fibroblast growth factor 23 new insights into chronic kidney disease
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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 - PowerPoint PPT PresentationTRANSCRIPT
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 25 180 251
FGF homology region
Specific region
25 180 251 251
CLEAVAGE
25
+
ACTIVE FGF23
INACTIVE FGF23RXX
R
FGF23, different assays Two different types of assays (ELISA)
Intact FGF23: active form Antibody against C-term fragment: total FGF23, active and inactive forms
Limited data in children 1 study (total FGF23), 26 children (Jonsson, NEJM 2003)
Renal function: not defined
25 180 251 25125
+
ACTIVE FGF23
INACTIVE FGF23У
λ λ
УУ
λ
FGF23, physiology and regulation
FGF23 regulation not yet clear Potential regulatory mechanisms
FGF 23
P, Ca, PTH
DMP1
MEPE
PHEX
1,25 OH D3
(+) (-)
(-)
(+)
No direct effect on FGF23 promoter
Direct effect on FGF23 promoter
(VDR in osteoblasts)
Bone mineralization
(-)
(+)BONE
KIDNEY
(-)
Klotho
FGF-R
FGF23
Erk Phosphorylation
(+)
(+)
Distal tubule
Bone cell
(-)
Decreased 1α OHase Increased 24
OHase
Decreased 1,25 OH D3
TRPV5
(+)Calcium
reabsorption
Npt2a/2c
(-)Phosphaturia
Proximal tubule
Parathyroid cell
Inhibition of osteoblastic differenciatio
n and mineralizatio
n
Inhibition of PTH secretion and
gene expression
Bone cell
Active FGF23
(+)
PTH,1-25 OH D3
Inactive
FGF23
FP convertase
(-)
(-)
Choroid plexus
?
Animal models of FGF23 deficiency
FGF 23 -/- Klotho -/-
Life span Shortened; accelerated aging
Reproductive function
Infertility
Bone Osteopenia
Calcifications Soft tissue and medial vascular calcification
Clinical features Skin atrophy, neuronal degeneration, pulmonary emphysema,
hypoglycemia
Biology Increased tubular phosphate reabsorption Hyperphosphatemia
Increased expression of Npt2a in kidneyIncreased 1,25 OH vitamin D3 serum level
Hypercalcemia
Clinical symptoms probably arise from excess of phosphate rather than vitamin D
Low phosphate diet: rescues phenotype and prevents vascular calcificationsLow vitamin D diet: improves survival but does not prevent vascular calcificationsTransfer of 1αOHase deficiency: rescues phenotype
Memon 2008
WT FGF23 -/-
FGF23 deficiency and related diseases
Familial tumoral calcinosis Peri-articular, visceral and vascular calcifications Hyperostosis, specific dental abnormalities Biology: hyperphosphatemia, hypoparathyroidism
Genetics: recessive and dominant autosomal inheritance FGF23 inactivating mutation GALNT3 mutation (impaired glycosylation of FGF23)
KLOTHO mutation : high FGF23 concentration
Topaz 2006 Ichikawa, JCI 2007
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 Morbidity and mortalitymortality
Ca-P HypocalcemiaHyperphosphatemia
Hormones HyperparathyroidismDecreased vitamin D
Bone Delayed bone maturation
Decreased bone massPain, deformationsIncreased fracture risk
Growth Resistance to GH
Muscles Proximal myopathy
Vessels Calcifications
Eye Corneal calcificationsBand keratopathy
Skin Soft tissue necrosisPruritus
Reduced nephron number
Decreased 1-25 OH vitamin D
Decreased number of CaR
and VDR
Decreased urine
phosphate
excretion
Hyperphosphatemia
Hypocalcemia
Vitamin D analog
Hyperparathyroidism
Increased FGF23 level
Urine phosphate excretion
(limitation due to reduced nephron
number)
Decreased FGF23
clearance?
FGF23 and CKD
Stimulatory and inhibitory effect
FGF23 and CKD Increased FGF23
Early stages of CKD, prior to hyperphosphatemia Both intact and C-term FGF23
FGF23: active in CKD? 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
FGF23: a novel independent risk factor of progression of CKD in 177 non diabetic adult patients
Prospective follow-up 53 months
Fliser et al., JASN 2007
GFR
Phosphate
PTH
C-t
erm
FG
F23
FGF23, CKD and therapeutic response
At short term (Imanishi, KI 2005) 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
Nakanishi, KI 2005
At long term (Kazama, KI 2005) Baseline intact FGF23
predictor of refractory hyperparathyroidism
2 years 103 non diabetic HD
patients
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)
0
20
40
60
80
100
120
140
0 50 100 150 200 250
FGF23 Cterminal assay
Inul
in c
lear
ance
KDOQI I KDOQI II KDOQI IIIHyperfiltration
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 J Bacchetta, et al.
Unpublished results
FGF23, CKD and vascular calcifications
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
1OHase
FGF23 and CKD Toxic? Beneficial? Monitoring?
FGF23 and cardiovascular protection? Future: rh-FGF23? FGF23 Ab?
PTH
P
FGF23Vit D
Ca
Acknowledgements Centre de Référence des Maladies Rénales
Rares, Hôpital Femme Mère Enfant, Lyon P Cochat, B Ranchin, A Liutkus P Abou-Jaoude, A Pinçon, M Afanetti
Service d’Exploration Fonctionnelle Rénale et Métabolique, Hôpital Edouard Herriot, Lyon L Dubourg
Département de Biologie Ostéoarticulaire, Hôpital Edouard Herriot, Lyon M Richard S Arnaud
INSERM U831, Lyon PD Delmas I Rondy