What is the evidence for withholding Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARB) in patients with Acute Kidney Injury (AKI)?

Management of ACE Inhibitors and ARBs in Acute Kidney Injury

ACE inhibitors and ARBs should be temporarily withheld during active AKI when volume depletion is present, but do not need to be discontinued for creatinine increases less than 30% from baseline in euvolemic patients, as these modest elevations reflect hemodynamic effects rather than true kidney injury. 1, 2

Distinguishing Hemodynamic Effects from True AKI

• Creatinine increases up to 30% from baseline with ACE/ARB therapy represent expected hemodynamic changes from reduced intraglomerular pressure—the mechanism underlying their long-term kidney protection—and should not be confused with actual AKI. 1, 2

• Analysis from the ACCORD BP trial demonstrated that patients with up to 30% creatinine increases on intensive blood pressure lowering had no increase in mortality or progressive kidney disease, and biomarkers for AKI showed no significant elevation despite creatinine rises. 1

• These medications should not be routinely discontinued for creatinine increases less than 30% in the absence of volume depletion. 1, 2

When to Withhold ACE/ARBs During AKI

Temporarily suspend ACE inhibitors and ARBs during high-risk clinical scenarios including: 2, 3

• Intercurrent acute illness with volume depletion 2, 3
• Planned IV radiocontrast administration 2
• Bowel preparation prior to colonoscopy 2
• Major surgery 2
• Active diarrhea or dehydration 4, 5

During active AKI, assess volume status first: 2

• If volume depleted: Temporarily hold ACE/ARB and restore euvolemia 2
• If euvolemic with creatinine rise <30%: Continue ACE/ARB at current dose 2
• If creatinine rises >30% or exceeds 3 mg/dL: Consider withdrawal of the medication 6

Evidence on Mortality and Long-Term Outcomes

The evidence presents a nuanced picture regarding continuation versus discontinuation:

• Continuation/early reinitiation after AKI appears beneficial for mortality: A propensity-matched study of 1,551 ICU patients showed that ACE/ARB prescription at ICU discharge was associated with significantly lower 1-year mortality in AKI patients (HR 0.48,95% CI 0.27-0.85). 7

• A large retrospective cohort of 46,253 patients demonstrated that ACE/ARB use within 6 months after hospital discharge was associated with lower 2-year mortality (adjusted HR 0.85,95% CI 0.81-0.89), though with higher risk of hospitalization for renal causes (adjusted HR 1.28,95% CI 1.12-1.46). 8

• However, observational data from emergency admissions showed higher AKI incidence among patients on target or above-target ACE/ARB dosages (49% vs 28%, p=0.001), particularly when combined with acute illness. 4

Specific Contraindications and Risk Factors

Absolute contraindications for continuing/restarting ACE/ARBs: 3, 9

• Serum potassium >5.5 mEq/L 3, 9
• Creatinine >220 μmol/L (2.5 mg/dL) without stabilization 9
• Unresolved symptomatic hypotension 9
• Concurrent use of ACE inhibitor plus ARB plus aldosterone antagonist 9

Higher risk populations requiring more cautious approach: 6, 10, 5

• Bilateral renal artery stenosis 6, 10
• Severe congestive heart failure with renin-angiotensin-aldosterone system-dependent renal function 6, 10
• Elderly patients with baseline CKD stage 3 or higher 5
• Patients receiving concurrent NSAIDs, which can cause acute renal failure when combined with ARBs 10

Protocol for Reintroduction After AKI Resolution

Wait for clinical stabilization before restarting: 2, 9

• GFR has stabilized (not necessarily returned to baseline) 2, 9
• Volume status is optimized 2, 9
• Acute precipitating illness has resolved 9

Restart protocol: 2, 9

• Begin with lower doses (e.g., candesartan 4-8 mg daily, valsartan 40 mg twice daily, or lisinopril at reduced dose) 9
• Recheck renal function and potassium within 1 week of restart 2, 9
• Monitor more frequently if eGFR <60 mL/min/1.73 m² 1

Common Pitfalls to Avoid

• Do not discontinue ACE/ARBs reflexively for all creatinine elevations—the 30% threshold is critical for distinguishing hemodynamic effects from true injury. 1, 2

• Do not assume ACE inhibitors and ARBs are equivalent in AKI risk—ACE inhibitors require renal dose adjustment and may carry higher AKI risk when overdosed in CKD patients, while ARBs are primarily hepatically cleared. 5

• Do not forget to advise patients to withhold these medications during acute intercurrent illness—this "sick day guidance" is essential but often overlooked. 4, 5

• Do not combine ACE/ARBs with other renin-angiotensin system blockers—dual blockade substantially increases risks of hyperkalemia, hypotension, and acute renal failure. 10