Sex-dependent divergence between skeletal and cardiac responses to phosphate load in experimental CKD.

Chronic kidney disease (CKD) induces a progressive decline in kidney function, leading to increased inorganic phosphate (Pi) load resulting in higher fibroblast growth factor 23 (FGF23) and cardiovascular complications including vascular calcifications (VC). Parallel rise of parathyroid hormone (PTH) increases bone resorption and release of calcium and Pi. These mineral and bone disorders (MBD) are central to the abnormalities observed in CKD. CKD has higher prevalence in women but higher cardiovascular impact on men, with increased risk of progressing to late stages. Here we characterize CKD-induced MBD in CD1 mice, and investigate sex differences. Twenty-week old male (M) and female (F) mice underwent 5/6 nephrectomy (Nx) then were fed either a normal (NP, 0.55% Pi) or a high phosphate diet (HP, 1.65% Pi) for 10 weeks. Nx mice showed increased markers of mineral metabolism, particularly under HP, including FGF23 (especially in F; HP vs NP: M +184%, F +770%), PTH (M +118%, F +201%) and osteopontin (M +92%, F +74%). Phosphatemia remained stable indicating that the phosphaturic effects of FGF23 were still sufficient, similar to early-stage CKD. Under HP cardiac hypertrophy was significant in M (+28% cardiomyocyte area vs NP) while bone disorders were more pronounced in F, with increased cortical porosity (+28% vs NP) and turnover. No VC was detected. Thus, HP diet induced a more severe mineral and bone phenotype in Nx CD1 female mice, making this strain a sensitive model to investigate female-predominant skeletal vulnerability in CKD.