What is the evidence-based approach to Angiotensin-Converting Enzyme (ACE) inhibitor/Angiotensin Receptor Blocker (ARB) cessation in patients with Acute Kidney Injury (AKI)?

Evidence-Based Approach to ACE/ARB Cessation in AKI

Immediate Management During Active AKI

ACE inhibitors and ARBs should be temporarily discontinued during acute kidney injury, as they can exacerbate kidney dysfunction through hemodynamic effects on glomerular filtration pressure. 1, 2

When to Stop ACE/ARB

• Discontinue immediately when AKI is diagnosed, particularly in the setting of:

  • Volume depletion or hypovolemia 1, 3
  • Intercurrent acute illness 2
  • Diarrhea or dehydration (30-fold increased risk of AKI when combined with ACE/ARB) 3
  • Planned IV radiocontrast administration 2
  • Bowel preparation prior to colonoscopy 2
  • Major surgery 2

• The mechanism of harm is hemodynamic, not nephrotoxic: ACE/ARBs block efferent arteriolar constriction, reducing glomerular filtration pressure in states where the kidney is already hypoperfused 4

• Critical distinction: This represents altered renal hemodynamics rather than tubular damage—true acute tubular necrosis would show positive biomarkers like NGAL and KIM-1, whereas hemodynamic creatinine rises do not 4

Common Pitfall to Avoid

• ACE inhibitor overdosing is a major contributor to AKI risk: 45% of patients using ACE inhibitors in one study experienced overdosing relative to their renal function, which accounted for most of the excess AKI risk 3
• Target or above-target dosing of ACE/ARB increases AKI risk significantly, while lower-than-recommended dosing does not 5

Reintroduction After AKI Resolution

ACE/ARBs should be reintroduced after GFR has stabilized and volume status is optimized, as continuing these medications after AKI recovery is associated with reduced mortality and cardiovascular events without increased recurrent AKI risk. 1, 6, 7

Criteria for Safe Restart

Before restarting ACE/ARB, verify ALL of the following 2, 8:

1. GFR stabilization: Creatinine has plateaued or is improving
2. Volume status optimized: Patient is euvolemic, not volume depleted
3. Resolution of acute precipitating illness 8
4. Serum potassium <5.5 mEq/L 2, 8
5. Mean arterial pressure >65 mmHg to avoid symptomatic hypotension 2

Restart Protocol

Step-by-step approach 2, 8:

1. Verify renal function and electrolytes before restarting 8

2. Start with low doses:

   • Candesartan 4-8 mg once daily 8
   • Valsartan 40 mg twice daily 8
   • Losartan at reduced initial dose 2

3. Recheck renal function and potassium within 1 week of restart 2, 8

4. Accept creatinine increases up to 30% from baseline as expected hemodynamic effects—this does NOT represent kidney injury and does not require stopping the medication 4

5. Titrate slowly while monitoring renal function and potassium levels 2

Absolute Contraindications to Restart

Do NOT restart ACE/ARB if 2, 8:

• Serum potassium >5.5 mEq/L 2, 8
• Creatinine >220 μmol/L (2.5 mg/dL) without stabilization 8
• Persistent symptomatic hypotension 8
• Patient is receiving simultaneous ACE inhibitor + ARB + aldosterone antagonist (triple RAAS blockade) 8
• Bilateral renal artery stenosis or stenosis in solitary kidney 4

Evidence Supporting Reintroduction

The highest quality recent evidence strongly favors restarting ACE/ARB after AKI recovery:

• Swedish observational study (2022): Stopping RASi after moderate-to-severe AKI was associated with 13% increased risk of the composite of death, MI, and stroke (HR 1.13,95% CI 1.07-1.19), with similar risk of recurrent AKI (HR 0.94,95% CI 0.84-1.05) 6

• English-Swedish parallel cohort study (2020): Previous ACE/ARB users who continued treatment after AKI had no increased risk of heart failure or subsequent AKI compared to those who stopped, but stopping was associated with increased mortality in the English cohort (HR 1.27,95% CI 1.15-1.41) 7

• European ICU study (2018): ACE/ARB prescription at ICU discharge in AKI patients was associated with 52% reduction in 1-year mortality (HR 0.48,95% CI 0.27-0.85) 9

Key Nuance in the Evidence

While KDIGO identified the need for more research on timing of ACE/ARB discontinuation and re-initiation 1, the most recent and highest quality observational data consistently shows harm from permanent discontinuation after AKI recovery 6, 7, 9. The risk-benefit ratio clearly favors reintroduction once stabilization criteria are met.

Alternative Antihypertensive Options During Active AKI

If blood pressure control is needed during the acute AKI phase 2:

• First-line: Dihydropyridine calcium channel blockers (amlodipine 2.5-10 mg daily) have minimal effects on renal hemodynamics 2
• If volume overload: Loop diuretics (furosemide) in moderate-to-severe kidney dysfunction 2
• If heart failure or ischemic heart disease: Beta-blockers 2
• If mild-moderate AKI (GFR >30 mL/min): Thiazide-like diuretics (chlorthalidone) with caution 2

Monitoring After Restart

Structured follow-up is essential 2, 8:

• Recheck creatinine and potassium within 1 week of restart 2, 8
• For eGFR <60 mL/min/1.73 m², monitor potassium periodically and assess creatinine/eGFR at least annually 4
• More frequent checks after ARB restart post-AKI 4

Management of Post-Restart Changes

• If creatinine increases 10-20%: This is acceptable and does not require suspension 2
• If creatinine increases >30%: Reassess volume status and consider dose reduction 4
• If potassium rises to 5.5-6.0 mEq/L: Reduce dose by half 8
• If potassium ≥6.0 mEq/L: Suspend immediately 8

Special Considerations

• ARBs vs ACE inhibitors: ARBs are mainly excreted by the liver and may be preferred over ACE inhibitors (which require renal dose adjustment) in patients with CKD to reduce AKI risk 3
• Avoid concomitant nephrotoxins: Do not combine with potassium supplements, potassium-sparing diuretics, or NSAIDs 2
• Patient education: Advise patients to temporarily withhold ACE/ARB during acute illnesses with volume depletion 5