I am deeply honored to receive the 2024 2-year Outstanding Graduate Scholar Award. I extend my heartfelt gratitude to the AUA and the Urology Care Foundation for recognizing the potential in and supporting my project exploring the role of toxic xenobiotics in kidney stone formation.

Urolithiasis, one of the most prevalent urologic maladies worldwide, imposes severe morbidity and significant financial burden. However, the etiology of this condition still remains enigmatic in many ways. Recent work by our group and others has demonstrated that the gut microbiome is connected to nephrolithiasis, where different bacterial communities and functionalities are observed in stone formers compared to healthy controls.¹,² However, precise mechanisms and causal factors are multifaceted and undefined. The average North American is exposed to a barrage of xenobiotics daily, from deliberately ingested antibiotics and other pharmaceuticals, to drinking water contaminated with heavy metals, pesticides in the food chain, and persistent organic pollutants in personal care and household products.^3,4 Importantly, these compounds also influence, and are influenced by, the gut microbiome.⁵ They also play a role in various diseases, including chronic kidney disease and diabetes—comorbid conditions of stone disease with well-established gut microbiome links.^6-8 The interplay between xenobiotics, the gut microbiome, and kidney stone disease present a yet-uncharted area of study.

The general hypothesis of the current research project is that the gut microbiota of kidney stone formers (KS) interacts with foreign compounds (xenobiotics) in a manner which predisposes them to elevated systemic calcification and kidney stone formation. The proposed mechanism for this interaction is illustrated in the Figure. We previously undertook a clinical study looking at the multi-site microbiome in KS compared to matched healthy controls, where we described the widespread deleterious alterations to the KS microbiome.¹ These effects included enriched xenobiotic toxin handling capabilities (including antibiotics, heavy metals, pesticides, etc.) in KS. These correlations may indicate that KS have higher levels of xenobiotic exposure, leading to enrichment of resistant microbes in the gut. We have successfully completed enrollment and sample collection in a second clinical study of calcium-based KS aimed to further dissect these concepts. Working alongside collaborators, we have also explored publicly available databases for relationships between nephrolithiasis and other diverse xenobiotics. Although analysis is ongoing, initial findings align with our original hypotheses, indicating promising validation of this research direction.

Tasian and colleagues previously demonstrated that antibiotic exposure is associated with significantly increased odds of kidney stone disease.⁹ With this in mind, in addition to our own gut microbiota findings in KS, we have initiated investigations into the stone-inducing capabilities of a wide array of antibiotics and other xenobiotic compounds using in vitro and in vivo models. The antibiotic classes of sulfas, cephalosporins, and fluroquinolones were previously shown to have the highest associated odds of stone disease, and we have demonstrated that drugs of these classes (trimethoprim/sulfamethoxazole, cefazolin, and ciprofloxacin) are significantly associated with stone development and poor health outcomes. These findings are currently in preparation for publication.

This work aims to further resolve the complex and multifaceted mechanisms of stone formation, identifying previously unknown potential environmental risk factors. Moreover, we hope these findings can inform future prescribing practices, such that individuals at elevated risk of stone development or recurrence receive medications with the lowest lithogenic potential. By doing so, we aim to enhance patient care and mitigate the burden of nephrolithiasis.

I am sincerely grateful to the Urology Care Foundation for their support, which has enabled me and inspired me to continue my work in this field that I am so passionate about. This 2-year research scholar award period has been formative and instrumental in my growth as a young scientist, allowing me to hone my translational research skills and mentorship abilities, and cultivate collaborations with esteemed colleagues worldwide. I am immensely thankful to my primary mentor at Western University, Dr Jeremy Burton, whose guidance has been invaluable throughout this journey. Drs Hassan Razvi, Jennifer Bjazevic, and John Denstedt have also played pivotal roles in my development, for which I am deeply appreciative. Collaborators and members of our research team that have contributed greatly to this project include Dr Frank Glover, Dr John Chmiel, Riley Fiddler, and Alexandria Roa Agudelo.