Hydrochlorothiazide and Prevention of Kidney Stone Recurrence: A #NephJC Editorial on the NOSTONE Trial

Kidney stones are a global health concern with increasing incidence and prevalence, affecting individuals regardless of age, sex, culture, or region.1Edvardsson V.O. Indridason O.S. Haraldsson G. Kjartansson O. Palsson R. Temporal trends in the incidence of kidney stone disease [published correction appears in Kidney Int.Kidney Int. 2013; 83 (2013 May;83(5):972): 146-152https://doi.org/10.1038/ki.2012.320Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar,2Romero V. Akpinar H. Assimos D.G. Kidney stones: a global picture of prevalence, incidence, and associated risk factors.Rev Urol. 2010 Spring; 12 (PMID: 20811557; PMCID: PMC2931286): e86-96PubMed Google Scholar Without effective treatment, recurrence rates for kidney stones are high, with 40% of patients experiencing a recurrence within five years and 75% within twenty years.3Worcester E.M. Coe F.L. Clinical practice. Calcium kidney stones.N Engl J Med. 2010 Sep 2; 363 (PMID: 20818905; PMCID: PMC3192488): 954-963https://doi.org/10.1056/NEJMcp1001011Crossref PubMed Scopus (283) Google Scholar Secondary prevention of kidney stones involves a multifaceted approach, including behavioral and nutritional interventions, as well as pharmacological treatment tailored to the specific type of stone. Thiazides and thiazide-like diuretics have been used for over five decades to prevent the formation of kidney stones.4Vigen R. Weideman R.A. Reilly R.F. Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion?.Int Urol Nephrol. 2011 Sep; 43 (Epub 2010 Aug 25. PMID: 20737209; PMCID: PMC3229098): 813-819https://doi.org/10.1007/s11255-010-9824-6Crossref PubMed Scopus (22) Google Scholar These medications augment the reabsorption of calcium in the proximal tubule, effectively reducing urinary calcium excretion and decreasing the risk of calcium crystal formation.5Bergsland K.J. Worcester E.M. Coe F.L. Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria.Am J Physiol Renal Physiol. 2013 Aug 15; 305 (Epub 2013 May 29. PMID: 23720347; PMCID: PMC3891266): F592-F599https://doi.org/10.1152/ajprenal.00116.2013Crossref Scopus (32) Google Scholar Multiple studies showed the benefit of these drugs in kidney stone prevention.6Pearle M.S. Roehrborn C.G. Pak C.Y. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis.J Endourol. 1999 Nov; 13 (PMID: 10608521): 679-685https://doi.org/10.1089/end.1999.13.679Crossref PubMed Scopus (162) Google Scholar,7Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, Brasure M, Kane RL, Monga M. Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventive Medical Strategies [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Jul. Report No.: 12-EHC049-EF. PMID: 22896859.Google Scholar Although they are considered to be a “cornerstone” of pharmacological nephrolithiasis prevention, the evidence for their efficacy compared to placebo is limited, with only few dose-response data available. A recent meta-analysis assessing the use of thiazide diuretics for the prevention of recurrent kidney stones concluded that the quality of evidence is low.8Li D.F. Gao Y.L. Liu H.C. Huang X.C. Zhu R.F. Zhu C.T. Use of thiazide diuretics for the prevention of recurrent kidney calculi: a systematic review and meta-analysis.J Transl Med. 2020; 18 (Published 2020 Feb 28): 106https://doi.org/10.1186/s12967-020-02270-7Crossref PubMed Scopus (16) Google Scholar Thus, there was a critical need for a well-designed, randomized controlled trial (RCT) to evaluate the efficacy of thiazides at preventing kidney stone recurrence. The standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE) was a double blind, randomized, placebo-controlled trial of low to high doses of hydrochlorothiazide (HCTZ) to assess the ability of thiazide diuretics to prevent recurrence of kidney stones done in multiple centers in Switzerland.9Dhayat N.A. Bonny O. Roth B. Christe A. Ritter A. Mohebbi N. et al.Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.N Engl J Med. 2023 Mar 2; 388 (PMID: 36856614): 781-791https://doi.org/10.1056/NEJMoa2209275Crossref Scopus (8) Google Scholar Those 18 years of age or older with recurrent kidney stones (≥ 2 events within 10 years) containing 50% or more of calcium oxalate/calcium phosphate/mixture of both were included in the study. Hypercalciuria was not mandatory for eligibility. Randomization was done 1:1:1:1 into 4 groups: placebo, 12.5 mg HCTZ/day, 25 mg HCTZ/day, or 50 mg HCTZ/day. Radiological monitoring was done by non-contrast CT imaging, at the start of randomization and then at the end of 3 years. With that, follow up visits were at 3 months then yearly, and telephone visits occurred every 3 months. The primary outcome was a composite of symptomatic recurrence (passage of stones, renal colic symptoms, or stone requiring surgical intervention) and radiological recurrence (appearance of new stones on CT or enlargement of pre-existing stones). Secondary outcomes were individual symptomatic recurrence and radiologic recurrence, calculated urine relative supersaturation ratios. A total of 416 patients were enrolled (104 in each group). Baseline characteristics were consistent in all groups, with male preponderance. Baseline hypercalciuria (>200 mg/24 hr) was common, present in 63%. Patients treated with HCTZ developed slightly lower urinary calcium excretion than those on placebo at follow-up, with the largest effect noted at the higher dose of 50 mg. However, there was no significant difference in urine relative supersaturation ratios for calcium oxalate and calcium phosphate between the placebo and HCTZ groups. Similarly, there was no statistical difference between the groups in primary outcome, as it occurred in 59% with placebo as well as 59%, 56%, and 49% in the 12.5, 25, and 50 mg/day HCTZ groups, respectively. There was no dose–response effect for the primary outcome. There was lower radiological recurrence only seen with higher doses (25 mg and 50 mg) of HCTZ, with no trend for a dose-response effect. Adverse events of new-onset diabetes mellitus, hypokalemia, gout, skin allergy, and an increase in creatinine >150% baseline were all more common among patients in HCTZ groups than placebo, though with no increase in serious adverse events. The NechJC Twitter chats occurred on April 11th and 12th 2023, with a total of 96 participants and 573 tweets. Participants included general nephrologists, nephrolithiasis experts, a study author, as well as medical trainees and educators. The importance of nephrolithiasis as a cause of chronic kidney disease (CKD) and kidney failure was highlighted, as well as the high rate of stone recurrence especially without treatment. The participants discussed their usual approach to kidney stone management which includes increasing fluid intake, lowering dietary sodium chloride, maintaining adequate dietary calcium, as well as using citrate salts and thiazide diuretics. It was argued whether one should employ all the strategies together, or base some interventions (including thiazides) on 24-hour urine studies to create a more individualized and patient-centered approach (Figure 1A). The available evidence for thiazide use in kidney stone recurrence was deemed insufficient given that most previous trials were small and had weak methodology. This was a subject of previous NephJC debate regarding ACP and AUA guidelines,10Pearle M.S. Goldfarb D.S. Assimos D.G. et al.Medical management of kidney stones: AUA guideline.J Urol. 2014 Aug; 192 (Epub 2014 May 20. PMID: 24857648): 316-324https://doi.org/10.1016/j.juro.2014.05.006Crossref PubMed Scopus (566) Google Scholar, 11Qaseem A. Dallas P. Forciea M.A. et al.Dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the American College of Physicians.Ann Intern Med. 2014 Nov 4; 161 (PMID: 25364887): 659-667https://doi.org/10.7326/M13-2908Crossref PubMed Scopus (96) Google Scholar, 12NephJC. The AUA v ACP guidelines. Fight! Accessed August 17, 2023. Published June 9, 2015 https://www.nephjc.com/news/2015/6/9/the-aua-guidelinesGoogle Scholar with many chat participants recalling the desire for transparency about the poor state of evidence. Despite this, thiazides continue to be used widely in this setting and remain a recommended therapy by more recent guidelines.13Fontenelle L.F. Sarti T.D. Kidney Stones: Treatment and Prevention.Am Fam Physician. 2019 Apr 15; 99 (PMID: 30990297): 490-496PubMed Google Scholar,14Pearle M.S. Goldfarb D.S. Assimos D.G. et al.Medical management of kidney stones: AUA guideline.J Urol. 2014 Aug; 192 (Epub 2014 May 20. PMID: 24857648): 316-324https://doi.org/10.1016/j.juro.2014.05.006Crossref PubMed Scopus (566) Google Scholar The NOSTONE results showing lack of thiazide benefit were surprising to many (Figure 1B). Despite the lower radiological recurrence at higher doses (a secondary outcome), there was no statistically significant dose-response effect. It was noted that the previous kidney stone trials used higher HCTZ doses of 50 to 100 mg daily, whereas in clinical practice lower doses are commonly used. Many participants expressed concern about thiazide side effects, especially in light of absence of benefit in the study. Though serious adverse events were not higher with the thiazide groups in NOSTONE, the known side effects of HCTZ including hypokalemia, gout, diabetes mellitus, elevated creatinine did manifest (Figure 1C), which is important in the context of an absence of benefit of HCTZ. Chat participants asked whether there is any role for other longer-acting and more potent thiazide-like diuretics, such as chlorthalidone and indapamide. Most nephrologists favor their use in this setting, though some noted concern for hypotension in otherwise normotensive young patients with recurrent stones. Notably, it is also likely that the adverse effects noted in this trial with HCTZ would be expected to be more common with the more potent thiazide-like agents. The follow up duration in this study was between 2 to 3 years, which can be a limitation since most stone prevention studies require at least 2 years to show a benefit. There was a debate about whether follow up should have been extended beyond 3 years and whether the benefit would have manifested later (e.g. some of the radiological recurrence turning into symptomatic recurrences), but some chat participants commented that the event numbers and rates needed for an adequate sample as planned were reached (overall 232 events in 416 patients, 57%), with no benefit seen quite clearly. Hence it’s very unlikely a longer period of follow up would have provided a different result. The lack of effect on urinary supersaturation for calcium oxalate and calcium phosphate despite the decrease in urinary calcium with HCTZ treatment also sparked some discussion as to whether this was due to an increase in urinary oxalate or some other unclear mechanism. Another point highlighted was that urinary sodium excretion was high at baseline and remained high during follow-up. In routine practice, there is an emphasis on reducing dietary and thus urinary sodium, increasing fluid intake as well adding HCTZ. Lastly, the role of potassium supplements also came up, since hypokalemia itself (spontaneous or HCTZ-induced) is a risk factor for hypocitraturia. This could explain the association of thiazides with hypocitraturia, and may have diluted the potential benefit of hypocalciuria from thiazides. Overall, the study was praised as having strong methods and answering the question it set out to. Some strengths are that it was a double blinded RCT, assessed symptomatic and radiologic recurrence, was adequately powered, and authors performed several sensitivity analyses which were quite consistent in reporting a lack of any benefit. Limitations were considered to be the population being mostly white men, though they have the highest prevalence of kidney stones. Patients with CKD and secondary nephrolithiasis as well as those on medications that interfere with kidney stone formation were excluded. Participants also proposed that future RCTs are needed to assess whether the use of additional treatment such as citrate, and use of higher doses HCTZ / long-acting thiazide-like diuretics are truly effective. Though a majority (57%) of participants said they would not initiate HCTZ to prevent kidney stones, a smaller plurality (37%) said they would discontinue HCTZ for patients who were on it to prevent recurrent kidney stones (Figure 2A). Even the discussion argues that we need nuance in interpreting any trial findings and incorporating new knowledge into existing recommendations (Figure 2B). NOSTONE did not demonstrate any benefit of hydrochlorothiazide (at doses up to 50 mg daily) for prevention of stones in patients with high risk of recurrence. A major limitation was the study duration of three years. Many nephrologists, clearly some of those participating in the NephJC tweetchat (Figure 2), are likely to continue using thiazide-diuretics in certain patients with special attention paid to 24-hour urine results.

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