Kidney Week 2025 Annual Meeting-Mechanistic Insights on Urinary Stone Formation

Video Transcription

Video Summary

The session opened with updates and introduced three talks on kidney stone pathophysiology and prevention.

Dr. Howells (Oxford) described large genome-wide association studies (25,000 cases; 750,000 controls) identifying 77 kidney-stone loci. Using Mendelian randomization, he showed adiposity causally increases stone risk (~30% per SD BMI), partly via higher serum calcium—even small “normal-range” calcium increases raised risk. A regional genetic approach implicated pathways near <strong>DGKD</strong> (calcium-sensing receptor signaling), <strong>SLC34A1</strong> (renal phosphate transport), and <strong>CYP24A1</strong> (vitamin D breakdown). Common risk alleles produced mild biochemical patterns resembling attenuated monogenic disorders and together could contribute substantially to population risk. Rare DGKD missense variants reduced CaSR signaling in vitro; cinacalcet (a CaSR modulator) restored signaling, and drug-target MR suggested CaSR/DGKD modulation might reduce stone risk, alongside potential targets in phosphate and vitamin D pathways. Discussion emphasized the need for recurrence-focused cohorts before clinical translation.

Dr. Fuster presented the SweetStone trial: a double-blind, placebo-controlled crossover study of <strong>empagliflozin</strong> in non-diabetic calcium vs uric-acid stone formers. Empagliflozin lowered <strong>calcium phosphate supersaturation</strong> in calcium stone formers and lowered <strong>uric acid supersaturation</strong> in uric-acid stone formers, largely via increased urinary citrate and pH changes (opposite directions by group). Urinary calcium rose in calcium stone formers. A phase 3 outcomes trial is planned using CT-detected recurrence and comparing personalized vs generic dietary counseling.

Dr. Aramilla (Cleveland Clinic) reviewed evidence that the urinary tract is not sterile and that antibiotics shift the urinary microbiome toward pathogenic profiles. Epidemiologic and mechanistic work linked prior antibiotics to future stones. Kidney tissue contains bacteria; transferring urinary microbial pellets from stone patients to germ-free mice increased renal calcium oxalate deposition. In bioreactors, E. coli promoted larger calcium oxalate crystals, while Lactobacillus inhibited growth, likely via metabolite differences. Stone-associated bacteria showed high antibiotic resistance and biofilm formation, supporting antibiotic stewardship and targeted microbiome-based therapies (e.g., Lactobacillus, quorum sensing inhibitors, bacteriophages).

Asset Subtitle

Moderator(s): Sonia Fargue, Anna Zisman

Presentation(s):

Using Genome-Wide Association Studies to Define Genetic Risks for Mineral Metabolism and Nephrolithiasis - Sarah Howles
SGLT2 Inhibitors and Calcium and Uric Acid Stones - Daniel Fuster
Antibiotics, Uropathogens, and Calcium Stone Formation - Aaron Miller

Meta Tag

Date 11/9/2025

Session ID 510225

Keywords

kidney stone pathophysiology

kidney stone prevention

genome-wide association study (GWAS)

Mendelian randomization

adiposity and BMI stone risk

serum calcium (normal-range)

DGKD and CaSR signaling

SLC34A1 renal phosphate transport

CYP24A1 vitamin D metabolism

cinacalcet CaSR modulator

empagliflozin SweetStone trial

urinary citrate and supersaturation

urinary microbiome and antibiotics