Hydrochlorothiazide Not Better Than Placebo at Preventing Kidney Stones

Kidney stones (nephrolithiasis) are a relatively common health condition that affects about 11% of U.S. adults.[1] Because patients who have had a kidney stone are at increased risk of recurrence, they are usually advised to take steps to prevent the formation of new stones or growth of ones they already have.[2] The recommended steps include lifestyle changes such as increased intake of fluids, eating more fruits and vegetables, limiting intake of sodium (a component of salt) and losing weight.

Medications are another approach to preventing the recurrence of kidney stones. For example, thiazide diuretics (known as water pills), such as hydrochlorothiazide (MICROZIDE and generics), are frequently prescribed to prevent recurring calcium-containing kidney stones.[3] The evidence for this use of the drug, however, is limited. A study published in March 2023 in the New England Journal of Medicine (NEJM)[4] found that hydrochlorothiazide did not lead to a lower risk of recurrent kidney stones as compared with placebo.

What are kidney stones?

Stones can form inside the kidney when urine contains sufficient amounts of certain minerals and salts that start to crystallize and form hard deposits.[5] These minerals may become too concentrated (for example, because the patient did not drink enough water), or the urine may lack substances that would prevent these minerals and salts from sticking together.[6] Although there are different types of kidney stones, the most common stones are calcium-based.[7]

There is usually not just one single reason why kidney stones form — diet, excess body weight, a family history of kidney stones, several medical conditions (such as inflammatory bowel disease or hyperparathyroidism) and some medications (including certain antibiotics or antiviral drugs) or supplements (such as large amounts of vitamin C, vitamin D or calcium) can increase the risk of kidney stones.[8],[9]

Kidney stones are typically between the size of a grain of sand and the size of a pea but can grow even larger. Stones can stay in the kidney for a long time without causing any symptoms or damage; they usually only cause pain when they move from the kidney through the urinary tract.[10] Most kidney stones pass without requiring treatment. However, if stones are too large, interventions (such as medications to help pass the stone or procedures that break stones up into smaller pieces) may be needed.

Thiazides to prevent recurrent kidney stones

Hydrochlorothiazide is a thiazide diuretic and is approved by the Food and Drug Administration (FDA) for the treatment of high blood pressure and as an adjunctive therapy in edema (excess fluid in body tissues).[11],[12] Hydrochlorothiazide also is prescribed off-label (meaning for an indication not approved by the FDA) for the prevention of kidney stones because it decreases the excretion of urinary calcium, which is thought to help reduce the likelihood of kidney stone formation.[13] However, the mechanism of how hydrochlorothiazide helps to prevent kidney stones remains unclear and the effectiveness of this drug has been called into question.

The 2023 NEJM study

In this study, researchers randomly assigned 416 people with recurring kidney stones to receive either hydrochlorothiazide or a placebo once daily. Individuals in the hydrochlorothiazide group were further randomized to receive daily dosages of either 12.5, 25 or 50 mg of the drug.[14]

Subjects included in this trial were 18 years or older, had at least two calcium-containing kidney stones in the past 10 years and were not taking any medications that could interfere with kidney stone formation.[15]

After a median follow-up of 2.9 years, the researchers found that the rate of serious adverse events was generally not higher for subjects in the hydrochlorothiazide groups than in the placebo group. However, patients receiving the drug were more likely to develop new-onset diabetes, hypokalemia (low blood levels of potassium) and gout.[16] At the same time, the rates of recurrent kidney stones were similar between patients on different doses of hydrochlorothiazide and those who had received the placebo.

For example, when recurrent kidney stones were classified as either symptomatic (visible passage or surgical removal of a stone) or radiologic (appearance of new or growing stones on computed tomography), 59% of patients in the placebo group had a recurrent stone, compared with 59% in the 12.5-mg hydrochlorothiazide group, 56% in the 25-mg group and 49% in the 50-mg group.[17] None of the results for the three hydrochlorothiazide groups were statistically different from the results with placebo.

When the analysis was limited to recurrent kidney stones that were symptomatic, the results were also generally similar between groups. However, when the analysis was limited to recurrent stones detected by computed tomography, subjects in the 25-mg (32%) and 50-mg (34%) hydrochlorothiazide groups had a lower incidence of kidney stones than subjects who had received either 12.5 mg (45%) or placebo (49%). This use of highly sensitive medical imaging technologies to detect kidney stones may not be clinically meaningful.[18]

A concern about the generalizability of the findings is that the follow-up time (almost three years) was not long enough to observe a difference in kidney stone prevention between groups. Moreover, the subjects were almost exclusively White, and only 20% were women; thus, these findings may not apply to other groups of patients.

What You Can Do

If you have been diagnosed with recurrent calcium-based kidney stones, discuss with your health care professional how you can help prevent existing kidney stones from growing or new ones from forming through lifestyle changes such as increasing how much you drink and limiting salt intake. If you are taking hydrochlorothiazide to prevent recurring stones, discuss whether this is a good option for you. Do not discontinue hydrochlorothiazide without first consulting your clinician.
 

References

[1] Hill AJ, Basourakos SP, Lewicki P, et al. Incidence of kidney stones in the United States: the continuous national health and nutrition examination survey. J Urol. 2022;207(4):851-856

[2] Preminger, G, Curhan, GC. Patient education: Kidney stones in adults (beyond the basics). Updated May 16, 2023.

[3] Curhan GC. Kidney stones in adults: Prevention of recurrent kidney stones. UpToDate. Updated March 10, 2023.

[4] Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and prevention of kidney-stone recurrence. N Engl J Med. 2023 Mar 2;388(9):781-791.]

[5] Preminger G, Curhan, GC. Patient education: Kidney stones in adults (beyond the basics). Updated May 16, 2023.

[6] Mayo Clinic. Kidney stones. https://www.mayoclinic.org/diseases-conditions/kidney-stones/symptoms-causes/syc-20355755?p=1. Accessed July 13, 2023.

[7] Weiss,C. Mayo Clinic Q and A: Preventing kidney stones. June 22, 2021. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-preventing-kidney-stones/. Accessed July 13, 2023.

[8] Mayo Clinic. Kidney stones. https://www.mayoclinic.org/diseases-conditions/kidney-stones/symptoms-causes/syc-20355755?p=1. Accessed July 13, 2023.

[9] Daudon M, Frochot V, Bazin D, et al. Drug-induced kidney stones and crystalline nephropathy: pathophysiology, prevention and treatment. Drugs. 2018;78:163-201.

[10] Preminger G, Curhan, GC. Patient education: Kidney stones in adults (beyond the basics). Updated May 16, 2023.

[11] Medline Plus. Hydrochlorothiazide. Revised February 15, 2021. https://medlineplus.gov/druginfo/meds/a682571.html. Accessed July 13, 2023.

[12] Aurobindo Pharma Limited. Hydrochlorothiazide. January 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e31bd548-29ae-419a-831a-80ebb26e042f&type=display. Accessed July 13, 2023.

[13] Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and prevention of kidney-stone recurrence. N Engl J Med. 2023 Mar 2;388(9):781-791.

[14] Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and prevention of kidney-stone recurrence. N Engl J Med. 2023 Mar 2;388(9):781-791.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Alexander RT. Do thiazides reduce the risk of kidney-stone recurrence? N Engl J Med. 2023; 388(9):841-842.