What is the role of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs) in patients with Chronic Kidney Disease (CKD)?

ACE Inhibitors and ARBs in Chronic Kidney Disease

ACE inhibitors and ARBs are first-line therapy for patients with CKD who have diabetes, hypertension, and albuminuria, and should be titrated to the maximum tolerated dose to achieve proven kidney and cardiovascular protection. 1

Primary Indications for ACEI/ARB Therapy

Strong indications (must treat):

• Patients with diabetes, hypertension, and albuminuria (UACR ≥30 mg/g) should receive ACEI or ARB therapy regardless of CKD stage 1
• Patients with CKD stages G1-G4 and moderately-to-severely increased albuminuria (A2 and A3) benefit from RAAS blockade independent of diabetes status 1
• Those with severe albuminuria (UACR ≥300 mg/g) or eGFR <60 mL/min/1.73 m² should receive these agents as first-line therapy even if normotensive 1, 2

Conditional indications (consider treatment):

• Normotensive diabetic patients with moderate albuminuria (UACR 30-299 mg/g) may benefit from ACEI/ARB therapy 1, 2
• Patients with normal to mildly increased albuminuria (A1) may receive ACEI/ARB for other indications like heart failure with reduced ejection fraction 1

Do NOT prescribe:

• Diabetic patients without hypertension, albuminuria, or reduced eGFR should NOT receive ACEI/ARB for kidney protection, as trials show no benefit and one demonstrated increased cardiovascular events 2

Dosing Strategy

Titrate to maximum approved doses that are tolerated, as clinical trials demonstrating efficacy used these doses 1. The renoprotective effects are dose-dependent, and many patients are undertreated due to concerns about rising creatinine 3. A titration process is necessary because patients who benefit from higher doses cannot be identified a priori 3.

Monitoring Requirements

Check serum creatinine, eGFR, and potassium within 2-4 weeks of initiation or dose increase 1:

• Continue therapy if creatinine rises <30% within 4 weeks 1
• If creatinine rises >30%, review for concurrent medications (NSAIDs, diuretics), volume depletion, or renal artery stenosis 1, 4
• Continue ACEI/ARB even when eGFR falls below 30 mL/min/1.73 m² 1

Managing Hyperkalemia

Hyperkalemia should be managed with potassium-lowering measures rather than immediately stopping ACEI/ARB 1:

• Review concurrent medications (potassium-sparing diuretics, NSAIDs, potassium supplements) 4, 5
• Moderate dietary potassium intake 1
• Correct volume depletion 1
• Only reduce dose or discontinue for uncontrolled hyperkalemia despite medical management 1

Risk factors for hyperkalemia include renal insufficiency, diabetes, and concomitant use of potassium-sparing agents 4, 6.

Advanced CKD Considerations (Stages 4-5)

Continue ACEI/ARB in advanced CKD unless symptomatic hypotension, uncontrolled hyperkalemia, or uremic symptoms develop 1. Evidence suggests benefits on mortality and slowed CKD progression persist even at eGFR <30 mL/min/1.73 m² 7. However, consider dose reduction or discontinuation when eGFR <15 mL/min/1.73 m² to reduce uremic symptoms 1.

For peritoneal dialysis patients with residual kidney function, ACEI/ARB therapy slows the decline in GFR independent of blood pressure effects 1. Studies showed ramipril 5 mg daily preserved approximately 1 mL/min greater GFR at one year, and valsartan 40-80 mg daily slowed GFR decline at 24 months 1.

Critical Contraindications and Warnings

Never combine ACEI with ARB or add a direct renin inhibitor—this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular or kidney benefits 1, 5, 8. A nationwide study of 14,117 pre-dialytic stage 5 CKD patients found dual RAAS blockade associated with significantly higher mortality (HR 1.49) compared to ARB monotherapy 8.

Discontinue immediately if pregnancy is detected or planned 1, 4. These drugs cause fetal renal dysfunction, oligohydramnios, and neonatal complications when used in second and third trimesters 4.

Common Pitfalls to Avoid

• Stopping therapy prematurely for modest creatinine increases (<30%): This represents expected hemodynamic changes from reduced intraglomerular pressure, not kidney injury 1
• Underdosing due to fear of adverse effects: Maximum tolerated doses provide optimal renoprotection 1, 3
• Discontinuing in advanced CKD: Benefits persist even at low eGFR unless specific complications arise 1, 9
• Using combination RAAS blockade: This practice is explicitly contraindicated 1, 5
• Avoiding nephrotoxins: NSAIDs (including COX-2 inhibitors) can precipitate acute kidney injury and should be avoided 1, 5

ARB vs ACEI Selection

While both classes are effective, one large observational study of stage 5 CKD patients found ARB monotherapy associated with lower mortality than ACEI monotherapy (HR 1.17 for ACEI vs ARB) 8. However, guideline recommendations do not distinguish between the two classes for initial therapy 1. The main practical difference is that ACEIs cause persistent nonproductive cough in some patients, which resolves with discontinuation 4.

Integration with SGLT2 Inhibitors

SGLT2 inhibitors should be added to ACEI/ARB therapy (not substituted) in patients with type 2 diabetes, CKD, and eGFR ≥20 mL/min/1.73 m² 1. All major kidney outcome trials with SGLT2 inhibitors tested these agents on top of background RAAS blockade 1.