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Crystalline nephropathy (CN) is characterized by deposition of microcrystals within the kidney tubular microstructure, specifically in the renal tubular cells. Nephropathic conditions have been observed in kidney stone patients as nephrocalcinosis, resulting from the deposition of calcium phosphate (CaP) microcrystals mainly within the renal tubule. CaP microcrystals trigger nephrotoxicity and cell death leading to acute and chronic kidney disease and in some cases end stage renal disease. Although supersaturation of calcium (Ca 2+ )- and phosphate (PO 4 3- ) ions in the urine was described as a main factor the precise mechanism of cell death by distinguishing the impact of supersaturated solution vs the crystalline substances is unclear. Here we show the differential effect of CaP solution vs preformed crystal (as crystalline CaP) on the nephrotoxicity and the degree and type of cell death using a murine kidney tubular cell line, LLCPK1. We examined the cellular [cell viability, lactate dehydrogenase (LDH) and H 2 O 2 releases and Annexin+ propidium iodide (PI) staining] and molecular events [gene expressions, oxidative and endoplasmic reticular (ER) stress] towards understanding the mechanism of CN. The results of the study demonstrated that CaP in solution exerts injury effect on LLCPK1 cells. The addition of CaP solution showed stronger necrosis than the preformed crystals as shown by PI staining and the releases of LDH and H 2 O 2 . Overall, the results in the study revealed a novel mechanism differentiating the kidney cell injury between the insult mediated by supersaturated CaP solution and preformed CaP crystals., (© 2025 Wiley Periodicals LLC.)