Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial

Abstract

BackgroundNephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. 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. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides 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.MethodsThe NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) 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). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo.The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response.DiscussionThe NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support.Trial registrationClinicalTrials.gov, NCT03057431. Registered on February 20 2017.

Impact of the SGLT2 inhibitor empagliflozin on urinary supersaturations in kidney stone formers (SWEETSTONE trial): protocol for a randomised, double-blind, placebo-controlled cross-over trial

“…Stone event rates in these pooled empagliflozin trials were similar to what has been observed in the general population in individuals with diabetes in three large prospective US cohorts (Nurses’ Health Study I, the Nurses’ Health Study II and the Health Professionals Follow-up Study) 16. RCTs testing dietary or pharmacologic measures for recurrence prevention typically included patients with stone event rates between 20 and 200 events/100 person-years 33 34. Hence, if recurrence prevention of kidney stones by SGLT2 inhibitors will indeed prove effective and safe, individuals with high rates of stone formation would especially benefit from treatment.…”

Efficacy of Obcordata A from Aspidopterys obcordata on Kidney Stones by Inhibiting NOX4 Expression

“…The sequence of events that triggers stone formation comprises of nucleation, growth, aggregation, and retention of crystals in the kidneys. Reportedly, controlling crystal-cell retentions is one of the best ways to treat urolithiasis [9]. Of note, NOX4 is a transmembrane transporter that transports electrons out of the serosa to produce superoxide and other reactive oxygen species (ROS).…”

Thiazide and thiazide-like diuretics in nephrolithiasis

“…Nowadays, lower doses of thiazides are often employed aiming to reduce metabolic adverse effects, but their efficacy as such is not well established 3,21,33 . In order to clarify these unsolved questions, a 3-year prospective double-blind ongoing trial was initiated in 2017 with the purpose of assessing the efficacy of standard and low dose HCTZ in the recurrence prevention of calcium stone formation 34 . Notwithstanding the evidence of lower stone recurrence on thiazides compared to placebo, it is worth mentioning that most of the aforementioned studies had been conducted along the 1980s and 1990s.…”