Phosphate and Klotho

Kidney Int Suppl. 2011 Apr;79(121):S20-3. doi: 10.1038/ki.2011.26. Epub 2011 Feb 23.

Abstract

Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone-kidney-parathyroid control of phosphate and calcium. Klotho⁻/⁻ mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor, or NaPi cotransporter). CKD can be seen as a state of hyperphosphatemia-induced accelerated aging associated with Klotho deficiency. Humans with CKD experience decreased Klotho expression as early as stage 1 CKD; Klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis D. Secreted Klotho protein, formed by extracellular clipping, exerts FGF-23-independent phosphaturic and calcium-conserving effects through its paracrine action on the proximal and distal tubules, respectively. We contend that decreased Klotho expression is the earliest biomarker of CKD and the initiator of CKD-MBD pathophysiology. Maintaining normal phosphate levels with phosphate binders in patients with CKD with declining Klotho expression is expected to reduce mineral and vascular derangements.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bone Diseases / etiology
  • Bone Diseases / metabolism*
  • Chronic Disease
  • Disease Models, Animal
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Humans
  • Kidney Diseases / complications
  • Kidney Diseases / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphates / metabolism*

Substances

  • Biomarkers
  • Phosphates
  • Glucuronidase
  • klotho protein