Indiana University-Purdue University Indianapolis (IUPUI) / Nephrolithiasis will affect one-in-eleven people, and more than half of those
individuals will have stone recurrence within a decade of their first episode. Despite
decades of biomedical research on nephrolithiasis and extraordinary advances in
molecular and cell biology, the precise mechanisms of kidney stone formation are not
fully understood. Currently, there are limited treatments or preventative measures for
nephrolithiasis. Therefore, it is crucial to scrutinize kidney stones from a molecular and
cell biology perspective to better understand its pathogenesis and pathophysiology; and
to, hereafter, contribute to effective therapeutic targets and preventative strategies.
Kidney stones are composed of an admixture of crystal aggregated material and
an organic matrix. 80% of all kidney stones are composed of calcium oxalate (CaOx) and
half of all CaOx patients grow their stones on to Randall’s plaques (RP). RP are
interstitial calcium phosphate mineral deposits in the renal papilla. Thus, we developed
and optimized methodologies to directly interrogate CaOx stones.
CaOx stones were demineralized, sectioned, and imaged by microscopy, utilizing
micro CT for precise orientation. Laser microdissection (LMD) of specific regions of
stone matrix analyzed by proteomics revealed various proteins involved in inflammation
and the immune response. Analyses on jackstone calculi, having arm protrusions that
extend out from the body of the stone, revealed that they are a rare subtype of CaOx stone
formation. Micro CT analyses on 98 jackstones showed a radiolucent, organic-rich core
in the arm protrusions. Fluorescence imaging on RP stones showed consistent differences in autofluorescence patterns between RP and CaOx overgrowth regions. Moreover, cell
nuclei were discovered with preserved morphology in RP regions, along with variable
expressions of vimentin and CD45. In comparing spatial transcriptomic expression of
reference and CaOx kidney papillae, CaOx patients differentially expressed genes
associated with pathways of immune cell activation, reactive oxygen damage and injury,
extracellular remodeling, and ossification.
Our findings provide novel methodologies to better understand the role of
molecules and cells in CaOx stone matrix. Several of the proteins and cells identified in
these studies may serve as potential biomarkers, and future therapeutic targets in
preventing kidney stone disease.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29298 |
| Date | 05 1900 |
| Creators | Canela, Victor Hugo |
| Contributors | Williams, James C., Ashkar, Tarek M., Blum, Janice S., Sankar, Uma |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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