It is estimated that in the United States there are approximately 8 million individuals who have moderate to severe chronic kidney disease (CKD). Among them hypertension is common and is often poorly controlled due to an expanded volume state; diuretics are frequently prescribed. Loop diuretics are potent and effective in lowering blood pressure (BP) but their use is associated with acute kidney injury. Thiazide diuretics, on the other hand, are less potent, their use may be associated with less acute kidney injury, but as yet there are no firm data to support that thiazide diuretic therapy can improve BP among subjects with advanced CKD. We found 13 studies on the use of thiazide diuretics in advanced CKD either alone or in combination with loop diuretics and concluded that thiazides may be useful. Thiazides cause a negative Na balance, increase Na excretion by 10-15% and weight loss by 1-2 kg in observational studies. Observational data show that thiazides lead to an improvement in seated clinic BP of about 10-15 mmHg systolic and 5-10 mmHg diastolic whereas randomized trials show about a 15 mmHg reduction in mean BP. Randomized trials had only between 7 and 23 subjects each; accordingly, larger studies are needed to evaluate their safety and efficacy in moderate to advanced CKD. We hypothesize that among subjects with severe CKD, the thiazide-like diuretic, chlorthalidone will result in improved 24-hour ambulatory BP. Furthermore, chlorthalidone will improve albuminuria over 12 weeks providing evidence for target organ protection. Cholrthalidone will produce these effects by shrinking the extracellular fluid volume. We choose chlorthalidone because it is 3x more potent as a diuretic compared to hydrochlorothiazide but it is about a tenth of the price of metolazone. Our preliminary studies show that BP can be improved with the use of chlorthalidone among subjects with moderate to advanced CKD. Preliminary data support each of the specific aims contained in the application. Our study is innovative because it will further our understanding of the role of excess volume in the pathogenesis of hypertension in CKD. Furthermore, evaluation of albuminuria will provide surrogate evidence for target-organ protection. Our study is significant because it will provide evidence for the specific role of thiazide diuretics in the management of hypertension in those with advanced CKD. The results will help support the use of a low-cost, but potentially effective, abandoned antihypertensive drug in the management of individuals with advanced CKD. The wider use of this therapy may improve the dismal control rates of hypertension in people with CKD.

Public Health Relevance

This double-blind, two-center, placebo-controlled, randomized trial will test the hypothesis that chlorthalidone will improve BP among subjects with advanced CKD and poorly controlled hypertension. The results of this trial will allow the safe and effective use of chlorthalidone among people with CKD and hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Einhorn, Paula
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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