Thiazide diuretics are back in CKD: the case of chlorthalidone

Abstract

Sodium and volume excess is the fundamental risk factor underlying hypertension in CKD patients that represent the prototypical population characterized by salt-sensitive hypertension. Low salt diets and diuretics constitute the centrepiece for blood pressure control in CKD. In patients with CKD stage 4, loop diuretics are generally preferred to thiazides. Furthermore, thiazide diuretics have long been held as being of limited efficacy in this population. In this review, by systematically appraising published randomized trials of thiazides in CKD, we show that this class of drugs may be useful even among people with advanced CKD. Thiazides cause a negative sodium balance and reduce body fluids by 1-2 L within the first 2-4 weeks and these effects go along with improvement in hypertension control. The recent CLICK trial has documented the antihypertensive efficacy of chlorthalidone, a long-acting thiazide-like diuretic, in stage 4 CKD patients with poorly controlled hypertension. Overall, chlorthalidone use could be considered in patients with treatment-resistant hypertension when spironolactone cannot be administered or must be withdrawn due to side effects. Hyponatremia, hypokalaemia, volume depletion, and acute kidney injury are side effects that demand a vigilant attitude by physicians prescribing these drugs. Well-powered randomized trials assessing hard outcomes are still necessary for more confidently recommending the use of these drugs in advanced CKD.

Combining loop and thiazide diuretics for acute heart failure across the estimated glomerular filtration rate spectrum: A post‐hoc analysis of the CLOROTIC trial

“…But not all thiazide or thiazide-like diuretics have the same pharmacological properties and efficacy. 17 All yield a similar effect by blocking the sodium-chloride co-transporter in the distal convoluted tubule, but they differ in terms of half-lives and off-target effects. 7,18 For this reason, in the authors' opinion, the efficacy and safety results of the CLOROTIC trial with HCTZ cannot be extrapolated to other thiazide diuretics with longer half-lives (e.g.…”

“…Recent trials have renewed interest in thiazides for controlling volume overload and hypertension in all chronic kidney disease stages, including severe and end‐stage disease (IV and V). But not all thiazide or thiazide‐like diuretics have the same pharmacological properties and efficacy 17 . All yield a similar effect by blocking the sodium–chloride co‐transporter in the distal convoluted tubule, but they differ in terms of half‐lives and off‐target effects 7,18 .…”

Thiazides in chronic kidney disease: “back to the future”

“…Despite the promising antihypertensive effect of chlorthalidone in advanced CKD, several issues should be evaluated in further studies. First, larger studies comparing the long-term antihypertensive and kidney effects among different thiazides and other widely used diuretics and antihypertensive agents in the whole spectrum of CKD patients are warranted [ 5 ].…”

“…As Minutolo et al [ 5 ] stated, thiazides may increase the risk of electrolytes disturbances (i.e. hypokalaemia, hyponatremia, hypomagnesemia), GFR decline and/or metabolic abnormalities (impaired glucose tolerance, hyperuricemia, acid-based alterations) in a dose-dependent manner.…”

“…Nonetheless, there is general reluctance to use these agents in patients with advanced chronic kidney disease (CKD) because of concerns about their efficacy and safety as kidney function declines. In this issue of Clinical Kidney Journal , Minutolo et al [ 5 ] elegantly reviewed published randomized trials to date of thiazides in this specific population, with a special focus on the Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease trial (CLICK) [ 6 ]. Based on the current literature, the authors conclude that thiazides may be useful among people with advanced CKD.…”