Diuretic, too, lowers BP in advanced kidney disease

The thiazide diuretic chlorthalidone significantly reduces systolic blood pressure (SBP) by an average of 10 mm Hg in patients with refractory hypertension and advanced chronic kidney disease (CKD), reveals the CLICK* study presented at ASN 2021 — thus debunking the conventional belief that thiazide diuretics do not work in patients with advanced CKD.

Available as a generic drug at just a few cents a day, chlorthalidone presents “a potential low-cost solution for the treatment of hypertension” in patients with advanced CKD, pointed out lead author Dr Rajiv Agarwal of Indiana University School of Medicine in Indianapolis, Indiana, US.

The double-blind study involved 160 patients (mean age 66 years, 78 percent male, 76 percent with diabetes) with stage 4 CKD who had poorly controlled hypertension despite treatment with an average of 3.4 antihypertensive medications at baseline. They were randomized 1:1 to receive chlorthalidone (initial dose of 12.5 mg/day, titrated every 4 weeks to a maximum dose of 50 mg/day, if needed) or placebo. [N Engl J Med 2021;doi:10.1056/NEJMoa2110730]

At 12 weeks, the primary outcome of 24-hour ambulatory SBP was reduced by 11.0 mm Hg from baseline in the chlorthalidone group compared with a nonsignificant reduction of 0.5 mm Hg from baseline in the placebo group (between-group difference, −10.5 mm Hg; p<0.001).

The corresponding difference between groups for diastolic BP was −3.9 mm Hg, in favour of chlorthalidone (95 percent confidence interval [CI], −6.3 to −1.5).

In addition, chlorthalidone also led to a larger drop in proteinuria than placebo, as indicated by percentage change in urinary albumin-to-creatinine ratio (UACR) as soon as within 4 weeks of initiating treatment, which persisted through week 12 (−52 percent vs −4 percent).

“The persistent reduction in the degree of albuminuria with the use of chlorthalidone suggests that the drug has the potential to provide cardiovascular and kidney protection in patients with chronic kidney disease,” said Agarwal and co-authors.

There were also reductions in the secondary endpoints of body volume, body weight, and NT-proBNP levels, while plasma renin and aldosterone levels increased within 4 weeks of treatment initiation.

“[This] suggest that the mechanism of BP reduction is consistent with the changes in effective arterial blood volume over time,” explained the researchers.

Nonetheless, Agarwal cautioned that clinicians should monitor patients for complications as chlorthalidone is a very potent drug.

"[It] is not an agent to prescribe and forget,” he said. “Chlorthalidone should be used with caution in patients receiving loop diuretics, especially because of the risk of an increase in the serum creatinine level.”

Hypokalaemia, hyperglycaemia, hyperuricaemia, reversible increases in serum creatinine, and dizziness were more common in the chlorthalidone arm than the placebo arm — although these were nothing surprising, according to experts.

“The lowest dose of chlorthalidone produced most of the BP-lowering effect, and this might be the safest dose to use,” suggested Agarwal and co-authors.

The main limitations of the trial were the relatively small population in which women and patients of Asian or Hispanic origin were underrepresented.

*CLICK: Chlorthalidone in Chronic Kidney Disease