hosphorus homeostasis at the organismal level is maintained by balancing phosphate intake and excretion. Specifically, the amount of phosphate excreted into urine is regulated so as to become equal to the amount of phosphate absorbed from the digestive tract. 1 The amount of urinary phosphate excretion is primarily regulated by the endocrine axis consisting of fibroblast growth factor-23 (FGF23) and its obligate coreceptor klotho. FGF23 is a hormone secreted from osteoblasts and osteocytes in response to phosphate intake. FGF23 binds to the binary complex of FGF receptor and klotho expressed in renal tubules and suppresses phosphate reabsorption, thereby promoting urinary

The western pattern diet is rich not only in fat and calorie but also in phosphate. Negative impacts of excessive fat and calorie intake on health are widely accepted, whereas potential harms of excessive phosphate intake are poorly recognized. Here we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the functioning nephron number, circulating fibroblast growth factor-23 (FGF23), a hormone that increases phosphate excretion per nephron, was increased to maintain phosphate homeostasis.FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubular fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubular lumen, which damaged tubular cells through binding to Toll-like receptor-4 expressed on them. Persistent tubular damage induced interstitial fibrosis, reduced the nephron number, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, progression of chronic kidney disease (CKD) ensued when the serum FGF23 level exceeded 53 pg/mL. The present study identified the calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

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