A Western Diet High in Phosphate Primes the Development of the CKD-Mineral Bone Disorder in an Alport Syndrome Model.

KEY POINTS: An animal protein high-phosphate diet decreased cardiac mitochondrial oxidative phosphorylation in mice with normal kidney function. The animal-based protein high-phosphate diet worsened the severity of several CKD-mineral bone disease components in CKD. The effects of the diet during normal renal function prime the development and severity of the CKD-mineral bone disease during kidney disease progression.

BACKGROUND: CKD-mineral bone disorder (CKD-MBD) is a syndrome that contributes to cardiovascular mortality. We have shown that CKD decreases cardiac mitochondrial function independent of vascular disease and before cardiac hypertrophy. Hyperphosphatemia, a component of the CKD-MBD occurring in later stages of CKD, has been shown to stimulate vascular calcification (VC). In a mouse model of Alport syndrome CKD resistant to VC, we examine the effects of a high-phosphate Western-type diet (HP) on the components of the CKD-MBD, including cardiac respiration.

METHODS: Col4a5 -deficient mice and wild-type (WT) littermates were fed an animal protein 1.2% high-phosphate diet or a standard vegetable protein 0.6% phosphate diet. At CKD progression equivalent to human CKD stages 4-5, we examined cardiac tissue for mitochondrial respiration, kidney histology for fibrosis, blood for BUN and CKD-MBD components, kidney tissue for klotho production, and aorta for VC.

RESULTS: The HP diet produced hyperphosphatemia in the CKD animals compared with WT. The diet increased plasma parathyroid hormone (PTH; 17-fold), fibroblast growth factor 23 (FGF23) intact (14-fold), and reduced kidney klotho mRNA and protein more than 50%. Alport CKD mice fed the HP diet showed a reduction in cardiac mitochondrial complex 2-mediated oxidative phosphorylation, and higher levels of plasma PTH and FGF23 than CKD mice fed the vegetable protein diet. Comparing WT groups, the HP diet increased PTH and intact FGF23, reduced renal klotho, and decreased cardiac mitochondrial oxidative phosphorylation capacity. VC was not induced by the HP diet.

CONCLUSIONS: The Western-style high-phosphate diet primed the development of the CKD-MBD in nondiseased animals and worsened the CKD-MBD during CKD progression. Cardiac respiration, renal klotho, FGF23, and PTH are affected by a high-phosphate diet even with normal kidney function, suggesting a need for early intervention in the management of phosphate homeostasis as a component of CKD therapy.