Investigating the clinical and microbial factors contributing to calcium-containing kidney stone disease
Abstract
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.