Apoptosis, ferroptosis, necrosis, necroptosis and pyroptosis in the formation of calcium oxalate kidney stones.

Kidney stones are one of the most common and debilitating urological disorders, putting substantial financial burden on healthcare services. Most common kidney stones are comprised of calcium oxalate often mixed with some calcium phosphate. Pathogenesis involves crystallization and retention of crystals within the kidneys, which is achieved either through the formation of crystalline plugs in the terminal collecting ducts blocking their openings into the renal pelvis, or formation of plaques of calcium phosphate on the renal papillary surface. The plugs are termed Randall's plugs and the plaques Randall's plaques. Several cell culture and animal model studies have been carried out to improve our understanding of the pathogenesis of calcium oxalate kidney stones to develop better treatments for the disease. Results of such studies have shown that exposure to oxalate and calcium oxalate/phosphate crystal leads to the production of reactive oxygen species and localized injury and inflammation. In addition, there are signs of autophagy and osteogenic changes in exposed cells. Modes of injury and cell death include apoptosis, ferroptosis, necrosis, necroptosis, and pyroptosis. Our review of relevant literature indicates that necrotic and necroptotic changes may be involved in the formation of Randall's plugs and associated kidney stones. Randall's plaque formation is most likely an outcome of the oxidant stress induced osteogenic changes in the tubular epithelium of the limbs of the loops of Henle and papillary collecting ducts and production of MMPs. Calcium phosphate deposition starts in the basement membrane, continues through the interstitium, mineralizing the collagen and membrane bound vesicles, until it reaches the papillary surface. The loss of urothelium most likely through the activation of MMPs exposes the plaque to the pelvic urine. Both plugs and plaque act as the platform for further deposition of crystals eventually developing into the stones.