Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease

Background: Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease. Methods: We randomly assigned patients with stage 4 chronic kidney-disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed. Results: A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (+/- SD) estimated glomerular filtration rate was 23.2 +/- 4.2 ml per minute per 1.73 m(2) of body-surface area and the mean number of antihypertensive medications prescribed was 3.4 +/- 1.4. At randomization, the mean 24-hour ambulatory-systolic blood pressure was 142.6 +/- 8.1 mmHg in the chlorthalidone group and 140.1 +/- 8.1 mmHg in the placebo group and the mean 24-hour ambulatory-diastolic blood pressure was 74.6 +/- 10.1 mmHg and 72.8 +/- 9.3 mmHg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mmHg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mmHg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mmHg (95% CI, -14.6 to -6.4) (P < 0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and -hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group. Conclusions: Among patients with -advanced chronic kidney disease and poorly controlled hypertension, -chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; ClinicalTrials.gov number, NCT02841280).