What is the recommended approach for managing resistant hypertension in patients with end-stage renal disease (ESRD)?

Management of Resistant Hypertension in End-Stage Renal Disease

In ESRD patients with resistant hypertension, achieving euvolemia through aggressive ultrafiltration and sodium restriction (<2400 mg/day) is the cornerstone of management and must be prioritized before escalating antihypertensive medications, as volume overload is the primary driver of treatment resistance in this population. 1, 2

Confirm True Resistant Hypertension

Before diagnosing resistant hypertension in ESRD, you must exclude pseudoresistance:

• Perform home blood pressure monitoring or 44-hour interdialytic ambulatory BP monitoring to exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant cases in dialysis patients 3, 2
• Verify medication adherence through direct questioning, pill counts, or pharmacy records, as nonadherence is responsible for roughly half of treatment resistance 3, 4
• Ensure proper BP measurement technique using appropriate cuff size (large arms require large cuffs to avoid falsely elevated readings) and correct positioning 3
• Confirm BP remains ≥130/80 mmHg despite adherence to ≥3 antihypertensive agents from different classes at maximally tolerated doses, including a diuretic, or requires ≥4 medications regardless of BP level 1

Address Volume Overload First (Critical Step)

Volume-mediated hypertension is the most important treatable cause of resistance in ESRD and must be addressed before medication escalation. 2

• Restrict dietary sodium to <2400 mg/day and use low-sodium dialysate to facilitate achievement of dry weight 1, 3, 2
• Ensure adequate dialysis time of at least 4 hours per session to deliver adequate dialysis dose and facilitate volume removal 2
• Aggressively challenge dry weight through incremental ultrafiltration adjustments, as volume overload is often unrecognized 3, 2
• Monitor for clinical signs of euvolemia including absence of edema, stable interdialytic weight gains, and improved BP control 2

Common pitfall: Intensifying antihypertensive therapy without adequately addressing volume status will likely fail and expose patients to unnecessary medication side effects. 2

Optimize the Three-Drug Regimen

Once volume status is optimized, ensure the baseline regimen includes:

• A long-acting dihydropyridine calcium channel blocker (amlodipine or nifedipine) 3, 5
• A renin-angiotensin system blocker (ACE inhibitor or ARB preferred for cardioprotective effects independent of BP reduction) 6, 5
• A beta-blocker (reasonable first-line agent with cardioprotective benefits) 5

For diuretic selection in ESRD:

• Use loop diuretics (furosemide, torsemide) if any residual renal function exists (eGFR <30 mL/min/1.73m²), as thiazides become ineffective at this level 1, 3
• Switch from hydrochlorothiazide to chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) if residual function permits, as thiazide-like diuretics are more effective 3, 7
• In anuric dialysis patients, diuretics provide minimal benefit and volume control must rely on ultrafiltration 2

Add Fourth-Line Agent

If BP remains ≥130/80 mmHg after optimizing volume status and the three-drug regimen:

• Add low-dose spironolactone (25-50 mg daily) as the most effective fourth-line agent, provided serum potassium is <4.5 mEq/L and the patient can undergo regular monitoring 1, 3, 7
• Monitor serum potassium and renal function within 1-2 weeks after initiation, especially in patients on RAS blockers 3, 7
• Increase to 50 mg daily if BP remains uncontrolled and medication is well-tolerated 3

If spironolactone is contraindicated or not tolerated:

• Eplerenone (50-200 mg daily) as first alternative with less gynecomastia but requiring higher dosing 1, 3
• Amiloride as second alternative (one trial found it more effective than spironolactone) 3
• Doxazosin, clonidine, or additional beta-blocker as other options 1, 3

Medication Timing Considerations in Dialysis

• Medications removed by dialysis (atenolol, lisinopril, enalapril) may be preferred in patients prone to intradialytic hypotension, as they can be dosed after dialysis 5
• Nondialyzable medications (amlodipine, carvedilol, losartan) are preferred for managing intradialytic hypertension 5
• Thrice-weekly dosing after dialysis has robust BP-lowering effects and may improve adherence in nonadherent patients 5

Exclude Secondary Causes

Screen for reversible causes of resistant hypertension:

• Primary aldosteronism (even with normal potassium) 3
• Obstructive sleep apnea 3
• Renal artery stenosis (particularly in patients with residual kidney function) 3
• Thyroid dysfunction (check TSH) 3
• Discontinue interfering substances: NSAIDs, stimulants, oral contraceptives, certain antidepressants 1, 3

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication or ultrafiltration adjustment 3, 7
• Target BP <130/80 mmHg per ACC/AHA guidelines, though individualize for elderly patients with high comorbidity burden 1, 7
• Use home BP monitoring to guide medication titration and improve adherence 3, 7
• Monitor for intradialytic hypotension when intensifying therapy, as this may indicate overaggressive volume removal 5

Specialist Referral

Refer to a hypertension specialist or nephrologist with expertise in resistant hypertension if BP remains uncontrolled (>130/80 mmHg) after optimizing the four-drug regimen with adequate volume management, or if complications arise such as severe hyperkalemia or progressive hemodynamic instability 1, 3, 7

Critical Pitfalls to Avoid

• Do not escalate antihypertensive medications without first achieving euvolemia through ultrafiltration and sodium restriction—this is the most common error in ESRD management 2
• Do not continue hydrochlorothiazide in patients with eGFR <30 mL/min/1.73m²—switch to loop diuretics or discontinue if anuric 1, 3
• Do not combine ACE inhibitor + ARB due to increased risk of hyperkalemia and renal dysfunction without additional benefit 7
• Do not rely solely on predialysis or postdialysis BP measurements—home or ambulatory monitoring is essential for accurate diagnosis 2
• Do not assume medication nonadherence without objective assessment—use pharmacy records or pill counts 4, 2