What is the most appropriate first‑line antihypertensive for a patient with chronic kidney disease stage 4 (eGFR 15–29 mL/min/1.73 m²)?

Best Antihypertensive for CKD Stage 4

ACE inhibitors or ARBs at the highest tolerated dose are the first-line antihypertensive agents for patients with CKD stage 4 (eGFR 15-29 mL/min/1.73 m²), particularly when albuminuria is present. 1, 2

First-Line Agent Selection

• ACE inhibitors (e.g., lisinopril up to 40 mg daily) or ARBs should be initiated and titrated to the maximum approved dose that is tolerated, as clinical trial benefits were achieved at these target doses 1, 2
• ARBs serve as the preferred alternative if ACE inhibitors cause intolerable cough or angioedema 2
• These agents provide both blood pressure control and renoprotection, even at advanced CKD stages 3, 4

Critical Monitoring Requirements

• Check serum creatinine and potassium within 2-4 weeks of initiating or increasing the dose of ACE inhibitors/ARBs 1, 2
• Continue therapy if creatinine rises ≤30% within 4 weeks, as this reflects expected hemodynamic changes rather than harm 1, 2
• Only consider discontinuation if symptomatic hypotension, uncontrolled hyperkalemia despite medical management, or uremic symptoms develop 1

Second-Line Agents

When blood pressure remains uncontrolled on maximally tolerated ACE inhibitor/ARB:

• Add a loop diuretic (not thiazide) as second-line therapy in CKD stage 4, since thiazides become ineffective when eGFR <30 mL/min or serum creatinine >2.0 mg/dL 1, 2
• Long-acting dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine) are appropriate as second-line or third-line agents 1, 3
• A typical multi-drug regimen consists of: ACE inhibitor or ARB + loop diuretic + dihydropyridine CCB 1

Blood Pressure Target

• Target systolic BP <120 mmHg when tolerated using standardized office BP measurement 1
• An acceptable alternative systolic BP range is 130-139 mmHg, particularly if intensive targets are not tolerated 1, 2

Adjunctive Therapy Considerations

• For diabetic patients with CKD stage 4, consider adding an SGLT2 inhibitor (canagliflozin or dapagliflozin) if eGFR ≥20 mL/min/1.73 m² for additional cardiovascular and renal protection 5, 6, 2
• Canagliflozin: may continue 100 mg daily if already on therapy, though initiation is not recommended in stage 4 5
• Dapagliflozin: may continue if tolerated for kidney and cardiovascular benefit until dialysis, though initiation not recommended with eGFR <25 mL/min/1.73 m² 5

Hyperkalemia Management

• Manage hyperkalemia with measures to reduce serum potassium levels (dietary restriction, potassium binders) rather than decreasing or stopping the ACE inhibitor/ARB 1
• This approach preserves the renoprotective benefits of RAS inhibition 1

Critical Contraindications

• Never combine ACE inhibitor + ARB + direct renin inhibitor, as this triple combination increases adverse events without benefit 1, 2
• Avoid dual RAS inhibition (ACE inhibitor + ARB) due to increased risk of hyperkalemia, hypotension, and acute kidney injury 2
• Avoid thiazide diuretics as monotherapy in stage 4 CKD, as they are ineffective at this level of renal function 1

Common Pitfalls to Avoid

• Do not discontinue ACE inhibitor/ARB for modest creatinine increases up to 30%, as this is an expected hemodynamic effect 1, 2
• Do not apply intensive BP targets (<120 mmHg) to non-standardized BP measurements 1
• Do not use thiazides when eGFR <30 mL/min; switch to loop diuretics 1, 2

Non-Pharmacological Adjuncts

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) to enhance diuretic efficacy and BP control 1
• Sodium restriction is particularly important to optimize the effectiveness of RAS inhibitors 3