperreninaemic hyperaldosteronism with hypokalaemic alkalosis and normal or low BP
Liddle syndrome - ENaC gain of function; low renin, low aldosterone, hypertension, hypokalaemia (amiloride-responsive)
Type 4 RTA (hyporeninaemic hypoaldosteronism) - diabetes, NSAIDs, calcineurin inhibitors
Renin-secreting juxtaglomerular cell tumour (rare)

Chronic RAS activation is adaptive in acute hypovolaemia and maladaptive in chronic disease - it drives fibrosis, remodelling and progressive organ damage
Every drug with a mortality benefit in heart failure and CKD interrupts this pathway
Aldosterone escape - aldosterone levels rise back toward baseline after months of ACEi/ARB therapy, which is the rationale for adding an MRA
Renin rises reactively on any RAS blocker - so measure the ARR only off interfering drugs
What to monitor: creatinine and K+ at 1-2 weeks after any change, then periodically; blood pressure; proteinuria as the therapeutic target

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