Fibroblast Growth Factor 23
NEW INSIGHTS INTO
CHRONIC KIDNEY DISEASE
ESPN Lyon 2008
J Bacchetta, Lyon
Outline

FGF23, the new hormone of the bone/kidney axis

FGF23, biochemical and structural properties

FGF23, physiological roles: regulation of phosphate and 1-25 OH
vitamin D

FGF23 deficiency and related diseases

FGF23 excess and related diseases

FGF23 and chronic kidney disease

Conclusion & perspectives
FGF23, the new hormone of the
bone/kidney axis

A phosphatonin described in the early 2000’s


FGF23 mutation in ADHR (Nat Genet. 2000)
Tumor-induced osteomalacia (Shimada, PNAS 2001)
FROM BEDSIDE TO BENCH

A protein synthesized by bone


Osteocytes, osteoblasts and odontoblasts
A complex of 3 elements for biological activity



FGF23
FGF-R: tyrosine kinase receptor
Klotho: cofactor
 Anti-aging protein
 Tissue-specific expression (kidney and parathyroid gland)
FGF23, biochemical and structural properties




Chromosome 12p13
Protein - 251 amino-acids, 30 kDa
FGF19 subfamily, the ‘endocrine’ FGFs
 Systemic action
 Stabilization of the β-trefoil structure by a disulfide
bond
Two forms: active/inactive
1
25
180
FGF homology region
CLEAVAGE
251
Specific region
ACTIVE FGF23
RXXR
INACTIVE FGF23
+
25
180
251
25
251
FGF23, different assays

25
Two different types of assays (ELISA)
 Intact FGF23: active form
 Antibody against C-term fragment: total
FGF23, active and inactive forms
λ
180
λ
251
λ
25
251
+
ACTIVE FGF23

У У
INACTIVE FGF23
Limited data in children
 1 study (total FGF23), 26 children
2003)

Renal function: not defined
У
(Jonsson, NEJM
FGF23, physiology and regulation


FGF23 regulation not yet clear
Potential regulatory mechanisms
Direct effect on FGF23
promoter
KIDNEY
No direct effect on
FGF23 promoter
(VDR in osteoblasts)
1,25 OH
D3
P, Ca, PTH
(+)
PHEX
(-)
(+)
(-)
FGF 23
MEPE
(-)
DMP1
(-)
(+)
Bone mineralization
BONE
Active FGF23
PTH,1-25 OH D3
FP convertase
(+)
Bone cell
Inactive
FGF23
FGF23
Klotho
FGF-R
Parathyroid cell
Inhibition of PTH
secretion and gene
expression
Distal tubule
(+)
Calcium
reabsorption
(+)
Erk Phosphorylation
Bone cell
(-)
(+)
TRPV5
(-)
Phosphaturia
(-)
Inhibition of
osteoblastic
differenciation
and
mineralization
Npt2a/2c
(-)
?
Decreased 1α OHase
Increased 24 OHase
Choroid plexus
Decreased 1,25 OH D3
Proximal tubule
WT
Animal models of FGF23
deficiency
FGF23 -/-
Memon 2008
FGF 23 -/Life span
Reproductive function
Bone
Calcifications
Clinical features
Biology
Clinical symptoms
probably arise from
excess of phosphate
rather than vitamin D
Klotho -/-
Shortened; accelerated aging
Infertility
Osteopenia
Soft tissue and medial vascular calcification
Skin atrophy, neuronal degeneration,
pulmonary emphysema, hypoglycemia
Increased tubular phosphate reabsorption Hyperphosphatemia
Increased expression of Npt2a in kidney
Increased 1,25 OH vitamin D3 serum level
Hypercalcemia
Low phosphate diet: rescues phenotype and prevents vascular
calcifications
Low vitamin D diet: improves survival but does not prevent vascular
calcifications
Transfer of 1αOHase deficiency: rescues phenotype
Topaz 2006
Ichikawa, JCI 2007
FGF23 deficiency and
related diseases

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Familial tumoral calcinosis
Peri-articular, visceral and vascular calcifications
Hyperostosis, specific dental abnormalities
Biology: hyperphosphatemia, hypoparathyroidism
Genetics: recessive and dominant
autosomal inheritance

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FGF23 inactivating mutation
GALNT3 mutation (impaired glycosylation of FGF23)
KLOTHO mutation : high FGF23 concentration
FGF23 excess and related diseases




Tumor-induced osteomalacia
McCune-Albright Sd and fibrous dysplasia
of bone
Epidermal nevus syndrome
Hypophosphatemic rickets




X-linked HR
 PHEX mutation (Xp22)
Autosomal dominant HR
 FGF23 mutation
Autosomal recessive HR
 DMP1 inactivating mutation
Other types
 HR + hypercalciuria
 Npt2c: autosomal recessive
 ClCN5: X-linked
 HR, hyperPTH and dysmorphy: Klotho activating translocation
FGF23 and CKD
Mineral and Bone Disorders in CKD children


GFR < 90 mL/min per 1.73 m2
Long term
 Bone damage
 Drug toxicity
 Inflammation
 Anemia
 Metabolic acidosis
 Resistance to GH

Vascular calcifications
Morbidity and mortality
Ca-P
Hypocalcemia
Hyperphosphatemia
Hormones
Hyperparathyroidism
Decreased vitamin D
Bone
Delayed bone maturation
Decreased bone mass
Pain, deformations
Increased fracture risk
Growth
Resistance to GH
Muscles
Proximal myopathy
Vessels
Calcifications
Eye
Corneal calcifications
Band keratopathy
Skin
Soft tissue necrosis
Pruritus
FGF23 and CKD
Reduced nephron number
Decreased
urine
phosphate
excretion
Decreased
FGF23
clearance?
Decreased 1-25 OH
vitamin D
Decreased number
of CaR and VDR
Hypocalcemia
Hyperphosphatemia
Vitamin D analog
Increased FGF23 level
Hyperparathyroidism
Urine phosphate excretion
(limitation due to reduced
nephron number)
Stimulatory and inhibitory effect
FGF23 and CKD

Increased FGF23



FGF23: active in CKD?


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Early stages of CKD, prior to hyperphosphatemia
Both intact and C-term FGF23
Accumulation in dialysis patients
Relative Klotho deficiency?
Sites with co-expression of Klotho and FGF-R


Cognitive function?
Growth?
FGF23 and CKD in adult patients

Fliser et al., JASN 2007
GFR
C-term FGF23

FGF23: a novel independent risk
factor of progression of CKD in 177
non diabetic adult patients
Prospective follow-up 53 months

Phosphate
PTH
FGF23, CKD and therapeutic response

At short term

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Intact FGF23 predictor of refractoriness to iv calcitriol therapy
In association with high serum PTH level (PPV 88 % and NPV 4 %)
24 weeks
62 HD patients
At long term

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(Imanishi, KI 2005)
(Kazama, KI 2005)
Baseline intact FGF23
predictor of refractory
hyperparathyroidism
2 years
103 non diabetic HD patients
Nakanishi, KI 2005
FGF23 and CKD children

141 children, 10.8±4 years (4.4-19.9), GFRinulin 100±34
mL/min per 1.73 m² (27-234)
KDOQI I
KDOQI II
KDOQI III
Hyperfiltration
N
71
33
16
20
GFR *
110 ± 11
76 ± 9
46 ± 8
151 ± 27
FGF23 *
63 ± 89
96 ± 235
103 ± 62
66 ± 52
PTH *
32 ± 11
49 ± 19
69 ± 22
34 ± 17
25OH
23 ± 9
23 ± 8
21 ± 7
21 ± 11
120 children, KDOQI 1,2,3
r= -0.426; P < 0.001
Inulin clearance
140
120
100
80
60
40
20
0
0
50
100
150
200
FGF23 Cterminal assay
250
J Bacchetta, et al.
Unpublished results
FGF23, CKD and vascular calcifications
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Association between reduced BMD and vascular calcifications
FGF23: not a biomarker of coronary calcifications in subjects with
normal kidney function Roos et al., Clin Endocrinol 2008
 64 subjects with normal kidney function
 No correlation between intact FGF23 and coronary artery score
FGF23: biomarker of medial peripheral artery calcification in CKD
patients? Inaba, Osteoporos Int. 2006
 Inversely correlated to hand arteries, not to aortic calcifications
FGF23 and vascular calcifications: unclear pathophysiology
 Direct inhibition of calcification?
 Indirect inhibition of vascular calcification
 By inhibiting hydroxylation of vitamin D?
 By lowering phosphate levels?
‘Take-home message’

FGF23/Klotho
 New insight to the understanding of Ca-P metabolism
 Two hormones - a strong interplay
 Two key roles: phosphaturia and inhibition of 1a-OHase
Ca

FGF23 and CKD
 Toxic?
 Beneficial?
 Monitoring?
PTH
Vit D


P
FGF23 and cardiovascular protection?
Future: rh-FGF23? FGF23 Ab?
FGF23
Acknowledgements

Centre de Référence des Maladies Rénales Rares,
Hôpital Femme Mère Enfant, Lyon


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Service d’Exploration Fonctionnelle Rénale et
Métabolique, Hôpital Edouard Herriot, Lyon


L Dubourg
Département de Biologie Ostéoarticulaire, Hôpital
Edouard Herriot, Lyon


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P Cochat, B Ranchin, A Liutkus
P Abou-Jaoude, A Pinçon, M Afanetti
M Richard
S Arnaud
INSERM U831, Lyon


PD Delmas
I Rondy