LOw DosE Spironolactone, chlorThAlidone oR Combination in CKD Trial

Highly prevalent among patients with chronic kidney disease (CKD) , poor blood pressure (BP) control is a modifiable risk factor for both kidney failure progression and cardiovascular (CV) disease. Although the mineralocorticoid receptor antagonist (MRA) spironolactone (SPL) is recommended to treat resistant hypertension in patients with CKD, 34% discontinue SPL within 12 weeks, mostly due to hyperkalemia. The potassium (K) binding agent patiromer reduced the discontinuation rate to 14%, but the added expense and potential drug interactions are of concern. SPL, a steroidal MRA, reduces albuminuria and rates of decline in eGFR. In type 2 diabetes and CKD, the non-steroidal MRA finerenone reduces kidney failure and CV outcomes but is not indicated for the treatment of hypertension. Due to concern of hyperkalemia, SPL is barely prescribed in these patients. In 2021, the investigators reported that chlorthalidone (CTD) in people with advanced CKD was effective in lowering BP and albuminuria by 50%. However, reversible changes in kidney function and hypokalemia were common. The investigators believe that a very low dose combination strategy of CTD + SPL will be effective in lowering BP, maintaining K, and providing target organ protection. However, the optimal dose to maintain K and lower BP remains unclear. To test this hypothesis, the investigators propose a pilot proof-of-concept study (phase 2A) followed by a larger phase 2B study. Proof of Concept, phase 2A: To test the hypothesis that low or very low dose CTD combined with SPL will improve BP, the investigators will perform a pilot, single-center, placebo-controlled, double-blind, randomized trial among patients with CKD and poorly controlled hypertension. After a two-week, patient-blind, placebo run-in, the investigators will randomize 50 hypertensive people to one of 4 groups in equal numbers: placebo; CTD very low dose; SPL very low dose QD; or a combination of CTD very low dose + SPL very low dose for 6 weeks. At 6 weeks, doses will be doubled for a further 6 weeks. The primary endpoint will be assessed by change from baseline to 6 weeks and 12 weeks in systolic AOBP and serum K for the combination group compared to placebo. If CTD + SPL is more effective than placebo, the investigators will perform the phase 2B trial. In this trial, the investigators will test the hypothesis that among patients with moderate to advanced CKD and poorly controlled hypertension, compared to add-on SPL or add-on CTD, treatment over 12 weeks with add-on combination of spironolactone (SPL) and chlorthalidone (CTD) will more effectively lower unattended systolic automated office blood pressure (uAOBP). Furthermore, combination therapy will reduce albuminuria more than either drug alone providing evidence for target organ protection. CTD will produce these effects by further reducing extracellular fluid volume in combination with SPL.

• Mediation of BP lowering by volume markers [Time frame: 12 weeks]