The hart and bone in concert - PDF Free Download

The hart and bone in concert Piotr Rozentryt III Department of Cardiology, Silesian Centre for Heart Disease, Silesian Medical University, Zabrze, Poland

Disclosure Research grant, speaker`s fee, travel grants from Genzyme, Roche Diagnostics

Functions of the skeleton Locomotion Organ protection Settlement for bone marrow Calcium and phosphorus* reservoir and endocrine activity measured in plasma as inorganic phosphate (phosphate / phosphorus used interchangebly)

Plan of talk Clasic concept of Ca and Pi physiology New concepts in Ca and Pi regulation role of bone Reasons for Pi overload Pi toxicity and off-target actions of calciotropic hormones What can we done today based on evidence?

Clasic concept of Ca and Pi physiology New concepts in Ca and Pi regulation central role of bone Reasons for Pi overload Pi toxicity and off-target actions of calciotropic hormones What can we do today based on evidence?

Calcium Phosphorus Bone & teeth (hydroxyepatite) Intracellular > 99% < 0,005% ~ 85% ~ 14-15% Blood < 0,5% < 1% Regulation Intestinal absorption ~ 80% Intestinal absorption ~ 30% under control of 1,25(OH 2 )D 3 Renal excretion ~ 70% under control of PTH and klotho. Translocation between bones and blood (control of PTH, and many others) under control of 1,25(OH 2 )D 3 Renal excretion ~ 70% under control of PTH, phosphatonins and other factors Translocation between compartments highly changeable (control of PTH for bone unknown for others) Peacoc M. Clin J Am Soc Nephrol 2010;5:s23-230 Razzaque MS. Clin Sci 2011;120:91-7

Classic concept of calcium / phosphate regulation Ca ++ Parathyroid VDR CaS (-) PTH Kidney 1,25(OH 2 )D 3 Ca ++ 1alpha hydroxylase-25d 3 Bone NaPi-IIa, NaPi-IIc 25(OH)D 3 Small intestine NaPi-IIb Osteoclasts resorption Osteoblasts - synthesis resorption Ca ++ Pi Ca ++ absorption Pi efflux Ca ++ Pi

Martin DR. Am J Physiol 2005;289:E729-E734.

Phosphatonin Circulating factor that induced renal inorganic phosphate wasting in patients with tumor-induced osteomalacia (TIO) Cai Q. N Engl J Med. 1994;330:1645-1649 FGF-23 fibroblast growth factor 23 is best described phosphatonin FGF-23 is secreted by osteocyts in response to rising concentration of phosphorus in small intestine or increased plasma level FGF-23 acts through FGF receptors but requires co-receptor klotho which defines target organs for FGF-23 active in phosphate homeostasis Kuro-O M. Trends Edocr Metab 2008;19:239-245

1500mg Pi/d 2300mg Pi/d 625mg Pi/d 13 healthy voluntiers Antoniucci DM. J Clin Endocrinol Metab 2006;91:3144-3149

Effects of FGF-23 neutralisation on plasma level of 1,25(OH 2 )D 3 in rats Effects of FGF-23 neutralisation on enzymatic activity of 1alphaOH hydroxylase and 24 hydroxylase in rats Hasegawa H. Kidney Int 2010;78:975-980

Klotho is expressed (organs that respond to FGF-23 using FGF receptors): Parathyroids Kidneys Brain (role of FGF23 not defined yet) Kuro-O M. Korean J Int Med. 2011;26:113-122

for FGF23 Gattineni J. Am J Physiol. 2009;297:F282 F291

Hamowanie PTH przez FGF-23 Komba H. Kidney Int 2010;77:292 298.

New concept of calcium / phosphate regulation PTH Parathyroid (+) FGFR1 Klotho VDR CaS Inactive metabolits (also catabolites of 25D3), 1,25(OH 2 )D 3 1,24 hydroxylase-25d 3 (+) FGF-23 Dietary or blood Pi Kidney (-) 1alpha hydroxylase-25d 3 FGFR1 Klotho NaPi-IIa, NaPi-IIc resorption Ca ++ Pi 25(OH)D 3 Small intestine Pi Ca ++ Bone Osteoclasts more active Osteoblasts less active (uncoupling) Modified Kuro-O. Kidney Int Suppl 2011;121:S20-S23.

To much phosphorus and/or to much rapidly absorbed phosphorus in food (inorganic phosphorus from preservatives, conservants is absorbed 100% within minutes, from organic sources only 40-60% in hours) Food questionaries DO NOT capture this hidden phosphorus estimated to add 20-70% Murphy-Gutekunst L. J Ren Nutr 2005;15:e1-e6 Benieni O. J Ren Nutr 2011;21:303-3-8 Reduced ability of kidneys to excreate phosphorus Rapid translocation from intracellular compartments ie. tumor lysis syndrome and tissue hypoxia Howard SC. N Engl J Med. 2011;364:1844-1854

Flynn at al.: Intake of selected nutrients from foods, from fortification and from supplements in various European countriesintake of selected nutrients from foods, from fortification and from supplements in various European countries. Food Nutr Res 2009 700 mg UNDERESTIMATION BY 20-70% DUE TO PRESENCE OF HIDDEN Pi

Tucker KL. Am J Clin Nutr 2006;84:936 42.

The likelihood of plasma Pi >3.5 mg/dl in relation to oedema-free weight change in hart failure OR, 95% CI Adjusted for age, gender, GFR, ALP 772 patients with chronic hart failure and verying degree of oedema-free weight loss Rozentryt P. unpublished

Meal with 400 mg of P Meal with 1200 mg of P preprandial postprandial 11 healthy voluntiers Shuto E. JASN 2009;20:1504-1512

The probability of CAC > 100 ua related to plasma phosphorus in patients with baseline normal CAC for each 1 mg/dl of Pi increase the probability of CAC>100 rose by 34% Follow-up = 17 years Baseline and follow-up CAC assessed by electron-beam computed tomography CARDIA Study N= 3015 mean baseline age = 25 y, mean Pi in diet = 1775 mg/d 3.9 mg/dl Foley RN. J Am Soc Nephrol 2009; 20: 397 404

Genetic inactivation of either klotho or FGF-23 n mice induces hyperphosphatemia and a phenotype of premature aging and shorter life span (vasular calcifications, osteoporosis, infertility, emphysema, muscle wasting, skin atrophy, central nervous system pathology) Biochemistry: Pi, Ca 1,25(OH 2 )D 3 Nakatani T. FASEB J 2009;23:433-441.

Interventions capable of rescuining premature aging phenotype in klotho KO or FGF23 KO mice Kuro-O M. Kidney Int Suppl. 2011;121:s20-s23. John GB. Am J Kidney Dis 2011;58:127-134.

Dhingra et al.: Relations of Serum Phosphorus and Calcium Levels to the Incidence of Cardiovascular Disease in the Community. Arch Int Med 2007 Tonelli at al.: Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease. Circulation 2005

Off-target action of hormones regulating phosphorus homeostasis Hyperparathyroidism Higher level of FGF-23 Reduction of 1,25(OH 2 )D 3 and 25(OH)D 3

High Pi intake and tissue hypoxia with Induction translcation from intracellular stores may shift it to the left MOST TYPICAL CARDIAC PATIENTS ARE HERE Wolf M. J Am Soc Nephrol 2010;21:!427-1435

Uppsala Longitudinal Study of Adult Men N= 958 men, median follow-up = 9.7 years Hagstrom E. Circulation 2009;119:2765-2771

The association of FGF23 and left ventricle hypethrophy N=795 Age =70 Mirza MAI. 207 (2009) 546 551

Median value within lowest quartile of FGF23 taken as a referent CRIK study N=3879 patients with chronic kidney disease Stage 2-4 Isakova T. JAMA 2011;305:2432-2439

Cardiovascular mortality in relation to 25(OH)D 3 N=1194 Michaelson K. Am J Clin Nutr 2010;92:841 8.

Reduction of nutritional Pi burden by diet? Type of diet may influence plasma phosphorus and FGF23 Moe SM. Clin J Am Soc Nephrol 2011;6:257-264

Reduction of nutritional Pi burden by binders? 127 dialysed patients treated with calcium containing Pi binder or with sevelamer non calcium containing Pi binder Block GA. Kidney International 2007; 71:38 441

Vitamin D supplementation? Autier P. Arch Intern Med. 2007;167(16):1730-1737

Summary Bones are an important endocrine organ FGF23 secreated by osteocytes is critical for systemic phosphorus balance Impairement of FGF23 endocrine functions may result in delataroius consequences We urgently need randomised trials to test interventions aiming at disrupted mineral homeostasis In patients free of significant kidney disease

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