When to start angiotensin-converting enzyme (ACE) inhibitors in a patient with diabetic chronic kidney disease (CKD) and acute kidney injury (AKI)?

When to Start ACE Inhibitors in Diabetic CKD with AKI

Do not start ACE inhibitors during active AKI; instead, wait until the acute kidney injury has resolved, GFR has stabilized, and volume status is optimized before initiating therapy. 1, 2

Management During Active AKI

Immediate Actions

• Temporarily withhold ACE inhibitors during the acute phase of AKI, particularly when volume depletion, hypotension, or hemodynamic instability is present 1, 2
• Assess and correct volume status first, as volume depletion converts the hemodynamic effects of ACE inhibitors into problematic acute kidney injury 2
• Review and discontinue other nephrotoxic medications (NSAIDs, diuretics if causing volume depletion) that may be contributing to AKI 1
• Investigate reversible causes of AKI including renal artery stenosis, especially bilateral stenosis which creates critical dependence on angiotensin II for maintaining filtration pressure 1, 2

Why ACE Inhibitors Should Be Held During AKI

• ACE inhibitors reduce efferent arteriolar constriction, decreasing glomerular filtration pressure, which can worsen AKI in the setting of renal hypoperfusion 2
• The risk-benefit ratio during active AKI does not favor ACE inhibitor use, as the acute hemodynamic effects may not be tolerable without proven benefit in this phase 1
• Hypotension and decreased filtration fraction are common adverse effects that can cause or exacerbate AKI 1

When to Initiate or Resume ACE Inhibitors

Timing Criteria (All Must Be Met)

• Wait for GFR stabilization: Serum creatinine should be stable or improving for at least several days 1, 2
• Achieve euvolemia: Volume status must be optimized before starting therapy 1, 2
• Ensure hemodynamic stability: Systolic blood pressure should be >90 mmHg to avoid symptomatic hypotension 1, 3
• Verify potassium is controlled: Serum potassium should be ≤5.3 mEq/L before initiation 3

Indications for ACE Inhibitor Therapy in Diabetic CKD

ACE inhibitors are indicated when the patient has diabetes with both hypertension AND albuminuria, and should be titrated to the highest approved dose tolerated 1

• For patients with diabetes, albuminuria, but normal blood pressure, ACE inhibitor therapy may still be considered 1
• The primary goal is kidney and cardiovascular protection through reduction of intraglomerular pressure 1

Initiation Protocol After AKI Recovery

Starting Dose and Titration

• Begin with low doses of proven agents (captopril, enalapril, lisinopril, ramipril, or perindopril) that have demonstrated mortality and morbidity reduction in clinical trials 1
• Start at lower than usual doses given recent AKI, then gradually increase if well tolerated 1, 2
• Target the highest approved dose that is tolerated, as clinical trial benefits were achieved at target doses 1, 4

Monitoring Schedule

• Check serum creatinine and potassium within 1 week after ACE inhibitor restart post-AKI (more frequent than the standard 2-4 week interval) 1, 2
• Continue monitoring within 2-4 weeks after each dose increase 1
• For patients with eGFR <30 mL/min/1.73 m² or baseline potassium >4.5 mEq/L, monitor within 1 week 4

Acceptable Changes After Initiation

• Continue therapy if creatinine rises ≤30% within 4 weeks of starting or increasing dose, as this reflects the desired hemodynamic effect of reducing intraglomerular pressure, not acute tubular injury 1, 4, 2
• Creatinine increases up to 30% do not represent actual kidney damage and are associated with long-term renoprotection 4, 2

When to Stop or Reduce Dose

• Discontinue if creatinine rises >30% within 4 weeks of initiation or dose increase 1, 4
• Stop for symptomatic hypotension unresponsive to volume optimization 1
• Stop for uncontrolled hyperkalemia despite potassium-lowering measures (dietary restriction, diuretics, sodium bicarbonate, GI cation exchangers) 1

Managing Hyperkalemia Without Stopping ACE Inhibitors

Hyperkalemia should be managed with potassium-lowering interventions rather than immediately discontinuing the ACE inhibitor 1, 4:

• Review and discontinue concurrent potassium-sparing medications
• Moderate dietary potassium intake
• Add or increase diuretics (thiazide use is associated with lower ACE inhibitor discontinuation rates) 3
• Consider sodium bicarbonate supplementation
• Use GI cation exchangers as needed
• Reduce dose or stop ACE inhibitor only as a last resort 1

Long-Term Continuation

Advanced CKD Management

• Continue ACE inhibitors even when eGFR falls below 30 mL/min/1.73 m², as benefits outweigh risks in advanced CKD 4
• Consider dose reduction or discontinuation only at eGFR <15 mL/min/1.73 m² if symptomatic hypotension, uncontrolled hyperkalemia, or uremic symptoms develop 1, 4
• There is no serum creatinine level that absolutely contraindicates ACE inhibitor use 4

Evidence for Benefit After AKI

• Meta-analysis demonstrates that continued ACE inhibitor use after AKI is associated with lower all-cause mortality (log OR -0.36), lower risk of recurrent AKI (log OR -0.25), and reduced progression to incident CKD 5
• Patients who resume ACE inhibitors after AKI have better survival than those who discontinue therapy 5
• The higher incidence of hyperkalemia (log OR 0.43) requires close monitoring but should not preclude use 5

Common Pitfalls to Avoid

• Do not start ACE inhibitors during active AKI or acute illness with volume depletion, as this significantly increases AKI risk 1, 6, 7
• Do not use excessive doses without renal function adjustment, as 45% of patients using ACE inhibitors experience overdosing, which causes most excess AKI risk 6
• Do not combine ACE inhibitors with ARBs or direct renin inhibitors, as dual RAS blockade is potentially harmful 1
• Do not stop ACE inhibitors for creatinine increases <30% in stable patients, as this represents beneficial hemodynamic effects 4, 2
• Do not forget to advise patients to temporarily withhold ACE inhibitors during intercurrent illness, bowel preparation, or dehydration episodes 2, 7