Modeling Calcium Phosphate and Struvite Kidney Stone-Forming Propensity in Rodents Using Topiramate

Background: Topiramate (TPM), a commonly used drug for migraines, seizures, and weight loss, is associated with increased risk of calcium phosphate (CaP) stones in patients. TPM is a carbonic anhydrase inhibitor that alters urinary chemistry in ways that increase CaP stone risk. We aimed to develop a rodent model of human CaP stone risk using chronic exposure to TPM and appropriate dietary manipulations, to create a preclinical model to evaluate preventive or therapeutic interventions. Methods: Mice and rats were fed TPM-containing chow (tested range: 10–500 mg/kg/day) for 1 to 4 months. Diets were modified to alter stone risk factors by altering calcium, phosphate, sodium, potassium, chloride, magnesium, and casein (a glutamine source) content. Urinary stone risk profiling was performed by analysis of mineral and electrolyte composition. Kidney mineralization was assessed by micro-computed tomography (µCT), and crystal composition was evaluated by Raman spectroscopy (RS). Results: The TPM diet consistently increased urine pH, decreased urinary citrate, and produced crystalluria, mirroring changes observed in humans on TPM. One surprising feature not seen in humans on TPM is the dramatic increase in urinary ammonium, which, in conjunction with hypocitraturia, suggests proximal tubule intracellular acidification induced by TPM. The high urinary ammonium drives struvite (magnesium ammonium phosphate) crystallization (confirmed by RS) competing with brushite crystal formation. In mice, TPM caused marked urinary biochemical propensity for CaP formation, and µCT revealed renal stones after as early as one month. In contrast, rats on high-dose TPM developed only modest renal stones (ex vivo µCT) after prolonged treatment. RS suggested mixed composition, with struvite predominating over CaP. To redirect crystallization toward CaP, magnesium-deficient and low-casein diets (reduced precursors for ammoniagenesis) are being combined with the TPM diet and are currently under evaluation. Conclusion: TPM-induced urinary chemical changes promote CaP stone formation, but high ammoniagenesis favors competing struvite formation. Continued dietary optimization is necessary to suppress struvite formation and enable development of a reliable CaP stone model. Establishing this model will enable downstream testing of interventions targeting CaP stone formation. Funding: NIDDK Support