Doctor of Philosophy
Microbiology and Immunology
Burton, Jeremy P.
Kidney stone disease affects nearly 10% of the population with calcium-containing stones being the most common type. Incidence of urolithiasis is rising but there have not been many significant advances in understanding the pathophysiology of stone formation nor in developing medicines to combat the disease. The major goals of this thesis were to challenge the current ideas in the field of urolithiasis and seek to develop new ideas on the etiology of stone disease. First, we set out to create new models to study urolithiasis. A simple cell-free agar model was developed to investigate the interaction of molecules on crystal forming dynamics. A 3-dimensional spheroid model was also built to explore how physiological parameters can contribute to calcium-containing stone formation. Using clinical data, machine learning models were developed to identify factors associated with different stone types, for which we found increased calcium titres to be a predominant marker of calcium-containing stone disease. Next, we characterized the bacterium Oxalobacter formigenes, a microbe with the unique ability to degrade oxalate, a common constituent in calcium oxalate stones, as its primary carbon source. This analysis revealed that O. formigenes can be split into three additional species each with distinctive metabolic capabilities. Oxalobacter aliiformigenes was identified as a potential candidate for human use because it can grow alongside bacteria from the human gut microbiome. Finally, we designed a clinical trial to study how vitamins contribute to urolithiasis. This trial revealed a network of dysregulated calcium handling that might be mediated by calcitriol, a biologically active vitamer of vitamin D. The collective scope of this work is expansive but is fundamental in advancing the understanding of the etiology of stone disease and elucidates novel mechanisms by which calcium-containing stones form. The results in this thesis have the potential to lead to the development of preventive or therapeutic measures for stone disease, advancing the field and improving patient outcomes.
Summary for Lay Audience
Kidney stones have existed with humans since the dawn of civilization. Nearly 10% of the present population has experienced an instance of a stone and rates of stone disease are increasing. Despite the long history that stone disease has with humans, not much is known about why some people form stones and others do not. This thesis aimed to develop new ideas surrounding stone disease to better understand what causes a stone to form. Like all good scientific studies, sufficient models are needed to experiment but the current models in the field are not adequate. We developed an agar plate model to study how crystals form and test molecules that could promote or inhibit stone formation. Using kidney cells, we also created a 3-dimensional sphere that represents a kidney. This sphere could develop stones and allow researchers to better understand how stones come to be in the kidney. Harnessing the power of machine learning, we analyzed a large dataset for a stone clinic to identify factors that differentiate different types of kidney stones. Calcium levels in the body were found to be the most important predictor of which type of kidney stone a person has. Taking it a step further, we wanted to understand how a specific bacterium, Oxalobacter formigenes¸ could be useful in stone disease. This bacterium can consume parts of kidney stones and our analysis revealed that it is more diverse than previously thought and some species of the bacterium could be more useful than others in surviving in humans to protect them against stone disease. We ended this thesis by conducting a clinical study to see what factors separate a person who forms kidney stones from someone who does not. The study revealed that kidney stone formers have an altered ability to process calcium which could set the stage for a kidney stone to develop. Altogether, this work contributes to improving our understanding of what causes stone disease, and it may be useful in developing interventions to finally split stone disease from our civilization.
Chmiel, John A., "Investigating the clinical and microbial factors contributing to calcium-containing kidney stone disease" (2023). Electronic Thesis and Dissertation Repository. 9757.
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