New Insights into Treatments for Kidney Stone Prevention

Kidney stones affect nearly 10% of the global population. For more than three decades, thiazide diuretics, a common medication used for high blood pressure, have been the standard of care for kidney stone prevention because they reduce the excretion of urinary calcium.

However, recent clinical trials have raised doubts about their efficacy in preventing kidney stones.

The NOSTONE trial, published in The New England Journal of Medicine in March 2023, failed to find a protective effect of thiazide diuretics on kidney stone disease.

A new Vanderbilt University Medical Center genetic association study of more than 1 million adults challenges those findings.

“We found that these genetic proxies of thiazide diuretics were associated with a 15% lower risk of kidney stones,” said Jefferson Triozzi, MD, the lead author.

“Furthermore, we examined serum laboratory values relevant to the treatment of kidney stones and found that the genetic proxies of thiazide diuretics were associated with higher serum calcium levels, supporting the notion that thiazides affect kidney stone risk by modulating calcium excretion in the urine.”

Most of the adults in the study were participants in the VA Million Veteran Program (MVP), a national research program that examines the effect of genetics, lifestyle and other factors on veterans’ health and wellness.

“Unique resources like the MVP, with extensive data on clinical conditions combined with genomic data, provide a valuable resource for genetically informed drug discovery and drug repurposing. Thiazide diuretics are recommended by international guidelines for the prevention of calcium kidney stones with long-term safety data.”

The all-VUMC team of researchers plans to investigate the underlying mechanisms by which thiazide diuretics lower the risk of kidney stones next.

“Our study highlights the importance of considering genetic proxies to estimate the long-term effects of medications and offers new evidence to support the use of thiazide diuretics for kidney stone prevention,” Triozzi said. “We believe genetic data can help us understand drug mechanisms and perhaps lead to new drug discovery for kidney stone disease.”


Jefferson L. Triozzi, Ryan S. Hsi, Guanchao Wang, Elvis A. Akwo, Lee Wheless, Hua-Chang Chen, Ran Tao, T. Alp Ikizler, Cassianne Robinson-Cohen, Adriana M. Hung, Sumitra Muralidhar, Jennifer Moser, Jennifer E. Deen, Philip S. Tsao, J. Michael Gaziano, Elizabeth Hauser, Amy Kilbourne, Shiuh-Wen Luoh, Michael Matheny, Dave Oslin, Lori Churby, Stacey B. Whitbourne, Jessica V. Brewer, Shahpoor (Alex) Shayan, Luis E. Selva, Saiju Pyarajan, Kelly Cho, Scott L. DuVall, Mary T. Brophy, Brady Stephens, Todd Connor, Dean P. Argyres, Tim Assimes, Adriana Hung, Henry Kranzler, Samuel Aguayo, Sunil Ahuja, Kathrina Alexander, Xiao M. Androulakis, Prakash Balasubramanian, Zuhair Ballas, Jean Beckham, Sujata Bhushan, Edward Boyko, David Cohen, Louis Dellitalia, L. Christine Faulk, Joseph Fayad, Daryl Fujii, Saib Gappy, Frank Gesek, Jennifer Greco, Michael Godschalk, Todd W. Gress, Samir Gupta, Salvador Gutierrez, John Harley, Kimberly Hammer, Mark Hamner, Robin Hurley, Pran Iruvanti, Frank Jacono, Darshana Jhala, Scott Kinlay, Jon Klein, Michael Landry, Peter Liang, Suthat Liangpunsakul, Jack Lichy, C. Scott Mahan, Ronnie Marrache, Stephen Mastorides, Elisabeth Mates, Kristin Mattocks, Paul Meyer, Jonathan Moorman, Timothy Morgan, Maureen Murdoch, James Norton, Olaoluwa Okusaga, Kris Ann Oursler, Ana Palacio, Samuel Poon, Emily Potter, Michael Rauchman, Richard Servatius, Satish Sharma, River Smith, Peruvemba Sriram, Patrick Strollo Jr., Neeraj Tandon, Gerardo Villareal, Agnes Wallbom, Jessica Walsh, John Wells, Jeffrey Whittle, Mary Whooley, Allison E. Williams, Peter Wilson, Junzhe Xu, Shing Shing Yeh. Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk. JAMA Network Open, 2023; 6 (11): e2343290 DOI: 10.1001/jamanetworkopen.2023.43290

Materials provided by Vanderbilt University Medical Center. Original written by Danny Bonvissuto. Note: Content may be edited for style and length.

Vanderbilt University Medical Center. “New study uses genetic data to support use of thiazide diuretics for kidney stone prevention.” ScienceDaily. ScienceDaily, 30 November 2023. <>.

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