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this review article will discuss the involvement of klotho in phosphate metabolism in ckd - mbd and propose the hypothesis that klotho deficiency is the earliest biomarker of ckd .
canonical fgf receptors ( fgfrs ) , which require cofactors for specific binding and signal transduction , are expressed in multiple tissues .
endocrine fgfs , however , including fgf-23 , use other cofactors ( or co - receptors ) .
klotho protein is a co - receptor specific for fgf-23 ( refs 7 , 8) .
kidney and parathyroid klotho expression identifies these organs as high - affinity fgf-23 endocrine targets .
the klotho / fgfr complex thus mediates fgf-23 participation in the bone  kidney  parathyroid endocrine axis . in the kidney , fgf-23
acting on klotho / fgfr suppresses phosphate reabsorption and 1,25(oh)2d3 synthesis ; in the parathyroid , fgf-23 suppresses parathyroid hormone secretion , which may also contribute to the ability of fgf-23 to reduce 1,25(oh)2d3 synthesis .
thus , fgf-23 is both a phosphaturic hormone and the counter - regulatory hormone to vitamin d in the bone  kidney 
parathyroid endocrine axis , and klotho is required for the effects of fgf-23 ( ref .
thus , fgf-23 can be identified as  phosphatonin ' , the bone - generated humoral phosphaturic factor postulated more than 10 years ago .
secretion of fgf-23 by bone is induced by phosphate and 1,25(oh)2d3(9 ) and possibly by parathyroid hormone . 

phosphate pathophysiology mediates complex aging - like phenotypes in mice with defects in the klotho 
low - phosphate diet improves the aging - like phenotypes of klotho mutant mice and fgf23 mice .
male homozygotes consuming 0.4  g phosphorus/100  g diet expressed the klotho protein in their kidneys and resumed normal spermatogenesis .
phosphate restriction corrected ckd - mbd - like fgf-23-null phenotypes ( hyperphosphatemia , vascular calcifications , and mortality ) even though serum calcium and 1,25(oh)2d3 levels remained elevated .
several other genetic and dietary interventions that rescue klotho and/or fgf23 phenotypes have lowered serum phosphate as their only common denominator ( table 1 ) .
phosphate retention may thus accelerate aging and/or age - related diseases in mice and humans .
patients with ckd are far more likely to die of cardiovascular disease than to live to require dialysis .
ckd - related cardiovascular disease is substantially fueled by hyperphosphatemia and can be seen as phosphate - related accelerated cardiovascular aging .
it may be hypothesized that ckd represents a state of accelerated aging associated with klotho deficiency and phosphate retention , and that klotho deficiency is the earliest biomarker of ckd and the initiator of ckd - related mineral dysregulation .
klotho expression declines progressively in ckd as fgf-23 expression increases progressively ; high serum phosphate and parathyroid hormone and low 1,25(oh)2d3 accompany these changes ( figure 2 ) .
the first measurable decline in urinary secreted klotho expression ( as detected by western blotting of concentrated urine samples , normalized to the same creatinine content ) occurs as early as stage 1 ckd and is potentially an early clinical marker of nascent acute renal damage .
klotho decline precedes fgf-23 increase as ckd develops in jck mice , a cystic kidney disease model of early progressive ckd .
renal klotho expression assays ( mrna measurement by rnase protection , protein measurement by western blotting , and immunohistochemistry ) in human kidney specimens from dialysis patients or controls showed that dialysis patients expressed renal membrane klotho at only 515% , most often < 5% , of control levels .
median klotho mrna levels in healthy kidney tissue represented slightly > 8% of the level of glyceraldehyde-3-phosphate dehydrogenase , a housekeeping mrna .
a sandwich enzyme - linked immunosorbent assay for secreted klotho in serum also exists and has shown that circulating secreted klotho in healthy adults ranges from 239 to 1266  pg / ml , decreasing with advancing age and increasing calcemia and increasing with phosphatemia levels .
more sensitive assays by multiple reaction monitoring using mass spectrometry are currently in progress . reducing serum fgf-23 increases serum 1,25(oh)2d3 and renal klotho expression .
parathyroidectomy is expected to reduce fgf-23 production , which in turn increases 1,25(oh)2d3 synthesis and then renal klotho expression .
vitamin d administration , peroxisome proliferator - activated receptor- agonists , or angiotensin ii inhibitors also increase klotho expression . large serum fgf-23 increases during ckd progression are efforts to maintain fgf-23 signaling as receptor availability decreases . in the normal kidney ,
as ckd progresses , ever - increasing serum fgf-23 acts on a resistant kidney with ever - fewer functional nephrons , each of which expresses less klotho than in a healthy kidney .
serum fgf-23 increases in an attempt to maintain normophosphatemia , but also suppresses 1,25(oh)2d3 synthesis .
klotho is a renoprotective factor ; when overexpressed it exerts a beneficial effect on mouse glomerulonephritis and acute kidney injury models .
decline in renal klotho expression precedes both fgf-23 overexpression and hyperphosphatemia , and may represent the initiating event of ckd .
however , klotho also exists as a secreted form produced by clipping the extracellular part of the molecule .
secreted klotho is found in blood , urine , and cerebrospinal fluid , and acts as an fgf-23-independent phosphaturic hormone .
however , klotho is expressed most intensely in renal dct and only weakly in proximal tubules .
two mechanisms for proximal tubule fgf-23 activity are possible : either fgf-23 acts directly on the proximal tubules and klotho 's function in the dct is unexplained , or fgf-23 acts through klotho on the dct to induce a paracrine signal to proximal tubules .
the extracellular portion of klotho protein is clipped by membrane proteases adam10 and adam17 ( ref .
34 ) and bace1 ( ref . 35 ) and secreted into blood , urine , and cerebrospinal fluid .
secreted klotho inhibits the sodium / phosphate transporters npt2a , npt2c , and npt3 ( refs 4 , 24 ) and activates ion channels trpv5 ( ref . 38 ) , trpv6 ( ref .
napi2a mediates proximal tubule phosphate reabsorption ( 7080% of total phosphate reabsorption ) ; studies on brush border membrane vesicles from proximal tubule cells show that secreted klotho inactivates napi2a .
some 70% of calcium reabsorption occurs in the proximal tubule and 15% in the dct ( utilizing trpv5 ; ref .
whole - cell patch - clamp experiments show that secreted klotho activates the calcium channel trpv5 ( ref .
we hypothesize that fgf-23 suppresses renal phosphate reabsorption and promotes calcium reabsorption by promoting the secretion of klotho from dct cells .
klotho entering the luminal fluid inhibits napi2a in proximal tubules to allow phosphate excretion and activates trpv5 in distal tubules to reabsorb calcium .
secreted klotho is present in the luminal fluid of proximal tubules , but how it is transported into the proximal tubular lumen is not yet known .
renal and parathyroid klotho co - receptors make fgfr specific for fgf-23 , the humoral phosphatonin secreted by bone . in the kidney , klotho mediates phosphate excretion and feedback inhibition of 1,25(oh)2d3 synthesis in response to fgf-23 .
klotho deficiency causes hyperphosphatemia and accelerated aging phenotypes , which are prevented in animals by resolving phosphate retention .
ckd and its complications , including ckd - mbd and vascular calcification , represent accelerated aging triggered by klotho deficiency .
klotho expression begins declining early in ckd and may precede both hyperphosphatemia and fgf-23 upregulation . further research is needed to determine whether klotho decline or increased fgf-23 drives the vicious cycle of phosphate pathology in ckd .
secreted klotho , an fgf-23-independent phosphaturic hormone , regulates renal sodium / phosphate cotransporters and calcium and potassium ion channels .
we hypothesize that fgf-23 induces secretion of klotho from dct cells , and secreted klotho is a paracrine signal to proximal tubule cells to inhibit phosphate reabsorption and stimulate calcium reabsorption .
decreased urinary secreted klotho may reflect decreased renal klotho expression and is one of the earliest biomarkers of ckd .
thus , maintaining normal phosphate levels with phosphate binders in patients with ckd with declining klotho expression is expected to reduce mineral and vascular derangements .
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 1-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 .