Indapamide and Chlorthalidone to Reduce Urine Supersaturation for Kidney Stone Prevention

Background and Rationale:

Kidney stones are the most common condition affecting the kidney. Both prevalence and incidence are increasing rapidly, driven by global warming, urbanization, dietary habits and occupational changes. Kidney stones are highly recurrent, associated with increased mortality, significant morbidity and reduced quality of life, and result in enormous health care expenditures. Hence, effective preventive measures are an undisputed medical need. Thiazide and thiazide-like diuretics ("thiazides") have been the cornerstone of pharmacologic recurrence prevention since \>50 years. The NOSTONE trial (NCT03057431), the only state-of-the-art trial ever performed for pharmacologic recurrence prevention, recently revealed that the most widely prescribed and best studied thiazide, hydrochlorothiazide, is not effectively preventing kidney stone recurrence. If these results also apply to the two more potent and long-acting thiazide-like diuretics indapamide and chlorthalidone is currently unknown. No head-to-head comparison of different thiazides for prevention of kidney stone recurrence has ever been performed. Thus, the role of thiazides in the prevention of kidney stone recurrence remains unclear. This poses the urgent need for a clinical trial that addresses this critical knowledge gap.

Objective:

The investigators plan to conduct a single-center, prospective, randomized, double-blind, crossover trial (INDAPACHLOR) to assess if indapamide and chlorthalidone are superior to hydrochlorothiazide in reducing urine supersaturations of calcium oxalate and calcium phosphate, the two best validated biochemical indicators of kidney stone recurrence risk.

Methodology:

Patients will be allocated to indapamide 2.5 mg once daily, chlorthalidone 25 mg once daily and hydrochlorothiazide 50 mg once daily in a random sequence. The three consecutive active treatment periods of 4 weeks each will be separated by wash-out periods of 4 weeks. The investigators will include 99 adult (\>18 years old) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium-containing kidney stones (containing ≥ 50% of calcium oxalate, calcium phosphate or a mixture of both). All patients will receive a state-of-the art concomitant non-pharmacologic intervention to prevent stone recurrence according to current guidelines. The primary outcome will be reduction of urine supersaturations of calcium oxalate and calcium phosphate at 4 weeks with indapamide or chlorthalidone compared to hydrochlorothiazide. Secondary outcomes will be changes in 24-hour urine and blood parameters, ambulatory blood pressure and adverse events elicited by indapamide or chlorthalidone compared to hydrochlorothiazide. In an exploratory outcome, the abundance of the thiazide target, the sodium/chloride co-transporter, will be analyzed in urinary extracellular vesicles at 4 weeks.

Expected significance:

INDAPACHLOR will provide long-sought evidence on the comparative efficacy of commonly used thiazides in lowering urine supersaturations and is thus expected to have a strong guideline-changing impact, which will transform patient care for this very common disease.

• Blood sodium level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood potassium level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood chloride level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood calcium level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood magnesium level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood phosphate level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Venous bicarbonate level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Venous pH change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Venous pCO2 change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood glucose level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood creatinine level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]
• Blood urea level change from baseline [Time frame: Data collected at baseline and at day 28 of each active treatment phase]