Topiramate-Associated Nephrolithiasis – A Literature Review

Abstract

Introduction and Purpose. Topiramate alters renal acid–base handling through carbonic anhydrase inhibition and can produce hypocitraturia, increased urinary pH, and metabolic acidosis, creating a urinary environment that favors stone formation. The extent to which these metabolic changes translate into clinically relevant nephrolithiasis is less certain. This review examines the mechanisms of topiramate-associated stone formation, the available evidence on clinical risk, and current approaches to risk assessment, monitoring, and prevention. Materials and Methods. A structured literature search of PubMed/MEDLINE was performed, with the final search completed on 16 August 2026. Clinical and observational studies, systematic reviews, and relevant mechanistic studies addressing topiramate-associated nephrolithiasis, urinary metabolic abnormalities, risk assessment, and preventive interventions were considered. Older studies were included when they provided relevant mechanistic or long-term clinical data. Evidence specific to topiramate was distinguished from studies in which topiramate was analyzed together with other carbonic anhydrase-inhibiting drugs, particularly zonisamide. Results. Topiramate produces a consistent lithogenic metabolic profile, particularly hypocitraturia and increased urinary pH, but the frequency of clinically apparent nephrolithiasis remains difficult to define. Reported estimates vary according to the population studied, duration of exposure, and the method used to identify stone disease. Metabolic abnormalities, imaging-detected stones, diagnosed urolithiasis, and symptomatic events requiring healthcare intervention have been used as different outcomes, limiting direct comparison between studies. Recent population-based analyses have also produced non-uniform estimates of clinical risk. No validated topiramate-specific model predicts which patients will develop nephrolithiasis. Potassium citrate can improve hypocitraturia in stone-forming patients who continue treatment, although evidence that this reduces subsequent stone events is lacking. Conclusions. Topiramate has a well-established lithogenic metabolic effect, but the absolute risk of clinically significant nephrolithiasis and the factors determining individual susceptibility remain incompletely defined. Metabolic findings can guide assessment and management once abnormalities or stone disease are identified, but they cannot currently provide reliable individual risk prediction. Preventive strategies should therefore be interpreted according to the strength of the available evidence, particularly because improvement in urinary parameters has not yet been shown to translate consistently into fewer clinical stone events.