npt2a and npt2c facilitate the efficient reabsorption of phosphate in the proximal tubule ; expression of both transporters is regulated by pth and fgf-23 . the acute pth - dependent regulation of npt2a and npt2c expression is mediated predominantly through the camp and protein kinase a signaling pathway . the pth - induced increase in urinary phosphate cyclic amp production requires gs , which appears to be derived in this portion of the kidney predominantly , if not exclusively , from the maternal allele , thereby potentially limiting the maximal amount of gs protein that can be generated in this tissue . as a consequence of this parent - specific expression of gs in the proximal renal tubules , maternally inherited , heterozygous gnas mutations cause pth resistance , that is , pseudohyperparathyroidism . inactivating gnas mutations in those exons that encode gs cause pseudohypoparathyroidism type ia , whereas microdeletions within or upstream of gnas cause pseudohypoparathyroidism type ib and are associated with gnas methylation changes . the mechanism by which camp is excreted into the urine remains unknown , but is expected to involve a specific transporter that is expressed in the proximal tubule . in the distal tubule , pth diminishes calcium excretion through camp / protein kinase a- and possibly also through inositol trisphosphate / protein kinase c - dependent actions on the function of calbindin - d and trpv5 . in contrast to the findings in proximal tubular cells , gs is expressed in the distal tubular cells from both parental alleles , and maternally inherited gnas mutations consequently leave the pth - induced regulation of calcium excretion intact . fgf-23 is secreted by bone cells in response to 1,25(oh)2d3 , which increases the mrna levels encoding this phosphaturic hormone . fgf-23 mediates its action in the kidney through an fgf receptor ( fgfr)/klotho complex to downregulate npt2a and npt2c expression in the proximal tubules . however , it is uncertain whether fgf-23 signals initially through receptors in the distal convoluted tubule cells in which erk phosphorylation occurs in response to fgf-23 . these cells are adjacent to npt2a - expressing proximal tubular cells and it has therefore been speculated that a paracrine signal from the distal to the proximal tubules is required for decreasing npt2a expression . even small changes in plasma fgf-23 levels are associated with significant changes in urinary phosphate excretion , as shown by the small increase in fgf-23 levels after unilateral nephrectomy in healthy kidney donors , which is associated with increased urinary phosphate excretion . besides its effect on tubular phosphate handling , fgf-23 reduces pth secretion , and it inhibits 1-hydroxylase leading to a decrease in 1,25(oh)2d3 production , which contributes to the development of hypocalcemia and leads to an increase in pth production . npt2a and npt2c facilitate the efficient reabsorption of phosphate in the proximal tubule ; expression of both transporters is regulated by pth and fgf-23 . the acute pth - dependent regulation of npt2a and npt2c expression is mediated predominantly through the camp and protein kinase a signaling pathway . the pth - induced increase in urinary phosphate cyclic amp production requires gs , which appears to be derived in this portion of the kidney predominantly , if not exclusively , from the maternal allele , thereby potentially limiting the maximal amount of gs protein that can be generated in this tissue . as a consequence of this parent - specific expression of gs in the proximal renal tubules , maternally inherited , heterozygous gnas mutations cause pth resistance , that is , pseudohyperparathyroidism . inactivating gnas mutations in those exons that encode gs cause pseudohypoparathyroidism type ia , whereas microdeletions within or upstream of gnas cause pseudohypoparathyroidism type ib and are associated with gnas methylation changes . the mechanism by which camp is excreted into the urine remains unknown , but is expected to involve a specific transporter that is expressed in the proximal tubule . in the distal tubule , pth diminishes calcium excretion through camp / protein kinase a- and possibly also through inositol trisphosphate / protein kinase c - dependent actions on the function of calbindin - d and trpv5 . in contrast to the findings in proximal tubular cells , gs is expressed in the distal tubular cells from both parental alleles , and maternally inherited gnas mutations consequently leave the pth - induced regulation of calcium excretion intact . fgf-23 is secreted by bone cells in response to 1,25(oh)2d3 , which increases the mrna levels encoding this phosphaturic hormone . fgf-23 mediates its action in the kidney through an fgf receptor ( fgfr)/klotho complex to downregulate npt2a and npt2c expression in the proximal tubules . however , it is uncertain whether fgf-23 signals initially through receptors in the distal convoluted tubule cells in which erk phosphorylation occurs in response to fgf-23 . these cells are adjacent to npt2a - expressing proximal tubular cells and it has therefore been speculated that a paracrine signal from the distal to the proximal tubules is required for decreasing npt2a expression . even small changes in plasma fgf-23 levels are associated with significant changes in urinary phosphate excretion , as shown by the small increase in fgf-23 levels after unilateral nephrectomy in healthy kidney donors , which is associated with increased urinary phosphate excretion . besides its effect on tubular phosphate handling , fgf-23 reduces pth secretion , and it inhibits 1-hydroxylase leading to a decrease in 1,25(oh)2d3 production , which contributes to the development of hypocalcemia and leads to an increase in pth production . fgf-23 appears to be an important biomarker for an abnormal regulation of phosphate homeostasis in ckd and is likely to be involved in ckd - mbd pathophysiology . as ckd progresses , plasma fgf-23 levels increase . this increase occurs earlier and to a greater extent than observed for serum phosphate ; in late ckd , plasma fgf-23 levels can be elevated by several orders of magnitude . findings in experimental renal disease suggest that the fgf-23 increase also precedes the increase in pth levels . in fact , bone biopsies of patients with ckd have shown increased expression of fgf-23 already by ckd stage 2 , along with a marked increase in dmp1 protein ( a negative regulator of fgf-23 ) , which may be improperly processed and could thus be inactive . furthermore , in a prospective study of patients with mild - to - moderate ckd , higher plasma fgf-23 levels were shown to predict a more rapid progression toward end - stage renal disease ( esrd ) ; similarly elevated fgf-23 levels predict ckd progression in patients with diabetic nephropathy . in addition , elevated fgf-23 levels are independently associated with left ventricular hypertrophy in patients with ckd , an important finding because ckd - mbd , and particularly hyperphosphatemia , worsen the cardiovascular prognosis in ckd . aortic calcification , a major reason for cardiovascular morbidity , in hemodialysis recipients is independently predicted by plasma fgf-23 . dietary phosphate loading increases fgf-23 expression , whereas phosphate depletion with binders decreases the circulating levels of this hormone . in mild ckd , fgf-23 seems to function as a protective factor , as it triggers adaptive changes that maintain normophosphatemia . for example , in animal models , fgf-23 protects against hyperphosphatemia by increasing urinary phosphate excretion and reducing 1,25(oh)2d3 production ; diminished 1,25(oh)2d3 levels lead to hypocalcemia and thus to an increase in pth levels , which further enhances renal phosphate excretion . the importance of fgf-23 in mediating these effects is shown by the effects of anti - fgf-23 antibodies in rats with experimental ckd . animals with early ckd that were treated with anti - fgf-23 antibodies showed an increase in 1,25(oh)2d3 levels , a normalization of serum calcium levels , and a decrease in pth levels . furthermore , fractional phosphate excretion decreased because of inactivation of fgf-23 resulting in hyperphosphatemia . as ckd progresses , elevated fgf-23 levels are no longer able to enhance urinary phosphate excretion , thus leading to the development of hyperphosphatemia . this may be partly related to declining klotho expression and a reduction in functional nephrons . when patients require treatment by dialysis , the levels of immunoreactive fgf-23 can be markedly elevated ( figure 1 ) . however , unlike the appearance of large amounts of c - terminal pth fragments , most of which are biologically inactive , practically all of the circulating fgf-23 present in patients with esrd is intact and biologically active . this conclusion is based on observations with a reporter - cell assay ( human embryonic kidney cells expressing klotho and a luciferase reporter expressed under the control of the egr-1 promoter ) designed to quantify biologically active fgf-23 , which demonstrated excellent correlation with immunoreactive measurement of fgf-23 . the immunometric assays used for these measurements quantify the intact fgf-23 molecule alone ( kainos assay ) or the intact protein along with a c - terminal fragment ( immutopics assay ) . consistent with the excellent correlation between bioactive and immunoreactive fgf23 , western blot analyses of plasma fgf-23 from dialysis patients showed that most of the circulating fgf-23 is intact . thus , with ckd progression , the excess of biologically active fgf-23 , which is thought to occur in response to hyperphosphatemia , ceases to be protective and may lead to pathological off - target effects that potentially contribute to the increase in mortality as fgf-23 increases in patients with esrd ( figure 2 ) . interventions that lower serum phosphate , such as oral phosphate binders to prevent intestinal absorption or possibly long - acting pth analogs that reduce npt2a or npt2c expression , may help prevent ckd - related fgf-23 increases ( figure 3 ) . for example , two recently reported , long - acting pth analogs ( m - pth(1 - 28 ) and trp1-m - pth(1 - 28 ) ) were found to efficiently reduce npt2a expression in proximal tubules , leading to sustained hypophosphatemia in wild - type mice . targeting the proximal tubules with long - acting pth agents in early ckd may add to the effects of phosphate binders in normalizing serum phosphate levels and may help avoid an increase in fgf-23 , unless pth has a role in the synthesis and/or secretion of fgf-23 . proactive interventions to avoid the development of transient hyperphosphatemia in ckd may thus prevent an increase in fgf-23 and the hormone 's putative off - target effects in ckd - mbd . in support of this conclusion , a recent post hoc analysis of a randomized clinical trial has shown that treatment with phosphate binders can markedly decrease fgf-23 levels in patients undergoing hemodialysis . fgf-23 is a bone - generated major regulator of phosphate homeostasis , which appears to be an important biomarker of phosphate homeostasis in patients with ckd . plasma fgf-23 concentrations begin to increase early in ckd , with increases by orders of magnitude by the time patients reach esrd . increasing fgf-23 levels are independently associated with left ventricular hypertrophy , ckd progression , and mortality , possibly through off - target actions . further research is needed to show whether lowering fgf-23 levels improves outcomes in patients with ckd .
fibroblast growth factor ( fgf)-23 is probably the most important regulator of serum phosphate and calcitriol ( 1,25(oh)2d3 ) levels . 
 it is secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased serum 1,25(oh)2d3 levels . in human chronic kidney disease ( ckd ) 
 , plasma fgf-23 appears to be a sensitive biomarker of abnormal renal phosphate handling , as fgf-23 levels increase during early stages of kidney malfunction . in humans and animals with ckd , 
 elevated fgf-23 levels increase fractional phosphate excretion , reduce serum phosphate levels , and reduce 1-hydroxylase activity , which reduces 1,25(oh)2d3 formation thereby increasing parathyroid hormone ( pth ) secretion . 
 fgf-23 thus has a key adaptive role in maintaining normophosphatemia . 
 plasma fgf-23 continues to increase as ckd progresses , increasing by orders of magnitude in end - stage renal disease . at the same time , 
 responsiveness to fgf-23 declines as the number of intact nephrons declines , which is associated with reduced expression of klotho , the co - receptor required for fgf-23 signaling . in late ckd 
 , fgf-23 can not reduce serum phosphate levels , and abnormally high plasma fgf-23 concentrations appear to exert unwarranted off - target effects , including left ventricular hypertrophy , faster ckd progression , and premature mortality 
 . lowering serum phosphate levels through the use of oral phosphate binders and/or long - acting pth agents may reduce fgf-23 levels in early ckd stages , thereby limiting off - target effects , which may improve patient outcomes .