The document discusses FGF-23 and Klotho, which are central regulators of phosphate homeostasis and calcitriol levels. FGF-23 is synthesized by bone cells and increases with declining renal function in CKD to regulate phosphate levels. It signals through Klotho and FGF receptors. Klotho exists in membrane and soluble forms and is necessary for FGF-23's phosphaturic effects. It has protective roles through antioxidant effects and inhibits TGF-β to prevent fibrosis. Higher FGF-23 levels in CKD are due to decreased clearance and a compensatory response to maintain phosphate levels.
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1. CKD-MBD- II
Dr. Sandeep G Huilgol
MBBS., DNB (Internal Medicine)., MMedSci(Nephrology)
2. FGF-23
• Seven known subfamilies of human FGFs have been
defined.
• The FGF-19 subfamily is composed of three proteins—FGF-
19, FGF-21, and FGF-23.
• FGF-23 is a central regulator of phosphate homeostasis and
calcitriol blood levels;
• FGF-19 inhibits the expression of enzyme cholesterol 7-
ahydroxylase (CYP7A1), which is the first and rate-limiting
• step in bile acid synthesis
• FGF-21 stimulates insulin independent glucose uptake in
adipocytes and lowers triglycerides.
• FGF-19, FGF-21, and FGF-23 contain a disulfide bond that is
absent inmost other subfamilies hence these are present in
blood stream to mediate their functions.
3. • FGF-23 is a 251-amino acid protein (MW 26 kDa)
synthesized and secreted by bone cells, mainly
osteoblast.
• Amino-terminal signal peptide (residues 1–24), “FGF-
like sequence” (residues 25–180) and a carboxyl-
terminal extended sequence (residues 181– 251) that
is unique compared with other members of the FGF
family .
• The half-life of intact FGF-23 in the circulation of
healthy individuals is 58min.
• 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.
4. Physiological Functions of FGF-23
• Renal phosphate excretion is physiologically regulated
mainly by proximal tubular cells, which express both
Na/Pi Type IIa and Na/Pi IIc cotransporters at their apical
membrane
• FGF-23 reduces the action of both cotransporters; in
addition, it may inhibit gastrointestinal phosphate
absorption by reducing intestinal Na/Pi IIb cotransporter
activity in a vitamin D-dependent manner.
• The principal physiological stimuli for increased FGF-23
expression both in vitro and in vivo are 1,25(OH)2D3 and
high dietary phosphate intake
5. • Persistent hyperphosphataemia triggers FGF-23, while rapid
changes in serum phosphate concentrations does not induce
an acute increment in serum FGF-23 levels .
• Therefore FGF-23 responds to the net phosphate balance
rather than to the serum phosphate level.
6. FGF-23, PTH, and Calcitriol
• FGF-23, PTH, and calcitriol influence each other in opposite manner.
• FGF-R and Klotho are expressed in parathyroid glands.
• FGF-23 might decrease PTH mRNA transcription
• FGF-23 activity is not dependent on PTH as the phosphaturic effects of
FGF-23 are maintained in animals after parathyroidectomy .
• Conversely, PTH may stimulate FGF-23 secretion by osteoblast.
• Experimental injection of recombinant FGF-23 reduces calcitriol levels
within hours by decreasing renal expression of 1a-hydroxylase (CYP27B1)
and increasing the expression of 24-hydroxylase (CYP24A1).
• Conversely, calcitriol itself stimulates FGF-23 generation by binding to a
vitamin D response region in the FGF-23 gene promoter.
7. FGF-23 in Subjects with Intact Renal Function
• Physiological role of FGF-23 in healthy subjects is to
regulate urinary phosphate excretion to maintain
stable serum phosphate levels.
• However, no correlation between FGF-23 and serum
phosphate levels has been found in individuals
without overt renal disease.
8. FGF-23 in CKD
• In CKD, circulating FGF-23 levels gradually increase
with declining renal function.
• In end-stage renal disease, FGF23 levels can be 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.
• In contrast, it was hypothesized that increased FGF-
23 levels in CKD result primarily from decreased
renal clearance.
9. • However, there is no increase in the accumulation of
degraded FGF-23 in advanced CKD.
• FGF-23 levels also 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.
• Release of unidentified FGF-23 stimulatory factors or
loss of a negative feedback factor(s) that normally
suppress FGF-23, by the failing kidney.
10. FGF-23,Mortality, and Cardiovascular End Points
• In patients starting hemodialysis, higher FGF-23 levels
were strongly associated with increased risk of 1-year
mortality.
• In early CKD, it is observed that higher FGF-23 is linked to
several dynamic measurements of vascular dysfunction
like arterial stiffness measured by pulse wave velocity
and endothelial dysfunction.
• FGF-23 levels can be assosiated with vascular
dysfunction, atherosclerosis, and left ventricular in
patients with a lower eGFR despite normal phosphate
levels.
11. 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.
• In mice, the deletion of Klotho gene causes a
– phenotype of premature human aging
– vascular calcification,
– altered calcium/phosphate metabolism with
hyperphosphataemia,
– shortened lifespan.
12. • Klotho protein exists in two forms:
– Type I transmembrane protein (1014 amino acids) with a
large extracellular domain and a short intracellular portion
(10 amino acids), predominantly expressed in the renal
tubules.
– A circulating soluble factor detectable in blood and in
lesser extent in other biological fluids.
13. • Soluble Klotho is produced either by proteolytic cleavage
of the extracellular domain of the transmembrane form
(130 kDa isoform) operated by the membrane-anchored
proteases ADAM10 and ADAM17 .
• Or by alternative mRNA splicing (isoform 70 kDa).
• The systemic effects of this protein appear to be
predominantly due to the circulating form.
• The transmembrane protein forms a complex with
fibroblast growth factor (FGF) receptors and works as a
coreceptor for FGF23 for phosphate excretion into urine.
14. • Hyperphosphataemia in Klotho and FGF23-
mutant mice is due to hypervitaminosis D and
increased expression/activity of renal sodium-
dependent phosphate cotransporters.
• Klotho-deficient mice display higher levels of
FGF23, and a low-phosphate diet reduces the
levels of FGF23 and results in a rescue of the
features of premature aging.
• This suggests that FGF23 per se cannot promote a
phosphaturic effect in absence of Klotho.
15. • Klotho/FGF23 signalling induces phosphaturia by suppressing
the sodium-dependent phosphate cotransporters type IIa
(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 sodiumdependent
phosphate cotransporters (Pit1 and Pit2) which are
ubiquitously expressed and mediate phosphate uptake
16. • High FGF23 levels in patients with chronic
kidney disease are due to
– Declining renal clearance
– Compensatory response to hyperphosphataemia.
17. Role of Klotho in Cardiovascular and Renal Disease
• Reduction in renal, serum, and urine levels of
Klotho has been observed with
– Normal ageing.
– Diabetes
– Hypertension
– Chronic kidney disease
– Acute kidney injury
– Kidney ischemia
– Glomerulonephritis
18. • There is evidence in animals that the
overexpression of soluble Klotho can
– Reverse the ageing process
– Provides cardiovascular-renal protection
– Mechanism
• inducing resistance to oxidative stress and protecting
tissues from oxidative damage
19. Nephroprotective Effects of Klotho
• Nephroprotective effects of this protein are mostly
attributable to the antioxidant properties of its soluble
form.
• Klotho expression is reduced experimentally in renal
distal tubules, urine, and blood of rats subjected to
bilateral renal ischemia
• The injection of an adenovirus harbouring the Klotho
or the administration of recombinant soluble Klotho
protein prior to the induction of the ischemic insult
blunts the increase in creatinine and attenuates the
tubulointerstitial damage.
20. • Klotho expression is also downregulated in an
animal model of spontaneous hypertension.
• The delivery of Klotho has been shown to prevent
the progression of hypertension, renal damage,
and the proteinuria.
• Possible explanations for these observations are
– Reduction of renal superoxide
– Suppression of NADPH oxidase activity that is the
main source of reactive oxygen species (ROS).
21. • Nephroprotective in animal model of
glomerulonephritis.
• In glomerulonephritis Klotho over expression
results in
– increased survival,
– attenuated glomerular and tubulointerstitial
changes, and
– reduced proteinuria and blood urea nitrogen.
22. • It prevents the acute renal fibrosis through the
inhibition of TGF-β1 signalling.
• Klotho binds to the type II receptor (TGFβR2)
suppressing the activation of the type I
receptor (TGFβR1) that phosphorylates
Smad2/3 proteins (transcription factors
regulating the expression of TGFβ1 target
genes
23. Vascular Protective Effects of Klotho
• Soluble Klotho has an important role in
maintaining endothelial wall homeostasis and
promoting the health of the vasculature.
• Endothelial dysfunction results from the
imbalance between the release of vasodilator
and vasoconstrictor factors.
• Klotho gene increases endothelium dependent
NO synthesis and prevents adverse vascular
remodelling.
24. • Involved in the modulation of endothelial
inflammation by suppressing the expression of
adhesion molecules involved in the
pathogenesis of vascular disease
– Intracellular adhesion molecule-1 (ICAM-1)
– vascular cell adhesion molecule-1 (VCAM-1)
• Klotho is a direct inhibitor of vascular smooth
muscle cell (VSMC) calcification.
25. References
• Giuseppe Maltese and Janaka Karalliedde. The Putative Role
of the Antiageing Protein Klotho in Cardiovascular and Renal
Disease. International Journal of Hypertension. Volume 2012.
• Domenico Russo and Yuri Battaglia. Clinical Significance of
FGF-23 in Patients with CKD. International Journal of
Nephrology. Volume 2011.