Phosphate salt selection affects mortality and vascular calcification in the adenine-induced chronic kidney disease mouse model

Patients with chronic kidney disease (CKD) are at an increased risk for vascular calcification (VC), a strong predictor of cardiovascular events. Rodent models with elevated dietary levels of adenine and phosphate are commonly used to study CKD-induced VC; however, dietary composition, regimen duration, and reported outcomes vary widely across studies. Researchers customize high-adenine, high-phosphate (AdeHP) diets by adjusting phosphate levels and selecting specific phosphate salts as the phosphate source. In this observational study, we found that the selection and amount of phosphate salt used as the dietary phosphate source in an AdeHP mouse model of CKD-induced VC influence disease severity and survival in a sex-specific manner. Mice were fed a high-adenine diet for 6 wk to induce CKD, followed by an AdeHP diet containing either sodium (AdeHP-HNa) or calcium (AdeHP-HCa) based phosphate salts for up to six additional weeks to induce VC. Mice on the AdeHP-HCa diet exhibited worse kidney function and higher circulating phosphate levels compared with those on the AdeHP-HNa diet, with males showing more severe outcomes than females. However, mice on the AdeHP-HCa diet showed lower VC levels compared with those on the AdeHP-HNa diet, with males developing more calcification than females after 6 wk of the AdeHP regimen. Most importantly, a pronounced sex-dependent difference in survival was observed in males on the AdeHP-HNa diet, with only 16.67% surviving. These findings underscore the importance of phosphate salt selection and sex-specific variability in modeling CKD-induced VC with the AdeHP diet, providing key insights and considerations for preclinical studies.<b>NEW & NOTEWORTHY</b> We identified that the type of phosphate salt used to increase dietary phosphate in the adenine-induced CKD mouse model of VC influences calcification severity, survival, renal function, and circulating phosphate levels in a sex- and time-specific manner, with males exhibiting more severe outcomes. These findings highlight the importance of selecting and reporting phosphate salts used to supplement custom-made diets to prevent animal mortality and effectively model CKD-induced VC.