Can chlorthalidone be used in a patient with chronic kidney disease who has elevated serum creatinine and hyperkalaemia?

Chlorthalidone Use in CKD with Elevated Creatinine and Hyperkalemia

Chlorthalidone can and should be used in patients with advanced CKD (even stage 4 with eGFR <30 mL/min/1.73 m²) and elevated creatinine, but hyperkalemia must be corrected first before initiation. 1, 2

Initial Assessment Before Starting Chlorthalidone

Address hyperkalemia before initiating chlorthalidone:

• If potassium is 5.5-6.0 mmol/L: reduce or stop potassium supplements and potassium-sparing diuretics, add or increase loop diuretics to promote potassium excretion 3
• If potassium is >6.0 mmol/L: initiate acute hyperkalemia treatment per standard protocols before considering chlorthalidone 3
• Chlorthalidone actually helps lower potassium levels and can mitigate hyperkalemia risk when used with ACE inhibitors/ARBs or spironolactone 4

Evaluate volume status and concurrent medications:

• Check for dehydration, excessive diuresis, or gastrointestinal losses that could worsen renal function 3
• Review nephrotoxic drugs and potassium-altering agents 3

Evidence Supporting Chlorthalidone Use in Advanced CKD

The CLICK trial (2021) provides the strongest evidence for chlorthalidone in stage 4 CKD:

• 160 patients with mean eGFR 23.2 mL/min/1.73 m² and poorly controlled hypertension were randomized to chlorthalidone versus placebo 2
• Chlorthalidone reduced 24-hour ambulatory systolic BP by 10.5 mmHg (95% CI -14.6 to -6.4, P<0.001) at 12 weeks 2
• In the subgroup with treatment-resistant hypertension (71% of participants), the BP reduction was even greater at 13.9 mmHg 5
• Urinary albumin-to-creatinine ratio decreased by 50% compared to placebo 2

Guidelines explicitly support thiazide-like diuretics in advanced CKD:

• KDOQI (2019) states that thiazide diuretic treatment should NOT be automatically discontinued when eGFR decreases to <30 mL/min/1.73 m² 1
• Chlorthalidone is superior to hydrochlorothiazide in advanced CKD 1
• One study showed chlorthalidone reduced 24-hour ambulatory BP by 10.5 mmHg in patients with mean eGFR 26.8 mL/min/1.73 m² 1

Dosing Strategy

Start with chlorthalidone 12.5 mg once daily:

• Escalate dose every 4 weeks if needed, up to maximum 50 mg daily based on BP response 2
• This conservative approach was validated in the CLICK trial 2

Chlorthalidone can be combined with loop diuretics:

• 60% of CLICK trial participants were on loop diuretics at baseline 2
• Maximal diuretic effects occur when thiazide diuretics are combined with loop diuretics, but potassium levels require close monitoring 1

Monitoring Protocol

Check electrolytes and creatinine within 2-4 weeks of initiation:

• Earlier monitoring (within 1 week) is recommended for patients with baseline eGFR <30 mL/min/1.73 m² or potassium >4.5 mEq/L 6
• KDOQI recommends checking basic metabolic profile within 2-4 weeks after addition or titration of medications affecting electrolytes 1

Subsequent monitoring schedule:

• Recheck at 1 month, then 3 months, then every 6 months if stable 3, 7
• For patients with eGFR <30 mL/min/1.73 m², monitor every 1-3 months 1, 7
• After any dose increase, restart the monitoring cycle with labs at 2-4 weeks 7

Acceptable creatinine increases:

• Continue chlorthalidone if creatinine rise is ≤30% from baseline, as this is expected and acceptable 3, 6
• If creatinine rise is >30% within 4 weeks, reduce dose by 50% and recheck labs in 1 week 3

Common Adverse Effects and Management

Expected side effects from CLICK trial:

• Hypokalemia (more common than hyperkalemia with chlorthalidone) 2, 5
• Reversible increases in serum creatinine 2, 5
• Hyperglycemia 2, 5
• Dizziness and orthostatic hypotension 2, 5
• Hyperuricemia 2, 5

Key safety consideration:

• All adverse effects occurred more frequently in the chlorthalidone group but were manageable with close monitoring 2, 5
• Caution is especially advised when patients are already on loop diuretics 5

Clinical Context

Chlorthalidone addresses a critical gap in CKD hypertension management:

• Treatment-resistant hypertension is common in advanced CKD, affecting 71% of CLICK trial participants 5
• Spironolactone is typically recommended for resistant hypertension, but hyperkalemia risk limits its use in CKD 1, 4
• Chlorthalidone provides an alternative that actually lowers potassium, potentially enabling safer concomitant use of spironolactone or ACE inhibitors/ARBs 4

Bottom line: The elevated creatinine alone is not a contraindication to chlorthalidone in CKD. First correct the hyperkalemia (which chlorthalidone will help maintain at lower levels), then initiate chlorthalidone at 12.5 mg daily with close electrolyte monitoring within 1-2 weeks. 1, 3, 2