NOSTONE: HCTZ for Prevention of Kidney-Stones
Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.
Dhayat NA, Bonny O, Roth B, et al.
N Engl J Med. 2023 Mar 2;388(9):781-791. [Full text]
Thiazides exert their effect on a NaCl transporter in the distal convoluted tubule. Indirectly, thiazides decrease urinary calcium excretion (possibly by increasing Ca reabsorption in the proximal tubules) and this effect has led to their use for prevention of calcium kidney stone recurrence. After a first symptomatic kidney stone, the risk of recurrence is 14% at 1 year, 35% at 5 years, and 52% at 10 years [1]. A systematic review of patients with multiple past calcium stones taking thiazides, most of whom were receiving increased fluid intake, showed moderate-strength evidence of benefit (RR, 0.52 [CI, 0.39 to 0.69]) [2]; however, the most recent double-blind study included in the review was from 1988 [3]! In this setting, Dhayat et al. designed the NOSTONE trial, a double-blind, randomized, placebo-controlled trial that was conducted to evaluate various hydrochlorothiazide (HCTZ) doses for the prevention of the kidney stone recurrence.
Patient population and Design
Patients were recruited from 12 centers in Switzerland. Adult patients (≥ 18 yrs) were eligible if they had ≥ 2 episodes of kidney stones in the past 10 years, and any previous kidney stone that contained at least 50% calcium oxalate, calcium phosphate, or a mixture of both.
Key exclusion criteria included:
- Patients with secondary causes of recurrent nephrolithiasis
– severe eating disorders, chronic IBD, bariatric surgery, intestinal surgery with malabsorbtion or chronic diarrhea, sarcoidosis, hyperparathyroidism) - Patients taking any medications that could interfere or influence stone formation
– diuretics, carbonic anhydrase inhibitors including topiramate, febuxostat, allopurinol, alkali, 1,25-Vit D, calcium, bisphosphonates, denusomab, or glucocorticoids - Miscellaneous: CKD4-5, renal transplant, frequent gouty arthritis, or hypokalemia < 3 mEq/L
Patients were randomly assigned into one of four groups (1:1:1:1 ratio) to receive HCTZ at a 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily for 2-3 years duration.
At enrollment, patients underwent a low-dose non-contrast computed tomographic (CT) study limited to the kidneys. All the patients had a clinical follow-up visit 3 months and then yearly, as well as a telephone visit every 3 months
Statistical Analysis and Outcomes
An estimated sample of 416 patients (104 patients in each group) would provide at least 80% power for the hypothesis that the HCTZ dose would have no relation to the recurrence of kidney stones, assuming recurrence would be 50% lower in the 50-mg HCTZ group and 35% lower in the 25-mg HCTX group compared to placebo, respectively.
The primary outcome was the dose-response relationship of HCTZ for stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes included the individual effect of each HCTZ dose on stone recurrence. The safety endpoint was the long-term safety and tolerability of HCTZ compared to placebo.
Results
Between March 30, 2017 and October 31, 2019, 416 of 1335 patients that underwent screening met eligibility criteria, and 387 patients (93%) completed follow-up as planned. Groups were similar at baseline with a median age of 49 years, 80% of which were men, and over 98% were white. At baseline, 63% had hypercalciuria (defined as a urinary calcium excretion rate >200 mg / 24 hrs).
Non-adherence, defined as missing >20% of the daily HCTZ or placebo doses occurred in about a quarter of patients in all groups (26% in the placebo group, 15% in the 12.5-mg HCTZ group, 24% in the 25-mg HCTZ group, and 26% in the 50-mg HCTZ group).
There was no evidence of a relation between the HCTZ dose and the occurrence of a primary end-point event (RR for trend, 0.98; 95% CI, 0.87 to 1.09; test for trend, P=0.66). A primary end-point event occurred in 59% in the 12.5-mg HCTZ group (RR vs. placebo, 1.33; 95% CI, 0.92 to 1.93), 56% in the 25-mg HCTZ group (RR, 1.24; 95% CI, 0.86 to 1.79), and 49% in the 50-mg HCTZ group (RR 0.92; 95% CI, 0.63 to 1.36).
By individual dose there was no difference compared to placebo in the rate of symptomatic or radiologic recurrence of stones.
Urinary calcium excretion was decreased in all doses of HCTZ compared to placebo, whereas statistically significant net oxalate excretion occurred in the 25 mg HCTZ dose group and citrate excretion was variably effected.
While relatively rare, new-onset diabetes mellitus (1% vs. 2-6%), hypokalemia, gout, skin allergy, and a plasma creatinine increase to ≥ 150% of baseline level were more common among patients in the HCTZ groups than placebo, but the overall incidence of serious adverse events was not different.
Discussion
In this double-blind trial of patients with recurrent calcium-containing kidney stones, the majority of which had hypercalciuria at basement (63%), HCTZ at doses of 12.5 mg, 25 mg, or 50 mg once daily had no observed effect on the rate of symptomatic or radiologic recurrence of kidney stones despite observed decreasing calcium excretion.
To explain this somewhat surprising result, the authors noted that while calcium excretion was decreased, oxalate and citrate were effects were inconsistent and could have negated the changes in urinary calcium. Furthermore, urine relative supersaturation ratios, which may better reflect the conditions for stone precipitation, where not consistently lower in the HCTZ groups.
Limitations include the sample-size calculation which assumed a higher reduction effect of 25 and 50 mg HCTZ than was observed. Also, the 3 year follow up period may have been too short to see an effect given that observed recurrence rates are reportedly 14% at 1 year, 35% at 5 years, and 52% at 10 years [1], But the authors thought this was unlikely as the impact after 3 years would have to be dramatic to make the result significant given the current observation. Finally, a high non-adherence rate (15-26%) could have affected the results
Despite the limitations, this study is the best evidence to date and does not support HCTZ use. Additionally, safety concerns, such as increased risk of DM and gout, dyslipidemia and electrolyte abnormalities should also make this treatment strategy for kidney stones be approached with caution. The most important result of the study may be that for preventing kidney stones, entirely new target of therapy should be considered.
| F: Follow up | Initial visit 3 mo after enrollment, then Q3 mo televisits, yearly in-person, for up to 2-3 years |
| R: Randomization | Yes, 1:1:1:1, ratified by episodes of kidney stones during the prior 10 years |
| I: Intention to treat | Yes, per-protocol also reported |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes, except per design |
| S: Source (funding) | Swiss National Science Foundation and Inselspital |
- Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Ann Intern Med. 1989 Dec 15;111(12):1006-9.
- Fink HA, Wilt TJ, Eidman KE, et al.; Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline. Ann Intern Med. 2013 Apr 2;158(7):535-43.
- Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol. 1988 Apr;139(4):679-84.
