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.

Inclusion criteria

• Study is limited to US Veterans
• GFR estimated by race-independent CKD-EPI formula < 45 ml/min/1.73m2 but 15 mL/min/1.73m2
• Hypertension

• The investigators will use clinic AOBP of at least 135/85 to define hypertension
• Treatment with antihypertensive drugs

• This would require the use of at least one antihypertensive drug
• One of the drugs should be either an ACE inhibitor or ARB or a beta-blocker at the time of randomization
• Serum K 3.5 to 5.2 mEq/L at the time of randomization

Exclusion criteria

• Clinic AOBP of >=160/100 mmHg
• Use of:

• SPL
• eplerenone
• amiloride
• triamterene
• finerenone
• thiazide
• thiazide-like drugs (CTD, HCTZ, metolazone, indapamide) or the use of K binders or fludrocortisone in the previous 4 weeks
• K supplementation would be allowed
• Myocardial infarction, heart failure hospitalization, or stroke 8 weeks prior to randomization
• If the patient is only on an alpha blocker, as the sole antihypertensive drug, they will be excluded
• Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception
• Known hypersensitivity or a prior documented adverse reaction to CTD or SPL