Novel insights into the role of the renal interstitial microenvironment in Randall's plaque formation (Review)

Randall's plaque (RP) consists of subepithelial hydroxyapatite (HAP) deposits within renal papillae and provides a well‑established attachment substrate for a subset of idiopathic calcium oxalate (CaOx) kidney stones. However, RP has traditionally been viewed as a passive mineral surface onto which crystals accrete, with comparatively less focus on the cellular and molecular events that build the plaque itself. The renal papillary interstitium has been indicated as a dynamic microenvironment that undergoes molecular remodeling during plaque‑associated mineralization. The present review aimed to organize the current evidence regarding interconnected processes that may overlap in vivo rather than occur in a fixed sequence. Physicochemical conditions in the inner medullary interstitium favor HAP nucleation and provide the foundation for plaque formation. Epithelial injury responses, regulated cell death, osteogenic‑like fibroblasts and immune remodeling may contribute to the development of a pro‑calcific microenvironment; however, the spatial relationship, temporal order and plaque specificity of these processes remain incompletely defined. Macrophage polarization may influence whether local crystal‑associated inflammation and mineralization are amplified or reduced. As interstitial HAP deposits enlarge and become exposed through focal disruption of the renal papillary epithelium, these deposits can interact with pelvic urine and support CaOx nucleation and overgrowth. Systemic metabolic abnormalities and urinary or gut microbiome alterations are associated with stone disease and may modify the papillary microenvironment; however, direct evidence that they alter human RP burden is lacking to date. Of note, available animal and cell models demonstrate selected aspects of mineralization or crystal injury but do not reproduce the chronic, progressive interstitial HAP plaque observed in humans. In conclusion, considering RP as an interstitial microenvironmental disorder may help identify potential biomarkers of early papillary remodeling and generate potential therapeutic strategies for stone prevention in the future.