Genetic diseases of renal phosphate handling

Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv45-54. doi: 10.1093/ndt/gfu217.


Renal control of systemic phosphate homeostasis is critical as evident from inborn and acquired diseases causing renal phosphate wasting. At least three transport proteins are responsible for renal phosphate reabsorption: NAPI-IIa (SLC34A1), NAPI-IIc (SLC34A3) and PIT-2 (SLC20A2). These transporters are highly regulated by various cellular mechanisms and factors including acid-base status, electrolyte balance and hormones such as dopamine, glucocorticoids, growth factors, vitamin D3, parathyroid hormone and fibroblast growth factor 23 (FGF23). Whether renal phosphate wasting is caused by inactivating mutations in the NAPI-IIa transporter is controversial. Mutations in the NAPI-IIc transporter cause hereditary hypophosphatemic rickets with hypercalciuria. Besides the primary inherited defects, there are also inherited defects in major regulators of phosphate homeostasis that lead to alterations in phosphate handling. Autosomal dominant hypophosphatemic rickets is due to FGF23 mutations leading to resistance against its own degradation. Similarly, inactivating mutations in the PHEX gene, which causes FGF23 inactivation, cause X-linked hypophosphatemia due to renal phosphate losses. In contrast, mutations in galactosamine:polypeptide N-acetyl-galactosaminyltransferase, responsible for O-glycosylation of FGF23, or in klotho, a cofactor for FGF23 signalling result in hyperphosphatemia. Acquired syndromes of renal phosphate wasting, hypophosphatemia and osteomalacia (tumour-associated osteomalacia) can be due to the excessive synthesis or release of phosphaturic factors (FGF23, FGF-7, MEPE and sFRP4) from mesenchymal tumours.

Keywords: bone, FGF23, kidney, phosphate, PTH.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Fibroblast Growth Factor-23
  • Genetic Markers / genetics*
  • Genetic Predisposition to Disease*
  • Humans
  • Kidney Diseases / genetics*
  • Kidney Diseases / metabolism
  • Kidney Diseases / therapy
  • Phosphates / metabolism*


  • FGF23 protein, human
  • Genetic Markers
  • Phosphates
  • Fibroblast Growth Factor-23