Do Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) work as antihypertensive agents in patients undergoing hemodialysis with hypertension?

ACE Inhibitors and ARBs as Antihypertensives in Hemodialysis Patients

Yes, ACE inhibitors and ARBs do work as antihypertensive agents in hemodialysis patients, though they are generally recommended as second-line therapy after beta-blockers or calcium channel blockers, with their primary value being cardioprotection and preservation of residual kidney function rather than blood pressure reduction alone. 1, 2

Primary Treatment Strategy

• Volume management through ultrafiltration and dietary sodium restriction remains the cornerstone of blood pressure control in hemodialysis patients, with a target predialysis blood pressure of 140/90 mmHg. 3, 2
• Lifestyle modifications, particularly salt restriction, should be continuously emphasized before initiating pharmacologic therapy. 3

Antihypertensive Efficacy of ACE Inhibitors/ARBs

Evidence for Blood Pressure Lowering

• ACE inhibitors and ARBs do effectively lower blood pressure in hemodialysis patients and are reasonable first-line agents for most patients. 4
• These agents reduce mean arterial pressure, aortic pulse wave velocity, and aortic systolic pressure augmentation in ESRD patients. 5
• However, the 2020 KDIGO guidelines note that fosinopril (an ACE inhibitor) did not reduce cardiovascular events and death compared with placebo in hemodialysis patients with left ventricular hypertrophy, and ARB trials have shown inconsistent results for cardiovascular outcomes. 1

Preferred First-Line Alternatives

• Beta-blockers demonstrate the strongest mortality benefit in dialysis patients and should be preferred for patients with previous myocardial infarction or established coronary artery disease. 2
• Atenolol showed fewer heart failure hospitalizations compared to the ACE inhibitor lisinopril in hemodialysis patients with hypertension and left ventricular hypertrophy. 1
• Calcium channel blockers (particularly amlodipine) reduced cardiovascular events compared with placebo in hemodialysis patients with hypertension and should be considered as first-line therapy for patients without specific cardiovascular indications for beta-blockers. 1, 2

Primary Benefits Beyond Blood Pressure Control

Cardioprotection

• ACE inhibitors and ARBs may reduce left ventricular mass index in hemodialysis patients, though this effect is not consistently associated with improved mortality. 1, 3
• ARBs may be more potent than ACE inhibitors for left ventricular hypertrophy reduction. 3
• One open-label randomized trial showed ARBs reduced fatal and nonfatal cardiovascular events by 49% (hazard ratio 0.51) in hemodialysis patients, though the small sample size means this large effect may be spurious. 6
• Observational studies suggest ACE inhibitors are associated with decreased mortality in ESRD patients, with a 52% risk reduction overall and 79% in patients ≤65 years old. 7

Preservation of Residual Kidney Function

• For patients with residual kidney function, ACE inhibitors or ARBs are particularly beneficial and should be preferred, as they slow the decline in residual kidney function. 1, 3, 2
• This benefit is especially pronounced in peritoneal dialysis patients, where ramipril preserved approximately 1 mL/min greater GFR at one year, and valsartan slowed GFR and urine volume decline at 24 months. 1
• The renoprotective effect appears to be independent of blood pressure changes. 1

Treatment Algorithm

1. First step: Achieve dry weight through ultrafiltration and enforce dietary sodium restriction. 3, 2

2. Second step: If blood pressure remains >140/90 mmHg despite optimal volume management, initiate pharmacologic therapy:

   • For patients with prior MI or coronary artery disease: Beta-blockers (preferred first-line). 3, 2
   • For patients without specific cardiac indications: Calcium channel blockers (preferred first-line). 2
   • For patients with significant residual kidney function: ACE inhibitors or ARBs (preferred first-line). 1, 3, 2

3. Third step: If monotherapy is inadequate, add ACE inhibitor/ARB as second-line agent if not already used, or add from a different class. 3, 2

4. Fourth step: For resistant hypertension (BP >140/90 mmHg despite three agents at optimal doses), evaluate for secondary causes and consider adding minoxidil. 3

Critical Safety Considerations and Pitfalls

Hyperkalemia Risk

• ACE inhibitors and ARBs should be used with caution in hemodialysis patients due to increased risk of hyperkalemia. 2
• Monitor serum potassium frequently when using these agents. 2
• Reduce dose by half if potassium increases to >5.5 mmol/L and discontinue immediately if ≥6.0 mmol/L. 8

Contraindications and Drug Interactions

• Avoid combination therapy with ACE inhibitors and ARBs, as this increases risks of hyperkalemia and acute kidney injury without improving outcomes. 1, 2
• Do not use ACE inhibitors in patients treated with polyacrylonitrile (AN69) dialysis membranes due to risk of anaphylactoid reactions. 3, 5
• ACE inhibitors can aggravate renal anemia and decrease erythropoiesis. 5, 9

Pharmacokinetic Considerations

• Hemodialysis removes some ACE inhibitors (enalapril, ramipril, lisinopril, perindopril) but not others (benazepril, fosinopril). 3, 9
• ARBs are not dialyzable, making them potentially preferable for consistent blood pressure control. 3, 9
• Lisinopril and atenolol have prolonged half-lives in ESRD; thrice-weekly supervised administration after hemodialysis can enhance blood pressure control. 5, 4

Adverse Effects

• ACE inhibitors cause cough and angioneurotic edema in hemodialysis patients, similar to the general population. 9
• ACE inhibitors can decrease thirst drive, which may be beneficial or problematic depending on volume status. 9
• ARBs have a remarkably bland adverse effect profile and rarely cause cough or angioedema. 9

Dosing Recommendations

• For losartan specifically: Start at 50 mg daily, titrate to 100 mg daily if needed for blood pressure control. 8, 10
• Verify creatinine and potassium within 2-4 weeks after initiation or dose increase. 8
• For ramipril in peritoneal dialysis: 5 mg daily was effective in preserving residual kidney function. 1
• For valsartan: 40-80 mg daily was effective in slowing GFR decline. 1