Management of Hypertension in Advanced Kidney Disease

Panagiotis I. Georgianos; Rajiv Agarwal


Curr Opin Nephrol Hypertens. 2022;31(4):374-379. 

In This Article

Chlorthalidone for Poorly Controlled Hypertension in Advanced Chronic Kidney Disease

International guidelines recommend the use of thiazide diuretics for the treatment of hypertension in patients with eGFR at least 30 ml/min/1.73 m2.[33] For those with more advanced CKD, most guidelines recommend the use of loop diuretics, because thiazide/thiazide-like diuretics are considered much less effective or ineffective when eGFR is reduced to levels less than 30 ml/min/1.73 m2.[1,13,34] However, in 2014, a pilot, single-arm interventional study enrolling 12 patients with eGFR of 20–45 ml/min/1.73 m2 and uncontrolled hypertension showed that the addition of the long-acting thiazide-like diuretic chlorthalidone (at a starting dose of 25 mg/day) to the background antihypertensive regimen was accompanied by a clinically meaningful reduction of 10.5/3.1 mmHg in 24-h ambulatory BP.[35] These provocative data provided the rationale for the design of CLICK (Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease), a larger phase 2 clinical trial aiming to investigate whether chlorthalidone is an effective BP-lowering medication in patients with advanced CKD.[36]

In CLICK, 160 patients with eGFR of at least 15 to less than 30 ml/min/1.73 m2 and uncontrolled hypertension, as confirmed by the 'gold-standard' method of 24-h ambulatory BP monitoring, were randomly assigned in a 1 : 1 ratio to chlorthalidone (at a starting dose of 12.5 mg/day) or placebo.[37] Over 12 weeks of follow-up, chlorthalidone provoked a placebo-subtracted change of -10.5 mmHg (95% CI: -14.6 to -6.4) in 24-h SBP and a change of -3.9 mmHg (95% CI: -6.3 to -1.5) in 24-h DBP.[37] Improvement in hypervolemia was the predominant mechanism that mediated the BP-lowering action of chlorthalidone. The treatment-induced reduction in ambulatory BP was accompanied by a parallel decrease in body weight, body volume and N-terminal pro-brain natriuretic peptide levels. Furthermore, chlorthalidone lowered (95% CI: 37--60) the urinary albumin-to-creatinine ratio by 50% as compared with placebo, preliminary evidence that this agent may offer cardiorenal protection.[37]

The impressive benefits of chlorthalidone on ambulatory BP and albuminuria in CLICK challenge the current 'dogma' that thiazide-like diuretics are generally ineffective and should not be used when the levels of eGFR are less than 30 ml/min/1.73 m2. However, treatment with chlorthalidone in patients with advanced CKD should be sensible and with careful monitoring of the patients for the prevention of side effects.[38] Over the course of CLICK trial,[37] hypokalaemia, hyperglycaemia, hyperuricemia, dizziness and reversible increases in serum creatinine levels were adverse events that occurred more commonly with chlorthalidone than with placebo. Incidence of these adverse events may be even higher in daily clinical practice, if treatment with chlorthalidone is more aggressive (i.e. with higher doses than those used in CLICK).[38] Notably, treatment with a higher dose of chlorthalidone may aggravate the risk for adverse events without any clinically meaningful benefit on BP control. In CLICK,[37] most of the BP-lowering action of chlorthalidone was exerted over the first 4 weeks of therapy, when the study drug was administered at the initial dose of 12.5 mg/day. Furthermore, the risk for adverse effects, particularly the risk for a reversible increase in serum creatinine, appeared to be higher in the subgroup of patients who were concomitantly receiving therapy with a loop diuretic.[38] In such patients, a lower dose of chlorthalidone (i.e. 12.5 mg three times per week) may be similarly effective but safer than the starting dose of 12.5 mg/day that was used in CLICK.[37]