Project

Secondary prevention; Hydrochlorothiazide; Nephrolithiasis; Dose response; Thiazide; Hypercalciuria

Lead
In dieser klinischen Studie wird die Wirksamkeit des Medikaments Hydrochlorothiazid zur Vorbeugung von Rückfällen kalziumhaltiger Nierensteine getestet.
Lay summary
Inhalt und Ziele des Forschungsprojektes: Nierensteine sind ein weltweites Gesundheitsproblem, etwa 10 % aller Menschen sind mindestens einmal im Leben davon betroffen. Nierensteine sind äusserst schmerzhaft, treten wiederholt auf und verursachen hohe direkte und indirekte Kosten. Eine effektive und kostengünstige Vorbeugung gegen Rückfälle von Nierensteinen ist deshalb äusserst wünschenswert. Etwa 80-90% aller Nierensteine enthalten Kalzium, eine vermehrte Ausscheidung von Kalzium im Urin ist die häufigste Stoffwechselstörung bei Patienten mit Nierensteinen. Thiazide reduzieren die Kalziumausscheidung im Urin und werden daher seit Jahrzehnten zur Vorbeugung von Rückfällen kalziumhaltiger Nierensteine eingesetzt. Deren Wirksamkeit wurde in den letzten 30 Jahren in mehreren Studien getestet. Leider war die Durchführung dieser Studien mangelhaft, die Gesamtzahl der untersuchten Patienten klein und es wurden hohe Medikamentendosen getestet, welche häufig Nebenwirkungen verursachen. Zur Zeit ist daher der Stellenwert der Thiazide in der Behandlung von Patienten mit Nierensteinen unklar. Ziel dieser Studie ist es, die Wirksamkeit von normal- und tiefdosiertem Hydrochlorothiazid zur Vorbeugung von Rückfällen kalziumhaltiger Nierensteine zu testen.  3. Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts: Das Nierensteinleiden gehört zu den häufigsten menschlichen Erkrankungen. Mit dieser klinischen Studie soll eine grosse Wissenslücke in der Nierensteinbehandlung geschlossen werden. Die Resultate dieser Studie werden die Behandlung von Nierensteinpatienten weltweit beeinflussen.

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Last update: 13.06.2016

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Introduction: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 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, up to 100 mg daily. At such high doses, side effects occur frequently and include electrolyte disturbances, orthostatic hypotension, gout, impaired glucose tolerance, skin rashes and erectile dysfunction. 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, we do not know whether the currently employed low dose thiazide regimens are effective in reducing the risk for stone recurrence.Rationale: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.Objective:We plan to conduct a 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. More specifically, we aim to assess the dose-response relationship for three different dosages of hydrochlorothiazide.Methodology:We will include 412 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). Patients with active pharmacologic metaphylaxis or with secondary causes of calcareous nephrolithiasis will be excluded from the study. Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. All patients will receive counseling for state-of-the art non-pharmacologic interventions to prevent stone recurrence according to current guidelines.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.