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.