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Recent advances in renal phosphate handling.

ABSTRACT: Phosphate is critical for the maintenance of skeletal integrity, is a necessary component of important biomolecules, and is central to signal transduction and cell metabolism. It is becoming clear that endocrine communication between the skeleton, kidney, and the intestine is involved in maintaining appropriate serum phosphate concentrations, and that the kidney is the primary site for minute-to-minute regulation of phosphate levels. The identification of genetic alterations in Mendelian disorders of hypophosphatemia and hyperphosphatemia has led to the isolation of novel genes and the identification of new roles for existing proteins--such as fibroblast growth factor 23 and its processing systems, the co-receptor alpha-klotho, and phosphate transporters--in the control of renal phosphate handling. Recent findings also indicate that fibroblast growth factor 23 has feedback mechanisms involving parathyroid hormone and vitamin D that control phosphate homeostasis. This Review will highlight genetic, in vitro and in vivo findings, and will discuss how these clinical and experimental discoveries have uncovered novel aspects of renal phosphate handling and opened new research and therapeutic avenues.

SUBMITTER: Farrow EG

PROVIDER: S-EPMC3050486 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Recent advances in renal phosphate handling.

Farrow Emily G EG White Kenneth E KE

Nature reviews. Nephrology 20100223 4

Phosphate is critical for the maintenance of skeletal integrity, is a necessary component of important biomolecules, and is central to signal transduction and cell metabolism. It is becoming clear that endocrine communication between the skeleton, kidney, and the intestine is involved in maintaining appropriate serum phosphate concentrations, and that the kidney is the primary site for minute-to-minute regulation of phosphate levels. The identification of genetic alterations in Mendelian disorde ...[more]

PMID: 20177401

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Project description:Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self-administered for 28 days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

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Recent advances in renal phosphate handling.

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Recent advances in renal phosphate handling.

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