Zinc-enriched Pathological Biominerals in the Human Kidney Encode their Anatomical Microenvironments.

Abstract

The fundamental mechanisms underlying kidney stone formation remain elusive despite extensive research, limiting prevention strategies and contributing to high recurrence rates. Traditionally understood to arise through systemic urine supersaturation and conceptualized as monolithic concretions, kidney stones exhibit marked structural and compositional heterogeneity across distinct renal microenvironments. We hypothesized that these heterogeneous biominerals preserve physicochemical signatures of their anatomical origin and spatial organization of zinc (Zn) reflects microenvironment-specific mineralization processes. Using multiscale correlative microspectroscopy workflow, we characterized three morphologically distinct biominerals from three anatomically distinct renal niches. Papillary plaques and mineralized papillary stems exhibited strong compositional similarity, whereas collecting system stones were predominantly Ca- and P-rich inorganic mineral. Spatial gradients in zinc, calcium, phosphorus, and organic matrix components distinguished papillary mineralization from collecting system stone maturation. Zinc, traditionally a trace element, emerged as a spatially organized constituent with region-dependent abundance. Zn was enriched in papillary interstitium, and cellular substructures, where it colocalized with phosphorus and formed discrete high-density domains. Conserved spherical micro- and nanoparticles composed primarily of calcium and phosphorus, with variable organic content, were present across all biomineral types, indicating shared nucleation units. Based on these findings, we hypothesize a hierarchical mineralization model in which Zn-associated domains are spatially associated with calcium phosphate and calcium oxalate deposits. The coexistence of intratubular and interstitial mineral features reconciles classical free- and fixed-particle theories, indicating that heterogeneous stone formation arises through complementary mechanisms. Collectively, the observed anatomy-specific biominerals encode the physicochemical environments and highlight the importance of targeting localized microenvironments for improved therapeutic interventions. STATEMENT OF SIGNIFICANCE: Traditionally, kidney stones are viewed as uniform masses formed by mineral supersaturation in urine. This study challenges that paradigm by demonstrating that stones are complex, anatomy-specific biominerals that encode signatures of their chemical microenvironments and formation pathways within their structure. Using high-resolution, correlative imaging, we identify zinc as a spatially organized component of early mineralization rather than a passive trace byproduct, revealing previously unrecognized mechanisms of stone initiation. These findings shift the focus from purely physicochemical precipitation to microenvironment-driven formation and highlight mineral-tissue interactions as key targets for earlier detection, prevention, and therapeutic intervention in recurrent stone formation.