title: Phosphate and Klotho.
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.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA. Makoto.Kuro-o@UTSouthwestern.edu
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001847:Bone Diseases / Q000209:etiology / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins