Osteo‐renal regulation of systemic phosphate metabolism

Abstract

Summary Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries.

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

“…Moreover, FGF23-induced hypophosphatemia in Hyp mice is reversed to hyperphosphatemia in the Hyp mice without alpha-klotho activity (Hyp/alpha-klotho double mutant mice), despite high serum FGF23 levels in double mutant mice. 3,36 In accordance with these animal studies, an inactivating mutation in the human alpha-klotho gene resulted in severe hyperphosphatemia, despite high serum FGF23 levels in a patient with tumoral calcinosis. 38 From the above-cited human and experimental studies, it is clear that alpha-klotho has an indispensable role in FGF23-mediated phosphate metabolism.…”

“…[97][98][99] In fact, it is becoming more evident from experimental and human observations that features of phosphate toxicity can appear after consumption of a high-phosphate diet, even when serum phosphate levels are within the normal range. 3,43,45,79 Recent survey results highlight that even future medical professionals and CKD patients undergoing hemodialysis are not adequately aware of the hidden source of phosphate in their diet, and emphasize the need for educational initiatives to raise awareness of the risk posed by dietary items with hidden phosphate ingredients. 100,101 Taking into account human and animal observations, maintaining phosphate balance through adequate dietary intake appears to be important for a healthy life and for longevity.…”

“…2,3 However, physiologic phosphate regulation cannot be fully explained by the actions of these hormones alone, [4][5][6][7][8] and the identification of fibroblast growth factor 23 (FGF23), which can influence both vitamin D and PTH functions, helped us gain further insights into the physiologic regulation of phosphate homeostasis. Skeletal-derived FGF23 exerts phosphate-lowering effects in the kidney via a complex endocrine network; studies have identified osteoblasts and osteocytes as the main FGF23-producing cells.…”

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

“…Pyrophosphate is a strong chemical inhibitor of bone mineral (hydroxyapatite) formation and is locally provided by the pyrophosphate channel ANK and ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) (7). On a whole-organism level, phosphate levels are regulated by controlling retention/secretion in the kidney via a hormonal network involving parathyroid hormone (PTH), FGF23, and 1,25(OH) 2 D 3 (8).…”

Vitamin D supplements: Magic pill or overkill?

“…[11][12][13] We believe that harmful consequences of cardiovascular effects following calcium and vitamin D ingestion may be partly related to dysregulated phosphate balance. 1,[14][15][16] A wide range of vitamin-D fortified food is currently consumed with the anticipation that such fortified food and drink can maintain bone health by preventing skeletal disorders, including rickets. Food fortification is an accepted practice in many countries, although many types of food fortification were historically outlawed in several European countries.…”