The investigators plan to assess the efficacy of standard and low dose HCTZ treatment in the recurrence prevention of calcium-containing kidney stones. More specifically, the investigators aim to assess the dose-response relationship for three different dosages of HCTZ.

Study intervention: HCTZ 12.5 mg, 25 mg or 50 mg once daily per os for 24 or 36 months. In addition, all patients in HCTZ treatment arms will receive state-of-the-art non-pharmacologic recommendations for stone prevention according to current guidelines.

Control intervention: Placebo once daily per os for 24 to 36 months. In addition, all patients in the placebo arm will receive state-of-the-art non-pharmacologic recommendations for stone prevention according to current guidelines.

Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Without specific treatment, 5- and 20-year recurrence rates are 40% and 75%, respectively. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach.

About 80-90% of stones are composed of calcium oxalate with various admixtures of calcium phosphate. Increased excretion of calcium in the urine, hypercalciuria, is the most common metabolic abnormality encountered in patients with recurrent nephrolithiasis. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. The effect of thiazides to reduce the risk of stone recurrence has been attributed to their ability to decrease urinary calcium excretion. However, other factors, such as reduction of urinary pH and urinary oxalate excretion, probably contribute to this effect. Efficacy of thiazides on recurrence prevention of calcareous nephrolithiasis was tested in 11 randomized controlled trials (RCTs). With the exception of two trials, thiazides significantly reduced stone recurrence. Most of these trials are from the 1980's and 90's and the cumulative number of patients studied is remarkably low for such a prevalent disease. Our systematic review of these RCTs revealed major methodological deficiencies in all trials, including: lack of double-blinding and intention-to-treat analysis, unclear allocation concealment, lack of adverse event and drop out reporting and unknown baseline risk of disease severity. Furthermore, high doses of thiazides were employed in all trials, in the case of the best studied thiazide, hydrochlorothiazide (HCTZ), up to 100 mg daily. At such high doses, side effects occur frequently. Nowadays, thiazides are widely used in the treatment of recurrent nephrolithiasis and arterial hypertension, but at significantly lower doses. In the case of recurrent nephrolithiasis, however, this practice is not supported by randomized evidence and consequently, the investigators do not know whether the currently employed low dose thiazide regimens are effective in reducing the risk for stone recurrence.

Thus, evidence for benefits and harms of thiazide diuretics in the prevention of calcium-containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known.

Inclusion Criteria:

1. Informed Consent as documented by signature
2. Age 18 years or older
3. Recurrent kidney stone disease (≥ 2 stone events within the last 10 years prior to randomization)
4. Any past kidney stone containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both

Exclusion Criteria:

1. Pharmacologic prevention for stone recurrence less than 3 months prior to randomization

2. Patients with secondary causes of recurrent calcareous nephrolithiasis including:

   • Severe eating disorders (anorexia or bulimia)
   • Chronic inflammatory bowel disease, bariatric surgery, intestinal surgery with malabsorption or chronic diarrheal status
   • Sarcoidosis
   • Primary hyperparathyroidism
   • Complete distal tubular acidosis
   • Active malignancy

3. Patients with the following medications:

   • Thiazide or loop diuretics
   • Carbonic anhydrase inhibitors (including topiramate)
   • Xanthine oxidase inhibitors (febuxostat or allopurinol)
   • Alkali, including potassium citrate or sodium bicarbonate
   • Treatment with 1,25-OH Vitamin D (calcitriol)
   • Calcium supplementation
   • Bisphosphonates
   • Denosumab
   • Teriparatide
   • Glucocorticoids

4. Obstructive uropathy, if not treated successfully

5. Urinary tract infection, if not treated successfully

6. Chronic kidney disease (defined as CKD-EPI eGFR < 30 mL/min per 1,73 m2 body surface area for more than 3 months)

7. Patients with a kidney transplant

8. > 3 gout arthritis episodes within one year prior to randomisation or gout arthritis requiring uric acid lowering therapy

9. Cystinuria at screening

10. Hypokalemia (blood potassium level < 3 mmol/L) at screening

11. Hyponatremia (blood sodium level < 125 mmol/L) at screening

12. Pregnant and lactating women [pregnancy test to be performed for women of child-bearing potential (defined as women who are not surgically sterilized/ hysterectomized, and/ or who are postmenopausal for less than 12 months)]

13. Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial

14. Inability to understand and follow the protocol

15. Known allergy to the study drug