In a 73‑year‑old woman with hypertension, coronary artery disease status post coronary artery bypass grafting, currently taking losartan 100 mg daily and metoprolol 100 mg daily, who developed hyperkalaemia on spironolactone and cannot tolerate amlodipine, and has chronic kidney disease stage 3 (eGFR 30‑59 mL/min), would a low‑dose thiazide diuretic be an appropriate next antihypertensive choice?

Thiazide Diuretics in CKD Stage 3: Appropriate Choice for This Patient

Yes, a low-dose thiazide-like diuretic—specifically chlorthalidone 12.5–25 mg daily—is an appropriate and evidence-based next antihypertensive choice for this patient with CKD stage 3 (eGFR 30–59 mL/min). 1

Why Thiazide-Like Diuretics Work in CKD Stage 3

Efficacy Despite Reduced Kidney Function

• Thiazide diuretics remain effective even in advanced CKD, including stage 4 (eGFR 15–29 mL/min), contrary to older teaching that recommended discontinuation at eGFR <30 mL/min. 2, 3
• The CLICK trial demonstrated that chlorthalidone effectively lowers blood pressure in stage 4 CKD patients with uncontrolled hypertension, including those with treatment-resistant hypertension. 4
• Small randomized controlled trials of hydrochlorothiazide in CKD showed significant mean arterial pressure reductions of 15 mmHg, and chlorthalidone studies using ambulatory blood pressure monitoring found significant improvements. 3

Guideline Support for Use in CKD

• The 2017 ACC/AHA guidelines recommend chlorthalidone as the preferred thiazide diuretic based on its prolonged half-life (40–60 hours) and proven cardiovascular disease reduction in clinical trials. 1, 5, 6
• Guidelines now recommend not automatically discontinuing thiazide diuretics when eGFR decreases to <30 mL/min/1.73 m², but instead assessing risks and benefits in each patient. 2
• Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options for CKD patients already on renin-angiotensin system blockade (which this patient is, with losartan). 4

Specific Drug Choice: Chlorthalidone Over Hydrochlorothiazide

Superior Efficacy

• Chlorthalidone 25 mg is comparatively more potent than hydrochlorothiazide 50 mg, particularly for overnight blood pressure reduction. 6
• In direct comparison, chlorthalidone 25 mg reduced 24-hour ambulatory systolic BP by 12.4 mmHg versus 7.4 mmHg with hydrochlorothiazide 50 mg (P=0.054), with nighttime reductions of 13.5 mmHg versus 6.4 mmHg (P=0.009). 7
• In advanced CKD specifically, chlorthalidone is superior to hydrochlorothiazide, with one study showing chlorthalidone 25 mg reduced 24-hour ambulatory BP by 10.5 mmHg over 12 weeks in stage 4 CKD. 5

Cardiovascular Outcomes

• Network meta-analyses demonstrate superior benefit of chlorthalidone over hydrochlorothiazide on clinical outcomes, including reduced stroke, heart failure, and cardiovascular disease events. 5
• In ALLHAT, chlorthalidone reduced new-onset atrial fibrillation by 23% compared with doxazosin, contributing to lower mortality. 5
• Among patients with metabolic syndrome (common in this age group with CAD), chlorthalidone was superior to lisinopril, amlodipine, and doxazosin in preventing cardiovascular and renal outcomes. 5

Practical Dosing Algorithm

Initial Dosing

• Start chlorthalidone 12.5 mg once daily added to her current regimen of losartan 100 mg and metoprolol 100 mg. 1, 5

Titration Strategy

• Reassess blood pressure in 2–4 weeks; if BP target not achieved, increase chlorthalidone to 25 mg once daily. 5
• The dose of 12.5–25 mg daily is optimal for endpoint protection based on major clinical trials. 5

Monitoring Requirements

• Check electrolytes (especially potassium and sodium), eGFR, uric acid, and calcium within 2–4 weeks of initiation or dose escalation. 1, 2, 5
• The greatest diuretic effect and most significant electrolyte shifts occur within the first 3 days, so early monitoring is critical. 2
• After achieving target BP, laboratory monitoring should occur every 3–6 months depending on patient stability. 2

Critical Safety Considerations in This Patient

Hyperkalemia Risk Mitigation

• This patient developed hyperkalemia on spironolactone, making her particularly suitable for a thiazide diuretic, which causes hypokalemia rather than hyperkalemia. 1
• Chlorthalidone can actually mitigate hyperkalemia risk when combined with renin-angiotensin system blockers like her current losartan. 4
• However, chlorthalidone carries a significantly higher risk of hypokalemia than hydrochlorothiazide (adjusted hazard ratio 3.06), so potassium monitoring is essential. 5

Metabolic Monitoring

• Monitor for hyponatremia, especially given her age (73 years)—elderly patients have heightened risk. 2
• Check uric acid levels before initiation and within 2–4 weeks, as thiazides can precipitate gout. 1, 5
• Use with caution given her CAD history, but thiazide-induced hyperuricemia does not contraindicate use if she's on uric acid-lowering therapy like allopurinol. 6

Renal Function Considerations

• Monitor creatinine and eGFR closely, as some increase in creatinine may occur with volume contraction. 8
• In a study of stage 3 CKD patients on losartan, adding hydrochlorothiazide 12.5 mg reduced proteinuria more effectively than increasing losartan alone, despite modest creatinine increases. 8

Common Pitfalls to Avoid

Don't Assume Thiazides Are Ineffective in CKD

• Older teaching that thiazides don't work below eGFR 30 mL/min is outdated—recent evidence shows efficacy even in stage 4 CKD. 2, 4, 3

Don't Use Hydrochlorothiazide Instead

• Hydrochlorothiazide has never been proven to reduce cardiovascular events in low-dose trials, whereas chlorthalidone has robust outcome data from ALLHAT and other trials. 5, 6

Don't Skip Early Electrolyte Monitoring

• Electrolyte abnormalities were common in CKD studies of thiazides, so monitoring within 2–4 weeks is mandatory, not optional. 3

Don't Combine with Other Potassium-Lowering Agents Without Monitoring

• Avoid combining with loop diuretics without close potassium monitoring, as the combination increases hypokalemia risk. 2

Don't Use Loop Diuretics as First-Line

• Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them; reserve them for clinically significant fluid overload or advanced renal failure. 6