Presentation on theme: "Fibroblast Growth Factor 23 NEW INSIGHTS INTO CHRONIC KIDNEY DISEASE ESPN Lyon 2008 J Bacchetta, Lyon."— Presentation transcript:
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 2000s 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 125180251 FGF homology region Specific region 25180251 CLEAVAGE 25 + ACTIVE FGF23INACTIVE FGF23 RXXR
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 25180251 25 + ACTIVE FGF23INACTIVE FGF23 У λλ 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 OH ase Increased 24 OH ase Decreased 1,25 OH D 3 TRPV5 (+) Calcium reabsorption Npt2a/2c (-) Phosphaturia Proximal tubule Parathyroid cell Inhibition of osteoblastic differenciation and mineralization Inhibition of PTH secretion and gene expression Bone cell Active FGF23 (+) PTH,1-25 OH D 3 Inactive FGF23 FP convertase (-) Choroid plexus ?
Animal models of FGF23 deficiency FGF 23 -/-Klotho -/- Life spanShortened; accelerated aging Reproductive functionInfertility BoneOsteopenia CalcificationsSoft tissue and medial vascular calcification Clinical features Skin atrophy, neuronal degeneration, pulmonary emphysema, hypoglycemia BiologyIncreased tubular phosphate reabsorption Hyperphosphatemia Increased expression of Npt2a in kidney Increased 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 calcifications Low vitamin D diet: improves survival but does not prevent vascular calcifications Transfer of 1αOHase deficiency: rescues phenotype Memon 2008 WTFGF23 -/-
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 2006Ichikawa, 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
Mineral and Bone Disorders in CKD children GFR < 90 mL/min per 1.73 m 2 Long term Bone damage Drug toxicity Inflammation Anemia Metabolic acidosis Resistance to GH Vascular calcifications Morbidity and mortality Morbidity and mortality Ca-PHypocalcemia Hyperphosphatemia HormonesHyperparathyroidism Decreased vitamin D BoneDelayed bone maturation Decreased bone mass Pain, deformations Increased fracture risk GrowthResistance to GH MusclesProximal myopathy VesselsCalcifications EyeCorneal calcifications Band keratopathy SkinSoft tissue necrosis Pruritus
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-term FGF23
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), GFR inulin 100±34 mL/min per 1.73 m² (27-234) KDOQI IKDOQI IIKDOQI IIIHyperfiltration N71331620 GFR *110 ± 1176 ± 946 ± 8151 ± 27 FGF23 *63 ± 8996 ± 235103 ± 6266 ± 52 PTH *32 ± 1149 ± 1969 ± 2234 ± 17 25OH23 ± 923 ± 821 ± 721 ± 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 1 OH ase 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 dExploration 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