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Fibroblast Growth Factor 23 NEW INSIGHTS INTO CHRONIC KIDNEY DISEASE

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

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Fibroblast Growth Factor 23 NEW INSIGHTS INTO CHRONIC KIDNEY DISEASE

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  1. Fibroblast Growth Factor 23NEW INSIGHTS INTO CHRONIC KIDNEY DISEASE ESPN Lyon 2008 J Bacchetta, Lyon

  2. 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

  3. 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)

  4. FGF23, biochemical and structural properties 1 25 180 251 FGF homology region Specific region CLEAVAGE ACTIVE FGF23 INACTIVE FGF23 RXXR + • 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 25 180 251 25 251

  5. FGF23, different assays λ λ λ 251 25 180 251 25 + У У У ACTIVE FGF23 INACTIVE FGF23 • 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

  6. FGF23, physiology and regulation Direct effect on FGF23 promoter (VDR in osteoblasts) KIDNEY No direct effect on FGF23 promoter 1,25 OH D3 PHEX P, Ca, PTH (+) (-) (+) (-) FGF 23 MEPE (-) (-) BONE DMP1 (+) FGF23 regulation not yet clear Potential regulatory mechanisms Bone mineralization

  7. Active FGF23 FP convertase PTH,1-25 OHD3 (+) Bone cell FGF23 Inactive FGF23 Parathyroid cell FGF-R Inhibition of PTH secretion and gene expression Klotho Distal tubule (+) Calcium reabsorption (+) Erk Phosphorylation (-) Bone cell Inhibition of osteoblastic differenciation and mineralization (+) TRPV5 (-) Phosphaturia (-) Npt2a/2c (-) ? Decreased 1α OHase Increased 24 OHase Choroid plexus Decreased 1,25 OH D3 Proximal tubule

  8. Animal models of FGF23 deficiency WT FGF23 -/- Memon 2008

  9. FGF23 deficiency and related diseases Topaz 2006 Ichikawa, JCI 2007 • Familial tumoral calcinosis • Peri-articular, visceral and vascular calcifications • Hyperostosis, specific dental abnormalities • Biology: hyperphosphatemia, hypoparathyroidism • Genetics: recessive and dominant autosomal inheritance • FGF23inactivating mutation • GALNT3 mutation (impaired glycosylation of FGF23) • KLOTHOmutation : high FGF23 concentration

  10. FGF23 excess and related diseases • X-linked HR • PHEXmutation (Xp22) • Autosomal dominant HR • FGF23mutation • Autosomal recessive HR • DMP1 inactivating mutation • Other types • HR + hypercalciuria • Npt2c: autosomal recessive • ClCN5: X-linked • HR, hyperPTH and dysmorphy: Klothoactivating translocation Tumor-induced osteomalacia McCune-Albright Sd and fibrous dysplasia of bone Epidermal nevus syndrome Hypophosphatemic rickets

  11. FGF23 and CKD

  12. 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

  13. FGF23 and CKD Reduced nephron number Decreased urine phosphate excretion Decreased FGF23 clearance? Decreased number of CaR and VDR Decreased 1-25 OH vitamin D Hypocalcemia Hyperphosphatemia Vitamin D analog Hyperparathyroidism Increased FGF23 level Urine phosphate excretion (limitation due to reduced nephron number) Stimulatory and inhibitory effect

  14. 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?

  15. 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 C-term FGF23 Phosphate PTH

  16. 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 • At long term(Kazama, KI 2005) • Baseline intact FGF23 predictor of refractory hyperparathyroidism • 2 years • 103 non diabetic HD patients Nakanishi, KI 2005

  17. 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) 120 children, KDOQI 1,2,3 r= -0.426; P < 0.001 J Bacchetta, et al. Unpublished results

  18. FGF23, CKD and vascular calcifications • Association between reduced BMD and vascular calcifications • FGF23: not a biomarker of coronary calcifications in subjects with normal kidney functionRoos 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?

  19. ‘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 • FGF23 and CKD • Toxic? • Beneficial? • Monitoring? • FGF23 and cardiovascular protection? • Future: rh-FGF23? FGF23 Ab? Ca P PTH Vit D FGF23

  20. 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

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