Enseignement DES Nphrologie

18/04/2014
Bertrand GONDOUIN
Chronic Kidney disease associated
mineral bone disorder
CKD-MBD
Plan
1. Introduction: CKD MBD un syndrome ?

2. Homostasie du Calcium et Phosphore

3. Troubles minraux associs: hyperparathyroidisme
secondaire

4. Interventions thrapeutiques (Les guidelines et leurs
limites)

5. CKD-MBD et association avec la mortalit
cardiovasculaire

6. Conclusion et perspectives
Introduction
CKD-MBD, un syndrome ?
Anomalies minrales chez lIRC: 2 consquences
principales
Survenue de calcifications vasculaires
Ostodystrophie

Prise en charge optimale est un dfi quotidien,
avec 2 objectifs principaux :
Prvention du risque fracturaire
Limitation des calcifications ectopiques et de la morbi
mortalit CV


Syndrome: syn: ensemble, dromos: course

Dfinition Larousse: un syndrome est
lassociation de plusieurs symptmes, signes ou
anomalies constituant une entit clinique
reconnaissable, soit par luniformit des
associations morbides, soit par le fait quelle
traduit latteinte dun organe ou dun systme bien
dfini.
Introduction
CKD-MBD, un syndrome ?
Depuis quelques annes, des donnes de
laboratoire sont utilises comme marqueur
prdictifs de morbidit ou mortalit (ex: syndrome
mtabolique etc)

CKD MBD nouvelle entit syndromique dcrite
rcemment (KDIGO 2009)
Introduction
CKD-MBD, un syndrome ?
Depuis quelques annes, des donnes de
laboratoire sont utilises comme marqueur
prdictifs de morbidit ou mortalit (ex: syndrome
mtabolique etc)

CKD MBD nouvelle entit syndromique dcrite
rcemment (KDIGO 2009)
Introduction
CKD-MBD, un syndrome ?
Un ou plusieurs de ces lments:

1. Des modifications de lhomostasie des
phosphates et du calcium ainsi que ses lments
rgulateurs principalement la PTH et la 1,25 OH
vitamine D3

2. De profondes modifications dans la structure
osseuse et le remodelage osseux

3. La survenue de calcifications vasculaires

Introduction
CKD-MBD, un syndrome ?
3 questions:
Est-ce que CKD MBD est un condition
Introduction
CKD-MBD, un syndrome ?

Homostasie du calcium et
phosphore
Ions indispensable lorganisme, rle indispensable
dans la minralisation du squelette

Constituent la base biochimique de lhydroxyapatite
[Ca10(PO4)6(OH)2]

Intervient dans de nombreux processus biologiques
comme la coagulation, lquilibre la contraction
musculaire, la conduction nerveuse (Ca); lquilibre
acide-base, mtabolisme nergtique cellulaire,
synthse de lADN (Ph)

Homostasie phospho calcique
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
Homostasie du calcium et
phosphore
Homostasie du calcium et
phosphore
+ 200
mg/j 0 mg/j
- 200
mg/j
Homostasie du calcium et
phosphore
Trois segments tubulaires sont impliqus dans ce
transport 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 (le
reste)
Homostasie du calcium et
phosphore
Tube proximal
Voie para-cellulaire +++
Homostasie du calcium et
phosphore
Branche ascendante large
la rabsorption de NaCl produit indirectement une diffrence de potentiel
transpithliale, lumire positive
Voie paracellulaire +++
Homostasie du calcium et
phosphore
le tubule contourn dista l/tubule collecteur
Voie transcellulaire+++
Homostasie du calcium et
phosphore
Synthtise dans la glande parathyroide sous la
forme dun peptide de 115 aa rapidement cliv en
88 aa: PTH intacte, biologiquement active.
Stocke dans des vsicules secretoires
Proteolyse in situ
La PTH circulante reprsente un mlange
htrogne de plusieurs fragments peptidiques
dont laiPTH et des fragments de PM diffrents
(problmes de dosages.)
Homostasie du calcium et phosphore
La PTH
Le Ca ++ rgule directement la synthse dARNm
de PTH via un rcepteur calcium sensible (CaSR)
qui dtecte les variations locales de Ca++

Relation inverse Ca++
et PTH

Courbe dplace vers la
droite dans lIRC

Dans lIRC
Homostasie du calcium et phosphore
La PTH
2 origines: exognes et endognes
Calcidiol
Calcitriol
Homostasie du calcium et phosphore
La Vitamine D
Principale action biologique: augmente
labsorption intestinale de Ca et Ph +++

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

Agit sur los: augmente la diffrenciation
ostoclastique et donc la rsorption osseuse

Inhibe la transcription de lARNm de la PTH
Homostasie du calcium et phosphore
La Vitamine D
Physiologie du Ca

phosphore
Physiologie du Ph
Phosphates 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
Reabsorption tubulaire proximale majoritaire

Physiologie du Ph
Physiologie du Ph
Physiologie du Ph
+ 800
mg/j
0 mg/j
- 800
mg/j
Physiologie du Ph
Rgulation par le FGF 23
Protine de 251 aa secrte par les ostocytes
Appartient la famille des Fibroblast Growth
Factor
Rcepteur FGF-R1 prfrentiellement
A la diffrence des autres membres de la famille,
action endocrine
Ncessit dune interaction avec protine
membranaire Klotho
Forme soluble de Klotho aussi trouve
Physiologie du Ph
Rgulation par le FGF 23
Huang JL Kidney Int 2010
Physiologie du Ph
Rgulation par le FGF 23
Physiologie du Ph
Rgulation par le FGF 23
A ce jour, aucun
rcepteur capable de
dtecter les variations
de Ph na t dcouvert
Physiologie du Ph
Rgulation par le FGF 23
Inhibition du FGF 23 ???

Rle de la protine PHEX ou DMP1 (dentin
matrix protein 1)

Martin C FASEB J 2010
Physiologie du Ph
Rgulation par la PTH
Augmentation de PTH diminue la rabsorption
rnale de phosphore

Effets opposs au FGF 23 sur la synthse rnale
de calcitriol

Les glandes parathyroidiennes expriment klotho,
cible du FGF 23
Physiologie du Ph
Rgulation par la PTH
Ph
Physiologie du Ph
Lien entre FGF 23 et PTH
Quarles LD Nature review Endocrinology 2010
Physiologie du Ph
Lien entre FGF 23 et PTH
Quarles LD Nature review Endocrinology 2010
Boucle de rgulation entre PTH et FGF 23
Physiologie du Ph

Quarles LD Nature Med 2011
Phosphore en post TX
Han SY transpl Proc 2011
Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Survient systmatiquement en cas dIRC

Manifestation biologique la plus marquante des
CKD-MBD

Associe une PTH leve, une
hyperphosphatmie, une hypocalcmie et un
dficite en calcitriol

Cintique dapparition non clairement identifie

Aucune modification de calcmie phosphormie
avant 20-30 ml/min de DFG

Tendance lhyperphosphormie serait le
primum movens
Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
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
HyperPTH, mcanisme compensatoire

Modle avec FGF 23 au centre pas encore consensuel

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





Action: maintien dune concentration de calcium ionis aussi
normale que possible
Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Yamazaki BBRC 2010
Au cours de lIRC svre, diminution des
expression des rcepteurs participant la
rgulation du mtabolisme phospho calcique:
VDR, CaSR, FGF-R, mKlotho
Dplacement du set point vers la droite


Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Diminution de lexpression des VDR par le srum
urmique Toell A J Cell Biochem 1999

Responsable dhyperplasie, ce stade, le
traitement par Vit D active ne permet plus de
freiner la PTH



Troubles minraux associs la maladie
rnale chronique
Hyperparathyroidie secondaire
Dsordres osseux lis la CKD-
MBD
Hyperpara: mcanisme de compensation
Se fait au dpens du tissu osseux
Modifications structurelles sur le niveau de
remodelage osseux (turnover), la minralisation
et la masse osseuse
Anciennement regroup sous le terme
d osteodystrophie rnale
Ncessite une biopsie osseuse qui nest plus
ralise en pratique clinique courante
Dsordres osseux lis la CKD-
MBD
Atteintes lies :

Une acclration du remodelage osseux (osteite
fibreuse, osteodystrophie mixte, osteoporose)

Un ralentissement du remodelage osseux (os
adynamique)

Un trouble pur de la minralisation (ostomalacie)
Dsordres osseux lis la CKD-
MBD
Indication de biopsie osseuse (KDIGO 2009)
Fractures pathologiques inexpliques
Et/ou
Hypophosphatmie/hypercalcmie inexplique
Classification TMV
Dsordres osseux lis la CKD-
MBD
Ostite fibreuse:
Due exposition prolonge hyperPTH
PTH: augmentation du nombre des osteoclastes,
fibrose mdullaire
Remodelage osseux acclr de faon inadequate,
san

Osteodystrophie mixte:
= ostite fibreuse mais avec dminralisation
Dsordres osseux lis la CKD-
MBD
Ostomalacie:
Rare
Dficit svre en vitamine D ou intoxication
aluminique

Os adynamique:
Diminution du remodelage osseux +++
Due hypoparathyroidie induite par PTX, doses
excessives de chlateurs et/ou vit D
Risque dhyper Ca et/ou Ph


Dsordres vasculaires
Calcifications vasculaires
Go AS NEJM 2004
Dsordres vasculaires
Calcifications vasculaires
Altrations du systme cardiovasculaire

Dysfonctionnement endothlial

Rigidit vasculaire

HVG

Calcifications vasculaires
Dsordres vasculaires
Calcifications vasculaires
Calcifications intimales
Calcifications mdiales:
sclrose de Monckeberg
Calcifications vasculaires
Calcifications vasculaires
Mesure 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 TS
JAMA 2010
Dsordres vasculaires
Calcifications vasculaires
Sigrist MK C JASN 2007
Dsordres vasculaires
Calcifications vasculaires
Sigrist MK C JASN 2007
Rle relevant ?
Mesure des calcifications Est-ce si
important ?
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 CAC
progression
correlates with worsening atherosclerosis and may facilitate prediction of future cardiac events.
These findings
support the notion that slowing CAC progression with therapeutic interventions might provide
prognostic benefit.
However, despite promising early data, such interventions (most notably with statin therapy) have
not 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
Calcifications vasculaires
Etudes dintervention
Disparit dans les rsultats.

Parler de la fetuin A
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 information

1
Department 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 been
associated with both heart disease and mortality. Recent studies show that FGF23, a protein synthesized by osteocytes, is also
present 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, vascular
calcification 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 UCLA
between February 2008 and 2010. Immunohistochemical staining for Klotho, DMP1, FGFR1, and FGFR3; calcium deposition; and
RNA 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 correlated
with declining kidney function, as evidenced by reduced creatinine clearance. FGFR1 and FGFR3 were detected throughout the
vascular tissue and in calcified plaques. Calcium deposition, Klotho expression and DMP1 expression correlated with FGF23
immunoreactivity.
CONCLUSIONS:
The findings suggest that the Klotho-FGF23-FGFR system is active in coronary arteries and its upregulation correlates with
impaired renal function and matrix calcium deposition.

Dans cardiovasculaire

Parler de a aussi
Nephrol 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 information

1
University of Tennessee Health Science Center, Memphis, TN, USA.
Abstract
Traditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemia
and obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials of
interventions targeting modifiable traditional risk factors have yielded disappointing results in this patient
population. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineral
metabolism have been proposed as potential explanations for the excess mortality seen in patients with
chronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of what
the most important pathophysiologic mechanisms of these risk factors are, which ones might be ideal
treatment targets and which therapeutic interventions may be effective and safe in targeting them. Among
the novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerful
predictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced by
osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolism
through activation of FGF receptor/-Klotho co-receptor complexes. It is possible that elevated FGF23 may
exert its negative impact through distinct mechanisms of action independent from its role as a regulator of
phosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with left
ventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on the
myocardium. While it is possible that 'off target' effects of FGF23 present in very high concentrations could
induce LVH, this possibility is controversial, since -klotho is not expressed in the myocardium. Another
possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' activation of other humoral
pathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated with
elevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects and
potential therapeutic strategies to treat these.

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 information

1
Department 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 into
the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the
first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any
cause.
RESULTS:
Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression
analysis: 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 decompensated
heart 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 for
both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third
versus 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 remained
significant 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 significantly
associated with future decompensated heart failure but not incident atherosclerotic events.


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 information
Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry
Hines Boulevard, Dallas, TX 75390-9072, USA. makoto.kuro-o@utsouthwestern.edu.
Abstract
High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate
excretion increases serum phosphate level and induces a premature-ageing phenotype.
Urinary phosphate levels are increased by dietary phosphate overload and might induce
tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by
forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to
in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that
can induce various cellular responses, including the osteogenic transformation of vascular
smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial
cells. Calciprotein particles are detected in the serum of animal models of kidney disease and
in 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 that
regulate phosphate homeostasis and ageing. These observations raise the possibility that
calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is
expected to provide novel diagnostic markers and therapeutic targets in CKD.