What medication adjustments can be made for a patient with stage three kidney disease (Impaired renal function), taking amlodipine (calcium channel blocker) 10 mg, metoprolol (beta blocker) 50 mg, and hydralazine (vasodilator) 50 mg, who continues to have elevated blood pressure (hypertension)?

Medication Adjustments for Uncontrolled Hypertension in Stage 3 CKD

Add a thiazide-like diuretic (chlorthalidone 12.5-25 mg daily preferred over hydrochlorothiazide) as your fourth antihypertensive agent to achieve guideline-recommended therapy for resistant hypertension in this patient with stage 3 CKD. 1

Current Regimen Assessment

Your patient is on three antihypertensive agents but notably lacks a diuretic, which is the cornerstone of resistant hypertension management and addresses the occult volume expansion that commonly underlies treatment resistance in CKD patients. 1

The current regimen includes:

• Amlodipine 10 mg (maximum dose calcium channel blocker) 1
• Metoprolol 50 mg (beta-blocker at moderate dose) 1
• Hydralazine 50 mg (direct vasodilator) 1

Primary Recommendation: Add a Thiazide-Like Diuretic

Add chlorthalidone 12.5-25 mg once daily as the preferred thiazide-like diuretic for this patient. 1 Chlorthalidone is superior to hydrochlorothiazide due to its longer half-life (providing 24-hour BP coverage) and proven cardiovascular outcomes data. 1

Rationale for Diuretic Addition

• The 2024 ESC guidelines explicitly recommend adding low-dose spironolactone OR thiazide/thiazide-like diuretics as first-line therapy for resistant hypertension (defined as uncontrolled BP despite three agents). 1
• With GFR 34 mL/min (stage 3b CKD), thiazide-like diuretics remain effective, though loop diuretics become necessary when GFR falls below 30 mL/min. 1
• Diuretics address volume expansion, which is particularly important in CKD patients who have impaired sodium excretion. 1

Alternative: Spironolactone

If volume overload is prominent or if the patient has resistant hypertension features, consider spironolactone 25 mg daily instead as the preferred fourth-line agent. 1 However, with GFR 34 and no mention of current potassium levels, careful monitoring is essential:

• Check serum potassium and creatinine within 1-2 weeks after initiation. 1
• Hold spironolactone if potassium rises above 5.5 mEq/L or creatinine increases significantly. 1
• Spironolactone provides additional BP reductions of 20-25/10-12 mmHg when added to triple therapy. 1

Secondary Consideration: Optimize Beta-Blocker Dosing

Before or concurrent with adding a diuretic, consider increasing metoprolol from 50 mg to 100-200 mg daily (or switching to metoprolol succinate for once-daily dosing), as the current dose is suboptimal. 1 However, this should not delay diuretic addition, which is the priority.

Replace Hydralazine with ACE Inhibitor or ARB

Strongly consider replacing hydralazine with an ACE inhibitor (e.g., lisinopril 10-40 mg daily) or ARB (e.g., losartan 50-100 mg daily) for superior renoprotection in stage 3 CKD. 1

Why This Change Matters

• ACE inhibitors and ARBs are specifically recommended as first-line therapy in CKD due to their ability to slow kidney disease progression beyond BP lowering alone. 1
• The 2024 ESC guidelines recommend RAS blockers (ACE inhibitors/ARBs) as more effective at reducing albuminuria than other antihypertensive agents in hypertensive patients with microalbuminuria or proteinuria. 1
• Hydralazine is listed as a second-line or third-line option in the 2024 ESC guidelines, reserved for when first-line agents are insufficient or not tolerated. 1
• The AASK trial demonstrated that ACE inhibitors (ramipril) reduced the clinical composite outcome (GFR decline ≥50%, ESRD, or death) by 38% compared to amlodipine in African Americans with hypertensive nephrosclerosis. 2

Implementation Strategy

1. Add chlorthalidone 12.5 mg daily (or hydrochlorothiazide 25 mg if chlorthalidone unavailable). 1
2. Simultaneously replace hydralazine 50 mg with lisinopril 10 mg daily (or losartan 50 mg if ACE inhibitor not tolerated). 1
3. Increase metoprolol to 100 mg twice daily or switch to metoprolol succinate 200 mg once daily. 1
4. Continue amlodipine 10 mg daily (already at maximum dose). 1

This creates the guideline-recommended combination: ACE inhibitor/ARB + calcium channel blocker + beta-blocker + thiazide diuretic. 1

Blood Pressure Targets in Stage 3 CKD

• Target BP <130/80 mmHg for patients with CKD, as recommended by the 2024 ESC guidelines and ACC/AHA guidelines. 1
• For patients with CKD and eGFR >30 mL/min/1.73 m² (which includes your patient with GFR 34), the 2024 ESC guidelines recommend targeting systolic BP to 120-129 mmHg if tolerated. 1
• Individualize BP targets based on tolerability and impact on renal function and electrolytes. 1

Critical Monitoring Parameters

Within 1-2 Weeks of Medication Changes:

• Serum potassium (risk of hyperkalemia with ACE inhibitor/ARB, especially in CKD; risk of hypokalemia with thiazide). 1
• Serum creatinine and eGFR (expect up to 30% increase in creatinine with ACE inhibitor/ARB initiation, which is acceptable; hold if >30% increase). 1
• Blood pressure (home BP monitoring preferred; target <135/85 mmHg by home monitoring, equivalent to <140/90 mmHg clinic BP). 1

Within 2-4 Weeks:

• Reassess BP control and adjust doses as needed. 1
• Check for orthostatic hypotension, especially in elderly patients. 1

Every 3-6 Months Once Stable:

• Monitor potassium, creatinine, and BP. 1
• Assess for proteinuria (urine albumin-to-creatinine ratio), as ACE inhibitors/ARBs should reduce proteinuria. 1

Critical Steps Before Medication Changes

Verify Medication Adherence

Non-adherence is the most common cause of apparent treatment resistance. 1 Confirm the patient is actually taking all three current medications as prescribed.

Rule Out Secondary Hypertension

With resistant hypertension (uncontrolled on three agents), screen for: 1

• Primary aldosteronism (check plasma aldosterone-to-renin ratio)
• Obstructive sleep apnea (especially if overweight, snoring, daytime somnolence)
• Renal artery stenosis (consider if abrupt worsening of BP control or flash pulmonary edema)
• Interfering medications (NSAIDs, decongestants, stimulants, licorice, oral contraceptives)

Reinforce Lifestyle Modifications

These provide additive BP reductions of 10-20 mmHg: 1

• Sodium restriction to <2 g/day (produces 5-10 mmHg systolic reduction, with greater benefit in CKD patients). 1
• Weight loss if overweight (10 kg weight loss associated with 6.0 mmHg systolic reduction). 1
• DASH diet (reduces systolic BP by 11.4 mmHg). 1
• Regular aerobic exercise (30 minutes most days produces 4 mmHg systolic reduction). 1
• Alcohol limitation to <100 g/week. 1

Common Pitfalls to Avoid

• Do not delay adding a diuretic in resistant hypertension—occult volume expansion is the primary mechanism of treatment resistance in CKD. 1
• Do not combine an ACE inhibitor with an ARB (dual RAS blockade increases adverse events like hyperkalemia and acute kidney injury without additional cardiovascular benefit). 1
• Do not use potassium-sparing diuretics (spironolactone, amiloride) without close potassium monitoring in stage 3 CKD, especially when combined with ACE inhibitors/ARBs. 1
• Do not use non-dihydropyridine calcium channel blockers (diltiazem, verapamil) if the patient has heart failure with reduced ejection fraction, as they have negative inotropic effects. 1
• Do not assume treatment failure without first confirming adherence and ruling out secondary causes. 1

If BP Remains Uncontrolled After These Changes

If BP remains uncontrolled despite optimized four-drug therapy (ACE inhibitor/ARB + amlodipine + beta-blocker + thiazide diuretic at maximum tolerated doses):

1. Add spironolactone 25-50 mg daily if not already used (preferred fifth-line agent for resistant hypertension). 1
2. Alternative fifth-line agents if spironolactone contraindicated: eplerenone, amiloride, doxazosin, or clonidine. 1
3. Consider referral to hypertension specialist if BP remains ≥160/100 mmHg despite five-drug therapy at optimal doses. 1
4. Evaluate for renal denervation at a high-volume center if BP uncontrolled despite three-drug combination and patient expresses preference after shared decision-making. 1