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      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

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          Nephrolithiasis 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.


          The 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.


          The 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 registration

          ClinicalTrials.gov, NCT03057431. Registered on February 20 2017.

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          Most cited references 26

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          Clinical practice. Calcium kidney stones.

           F Coe,  E Worcester (2010)
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            Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management?

            More than 5% of the United States population has been diagnosed with nephrolithiasis and about one half of (first-time) stone formers will have a recurrence within 5 years. The prevalence of nephrolithiasis is concentrated among working age adults, yet little prior work has examined the economic burden of the disease on employers and their employees. We sought to estimate the direct and indirect costs of nephrolithiasis for working age adults (18-64) with employer-provided insurance.
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              Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline.

              Optimum management to prevent recurrent kidney stones is uncertain. To evaluate the benefits and harms of interventions to prevent recurrent kidney stones. MEDLINE, Cochrane, and other databases through September 2012 and reference lists of systematic reviews and randomized, controlled trials (RCTs). 28 English-language RCTs that studied treatments to prevent recurrent kidney stones and reported stone outcomes. One reviewer extracted data, a second checked accuracy, and 2 independently rated quality and graded strength of evidence. In patients with 1 past calcium stone, low-strength evidence showed that increased fluid intake halved recurrent composite stone risk compared with no treatment (relative risk [RR], 0.45 [95% CI, 0.24 to 0.84]). Low-strength evidence showed that reducing soft-drink consumption decreased recurrent symptomatic stone risk (RR, 0.83 [CI, 0.71 to 0.98]). In patients with multiple past calcium stones, most of whom were receiving increased fluid intake, moderate-strength evidence showed that thiazides (RR, 0.52 [CI, 0.39 to 0.69]), citrates (RR, 0.25 [CI, 0.14 to 0.44]), and allopurinol (RR, 0.59 [CI, 0.42 to 0.84]) each further reduced composite stone recurrence risk compared with placebo or control, although the benefit from allopurinol seemed limited to patients with baseline hyperuricemia or hyperuricosuria. Other baseline biochemistry measures did not allow prediction of treatment efficacy. Low-strength evidence showed that neither citrate nor allopurinol combined with thiazide was superior to thiazide alone. There were few withdrawals among patients with increased fluid intake, many among those with other dietary interventions and more among those who received thiazide and citrate than among control patients. Reporting of adverse events was poor. Most trial participants had idiopathic calcium stones. Nearly all studies reported a composite (including asymptomatic) stone recurrence outcome. In patients with 1 past calcium stone, increased fluid intake reduced recurrence risk. In patients with multiple past calcium stones, addition of thiazide, citrate, or allopurinol further reduced risk. Agency for Healthcare Research and Quality.

                Author and article information

                +41 (0)31 632 31 44 , daniel.fuster@insel.ch
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                10 December 2018
                10 December 2018
                : 19
                [1 ]Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
                [2 ]Department of Nephrology, CHUV, University Hospital Lausanne, University of Lausanne, Lausanne, Switzerland
                [3 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Department of Nephrology, , University Hospital Zurich, ; Zürich, Switzerland
                [4 ]Department of Nephrology, Regional Hospital Lugano, Lugano, Switzerland
                [5 ]Department of Nephrology, Cantonal Hospital Chur, Chur, Switzerland
                [6 ]ISNI 0000 0001 2294 4705, GRID grid.413349.8, Department of Nephrology and Transplantation Medicine, , Cantonal Hospital St. Gallen, ; St. Gallen, Switzerland
                [7 ]Department of Nephrology, Regional Hospital Bellinzona, Bellinzona, Switzerland
                [8 ]Medical Outpatient Department, University Hospital Basel, University of Basel, Basel, Switzerland
                [9 ]ISNI 0000 0000 8587 8621, GRID grid.413354.4, Department of Nephrology, , Cantonal Hospital Luzern, ; Luzern, Switzerland
                [10 ]ISNI 0000 0000 8704 3732, GRID grid.413357.7, Division of Nephrology, Dialysis and Transplantation, Cantonal Hospital Aarau, ; Aarau, Switzerland
                [11 ]Department of Nephrology, HUG, University Hospital Geneva, University of Geneva, Geneva, Switzerland
                [12 ]Service de Nephrology, Centre Hospitalier du Valais Romand (CHVR), Sion, Switzerland
                [13 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Clinical Trials Unit, , University of Bern, ; Bern, Switzerland
                [14 ]Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 33IC30_166785/1
                Award Recipient :
                Study Protocol
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                © The Author(s) 2018


                nephrolithiasis, kidney stones, recurrence, prevention, hydrochlorothiazide


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