2. FGF 23
• Seven known subfamilies of human FGFs have been
defined
• FGF-23 is a 251-amino acid protein (MW 26 kDa)
synthesized and secreted by bone cells, mainly osteoblast
• It is composed of an
a) amino-terminal signal peptide (residues 1–24),
b) followed by an “FGF-like sequence” (residues 25–180) and
c) a carboxyl-terminal extended sequence (residues 181–
251) that is unique compared with other members of the
FGF family
3. • T ½- 58 min
• FGF-23 exerts its biological effects through
activation of FGF receptors (FGF-Rs); this
activation is Klotho dependent as a Klotho/FGF-R
complex binds to FGF-23 with higher affinity than
does FGF-R or Klotho alone
5. Active form of vitamin D (1,25-dihydroxyvitamin
D3) binds to vitamin D receptor (VDR) in the bone
(osteocytes).
The ligand-bound VDR forms a heterodimer with a
nuclear receptor retinoid X receptor (RXR) and
transactivates expression of the FGF23 gene.
6. FGF23 secreted from bone acts on the Klotho–FGF
receptor (FGFR) complex expressed in the
a) kidney (the bone−kidney axis) and
b) parathyroid gland (the bone−parathyroid axis)
7. In the kidney
• Downregulates luminal sodium/phosphate
cotransporters in the proximal tubule NPt IIa,
decreasing phosphorus reabsorption and
therefore increasing its excretion
• FGF23 suppresses synthesis of active vitamin D
by downregulating expression of the Cyp27b1
gene and
• Promotes its inactivation by upregulating
expression of the Cyp24 a1 (24-hydroxylase)
8. In the parathyroid gland,
• FGF23 suppresses production and
• Secretion of parathyroid hormone (PTH).
PTH binds to the PTH receptor (PTHR) expressed on
renal tubular cells, leading to upregulation of the
Cyp27b1 gene expression.
Thus, suppression of PTH by FGF23 reduces
expression of the Cyp27b1 gene (1alfa hydroxylase)
and serum levels of 1,25-dihydroxyvitamin D3.
9. The principal physiological stimuli for increased FGF-23
expression both in vitro and in vivo are
a)1,25(OH)2D3 and
b)high dietary phosphate intake
Persistent hyperphosphataemia is an effective trigger for
FGF-23, while rapid changes in serum phosphate
concentrations may not induce an acute increment in serum
FGF-23 levels
It is therefore possible that FGF-23 responds to the net
phosphate balance rather than to the serum phosphate
level, but experimental data supporting this hypothesis are
scarce.
10. FGF-23 CKD
• In CKD, circulating FGF-23 levels gradually increase with
declining renal function up to 1000-fold above the
normal range.
• The increase in FGF-23 begins at a very early stage of
CKD as a physiological compensation to stabilize serum
phosphate levels as the number of intact nephrons
declines trading off with hypovitaminosis D and
secondary HPT
• It is also likely that FGF-23 levels depend on an
increased secretion due to an end-organ resistance to
the phosphaturic stimulus of FGF-23 because of a
deficiency of the necessary Klotho cofactor .
11. FGF-23,Mortality,
and Cardiovascular End Points
• Indeed, in patients starting hemodialysis, higher
FGF-23 levels were strongly associated with
increased risk of 1-year mortality, reaching a
nearly 6-fold higher risk.
• FGF-23 was stronger predictor of mortality than
the serum phosphate level.
• FGF23 did not associate to mortality in patients
within the highest quartile of serum phosphate
suggesting that the prognostic value of FGF23 is
blunted in the presence of severe
hyperphosphatemia N Engl J Med 2008;359:584-92.
12. • Higher FGF-23 was linked to several dynamic
measurements of vascular function, including
arterial stiffness and endothelial dysfunction.
• Higher FGF-23 level was associated with higher
atherosclerosis score and coronary and
peripheral vasculature calcification score
• Consequent LVH noted
13. KLOTHO
Klotho is a gene that
encodes a novel
protein regulating
multiple functions,
discovered in 1997 by
Kuroo and colleagues
and named after the
goddess who spins the
thread of life in Greek
mythology
14. In mice, the deletion of Klotho gene causes a
phenotype of
• premature human aging
• including vascular calcification,
• altered calcium/phosphate metabolism with
hyperphosphataemia,
• and shortened lifespan.
15. Klotho protein exists in two forms:
Type I transmembrane protein (1014 AA)
• with a large extracellular domain and a short
intracellular portion
• predominantly expressed in the renal tubules,
Circulating soluble factor
• detectable in blood and in lesser extent in other
biological fluids
16. • The systemic effects of this protein appear to be
predominantly due to the circulating form.
• Klotho is predominantly expressed in the renal
distal tubularcells
• The transmembrane protein forms a complex
with fibroblast growth factor (FGF) receptors and
works as an obligate coreceptor for FGF23
• FGF23 per se cannot promote a phosphaturic
effect in absence of Klotho
17. • Klotho/FGF23 signalling induces phosphaturia by
suppressing (NPT2a) expressed on the brush border
membrane of renal tubular cells.
• Soluble Klotho has also been found to regulate
directly the phosphate transport, in the proximal tubule of
the kidney by deglycosylation of NaPi-2a cotransporters .
• The resulting reduction in number and activity of NaPi-2a
promotes phosphaturia independently of FGF-23.
• Soluble Klotho also inhibits type III sodium dependent
phosphate cotransporters (Pit1 and Pit2) which are
ubiquitously expressed and mediate phosphate uptake
18. • The reduction in Klotho expression observed in
Chronic kidney disease may be an important event
contributing to accumulation of FGF23 being a
Compensatory mechanism to the increase of
phosphate levels driven by the primary reduction in
Klotho.
• Changes in Klotho levels appear to precede
changes in phosphate levels, the key driver of
FGF23 balance in renal disease
19. Nephroprotective Effects of Klotho
• Nephroprotective effects of this protein are
mostly attributable to the antioxidant
properties of its soluble form
• Causes reduction of renal superoxide and
suppression of NADPH oxidase activity that is
the main source of reactive oxygen species
(ROS) which are all involved in the
pathogenesis of renal disease.
20. • Decresed levels seen in ischemia,hypertension
• Delivery to distal tubule by adenovirus with
klotho gene causes prevention of the
progression of hypertension, renal damage,
and the proteinuria
21.
22. • Klotho may be an early clinical biomarker of
acute and chronic renal injury CKD as its
diminution precedes changes of other well-
establishedmarkers/factors involved in the
progression of renal failure.
• Urinary Klotho levels have been tested for the
same.
23. Vascular Protective Effects of Klotho
In experimental models, the absence of Klotho
gene is associated with
• endothelial dysfunction and
• diffuse vascular calcification
