Diuretic Bolstered Blood Pressure Control in Advanced CKD

Chlorthalidone therapy was effective at improving blood pressure control in patients with hypertension and stage IV chronic kidney disease (CKD), the CLICK study found.

In a randomized trial of 160 patients, those on a maximum daily dose of 50 mg of chlorthalidone had an average drop in systolic blood pressure of 11 mm Hg (95% CI -13.9 to -8.1) from baseline to week 12, reported Rajiv Agarwal, MD, of Indiana University School of Medicine in Indianapolis, and colleagues.

In comparison, those on placebo saw only a modest change of 0.5 mm Hg (95% CI -3.5 to 2.5) in 24-hour systolic blood pressure from baseline, equating to a significant 10.5 mm Hg (95% CI -14.6 to -6.4, P<0.001) between-group difference -- meeting the study's primary endpoint.

The findings were presented at the American Society of Nephrology's virtual Kidney Week and simultaneously published in the New England Journal of Medicine.

As for one of the secondary outcomes, the percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower by 50% (95% CI -60% to -37%) for patients on chlorthalidone versus placebo. This reduction was "a magnitude that was large and a pleasant surprise," Agarwal told MedPage Today.

"This magnitude of reduction suggests that the drug may produce cardiorenal protection in the long term," he explained.

And 2 weeks after the treatment regimen was discontinued, this benefit seemed to slowly dissipate as the percent change in the urinary albumin-to-creatinine ratio was then only 34% (95% CI -48% to -16%) lower in the chlorthalidone group, the researchers reported.

In another secondary endpoint, the percent change in N-terminal pro–B-type natriuretic peptide level was 21% (95% CI -35% to -4%) lower in the chlorthalidone group versus placebo by week 12.

Regarding changes in plasma renin and aldosterone levels, these changes were consistent with the changes in body volume over time in the chlorthalidone group -- decreasing during treatment and increasing after treatment discontinuation, the team noted. Total body volume changes were also consistent with the diuretic effect of chlorthalidone.

For the Chlorthalidone in Chronic Kidney Disease (CLICK) trial, a total of 160 patients were randomized in a 1:1 fashion. All participants had stage IV chronic kidney disease (an estimated glomerular filtration rate (eGFR) of 15 to <30 mL/min/1.73 m²) paired with poorly controlled hypertension, which was confirmed with 24-hour ambulatory blood-pressure monitoring defined as a systolic blood pressure of 130 mm Hg or higher or diastolic of 80 mm Hg or higher while on at least one antihypertensive drug.

Among the cohort, 121 patients (76%) also had comorbid diabetes -- more than half for whom diabetes was the cause of their CKD -- and 96 (60%) were receiving loop diuretics. To be included in the study, participants needed to be receiving an angiotensin-converting-enzyme inhibitor, an angiotensin-receptor blocker, or a beta-blocker at the time of randomization.

The average age of those in the cohort was around 66 and more than 75% were male; about 60% were white and 40% were Black.

At baseline, the average 24-h systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group, and average diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively.

Among those randomized to receive chlorthalidone, the average daily dose was 11.5 mg at 4 weeks after, 18.3 mg/day at 8 weeks, and 23.1 mg/day at 12 weeks. Overall, the chlorthalidone group received a median cumulative dose of 1,063 mg during the trial.

As would be expected, reports of hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia were all more frequently reported among those on chlorthalidone, the researchers reported. Adverse events led to four patients on chlorthalidone and one patient on placebo discontinuing treatment.

Regarding eGFR, the mean change from baseline was 2.2 mL/min/1.73 m² (95% CI -3.3 to -1.0) lower in the treatment group compared with placebo at week 12. However, this was remedied after chlorthalidone discontinuation, with a between-group difference of only 0.2 mL/min/1.73 m² (95% CI -1.0 to 1.4) 2 weeks after discontinuation.

"In patients who are treated with chlorthalidone -- particularly those also on loop diuretics -- there may be reversible reductions in GFR," Agarwal said. "To mitigate this risk, lowering the dose of loop diuretics or using chlorthalidone 12.5 mg three times a week would be a reasonable strategy."

"Accordingly, monitoring electrolytes, blood pressure, and kidney function a few weeks after starting chlorthalidone would be prudent," he advised, adding that "clinicians may be appropriately concerned about declines in GFR in patients with advanced CKD."

However, he highlighted that his group didn't find any evidence that the use of chlorthalidone was associated with kidney replacement therapy or death.

The researchers ultimately concluded that chlorthalidone "should be used with caution in patients receiving loop diuretics, especially because of the risk of an increase in the serum creatinine level," and that the "lowest dose of chlorthalidone produced most of the blood-pressure-lowering effect, and this might be the safest dose to use."

The investigators also suggested that a reduction in the dose of the loop diuretic might be necessary.

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