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For many years, the existence of “phosphatonins”–substances secreted by certain tumors which result in profound renal phosphorus wasting and resultant osteomalacia–has been postulated.

Evidence has recently been accumulating that fibroblast growth factor 23 (FGF-23) is the phosphatonin we have been searching for:

High circulating levels of FGF23 are associated with hypophosphatemia, decreased 1,25 (OH) vitamin D levels, and rickets/bone disease.

The disease autosomal dominant hypophosphatemic rickets is caused by gain-of-function mutations in FGF23caused by splice site mutations. Conversely, the genetic disease inherited tumoral calcinosis, characterized by hyperphosphatemia, increased 1,25 (OH) vitamin D levels, and metastatic calcifications.

In ESRD, FGF23 levels are appropriately elevated in response to hyperphosphatemia, but due to a reduced GFR is unable to induce adequate phosphaturia.

How it works at a molecular level: FGF23 interacts with FGF receptors at the proximal tubule, resulting in decreased Na-PO4 exchange, as well as decreasing 1,25-alpha hydroxylase activity.

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