When to initiate Angiotensin-Converting Enzyme (ACE) inhibitors in patients with Chronic Kidney Disease (CKD) without diabetes and hypertension?

When to Start ACE Inhibitors in CKD Patients Without Diabetes and Hypertension

ACE inhibitors should be initiated in non-diabetic, non-hypertensive CKD patients who have albuminuria ≥300 mg/24 hours (severely increased albuminuria) regardless of blood pressure level. 1

Indications for ACE Inhibitor Therapy Based on Albuminuria Level

Severely Increased Albuminuria (≥300 mg/24h)

• ACE inhibitors are strongly recommended as first-line therapy in non-diabetic CKD patients with severely increased albuminuria (≥300 mg/24h or ≥300 mg/g albumin-to-creatinine ratio), even in the absence of hypertension 1
• This recommendation is based on strong evidence showing that ACE inhibitors reduce the risk of kidney failure and cardiovascular events in this population 1
• Treatment with an ACE inhibitor has been shown to slow kidney disease progression in this high-risk group 1

Moderately Increased Albuminuria (30-300 mg/24h)

• For non-diabetic CKD patients with moderately increased albuminuria (30-300 mg/24h), ACE inhibitors may be considered even without hypertension, though the evidence is less robust (Grade 2C recommendation) 1
• The benefit in this population is primarily related to cardiovascular risk reduction rather than kidney protection 1
• The HOPE trial demonstrated cardiovascular benefits of ACE inhibition in patients with moderately increased albuminuria, independent of blood pressure effects 1

Normal to Mildly Increased Albuminuria (<30 mg/24h)

• There is insufficient evidence to recommend ACE inhibitors for non-diabetic, non-hypertensive CKD patients with normal to mildly increased albuminuria (<30 mg/24h) 1
• In these patients, ACE inhibitors should be initiated only if hypertension develops (BP consistently >140/90 mmHg) 1

Monitoring and Safety Considerations

• When initiating ACE inhibitors in non-hypertensive CKD patients:

  • Check basic metabolic profile within 2-4 weeks after starting therapy to monitor for hyperkalemia and changes in kidney function 1
  • A small initial decline in eGFR (up to 30%) may occur and is generally reversible; this should not necessarily prompt discontinuation 2
  • Monitor for hypotension, especially in volume-depleted patients 1
  • Patients should be educated to temporarily reduce or hold ACE inhibitor doses during periods of decreased oral intake, vomiting, or diarrhea to prevent acute kidney injury 1

• Common pitfalls to avoid:

  • Failure to recognize the risk of hyperkalemia, especially in advanced CKD (stages G4-G5) 3
  • Combining ACE inhibitors with ARBs, which increases risk of adverse events without additional benefit 1
  • Inadequate monitoring of kidney function and electrolytes after initiation 1

Special Considerations

• For elderly CKD patients without albuminuria, carefully consider the risk-benefit ratio before starting ACE inhibitors in the absence of hypertension 1
• In patients with bilateral renal artery stenosis or severe heart failure, ACE inhibitors may precipitate acute kidney injury and should be used with caution 2
• Sodium restriction can enhance the antiproteinuric effect of ACE inhibitors but may also potentiate their adverse effects 2

Algorithm for ACE Inhibitor Initiation in Non-Diabetic, Non-Hypertensive CKD

1. Assess albuminuria level:

   • If ≥300 mg/24h: Start ACE inhibitor (strong recommendation) 1
   • If 30-300 mg/24h: Consider ACE inhibitor based on cardiovascular risk profile (conditional recommendation) 1
   • If <30 mg/24h: Monitor for development of hypertension or increased albuminuria before initiating therapy 1

2. Before initiating therapy:

   • Check baseline kidney function, electrolytes, and urinary albumin excretion 1
   • Rule out bilateral renal artery stenosis if clinically suspected 2
   • Ensure patient is not volume depleted 1

3. Dosing approach:

   • Start with a low dose and titrate upward as tolerated 1
   • Target doses used in clinical trials showing benefit 1

4. Monitoring after initiation:

   • Check kidney function and electrolytes within 2-4 weeks 1
   • Assess for symptomatic hypotension 1
   • Monitor albuminuria response at 3-6 months 1

The 2021 KDIGO guidelines represent the most current evidence-based approach, recommending ACE inhibitor use in non-hypertensive CKD patients with albuminuria, with the strength of recommendation increasing with the degree of albuminuria 1.