Chronic Kidney disease associated mineral bone disorder.pptx

7/22/2019 Chronic Kidney disease associated mineral bone disorder.pptx

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Enseignement DES Nphrologie

18/04/2014Bertrand GONDOUIN

Chronic Kidney disease associatedmineral bone disorder

CKD-MBD


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Plan1. Introduction: CKD MBD un syndrome ?

2. Homostasie du Calcium et Phosphore

3. Troubles minraux associs: hyperparathyroidismesecondaire

4. Interventions thrapeutiques (Les guidelines et leurslimites)

5. CKD-MBD et association avec la mortalitcardiovasculaire

6. Conclusion et perspectives


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IntroductionCKD-MBD, un syndrome ?

Anomalies minrales chez lIRC: 2 consquencesprincipales

Survenue de calcifications vasculaires

Ostodystrophie

Prise en charge optimale est un dfi quotidien,avec 2 objectifs principaux :

Prvention du risque fracturaireLimitation des calcifications ectopiques et de la morbimortalit CV


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Syndrome: syn : ensemble, dromos : course

Dfinition Larousse: un syndrome est

lassociation de plusieurs symptmes, signes ouanomalies constituant une entit cliniquereconnaissable, soit par luniformit desassociations morbides, soit par le fait quelletraduit latteinte dun organe ou dun systme biendfini.



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Depuis quelques annes, des donnes delaboratoire sont utilises comme marqueurprdictifs de morbidit ou mortalit (ex: syndromemtabolique etc )

CKD MBD nouvelle entit syndromique dcritercemment (KDIGO 2009)



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Depuis quelques annes, des donnes delaboratoire sont utilises comme marqueurprdictifs de morbidit ou mortalit (ex: syndromemtabolique etc )

CKD MBD nouvelle entit syndromique dcritercemment (KDIGO 2009)



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Un ou plusieurs de ces lments:

1. Des modifications de lhomostasie desphosphates et du calcium ainsi que ses lmentsrgulateurs principalement la PTH et la 1,25 OHvitamine D3

2. De profondes modifications dans la structureosseuse et le remodelage osseux

3. La survenue de calcifications vasculaires



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3 questions:Est-ce que CKD MBD est un condition



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Homostasie du calcium etphosphore

Ions indispensable lorganisme, rle indispensabledans la minralisation du squelette

Constituent la base biochimique de l hydroxyapatite[Ca 10(PO4) 6(OH) 2]

Intervient dans de nombreux processus biologiquescomme la coagulation, lquilibre la contractionmusculaire, la conduction nerveuse (Ca); lquilibreacide-base, mtabolisme nergtique cellulaire,synthse de lADN (Ph)

Homostasie phospho calcique


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1000 mg de Ca: 99% dans le squelette

40 % lie aux protines et 60 % libre

[Ca ionis] = 1.1 et 1.35 mM, calcium biologiquement actif

Mouvements travers plusieurs compartiments



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+ 200mg/j 0 mg/j

- 200mg/j



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Trois segments tubulaires sont impliqus dans cetransport tubulaire rnal de Ca :

le tubule proximal (50-60 % de la rabsorption)

la branche large ascendante de lanse de Henle(20-25 % de la rabsorption)

le tubule contourn dista l/tubule collecteur (lereste)



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Tube proximal

Voie para-cellulaire +++



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Branche ascendante largela rabsorption de NaCl produit indirectement une diffrence de potentieltranspithliale, lumire positive

Voie paracellulaire +++



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le tubule contourn dista l/tubule collecteur

Voie transcellulaire+++



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Synthtise dans la glande parathyroide sous laforme dun peptide de 115 aa rapidement cliv en88 aa: PTH intacte, biologiquement active.Stocke dans des vsicules secretoiresProteolyse in situLa PTH circulante reprsente un mlangehtrogne de plusieurs fragments peptidiques

dont laiPTH et des fragments de PM diffrents(problmes de dosages.)

Homostasie du calcium et phosphoreLa PTH


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Le Ca ++ rgule directement la synthse d ARNmde PTH via un rcepteur calcium sensible (CaSR)qui dtecte les variations locales de Ca++

Relation inverse Ca++et PTH

Courbe dplace vers ladroite dans lIRC

Dans lIRC

Homostasie du calcium et phosphoreLa PTH


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2 origines: exognes et endognes

Calcidiol

Calcitriol

Homostasie du calcium et phosphoreLa Vitamine D


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Principale action biologique: augmentelabsorption intestinale de Ca et Ph +++

Augmente lexpression de TRPV6, calbindine 9K,pompe Ca ATP dpendante au niveau desenterocytes

Agit sur los: augmente la diffrenciation

ostoclastique et donc la rsorption osseuse

Inhibe la transcription de l ARNm de la PTH

Homostasie du calcium et phosphoreLa Vitamine D


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Physiologie du Ca

phosphore


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Physiologie du PhPhosphates osseux: 85 % des Ph de lorganisme 2 formes dans le plasma

organique (phsopholipides,esthers phosphors ADP ATP)Inorganique 85 %

Absorption intestinale: voie passive et voie active(co transporteur sodium phosphate: NPT2b)50/50


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Reabsorption tubulaire proximale majoritaire

Physiologie du Ph


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Physiologie du Ph


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Physiologie du Ph

+ 800mg/j 0 mg/j

- 800mg/j


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Physiologie du PhRgulation par le FGF 23

Protine de 251 aa secrte par les ostocytes Appartient la famille des Fibroblast GrowthFactorRcepteur FGF-R1 prfrentiellement

A la diffrence des autres membres de la famille,action endocrineNcessit dune interaction avec protine

membranaire KlothoForme soluble de Klotho aussi trouve


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Huang JL Kidney Int 2010


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A ce jour, aucunrcepteur capable dedtecter les variations

de Ph na t dcouvert


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Inhibition du FGF 23 ???

Rle de la protine PHEX ou DMP1 (dentinmatrix protein 1)

Martin C FASEB J 2010


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Physiologie du PhRgulation par la PTH

Augmentation de PTH diminue la rabsorptionrnale de phosphore

Effets opposs au FGF 23 sur la synthse rnalede calcitriol

Les glandes parathyroidiennes expriment klotho,cible du FGF 23


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Physiologie du PhRgulation par la PTH

Ph


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Physiologie du PhLien entre FGF 23 et PTH

Quarles LD Nature review Endocrinology 2010


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Physiologie du PhLien entre FGF 23 et PTH

Quarles LD Nature review Endocrinology 2010

Boucle de rgulation entre PTH et FGF 23


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Physiologie du Ph

Quarles LD Nature Med 2011


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Phosphore en post TX

Han SY transpl Proc 2011

Troubles minraux associs la maladie


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Troubles minraux associs la maladiernale chroniqueHyperparathyroidie secondaire

Survient systmatiquement en cas dIRC

Manifestation biologique la plus marquante desCKD-MBD

Associe une PTH leve, unehyperphosphatmie, une hypocalcmie et un

dficite en calcitriol



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Cintique dapparition non clairement identifie

Aucune modification de calcmie phosphormieavant 20-30 ml/min de DFG

Tendance l hyperphosphormie serait le primum movens




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Taux de FGF 23 slvent ds les stades prcoces de lIRC Mcanisme compensatoire luttant contre la rtention des phosphates

van Husen M Kidney Int 2010



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HyperPTH, mcanisme compensatoire

Modle avec FGF 23 au centre pas encore consensuel

Autres modles: rduction dexpression de Klotho rnal, desKlotho rsistance daction du FGF 23 et donc augmentation desa production

Action: maintien dune concentration de calcium ionis aussinormale que possible


Yamazaki BBRC 2010



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Au cours de lIRC svre, diminution desexpression des rcepteurs participant largulation du mtabolisme phospho calcique:VDR, CaSR, FGF-R, mKlotho

Dplacement du set point vers la droite




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Diminution de lexpression des VDR par le srumurmique Toell A J Cell Biochem 1999

Responsable dhyperplasie, ce stade, letraitement par Vit D active ne permet plus defreiner la PTH



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Dsordres osseux lis la CKD-MBD

Hyperpara: mcanisme de compensationSe fait au dpens du tissu osseuxModifications structurelles sur le niveau deremodelage osseux (turnover), la minralisationet la masse osseuse

Anciennement regroup sous le termed osteodystrophie rnale

Ncessite une biopsie osseuse qui nest plusralise en pratique clinique courante


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Atteintes lies :

Une acclration du remodelage osseux (osteitefibreuse, osteodystrophie mixte, osteoporose)

Un ralentissement du remodelage osseux (osadynamique)

Un trouble pur de la minralisation (ostomalacie)


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Indication de biopsie osseuse (KDIGO 2009)Fractures pathologiques inexpliques

Et/ouHypophosphatmie/hypercalcmie inexplique

Classification TMV


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Ostite fibreuse:Due exposition prolonge hyperPTHPTH: augmentation du nombre des osteoclastes,fibrose mdullaire

Remodelage osseux acclr de faon inadequate,san

Osteodystrophie mixte:= ostite fibreuse mais avec dminralisation

d l l


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Ostomalacie:RareDficit svre en vitamine D ou intoxicationaluminique

Os adynamique:Diminution du remodelage osseux +++Due hypoparathyroidie induite par PTX, dosesexcessives de chlateurs et/ou vit DRisque dhyper Ca et/ou Ph

d l


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Dsordres vasculairesCalcifications vasculaires

Go AS NEJM 2004

D d l i


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Altrations du systme cardiovasculaire

Dysfonctionnement endothlial

Rigidit vasculaire

HVG

Calcifications vasculaires

D d l i


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Calcifications intimales

Calcifications mdiales:

sclrose de Monckeberg

Calcifications vasculaires

C l ifi i l i


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Calcifications vasculairesMesure des calcifications

Gold standard coronary CT scan

Score CAC en unit Agatston

Pas de distinction entre intimal et mdial

Facteur prdictif de mortalit chez ICRT Shantouf RS Am J Nephrol 2010 , et population gnrale Polonsky TSJAMA 2010

D d l i


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Sigrist MK C JASN 2007

D d l i


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Sigrist MK C JASN 2007Rle relevant ?

Mesure des calcifications Est ce si


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Mesure des calcifications Est-ce siimportant ?

We conducted a comprehensive review of published reports on CAC progression.Increased CAC progression is associated with many known cardiac risk factors. We found that CACprogressioncorrelates with worsening atherosclerosis and may facilitate prediction of future cardiac events.These findingssupport the notion that slowing CAC progression with therapeutic interventions might provideprognostic benefit.However, despite promising early data, such interventions (most notably with statin therapy) havenot been shown to slow the progression of CAC in any randomized controlled trial to date,outside of post hoc subgroup analyses.

J Am Coll Cardiol 2010

C l ifi ti l i


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Calcifications vasculairesEtudes dintervention

Disparit dans les rsultats.


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Parler de la fetuin A


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Nephrol Dial Transplant. 2014 Jan 23. [Epub ahead of print]

FGF23 protein expression in coronary arteries is associated with impaired kidney function.van Venrooij NA 1, Pereira RC , Tintut Y , Fishbein MC , Tumber N , Demer LL , Salusky IB , Wesseling-Perry K .

Author information1Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Abstract

BACKGROUND:

Fibroblast growth factor 23 (FGF23) levels are elevated in chronic kidney disease (CKD) and elevated values have beenassociated with both heart disease and mortality. Recent studies show that FGF23, a protein synthesized by osteocytes, is alsopresent in calcified atherosclerotic plaques and may be induced by heart disease. Whether vascular expression of FGF23 is

associated with progressive CKD, however, remains unknown. Therefore, the relationship between kidney function, vascularcalcification and FGF23 expression was evaluated in patients with heart disease.

METHODS:

Immunohistochemistry for FGF23 was performed in coronary arteries of all patients undergoing heart transplantation at UCLAbetween February 2008 and 2010. Immunohistochemical staining for Klotho, DMP1, FGFR1, and FGFR3; calcium deposition; andRNA expression of Klotho and DMP1 were assessed in a subset of eight samples.

RESULTS:

FGF23 was detected by immunohistochemistry in 56% of the coronary artery specimens. Vascular FGF23 expression correlatedwith declining kidney function, as evidenced by reduced creatinine clearance. FGFR1 and FGFR3 were detected throughout thevascular tissue and in calcified plaques. Calcium deposition, Klotho expression and DMP1 expression correlated with FGF23immunoreactivity.

CONCLUSIONS:

The findings suggest that the Klotho-FGF23-FGFR system is active in coronary arteries and its upregulation correlates withimpaired renal function and matrix calcium deposition.
http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Venrooij%20NA[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Pereira%20RC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tintut%20Y[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Fishbein%20MC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tumber%20N[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Demer%20LL[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Salusky%20IB[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Wesseling-Perry%20K[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Wesseling-Perry%20K[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Wesseling-Perry%20K[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Wesseling-Perry%20K[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Salusky%20IB[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Salusky%20IB[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Salusky%20IB[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Demer%20LL[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Demer%20LL[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Demer%20LL[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tumber%20N[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tumber%20N[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tumber%20N[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Fishbein%20MC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Fishbein%20MC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Fishbein%20MC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tintut%20Y[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tintut%20Y[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Tintut%20Y[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=Pereira%20RC[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Venrooij%20NA[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Venrooij%20NA[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Venrooij%20NA[Author]&cauthor=true&cauthor_uid=24459137http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Venrooij%20NA[Author]&cauthor=true&cauthor_uid=24459137


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Dans cardiovasculaire


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Parler de a aussiNephrol Dial Transplant. 2013 Sep;28(9):2228-36. doi: 10.1093/ndt/gft065. Epub 2013 Apr 25.

Fibroblast growth factor-23: what we know, what we don't know, and what we need to know.Kovesdy CP 1, Quarles LD .Author information1University of Tennessee Health Science Center, Memphis, TN, USA.AbstractTraditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemiaand obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials ofinterventions targeting modifiable traditional risk factors have yielded disappointing results in this patientpopulation. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineralmetabolism have been proposed as potential explanations for the excess mortality seen in patients withchronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of whatthe most important pathophysiologic mechanisms of these risk factors are, which ones might be idealtreatment targets and which therapeutic interventions may be effective and safe in targeting them. Amongthe novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerfulpredictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced byosteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolismthrough activation of FGF receptor/ -Klotho co-receptor complexes. It is possible that elevated FGF23 mayexert its negative impact through distinct mechanisms of action independent from its role as a regulator ofphosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with leftventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on themyocardium. While it is possible that 'off target' effects of FGF23 present in very high concentrations couldinduce LVH, this possibility is controversial, since -klotho is not expressed in the myocardium. Anotherpossibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' activation of other humoralpathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated withelevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects andpotential therapeutic strategies to treat these.
http://www.ncbi.nlm.nih.gov/pubmed?term=Kovesdy%20CP[Author]&cauthor=true&cauthor_uid=23625971http://www.ncbi.nlm.nih.gov/pubmed?term=Quarles%20LD[Author]&cauthor=true&cauthor_uid=23625971http://www.ncbi.nlm.nih.gov/pubmed?term=Quarles%20LD[Author]&cauthor=true&cauthor_uid=23625971http://www.ncbi.nlm.nih.gov/pubmed?term=Kovesdy%20CP[Author]&cauthor=true&cauthor_uid=23625971http://www.ncbi.nlm.nih.gov/pubmed?term=Kovesdy%20CP[Author]&cauthor=true&cauthor_uid=23625971http://www.ncbi.nlm.nih.gov/pubmed?term=Kovesdy%20CP[Author]&cauthor=true&cauthor_uid=23625971


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Clin J Am Soc Nephrol. 2014 Mar 27. [Epub ahead of print]

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2-4.Seiler S 1, Rogacev KS , Roth HJ , Shafein P , Emrich I , Neuhaus S , Floege J , Fliser D , Heine GH .

Author information1Department of Internal Medicine IV- Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;, Labor Dr Limbach und Kollegen,Medizinisches Versorgungszentrum , Heidelberg, Germany, Division of Nephrology and Immunology, RWTH University of Aachen, Germany.

Abstract

BACKGROUND AND OBJECTIVES:

CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho).Recent experimental evidence suggests sKlotho has vasculoprotective functions.

DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS:

Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 intothe ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) thefirst occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from anycause.

RESULTS:

Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regressionanalysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensatedheart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk forboth end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for thirdversus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remainedsignificant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).

CONCLUSIONS:

In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantlyassociated with future decompensated heart failure but not incident atherosclerotic events.
http://www.ncbi.nlm.nih.gov/pubmed?term=Seiler%20S[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Rogacev%20KS[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Roth%20HJ[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Shafein%20P[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Emrich%20I[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Neuhaus%20S[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Floege%20J[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Fliser%20D[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Heine%20GH[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Heine%20GH[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Fliser%20D[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Fliser%20D[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Fliser%20D[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Floege%20J[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Floege%20J[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Floege%20J[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Neuhaus%20S[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Neuhaus%20S[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Neuhaus%20S[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Emrich%20I[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Emrich%20I[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Emrich%20I[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Shafein%20P[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Shafein%20P[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Shafein%20P[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Roth%20HJ[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Rogacev%20KS[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Rogacev%20KS[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Rogacev%20KS[Author]&cauthor=true&cauthor_uid=24677555http://www.ncbi.nlm.nih.gov/pubmed?term=Seiler%20S[Author]&cauthor=true&cauthor_uid=24677555


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Nat Rev Nephrol. 2013 Nov;9(11):650-60. doi: 10.1038/nrneph.2013.111. Epub 2013 Jun 18.Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism.Kuro-o M .Author informationDepartment of Pathology, University of Texas Southwestern Medical Center, 5323 HarryHines Boulevard, Dallas, TX 75390-9072, USA. [email protected] concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphateexcretion increases serum phosphate level and induces a premature-ageing phenotype.Urinary phosphate levels are increased by dietary phosphate overload and might inducetubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects byforming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred toin this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands thatcan induce various cellular responses, including the osteogenic transformation of vascularsmooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelialcells. Calciprotein particles are detected in the serum of animal models of kidney disease andin patients with chronic kidney disease (CKD) and might be associated with a(mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos thatregulate phosphate homeostasis and ageing. These observations raise the possibility thatcalciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, isexpected to provide novel diagnostic markers and therapeutic targets in CKD.
http://www.ncbi.nlm.nih.gov/pubmed?term=Kuro-o%20M[Author]&cauthor=true&cauthor_uid=23774819http://www.ncbi.nlm.nih.gov/pubmed?term=Kuro-o%20M[Author]&cauthor=true&cauthor_uid=23774819http://www.ncbi.nlm.nih.gov/pubmed?term=Kuro-o%20M[Author]&cauthor=true&cauthor_uid=23774819http://www.ncbi.nlm.nih.gov/pubmed?term=Kuro-o%20M[Author]&cauthor=true&cauthor_uid=23774819

Chronic Kidney disease associated mineral bone disorder.pptx

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