The Cascade

Juxtaglomerular apparatus detects ↓ perfusion pressure / ↓ Na+ delivery
                        ↓
            Renin release from granular cells
                        ↓
        Angiotensinogen (hepatic) → Angiotensin I
                        ↓
    ACE (lung endothelium) → Angiotensin II
                        ↓
    AT1 receptor activation (kidney, vessels, heart)
                        ↓
    ↑ GFR (efferent vasoconstriction), ↑ Na+ reabsorption,
    ↑ sympathetic tone, ↑ aldosterone, ↑ vasopressin

Physiologic Effects of Angiotensin II (AT1 Receptor)

Counter-Regulatory Mechanism: Bradykinin

• ACE (angiotensin-converting enzyme) is identical to kininase II
• Inhibiting ACE → ↑ bradykinin accumulation
• Bradykinin effects: ↓ vasoconstriction, ↑ nitric oxide, ↑ prostaglandins
• Clinical manifestation: ACEi cough (15–20% incidence) due to pulmonary bradykinin accumulation

Mechanism of Action

ACE inhibitors competitively block angiotensin-converting enzyme, preventing conversion of angiotensin I → angiotensin II. Result: ↓ Ang II-mediated efferent vasoconstriction, ↓ aldosterone, ↓ sympathetic tone.

Pharmacokinetics

Key Points: - Lipophilic agents (ramipril, perindopril) may have superior tissue penetration - Renal excretion (lisinopril) allows accumulation in renal insufficiency - Hepatic metabolism (enalapril, fosinopril) safer in ESRD

Renal Hemodynamic Effects

Acute Effects (hours–days): - ↓ Efferent arteriolar vasoconstriction → ↓ intraglomerular pressure - ↓ GFR (expected, typically 10–30% drop) - ↑ Renal plasma flow (afferent remains relatively constant) - ↓ Glomerular hyperfiltration (beneficial in proteinuria)

Chronic Effects (weeks–months): - ↓ Glomerulosclerosis (reduced Ang II-mediated fibrosis) - ↓ Interstitial fibrosis - ↓ Proteinuria (via hemodynamic + tubular effects) - Slowing of GFR decline in CKD

Clinical Efficacy

Hypertension: - ↓ BP 8–15 mmHg systolic; effect modest, synergistic with other agents - Works best in renin-dependent hypertension (renovascular, RAS-activated states)

Proteinuric CKD: - ↓ Proteinuria 30–50% independent of blood pressure lowering - KDIGO 2021: ACEi/ARB recommended for CKD with albuminuria (regardless of hypertension status) - ↓ ESRD progression: Landmark trials (Collaborative Study Group trial 1993) show ACEi slows progression of diabetic nephropathy

Heart Failure: - ↓ Mortality 16% (SAVE trial, post-MI LV dysfunction) - ↓ HF hospitalizations - ↓ Ventricular remodeling

Post-MI: - ↓ Mortality, reinfarction, HF when started early

Adverse Effects

Contraindications and Cautions

Mechanism of Action

ARBs are selective antagonists of AT1 receptors, blocking Ang II action without affecting bradykinin. Result: ↓ Ang II effects WITHOUT ↑ bradykinin (hence, no cough).

Note: AT2 receptors (minority) promote vasodilation, anti-fibrosis; ARBs block AT1, leaving AT2 unopposed—possible additional benefit.

Pharmacokinetics

Key Points: - All ARBs reach similar efficacy (no superiority demonstrated) - Telmisartan longest half-life; once-daily dosing convenient - Losartan undergoes hepatic activation to metabolite EXP3174 (more potent)

Renal and Cardiovascular Effects

Similarities to ACEi: - ↓ Efferent vasoconstriction → ↓ intraglomerular pressure - ↓ Proteinuria (30–50% reduction) - ↓ GFR acutely (10–30% expected) - ↓ ESRD progression in proteinuric CKD - ↓ Mortality post-MI and in HF

Differences from ACEi: - NO cough (no bradykinin) - NO angioedema (rare; <0.1% vs. ACEi 0.5%) - Equipotent BP lowering - Equipotent renal protection

Clinical Efficacy

Hypertension: - ↓ BP 8–15 mmHg (similar to ACEi)

CKD with Proteinuria: - ↓ Proteinuria 30–50% - ↓ ESRD progression (IDNT, RENAAL trials vs. placebo in diabetic nephropathy)

Heart Failure: - ↓ Mortality, HF hospitalizations (CHARM, VALSARTAN trials)

Post-MI: - ↓ Mortality, reinfarction (similar to ACEi)

Adverse Effects

Hyperkalemia (same as ACEi) - ↓ Aldosterone → ↓ K⁺ excretion - Monitor K⁺; caution with eGFR <30, NSAIDs, other RAAS inhibitors

Hypotension (same as ACEi) - ↓ Ang II vasoconstriction - Risk in volume depletion, acute illness

AKI/Creatinine Rise (same as ACEi) - ↓ Efferent vasoconstriction - Expected 10–30% rise; monitor for >30% rise - Caution in RAS, single kidney, dehydration

Angioedema (rare; <0.1%) - Much rarer than ACEi - Mechanism unclear (not bradykinin-related) - If angioedema occurs → DO NOT switch to ACEi (cross-reactivity risk)

Cough: ABSENT (major advantage over ACEi)

Hyperuricemia: ARBs (particularly losartan) have mild uricosuric effect (losartan blocks urate reabsorption in proximal tubule)—slight ↓ in uric acid with losartan vs. other ARBs

Contraindications

• Bilateral RAS or single kidney with RAS (AKI risk)
• Pregnancy (teratogenicity, 2nd–3rd trimester)
• K⁺ >5.0 mmol/L
• Acute decompensation/hypotension (caution)

Mechanism

Aliskiren directly binds the active site of renin, blocking the initial step of the RAAS cascade (renin release → angiotensinogen cleavage).

Theoretical advantage: More “upstream” blockade than ACEi/ARB; prevents all Ang II production.

Pharmacokinetics

Clinical Efficacy

Limited evidence: - ↓ BP 8–10 mmHg (similar to ACEi/ARB) - ↓ Proteinuria (modest; less robust than ACEi/ARB) - NO mortality benefit demonstrated in CKD or HF (unlike ACEi/ARB)

ALICANTE trial (2013): Aliskiren added to losartan in CKD + hypertension → no difference in renal outcomes vs. losartan alone; safety concerns (hyperkalemia, AKI)

Adverse Effects

• Hyperkalemia: ↑ risk when combined with ACEi/ARB (see dual RAAS blockade below)
• AKI: Similar to ACEi/ARB; caution in volume depletion
• Diarrhea: 2–3% (unique to aliskiren; often reversible)
• Cough/Angioedema: NOT increased (unlike ACEi)

Clinical Role

Limited; rarely used monotherapy due to: - Modest efficacy - No mortality benefit - Poor bioavailability - Drug interactions (CYP3A4) - Hyperkalemia risk when combined

Specific use: Occasionally added in resistant hypertension (as triple therapy), but ACEi/ARB preferred first-line.

Mechanism: Sacubitril/Valsartan (Entresto)

Dual mechanism: 1. Valsartan = ARB component (Ang II blockade) 2. Sacubitril = Neprilysin inhibitor (↑ natriuretic peptide degradation ↓)

Key biology: Neprilysin breaks down natriuretic peptides (ANP, BNP, C-type NP). Inhibiting neprilysin → ↑ circulating NP levels → enhanced natriuresis, vasodilation, anti-fibrosis.

Pharmacokinetics

Clinical Efficacy: Heart Failure

PARADIGM-HF Trial (2014)—Landmark: - Population: ~8,400 patients with HFrEF (LVEF ≤35%) - Primary endpoint: CV death or HF hospitalization - Result: Sacubitril/valsartan ↓ primary endpoint 20% vs. enalapril - Mortality: ↓ CV death 16%; ↓ all-cause death 16% - Conclusion: Superior to ACEi monotherapy in HFrEF

PROVE-HF Trial (2019): - ARNI ↓ natriuretic peptides more effectively than ACEi, suggesting superior neurohormonal modulation

Efficacy in CKD + Proteinuria

PIONEER Trial (2019): - Population: CKD Stage 3–4 + diabetes, proteinuria - Design: Sacubitril/valsartan vs. losartan - Result: ↓ Albuminuria 36% vs. 24% with losartan (modest additional benefit) - Renal outcomes: Similar to losartan - Note: ARNI not established as superior to ARB monotherapy for renal outcomes

Adverse Effects

Similar to ARB + neprilysin-specific:

Drug Interactions

• ACEi/ARB cannot be combined with ARNI (dual Ang II blockade—hyperkalemia, AKI)
• NSAIDs + ARNI: Triple whammy if diuretic added
• Lithium: ↑ lithium levels (neprilysin inactivates lithium metabolism)

Contraindications

• Bilateral RAS or single kidney RAS
• K⁺ >5.0 mmol/L
• eGFR <15 (caution; limited data)
• Pregnancy (2nd–3rd trimester; teratogenicity)
• History of ACEi/ARB angioedema (avoid ARNI as well)

Mechanism

Finerenone is a non-steroidal mineralocorticoid receptor (MR) antagonist—selective MR antagonist with reduced androgen/progesterone receptor interactions vs. spironolactone.

Mechanism distinct from spironolactone: - Does NOT directly inhibit aldosterone synthesis - Binds MR with subtype selectivity (MR over AR, PR) - Transrepressive mechanism (blocks pro-inflammatory/pro-fibrotic genes) - Anti-inflammatory, anti-fibrotic independent of Na⁺-K⁺ exchange

Pharmacokinetics

Clinical Efficacy: Landmark Trials

Proposed Renal Mechanisms Beyond Aldosterone

1. Transrepression: Blocks MR-mediated inflammation, reduces IL-6, TNF-α
2. Anti-fibrotic: ↓ TGF-β signaling, ↓ myofibroblast activation
3. Endothelial: ↑ nitric oxide, ↓ oxidative stress
4. Podocyte: ↓ proteinuria via reduced foot process effacement
5. Glomerular: ↓ SGLT1 expression (possible glucose-related protection)

Adverse Effects

Hyperkalemia (most clinically significant) - Incidence: 2–3% in FIDELIO (vs. 1% placebo) - Risk factors: eGFR <30, diabetes, concurrent ACEi/ARB, NSAIDs - Management: K⁺ monitoring baseline, week 4, then every 3 months; consider potassium-lowering agent (sodium zirconium cyclosilicate, patiromer) if K⁺ rises; dose reduction or discontinuation if K⁺ >6.0 mmol/L

Hypotension - Incidence: 3–4% - Mechanism: ↓ Aldosterone → Na⁺ wasting - Management: Monitor BP; adjust diuretics/other agents if needed

Urinary Tract Infection (UTI) - Incidence: 4.5% (finerenone) vs. 3.6% (placebo) in FIDELIO - Mechanism: Unclear; possibly immune modulation - Management: Standard UTI management; not contraindication

Anemia (modest) - Incidence: 1–2% - Mechanism: Possible effect on erythropoiesis

Hypoglycemia (paradoxically) - Incidence: Slight ↑ with finerenone + SGLT2i in some analyses - Mechanism: Potential SGLT-related effect; unclear

Contraindications and Cautions

Clinical Role and Integration

KDIGO 2021 Update: - Finerenone recommended for CKD + diabetes + albuminuria, independent of RAAS inhibitor use - Position: Add to ACEi/ARB (not alternative)

Modern renoprotective regimen: 1. SGLT2 inhibitor (e.g., dapagliflozin, empagliflozin) — 39% ↓ ESRD progression 2. ACEi or ARB (not dual) — 30–50% ↓ proteinuria 3. Finerenone (if eGFR >25, K⁺ <5.5) — additional 18–25% renal benefit 4. GLP-1 agonist (if T2DM + overweight) — weight loss, CV benefit

Historical Context: Rationale for Dual Blockade

• Concept: Block RAAS at multiple points → greater neurohormonal suppression → better renal protection
• Theoretical basis: ACEi ↓ Ang II but ↑ renin (compensatory); ARB ↓ Ang II but ↑ renin; combination = maximal Ang II suppression
• 1990s–2000s enthusiasm: Multiple small studies suggested dual blockade benefit

Major Clinical Trials: Null Results

Mechanisms of Dual RAAS Blockade Failure

1. Hyperkalemia: Sequential ↓ aldosterone → severe K⁺ retention
2. AKI: Efferent vasoconstriction from dual ↓ Ang II + volume depletion risk
3. Counter-regulatory activation: Renin ↑ dramatically with dual blockade (feedback loop); breakthrough Ang II production possible
4. Glomerular hemodynamic collapse: Too much efferent vasodilation → loss of driving pressure for filtration
5. Blunted efficacy: Physiologic adaptation/escape (aldosterone escape phenomenon observed in some dual-therapy patients)

Current Consensus

Guidelines unanimously recommend: - Monotherapy with ACEi OR ARB (NOT both) - Exception: ARNI (sacubitril/valsartan) = ARB + neprilysin inhibitor (different mechanism—valsartan component within ARNI is permissible) - Addition of finerenone: OK with ACEi/ARB monotherapy (non-overlapping mechanism)

Baseline Assessment (Pre-Initiation)

Post-Initiation Monitoring

First 1–2 weeks: - Cr + eGFR: Check at 1 week; expect 10–30% rise - K⁺: Check at 1 week; expect modest ↑ - BP: Monitor for hypotension - Symptoms: Dizziness, syncope, hyperkalemia signs (palpitations, weakness)

Weeks 2–8: - Cr + eGFR: Check again at 2 weeks if initial rise >30% - K⁺: Check at 2 weeks if on diuretic or eGFR <45 - BP: Titrate dose to target

Months 2–3 onward: - Cr, eGFR, K⁺: Every 3 months × 1 year, then annually if stable - More frequent monitoring (monthly) if: - eGFR <45 - K⁺ at upper limit of normal - Recent dose escalation - Concurrent NSAIDs or diuretics

Interpretation of Creatinine Rise

When to Hold or Discontinue RAAS Inhibitors

Scenario 1: CKD Stage 3b + Type 2 Diabetes + Proteinuria

Clinical: 58-year-old male with T2DM, BP 145/92, eGFR 38, uACR 180 mg/g (overt albuminuria), on metformin monotherapy, no current antihypertensive.

Labs: - Cr 1.6 mg/dL - K⁺ 4.3 mmol/L - Urine dip: 2+ protein

Plan: 1. Start ACEi (lisinopril 10 mg daily) or ARB (losartan 50 mg daily) - Both equipotent for proteinuria reduction and renal protection - Lisinopril slightly cheaper; losartan if cough develops 2. Check Cr + K⁺ at 1 week - Expect Cr ↑ 10–30% (acceptable) - K⁺ should remain <5.0 3. Goal BP: <120 systolic (SPRINT-CKD suggests benefit of intensive control in CKD) 4. Add SGLT2i (dapagliflozin 10 mg daily) - ↓ ESRD progression, CV death - Continue metformin 5. Lifestyle: Sodium restriction <3 g/day, weight loss if overweight 6. 3-month reassess: Recheck eGFR, K⁺, proteinuria; if stable and K⁺ <5.0, consider adding finerenone 10 mg daily 7. Target: CKD stabilization, ↓ proteinuria, BP control

Scenario 2: Heart Failure with Reduced EF + Diabetes

Clinical: 62-year-old female with HFrEF (LVEF 28%), hypertension, T2DM, on carvedilol 25 mg BID.

Presentation: Dyspnea on exertion, 2+ lower extremity edema.

Labs: - Cr 1.3 mg/dL (eGFR 48) - K⁺ 4.5 mmol/L - BNP 650 pg/mL

Plan: 1. Start ACEi (lisinopril 5 mg daily) or ARNI (sacubitril/valsartan 49/97 mg BID) - ARNI preferred in HFrEF (PARADIGM-HF 20% mortality reduction) - If cost/access issue, ACEi acceptable - Do NOT start both ACEi and ARB (dual blockade) 2. Verify not on NSAIDs or diuretics causing volume depletion 3. Check Cr + K⁺ at 1 week - Expected Cr ↑ 10–30% - K⁺ should remain <5.5 4. Titrate to target dose: - ARNI: Escalate to 97/194 mg BID (if tolerated) - Lisinopril: Target 10 mg daily 5. Add beta-blocker (carvedilol already on board) + aldosterone antagonist (spironolactone 25 mg daily or eplerenone 25 mg daily) - RALES trial: ↓ mortality 30% with spironolactone in HF - Monitor K⁺ closely (goal K⁺ 4.5–5.5) 6. Diuretics: If volume-overloaded, add furosemide (separate handout); do NOT defer diuretics to start RAAS inhibitors 7. SGLT2i: Add dapagliflozin 10 mg daily (↓ HF hospitalization) 8. 3-month reassess: BNP, Cr, K⁺, weight, EF (echo); adjust doses

Scenario 3: Dual RAAS Blockade (Incorrect) to Monotherapy (Correct)

Clinical: 72-year-old male with CKD Stage 4 (eGFR 22) referred on losartan 100 mg daily + lisinopril 10 mg daily (prescribed by cardiologist post-MI).

Recent labs: - K⁺ 5.7 mmol/L (elevated) - Cr 2.8 mg/dL (Cr baseline pre-MI was 2.0; rise ↑0.8 in 3 months) - BP 128/76 (well-controlled)

Recognize: Dual RAAS blockade causing hyperkalemia + AKI

Plan: 1. STOP lisinopril immediately - Continue losartan 100 mg daily as monotherapy - Avoid ACEi/ARB combination (VA NEPHRON-D data) 2. Recheck K⁺ in 1 week - Expect modest ↓ in K⁺ (off one RAAS blocker) - Goal K⁺ <5.0 3. Recheck Cr in 1–2 weeks - Expect Cr to stabilize/improve (off dual blockade) 4. If K⁺ remains >5.5 or Cr continues rising: - Reduce losartan to 50 mg daily - Recheck K⁺, Cr 5. Add orthogonal agent for post-MI benefit: - If ACEi stopped due to K⁺/AKI, consider ARB monotherapy (already on losartan) - Alternative: Beta-blocker optimization, ACE-free regimen with eplerenone (selective MRA) 6. Dietary counseling: K⁺-restricted diet, fluid restriction if volume overloaded

Question 1

A 52-year-old woman with CKD Stage 3a (eGFR 56) and hypertension (BP 162/98) is started on lisinopril 10 mg daily. After 1 week, she develops a persistent dry cough and her serum creatinine has risen from 1.0 to 1.15 mg/dL. K⁺ is 4.6 mmol/L.

Which of the following is the MOST appropriate next step?

1. Continue lisinopril; cough is expected and will resolve
2. Increase lisinopril to 20 mg daily to improve BP control
3. Switch to losartan 50 mg daily for ACEi cough
4. Discontinue lisinopril and start amlodipine 5 mg daily
5. Add spironolactone 25 mg daily for additional BP control

Answer: C (switch to ARB; cough resolves in 50–80%)

Rationale: - ACEi cough affects 15–20% of patients; related to bradykinin accumulation in lungs - Cough NOT dangerous but intolerable if persistent - ARB substitution resolves cough in majority (no bradykinin effect) - Cr rise 10–30% expected (acceptable); K⁺ stable - Continue monitoring Cr; expect stabilization in 2–4 weeks - Amlodipine suitable alternative if ARB cough develops (rare)

Question 2

A 65-year-old male with LVEF 32%, CKD Stage 4 (eGFR 28), and hypertension is on lisinopril 10 mg daily and carvedilol 25 mg BID. He is referred for worsening dyspnea. Labs show K⁺ 5.8 mmol/L, Cr 1.9 mg/dL (baseline 1.7), BNP 750 pg/mL.

Which of the following represents the BEST next step in pharmacologic management?

1. Increase lisinopril to 20 mg daily for additional neurohormonal suppression
2. Add eplerenone 25 mg daily for aldosterone antagonism
3. Add spironolactone 25 mg daily and monitor K⁺ closely
4. Discontinue lisinopril; start sacubitril/valsartan 49/97 mg BID
5. Add furosemide 40 mg daily without changing RAAS inhibitors

Answer: D (ARNI superior in HFrEF; allows removal of one RAAS inhibitor to improve K⁺)

Rationale: - Hyperkalemia (K⁺ 5.8) limits adding MRA (spironolactone, eplerenone) - Increasing lisinopril worsens hyperkalemia - ARNI (sacubitril/valsartan) provides ARB component + neprilysin inhibition (superior to ACEi in HFrEF per PARADIGM-HF) - Switching from lisinopril to ARNI = removes one RAAS inhibitor, lowers K⁺ - Once K⁺ improves, can add aldosterone antagonist if needed - Diuretics (furosemide) necessary for volume management but don’t address hyperkalemia

Question 3

A 48-year-old male with Type 2 diabetes, hypertension, CKD Stage 3b (eGFR 42), and overt albuminuria (uACR 220 mg/g) is on metformin and lisinopril 20 mg daily. His BP is 138/86 and his recent K⁺ is 4.9 mmol/L. His cardiologist recommends adding losartan 50 mg daily for additional renal protection.

Which of the following is the MOST appropriate response?

1. Agree with cardiologist; dual RAAS blockade provides additional renal benefit
2. Agree, but reduce lisinopril to 10 mg daily and start losartan 50 mg daily
3. Disagree; instead, optimize lisinopril dose and add finerenone 10 mg daily
4. Disagree; instead, add SGLT2 inhibitor (dapagliflozin) and continue lisinopril
5. Both C and D are correct

Answer: E (monotherapy RAAS inhibitor + finerenone + SGLT2i optimal; avoid dual blockade)

Rationale: - VA NEPHRON-D and ONTARGET trials: Dual RAAS blockade (ACEi + ARB) = ↑ hyperkalemia, ↑ AKI, NO additional renal benefit - KDIGO 2021: Avoid dual RAAS blockade in CKD - Optimal modern approach: 1. RAAS monotherapy: Continue lisinopril (already optimized 20 mg) 2. Finerenone: Add for additional renal protection (18–25% ↓ ESRD progression; FIDELIO-DKD data; different mechanism from ACEi) 3. SGLT2i: Add dapagliflozin for 39% ↓ ESRD progression (independent of RAAS inhibitors) 4. BP target: <130/80 per KDIGO 5. Monitor K⁺ monthly initially (goal <5.5)

Related Student Handouts

• Diuretics
• Immunosuppressive Therapy in Nephrology
• CKD Overview and Classification
• Diabetic Kidney Disease
• Hypertension Management
• GDMT: Four Pillars of Therapy
• SGLT2 Inhibitors in Kidney Disease

Clinical Content (01-Clinical-Medicine/Nephrology)

• Essential Renal Laboratory Tests
• Hypertension Management Hub
• CKD Hub - Full Clinical Reference
• Cardio-Renal Ecosystem Hub

Atomic Notes (ZK)

• RAAS System and Blood Pressure Regulation

Butler-COM Resources

• Butler COM - Nephrology Deep Dive
• Butler COM - Heart Failure GDMT Deep Dive

Created: 2026-02-12 Last Updated: 2026-02-12 Suggested Citation: “Renal Pharmacology: RAAS Inhibitors and Renoprotective Therapy.” Medical Education Handout, 2026.