Please summarize current evidence of chlorothalidone for hypertension in CKD since the CLICK trial.

Comment by InpharmD Researcher

Since the CLICK trial was published in 2021, the European Society of Hypertension (ESH) 2023 guidelines now formally recommend chlorthalidone as a potential add-on therapy for treatment-resistant hypertension in CKD patients. However, aside from the CLICK trial, there is a notable lack of follow-up studies with the majority focusing on secondary analyses from CLICK. One randomized controlled trial in older hypertensive patients found chlorthalidone to be similar to hydrochlorothiazide for CKD progression while another study found combination chlorthalidone with bumetanide to potentially be more effective in reducing volume overload than bumetanide alone.

Background

The guidelines from the 2025 American College of Cardiology/American Heart Association for hypertension and 2024 Kidney Disease: Improving Global Outcomes (KDIGO) for management of chronic kidney disease (CKD) notably do not discuss the use of chlorthalidone or thiazide diuretics for treatment of hypertension in CKD patients. However, the 2023 European Society of Hypertension (ESH) guidelines for managing arterial hypertension had included chlorthalidone as a preferred add-on treatment option in patients with CKD stage 4 and 5 (not on dialysis) who failed two previous regimens and present with true resistant hypertension. Supporting reviews also discuss the emergence of chlorthalidone as an option for hypertension in CKD, primarily because of the results from the CLICK trial. However, further follow-up studies appear limited as CLICK remains the primary source when recommending chlorthalidone for treatment. [1], [2], [3], [4], [5], [6]

A 2023 review assessed chlorthalidone for treatment-resistant hypertension in advanced CKD, summarizing the randomized, placebo-controlled CLICK trial and an additional secondary analysis of 113 patients with resistant hypertension within the trial. The CLICK trial randomized 160 patients with stage 4 CKD and uncontrolled hypertension to chlorthalidone or placebo and demonstrated a reduction in 24-hour systolic ambulatory blood pressure of 10.5 mmHg over 12 weeks. The secondary analysis further evaluated patients meeting criteria for treatment-resistant hypertension within this cohort and showed greater reductions in 24-hour systolic (−13.9 mmHg) and diastolic (−5.8 mmHg) ambulatory blood pressure, with effects observed during both daytime and nighttime periods. Urinary albumin-to-creatinine ratio decreased by approximately 54% at 12 weeks and remained reduced after discontinuation. Blood pressure reductions were evident within 4 weeks and sustained through 12 weeks, with most of the effect achieved at the lowest dose (12.5 mg daily). Reversible increases in serum creatinine occurred more frequently with chlorthalidone, particularly in patients receiving loop diuretics, along with higher rates of hypokalemia and other metabolic adverse effects. The authors concluded that chlorthalidone effectively reduces both systolic and diastolic 24-hour ambulatory blood pressure in patients with stage 4 CKD and resistant hypertension, independent of loop diuretic use. However, caution is advised when treating patients, particularly those receiving concomitant loop diuretics due to higher rates of reversible increases in serum creatinine. [7]

A 2022 analysis of the CLICK trial focused specifically on participants with resistant hypertension and stage 4 chronic kidney disease (CKD). Among 113 such patients (71% of the original cohort), chlorthalidone 12.5 mg daily reduced 24‑hour ambulatory systolic blood pressure by a placebo‑subtracted 13.9 mmHg (95% CI, −19.4 to −8.4; p<0.0001). This effect was rapid (81% achieved at 4 weeks) and persisted for at least 2 weeks after drug discontinuation, and it was independent of baseline loop diuretic use. Chlorthalidone also lowered the urine albumin‑to‑creatinine ratio by 54% compared with placebo (95% CI, −65% to −40%). While spironolactone is standard for resistant hypertension in the general population, its use in advanced CKD is limited by hyperkalemia risk. Chlorthalidone is suggested to offer an alternative with virtually no hyperkalemia but requires monitoring for hypokalemia, reversible creatinine increases (especially in patients on loop diuretics), hyperglycemia, dizziness, orthostatic hypotension, and hyperuricemia. The authors conclude that chlorthalidone is an attractive option for managing resistant hypertension in advanced CKD. [8]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Please summarize current evidence of chlorothalidone for hypertension in CKD since the CLICK trial.

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension
Design	Prespecified secondary analysis of the Diuretic Comparison Project, a randomized clinical trial N= 12,265
Objective	To compare kidney outcomes in patients with hypertension taking chlorthalidone and hydrochlorothiazide
Study Groups	Chlorthalidone (n= 6118) Hydrochlorothiazide (n= 6147)
Inclusion Criteria	Veterans 65 years or older with hypertension who were taking hydrochlorothiazide
Exclusion Criteria	No exclusion criteria related to kidney function
Methods	Participants were randomized to continue hydrochlorothiazide or switch to chlorthalidone at what were assumed to be pharmacologically comparable doses (eg, from 25mg/d of hydrochlorothiazide to 12.5 mg/d of chlorthalidone). Data were collected from Veterans Affairs facilities nationwide.
Duration	June 1, 2016, to December 31, 2023
Outcome Measures	CKD progression (doubling of serum creatinine, terminal eGFR <15 mL/min, or dialysis initiation)
Baseline Characteristics		Chlorthalidone group (n = 6118)	Hydrochlorothiazide group (n = 6147)
	Age, years	71 (69-75)	71 (69-75)
	BMI	31.1 (27.8-35.0)	31.2 (27.9-35.2)
	Female	198 (3.2%)	191 (3.1%)
	Black	915 (15.0%)	922 (15.0%)
	White	4745 (77.6%)	4773 (77.6%)
	Diabetes	2763 (45.2%)	2862 (46.6%)
	Heart failure	488 (8.0%)	487 (7.9%)
	eGFR, mL/min/1.73 m²	71.6 (68.9-84.4)	70.8 (58.7-84.8)
Results		Chlorthalidone group (n = 6118)	Hydrochlorothiazide group (n = 6147)	p-value
	CKD progression	369 (6.0%)	396 (6.4%)	0.37
	Incident CKD	961/4520 (21.3%)	939/4518 (20.8%)	0.59
	Hospitalization for acute kidney injury	391 (6.4%)	379 (6.2%)	0.63
	Hypokalemia	545 (8.9%)	426 (6.9%)	<0.001
Adverse Events	See Results
Study Author Conclusions	Chlorthalidone was not superior to hydrochlorothiazide for kidney outcomes but was associated with an increased risk for hypokalemia. Clinicians can use either agent for hypertension treatment.
Critique	The study's strengths include its large sample size and randomized design, which provide robust data on the comparative effectiveness of chlorthalidone and hydrochlorothiazide. However, the study's pragmatic nature and reliance on existing clinical data may limit the precision of outcome measurements. Additionally, the study population was predominantly male and older, which may affect the generalizability of the findings to other populations.

References:
[1] [1] Ishani A, Hau C, Raju S, et al. Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024;7(12):e2449576. Published 2024 Dec 2. doi:10.1001/jamanetworkopen.2024.49576

Mechanisms of Antihypertensive Effect of Chlorthalidone in Advanced Chronic Kidney Disease: A Causal Mediation Analysis
Design	Prespecified analysis of a randomized, placebo-controlled, double-blind trial N= 140
Objective	To explore the mechanisms underlying the antihypertensive effect of chlorthalidone (CTD) in patients with advanced chronic kidney disease (CKD)
Study Groups	CTD (n= 67) Placebo (n= 73)
Inclusion Criteria	Patients with stage 4 CKD (eGFR <30 ml/min per 1.73 m2 but ≥15 ml/min per 1.73 m2) and uncontrolled hypertension confirmed by 24-hour ambulatory BP monitoring
Exclusion Criteria	Patients with 24-hour ambulatory BP monitoring (ABPM) ≥160 mm Hg systolic or ≥100 mm Hg diastolic, recent stroke, myocardial infarction, or heart failure hospitalization, on high-dose loop diuretics, or using thiazide or thiazide-like diuretics in the previous 12 weeks
Methods	A prespecified analysis of the CLICK trial assessed mechanisms of chlorthalidone’s antihypertensive effect using causal mediation analysis. The analysis included 140 of 160 randomized patients with stage 4 CKD and uncontrolled hypertension who had paired ambulatory blood pressure measurements. Patients were randomized to chlorthalidone or placebo in a double-blind manner, stratified by loop diuretic use. Mediators evaluated included baseline 24-hour urinary sodium and aldosterone, and changes from baseline to 4 weeks in weight, total body volume, plasma renin, plasma aldosterone, aldosterone-to-renin ratio, and NT-proBNP. Linear regression models were used to estimate treatment effects on mediators and the association of mediators with change in 24-hour systolic ambulatory blood pressure, with calculation of direct, indirect, and total effects using bootstrap methods.
Duration	12 weeks
Outcome Measures	Primary: Change in 24-hour systolic ambulatory BP Other: Contributions of volume markers and renin-angiotensin-aldosterone system (RAAS) activation to BP reduction
Baseline Characteristics		Placebo (n= 72)	CTD (n= 67)	Total (N= 140)
	Age, years	67.3 ± 10.8	66.3 ± 11.3	66.9 ± 11
	Men	58 (79.5%)	51 (76.1%)	109 (77.9%)
	Black race	28 (38.4%)	27 (40.3%)	55 (39.3%)
	Antihypertensive medications	3.4 ± 1.5	3.4 ± 1.3	3.4 ± 1.4
	Using ACEi or ARB	40 (54.8%)	48 (71.6%)	88 (62.9%)
	Using loop diuretics	42 (57.5%)	42 (62.7%)	84 (60%)
	Using K-sparing diuretics	10 (13.7%)	3 (4.5%)	13 (9.3%)
	Systolic BP, mm Hg	138.1 ± 15.4	140.7 ± 15.1	139.3 ± 15.3
	Diastolic BP, mm Hg	67.2 ± 13.8	68.4 ± 12.3	67.8 ± 13.1
	eGFR, ml/min per 1.73 m2	22.9 ± 4.3	23.5 ± 4.1	23.2 ± 4.2
	Spot urine albumin-to-urine creatinine ratio, mg/g (IQR)	889 (96–1736)	449 (175–1972)	597 (140–1850)
	Urinary Na excretion, mEq/24 h (IQR)	109 (75–148)	135 (94–173)	122 (86–163)
	Urinary aldosterone excretion, mcg/24 h, median (IQR)	4.44 (2.47–6.41)	4.71 (2.91–6.47)	4.71 (2.73–6.46)
	Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; IQR, interquartile range.
Results	Decomposition of total 24-hour systolic BP change at 12 weeks into direct, indirect, and total effects and percent mediated	Indirect Effect	Direct Effect	Total Effect	Percent Mediation
	Weight, kg	−0.9 (−4.2 to 2.5)	−10 (−15.7 to −4.2)	−10.8 (−16 to −5.7)	8.1 (−22.4 to 38.5)
	Total body volume, L	−0.2 (−3.1 to 2.7)	−11 (−16.3 to −5.7)	−11.2 (−15.8 to −6.6)	1.7 (−24 to 27.3)
	Plasma renin concentration	−0.8 (−5 to 3.5)	−10 (−15.9 to −4)	−10.7 (−15 to −6.5)	7.1 (−32.3 to 46.5)
	Serum aldosterone concentration	0.5 (−1 to 1.9)	−11.2 (−16.1 to −6.4)	−10.8 (−15.3 to −6.2)	−4.5 (−17.9 to 8.9)
	Ratio of aldosterone to renin	0 (−0.7 to 0.6)	−10.8 (−15.4 to −6.2)	−10.8 (−15.4 to −6.2)	0.2 (−6 to 6.4)
	24-h urine aldosterone	−1.7 (−4.3 to 0.9)	−9.2 (−13.8 to −4.5)	−10.9 (−15.8 to −6)	15.8 (−6.7 to 38.3)
	24-h urine sodium	−0.3 (−1.3 to 0.6)	−10.3 (−15.1 to −5.6)	−10.6 (−15.2 to −6.1)	2.9 (−6.1 to 12)
	NT-proBNP	−0.9 (−2.2 to 0.3)	−10.4 (−15.4 to −5.4)	−11.3 (−16.3 to −6.4)	8.3 (−3.2 to 19.8)
	Abbreviations: NT-proBNP, N-terminal pro-B-type natriuretic peptide. Mediation variables were defined as log-transformed changes from baseline for each variable, adjusted for baseline levels, except for 24-hour urine sodium and aldosterone, where only baseline values were analyzed. Values reported in parentheses represent 95% confidence intervals (CIs). Both mediator and outcome models were adjusted for age, sex, race, use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, loop diuretic use, and potassium-sparing diuretic use. Missing data included weights (n= 3), volume (n= 7), and NT-proBNP (n= 20) at 4 weeks, and baseline 24-hour urine sodium (n= 3) and aldosterone (n= 5). At 4 weeks, chlorthalidone reduced weight and total body volume, increased plasma renin and aldosterone, and decreased NT-proBNP, with no change in the aldosterone-to-renin ratio. Despite these changes, mediation analysis showed that these markers contributed minimally to systolic blood pressure reduction, accounting for <2 mmHg of the approximately 11 mmHg total reduction, with all 95% confidence intervals crossing zero. Plasma renin and NT-proBNP accounted for 7% and 8% of the effect, respectively, and baseline urinary sodium and aldosterone were not associated with blood pressure change. Sensitivity analysis using principal component modeling showed an indirect effect of −0.3 mmHg (95% CI −3.4 to 2.8), accounting for 2.5% of the total effect.
Adverse Events	Not assessed
Study Author Conclusions	In conclusion, factors other than volume per se or stimulation of the renin-angiotensin system are therefore important in the BP-lowering effect seen among patients with advanced CKD. It is the response to volume depletion that is important. Therefore, we postulate that diuretic treatment in patients with advanced CKD either results in an increase in the production of vasodilators or mitigates the vasoconstrictor effects of circulating mediators, culminating in BP lowering.
Critique	The study provides valuable insights into the mechanisms of BP reduction with CTD in advanced CKD. However, the study is limited by its focus on a specific population with advanced CKD, which may not be generalizable to other stages of CKD or more diverse populations. The lack of statistical significance in some mediation effects suggests that larger studies may be needed to confirm these findings. Additionally, the study did not measure all biomarkers at 4 weeks, which could have provided more comprehensive insights into the mechanisms involved.

References:
[1] [1] Agarwal R, Sinha AD, Tu W. Mechanisms of Antihypertensive Effect of Chlorthalidone in Advanced Chronic Kidney Disease: A Causal Mediation Analysis. Clin J Am Soc Nephrol. 2024;19(8):1025-1032. doi:10.2215/CJN.0000000000000484

Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4–5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial
Design	Double-blind randomized study N= 32
Objective	To assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4–5 KDIGO
Study Groups	Bumetanide plus chlorthalidone (n= 16) Bumetanide plus placebo (n= 16)
Inclusion Criteria	Uncontrolled hypertension (SBP >140 mmHg and/or DBP >90 mmHg), volume overload, chronic loop diuretic use (at least three months), CKD stages 4 or 5 diagnosed at least three months previously, age between 18 and 75 years, signed informed consent
Exclusion Criteria	Contraindications for chlorthalidone use, pregnancy, breastfeeding, cognitive deterioration, NSAID use, acute heart failure, chronic liver failure, respiratory insufficiency, any cancer
Methods	Patients were randomized to receive either 3 mg bumetanide + 50 mg chlorthalidone or 3 mg bumetanide + placebo. Bumetanide was administered as 2 mg at 10 am and 1 mg at 4 pm, chlorthalidone at 50 mg at 12 pm. Dosage was escalated to 4 mg bumetanide + 100 mg chlorthalidone or bumetanide 4 mg + placebo if no contraindications were noted. Follow-up evaluations were conducted on Day 7 and Day 30.
Duration	June 18, 2019 to October 28, 2019
Outcome Measures	Primary: Differences in TBW, extracellular water (ECW), and ECW/TBW between baseline and Days 7 and 30 Secondary: Differences in systolic blood pressure (SBP), diastolic blood pressure (DBP)
Baseline Characteristics		Bumetanide plus chlorthalidone (n= 16)	Bumetanide plus placebo (n= 16)
	Age X ± SD (years)	54.8 ± 10	59.6 ± 8.1
	Gender Women (%)	10 (62.5)	12 (75)
	Weight X ± SD (kg)	74.6 ± 14.4	67.9 ± 10.1
	BMI X ± SD (kg/m2)	30.1 ± 4.9	28.1 ± 3.1
	CKD etiology - Diabetes (%)	11 (68.7)	11 (68.7)
	CKD etiology - Unknown (%)	4 (25)	3 (18.7)
	CKD etiology - Hypertension (%)	1 (6.3)	1 (6.3)
	CKD etiology - Others (%)	0 (0)	1 (6.3)
	Comorbidities - Hypertension (%)	16 (100)	16 (100)
	Comorbidities - Smoking (%)	7 (43.8)	8 (50)
	Comorbidities - Diabetes (%)	11 (68.8)	11 (68.8)
	Comorbidities - Lupus (%)	0 (0)	1 (6.3)
	TBW median ± range (liters)	32.7 (23.4–70.6)	33.1 (20–53.7)
	ECW median ± range (liters)	16.4 (12.8–35.7)	16.2 (10.7–25.8)
	ECW/TBW median ± range (%)	50 ± 3.6	50.9 ± 3.5
	SBP X ± DE (mmHg)	142 ± 22.6	146.8 ± 18.2
	DBP X ± DE (mmHg)	81 ± 10.9	77.8 ± 11.3
	MAP X ± DE (mmHg)	102.1 ± 10.9	100.6 ± 12.8
	Creatinine median, CI95% (mg/dL)	3.6 (1.8–16.6)	3.5 (1.9–15)
	Urea median, CI95% (mg/dL)	125 (57.9–244.9)	124(85.4–269)
	GFR median, CI95% (ml/min/1.73 m2)	16.52 ± 8.76	15.69 ± 7.64
	Serum sodium X ± DE (mEq/l)	137.4 ± 4.9	138.3 ± 4.3
	Serum potassium X ± DE (mEq/l)	5.3 ± 0.64	5.1 ± 0.74
	Serum bicarbonate X ± DE (mEq/l)	18.4 (14.2–23.7)	18.5 (14.1–24.6)
	Serum BNP median ± range (pg/mL)	67.1 (10–960)	112(24.7–424-6)
	Serum uric acid median ± range (mg/dL)	6.6 (3.1–14.1)	7.3 (3.6–11.6)
	Serum albumin median ± range (g/L)	3.8 (1.78–4.4)	3.8 (2.9–5)
	Urinary Sodium X ± SD (mEq/l)	62.7 ± 20.6	64.7 ± 23.4
	Urinary Chlorine X ± SD (mEq/l)	62.3 ± 18.6	60.2 ± 27.4
	Fraction of sodium excreted, median ± range (%)	3.6 (1.4–8.42)	4.8 (0.9–17.9)
	24-h Urine Volume X ± SD (ml)	1832 ± 729	1646 ± 673
	Antihypertensive Drugs - ACE-Inhibitor (%)	2 (12.5)	4 (25)
	Antihypertensive Drugs - ARB (%)	11 (68.75)	12 (75)
	Antihypertensive Drugs - Alfa Blocker (%)	5 (31.25)	4 (25)
	Antihypertensive Drugs - Beta Blocker (%)	6 (37.5)	5 (31.25)
	Antihypertensive Drugs - Calcium Channel Blocker (%)	14 (87.5)	12 (75)
	Number antihypertensive Drugs - 1 (%)	0 (0)	1 (6.3)
	Number antihypertensive Drugs - 2 (%)	6 (37.5)	4 (25)
	Number antihypertensive Drugs - ≥3 (%)	10 (62.5)	11 (68.7)
	Type of loop diuretic - Furosemide (%)	14 (87.5)	16 (100)
	Type of loop diuretic - Bumetanide (%)	2 (12.5)	0 (0)
	Time on loop diuretic (median ± range) (months)	9 (2–60)	15 (2–36)
Results		Bumetanide plus chlorthalidone (n= 16)	Bumetanide plus placebo (n= 16)	p-value
	Change in TBW on Day 7 (liters)	-2.5	-0.59	0.003
	Change in TBW on Day 30 (liters)	-5.3	-0.07	0.016
	Change in ECW on Day 7 (liters)	-1.58	-0.43	<0.001
	Change in ECW on Day 30 (liters)	-3.05	-0.15	<0.000
	Change in SBP on Day 7 (mmHg)	-18	-7.5	0.073
	Change in SBP on Day 30 (mmHg)	-26.1	-10	0.028
	Change in DBP on Day 7 (mmHg)	-8.5	-2.25	0.059
	Change in DBP on Day 30 (mmHg)	-13.5	-3.4	0.018
Adverse Events	Increased creatinine levels were more common in the intervention group (68.75%) compared to the control group (25%). Other adverse events included hyponatremia (6% vs. 12%), hypokalemia (0% vs. 12%), and hyperuricemia (25% in both groups). One cardiovascular event occurred in the intervention group
Study Author Conclusions	In CKD stage 4–5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.
Critique	The study demonstrated significant efficacy of the combination therapy in reducing volume overload and blood pressure. However, the small sample size and short follow-up period limit the generalizability of the findings. Additionally, the study was conducted at a single center, which may affect the applicability of the results to broader populations. The lack of long-term safety data is also a limitation.

References:
[1] Solis-Jimenez F, Perez-Navarro LM, Cabrera-Barron R, et al. Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial. BMC Nephrol. 2022;23(1):316. Published 2022 Sep 20. doi:10.1186/s12882-022-02930-4