Regulated Cell Death in Calcium Oxalate Stone Disease: From Tubular Epithelial Injury to Inflammatory Amplification
TL;DR
Overall, crystal injury, regulated cell death, and inflammatory responses appear to interact across several CaOx-related lesion settings, with emphasis on lesion context and evidence depth.
Abstract
Abstract Calcium oxalate (CaOx) stone disease begins with urinary supersaturation. However, crystallization alone does not explain crystal retention, lesion progression, or inflammatory amplification. Current evidence suggests that crystal-exposed renal epithelium undergoes regulated stress responses that alter adhesion, membrane integrity, organellar homeostasis, and inflammatory signaling. These epithelial responses link luminal crystal contact to tissue injury and persistence. This review evaluates regulated cell death pathways in CaOx nephrolithiasis, oxalate nephropathy, and related crystal-induced renal injury, with emphasis on lesion context and evidence depth. Ferroptosis and pyroptosis currently have the strongest direct support in epithelial and preclinical CaOx-related models, but this pattern is not uniform across all lesion settings. Apoptosis is well supported but is best viewed as one output of broader epithelial stress. Regulated necrosis is documented mainly in crystal nephropathy, nephrocalcinosis, and acute oxalate injury. Autophagy requires context- and flux-aware interpretation, whereas mitophagy appears more consistently protective through the removal of damaged mitochondria. Immune-cell membrane rupture and neutrophil extracellular trap formation may add an inflammatory amplification layer. Direct evidence for cuproptosis and PANoptosis remains preliminary. Overall, crystal injury, regulated cell death, and inflammatory responses appear to interact across several CaOx-related lesion settings. Lesion-specific human validation remains limited.