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Microenvironment-Specific Zinc Enrichment and Structural Heterogeneity in Human Kidney Stones
Benjamin Greenfield, MS1, Jorge Mena, MD2, Sudarshan Srirangapatanam, MD2, Misun Kang, PhD2, Samuel Webb, PhD3, Marshall Stoller, MD2, Sunita Ho, PhD2.
1Tufts University School of Medicine, Boston, MA, USA, 2University of California, San Francisco, San Francisco, CA, USA, 3Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory,, Menlo Park, CA, USA.
BACKGROUND: Kidney stone formation is commonly attributed to systemic urine supersaturation, yet the extent to which local renal microenvironments shape biomineral composition remains incompletely understood. This study investigated whether papillary plaques, papillary stem-stones, and collecting-system stones differ in mineral density, elemental organization, and microstructure, with particular focus on zinc as a potential modulator of renal biomineralization.
METHODS: Intact papillae and stones were collected from patients with recurrent nephrolithiasis and grouped as medullo-papillary complexes/papillary plaques (N=4), stem-stones (N=4), and collecting-system stones (N=3). Specimens were analyzed using multimodal correlative imaging, including micro-X-ray computed tomography, X-ray fluorescence microprobe, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and laser ICP-OES. Mineral density distributions, elemental colocalization, and particle morphology were compared across anatomical zones.
RESULTS: Papillary plaques and stem regions showed marked heterogeneity, whereas collecting-system stones were more compositionally uniform and laminated. Zinc was enriched in papillary plaques and especially in stem regions, where Zn-P domains frequently surrounded or overlapped Ca-P regions and aligned with higher-density mineral zones. In contrast, mature collecting-system stones were dominated by Ca-P laminates with relatively limited zinc organization. Across all anatomical zones, spherical micro- and nanoparticles were identified as shared structural units, with increasing particle size and greater inorganic character from papilla to collecting system, supporting a hierarchical continuum of mineral maturation.
CONCLUSIONS: Human kidney stones are anatomy-specific biominerals whose structure and chemistry encode the local microenvironment in which they form. Zinc appears to be a microenvironment-dependent modulator of early renal biomineralization, suggesting that localized renal environments, rather than systemic chemistry alone, may be critical therapeutic targets for preventing stone initiation and recurrence.
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