Le calcium et le dialysLe calcium et le dialys: une : une question de stratquestion de stratgiegie

Guillaume JEANCentre de Rein Artificiel de TassinSymposium Fresenius Medical CareSminaire dUro-Nphrologie de la PitiParis 21 Janvier 2009

et det dexpexprience.rience.

PrPrvalence des calcifications valence des calcifications vasculaires des dialysvasculaires des dialysss

RRpartition des scores de partition des scores de calcifications vasculaires pcalcifications vasculaires priphriphriquesriques

G. Jean et al, NDT 2009

84% des dialyss porteurs de calcifications vasculaires

Calcifications et survie des dialysCalcifications et survie des dialysss

0 100 200 300 400 500 600

100

95

90

85

80

75

70

65

60

Time (days)

Surv

ival

pro

babi

lity

(%)

G. Jean et al, NDT 2009

0

1

2

3

P

PrPrvalence de lvalence de lostostoporoseoporose

50% de T50% de T--score < score < --2,5 (col du f2,5 (col du fmur)mur)

-5.4

-4.9

-4.4

-3.9

-3.4

-2.9

-2.4

-1.9

-1.4

-0.9

-0.4 0.1

0.6

1.1

1.6

2.1

2.6

3.1

0.00

0.05

0.10

0.15

0.20

-2,21,4 (mdiane 2,5)

T score fmur

Freq

uenc

e

G. Jean et al, ASN 2008

poignet Zfemur T

0 20 40 60 80 100

100

80

60

40

20

0

100-Specificity

Sens

itivi

ty

Association des scores DMO avec Association des scores DMO avec les antles antccdents de fracturesdents de fractures

Score Sensitivity Specificity AUCMidradius T 4.2 63 78.8 72Midradius Z 2.5 53 84.6 68HipT 2.2 83 47 67Hip Z 0.8 70 58 63Spine T 1 78 48 65SpineZ 0.6 51 68 60

G. Jean et al, ASN 2008

RR de fracture:6 pour un Z-score du radius < -2,5

Association ostAssociation ostoporose oporose calcifications aortiquescalcifications aortiques

Schulz J Clin Endocrinol Metab 2004,89:4246.

Rle du calcium dans lRle du calcium dans lostostoporoseoporose

R. Rizzoli, Osteoporosis vol 2, 70: 1651

Effet favorable de lEffet favorable de lapport de apport de calcium sur la DMOcalcium sur la DMO

R. Rizzoli, Osteoporosis vol 2, 70: 1651

Calcifications coronariennes plus frCalcifications coronariennes plus frquentes quentes en cas de carence en calcitriol dans la en cas de carence en calcitriol dans la population gpopulation gnnralerale

Watson, CIRCULATION 1997,96:1755.

Os adynamique iatrogOs adynamique iatrogne: balance ne: balance vitaminovitamino--calcique excessivecalcique excessive

Calcium

Phosphore

Magnsium

Os adynamique PTH

Vitamine D

CaCo3Calcium dialysat

Cinacalcet

HyperparathyroHyperparathyrodie secondaire die secondaire une une balance vitaminobalance vitamino--calcique insuffisantecalcique insuffisante

Hyperplasie des glandes parathyrodiennes

PTH

Dcouplage formation - rsorption osseuse

Calcium

Phosphore

Magnsium

Carence en vitamine D+ Calcium

Copyright 2008 American Society of Nephrology

London, G. M. et al. J Am Soc Nephrol 2008;19:1827-1835

Le CaCO3 est associLe CaCO3 est associ aux calcifications aux calcifications CV en cas dCV en cas dos adynamiqueos adynamique

CalcCalcmie totale normale mie totale normale

Hypocalcmie svre < 1,9 mmol Hypocalcmie modre 1,9 - 2,1 mmol Normo calcmie 2,1 2,55 mmol/L Hypercalcmie lgre 2,55 - 3 mmol Hypercalcmie modre 3 - 3,3 mmol Hypercalcmie svre > 3,3 mmol

Calcium, Lancet 1998,352:306.

2,1 2,55

Quel calcium de rQuel calcium de rffrence ?rence ?

K/DOQI: pas de rfrence de Ca ionisMesure du calcium ionis: time consuming and money consuming Formules: Corrected ca= Tot Ca (mg/dl) + 0,0704 X

[34 alb g/L] Corrected ca= Tot Ca + 0,8 x [40 alb]

Les formules de calcLes formules de calcmies corrigmies corriges es nnapportent rienapportent rien

Ionized ca Albumin corrected ca

Total ca

Hypocalcemia 15% 3% 9%

Normocalcemia 76% 68% 71%

Hypercalcemia 9% 29% 20%

Albuminemia 25 46 g/l Goransson LG: NDT 2005

RRpartition du calciumpartition du calcium

LiquideLiquideInterstitielInterstitiel16 mmol16 mmol

Plasma7 mmol

Cellules0,25 mmol

Os25 000mmol

(1000 g)

25 mmol/j (1g)

20 mmol/j

7 mmol/j10 mmol/j

5 mmol/j

La balance calcique en La balance calcique en dialysedialyse

(1,25 OHD3)(1,25 OHD3)

PTHPTH1,25 OHD31,25 OHD3

Sueur ?

Selon calcium dialysat

OstOstodystrophie rodystrophie rnalenale

Salusky et Goodman 1995

Hyperphosphatmie

FGF 23

Hyperphosphatmie

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

1,25 (OH)2 D

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

1,25 (OH)2 D

Dette en calcium + Vit D

Emprunt los

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

1,25 (OH)2 D

Excdents calcium et vit D

La banque ferme

Cycle circadien calcium et PTH (patient non Cycle circadien calcium et PTH (patient non dialysdialys) ) Joseph, F.,et al. (2007J Clin Endocrinol Metab 92(8): 3230-8,Calvo, M. S.,, et al. (1991). Calvo, M. S.,, et al. (1991). J Clin Endocrinol Metab J Clin Endocrinol Metab 72(1): 6972(1): 69--76.76..

LLhyperparathyrohyperparathyrodie secondairedie secondaire

Filtration glomrulaire

Rtention des phosphates Hyperphosphatmie

1,25(OH)2 D Hypocalcmie

Synthse et scrtion de PTH+ Hyperplasie glandulaire

VDR CaR

Inhibition 1Hydroxylase (FGF 23)

Rsistance osseuse la PTHabsorption intestinale Ca

Carence 25-OH

Adapt de Silver J: Adv Renal ReplacementTher 9;159-167, 2002.

Progression de lProgression de lHPT II HPT II IIIIII

NormalDiffuse

Earlynodularity

Nodular

Single nodule

Continuous functional demand

Gla

nd v

olum

e

Secretorycells

Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:33641

VDR

CaR

Normal Very highPTH

VDRCaR

Evolution du setEvolution du set--point avec lpoint avec lHPTHPT

HPT hypercalcmiques

HPT normocalcmiques

Sujets normaux

Malberti, F., M. Farina, et al. (1999). Nephrol Dial Transplant 14(10): 2398-406.

Le setLe set--point = calcpoint = calcmie spontanmie spontaneeMalberti, F., M. Farina, et al. (1999" Nephrol Dial Transplant 14(10): 2398-406.

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

1,25 (OH)2 D

HypercalcmieHPT III

Emprunt los

Les acteurs (les outils) de la balance Les acteurs (les outils) de la balance vitaminovitamino--calciquecalcique

Prioritaires: Calcium dialysat Chlateur et supplmentation calcique Vitamine D active

Moindres: Apports calciques alimentaires Vitamine D native Rsine changeuse K / Ca

Les apports calciques alimentairesLes apports calciques alimentaires

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300

25

20

15

10

5

0

Ca intake

Freq

uenc

y

G Jean et al, SN-SFD 2008

Moyenne: 600 mg/j

LLabsorption du calcium alimentaire est absorption du calcium alimentaire est vitamine D vitamine D --(1,25OH(1,25OH22D) dD) dpendantependante

Gotch, F. (2008)." Contrib Nephrol 161: 210-4.

Transfert Transfert de masse de masse du calcium du calcium en dialyse en dialyse

Gotch, F. (2008)." Contrib Nephrol 161: 210-4.

Selon le gradient calcium dialysat calcium ultra filtrable et lUF

1.75

Autres Autres tudes, autres rtudes, autres rsultatssultats

1,75

1,5

1,25

A Argiles, Kidney Int 1993,43:630.

Le calcium du dialysat: en pratique Le calcium du dialysat: en pratique 1/21/2

Homme de 50 ans, dbut de dialyse, PTH 670 pg/ml, calcium total 2,21 mmol/L, Phosphore 2,2 mmol/L

Ca1,75 Heure 0 1 5Caionis 1,1 1,32 1,5PTH 670 430 180

Ca1,5 Heure 0 1 5Caionis 1,1 1,2 1,3PTH 680 520 390

Ca1,25 Heure 0 1 5Caionis 1,11 1,1 1,13PTH 650 540 550

Balance ++

Balance +

Balance =

Calcium dialysat en pratique 2/2Calcium dialysat en pratique 2/2Aprs 3 mois dun calcium de dialysat 1,75 mmol/L + 2g/J deCaco3

Ca1,75 Heure 0 1 5Caionis 1,29 1,34 1,5PTH 100 60 30

Ca1,5 Heure 0 1 5Caionis 1,29 1,29 1,3PTH 100 88 90

Ca1,25 Heure 0 1 5Caionis 1,29 1,2 1,14PTH 100 180 300

Balance -

Balance =

Balance +

Exemple: changement de chExemple: changement de chlateur 1lateur 1

T-0

PTH pg/ml 230

Calcmie mmol/L 2,42

Phosphore 1,6

Ca dialysat 1,5

Sevelamer mg/j 0

Caco3 mg/j (Ca el) 3000

Alfacalcidol g/s 1,5

PAL os g/L 23

Dedrogyl g/j 0

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH

1000

200

600

RO

RO

Changement de chChangement de chlateur 1lateur 1

T-0 T-3

PTH pg/ml 230 490

Calcmie mmol/L 2,42 2,38

Phosphore 1,6 1,5

Ca dialysat 1,5 1,5

Sevelamer mg/j 0 4800

Caco3 mg/j (Ca el) 3000 0

Alfacalcidol g/s 1,5 1,5

PAL os g/L 23 43

Dedrogyl g/j 0 0

= Dette en calcium

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH

1000

200

600

RO

RO

Changement de chChangement de chlateur 1lateur 1

T-0 T-3 T-6 T-9

PTH pg/ml 230 490 310 250

Calcmie mmol/L 2,42 2,38 2,42 2,40

Phosphore 1,6 1,5 1,6 1,7

Ca dialysat 1,5 1,5 1,5 1,5

Sevelamer mg/j 0 4800 4800 4800

Caco3 mg/j (Ca el) 3000 0 0 0

Alfacalcidol g/s 1,5 1,5 3 0,5

PAL os g/L 23 43 32 27

Dedrogyl g/j 0 0 25 25

= paiement de la dette par les vitamines D

InversementInversementT-0 T-2 T-4

PTH pg/ml 250 110 240

Calcmie mmol/l 2,3 2,35 2,3

Phosphatmie 1,6 1,6 1,6

PAL os g/L 18 12 20

Ca dialysat 1,5 1,5 1,5 1,25

CaCO3 mg/j 0 3000 3000

Sevelamer mg/j 4800 0 0

Alfacalcidol g/sem 0,5 0,5 0

Dedrogyl g/j 25 25 25

calcium dialysat + vit D

=Excs de calcium

Les KDOQI (1)Les KDOQI (1)Chlateurs du calcium

Les KDOQI (2)Les KDOQI (2)

Si calcmie > 2,54 mmol/L (Opinion) < Calcium p.o < Vitamine D active < calcium dialysat 1 ou 1,25 mmol/L

Si calcmie < 2,1 mmol/L et symptmes ou PTH > 300 pg/ml: > Apport calcique ou vit D (Evidence)

(si PTH < 150)

KDOQI (3)KDOQI (3)

Dialysat =1,25 mmol/L, si apport de calcitriol iv (opinion)La calcium du dialysat doit tre individualis mais ce nest pas conomiquement faisable (?!)Augmenter le calcium du dialysat pour freiner la PTH (1,75 mmol/L) et le diminuer (1 1,25 mmol/L) pour stimuler la PTH (Evidence)

Carbonate de calcium Carbonate de calcium (ARNOS 2005, (ARNOS 2005, Registre RhneRegistre Rhne--Alpes du mAlpes du mtabolisme mintabolisme minral et osseux)ral et osseux)

0 1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

56%

CaCo3

Frq

uenc

e

D. Fouque et col

CaCO3 posologie CaCO3 posologie (ARNOS 2005)(ARNOS 2005)

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

0.000.010.020.030.040.050.060.070.080.090.100.110.120.130.140.15 20002200 (Mediane 2000; 500 - 8000) mg/J

posologie CaCo3 mg/j ca E

Frq

uenc

e

Utilisation du CaCO3: effet centreUtilisation du CaCO3: effet centre((ARNOS 2005)ARNOS 2005)

Means (error bars: 1 SEM)

1,0

0,9

0,8

0,7

0,6

0,5

0,4

0,3

0,2

0,1

0,0

centre

Cac

o3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Tassin

PTH et chPTH et chlateurs lateurs (ARNOS 2005)(ARNOS 2005) Means (error bars: 95% CI for mean)

380

360

340

320

300

280

260

240

220

200

CHELATEUR

PTH

0 1 2 3

P=0,003Pas de chlateur Caco3

Sevelamer

Sevelamer+caco3

Besoins de chBesoins de chlateur = meilleur lateur = meilleur survie (nutrition) survie (nutrition)

0,24

0,22

0,20

0,18

0,16

0,14

0,12

0,10

0,08

Chlateur

Surv

ie

12

moi

s

0 1 2 3

Pas de chlateur

CaCO3

Sevelamer

Les 2

p< 0,001

ARNOS 2005

*

ns

Calcium du dialysat Calcium du dialysat (ARNOS 2005)(ARNOS 2005) Means (error bars: 1 SEM)

1,8

1,7

1,6

1,5

1,4

1,3

1,2

centre

CaD

ial

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1,5 0,12 mmol/L

Le calcium et le DOPPS Le calcium et le DOPPS Tentori et al, AJKD 2008Tentori et al, AJKD 2008

DCORSuki, KI 2007, 72:1130

Balance vitamino-calcique inadapte ?

Calcmie PTH

Bras Ca 2,38 0,1 226

Bras Sevelamer 2,3 0,1 ** 278**

Treat to goal Treat to goal (Chertow, KI 2002)(Chertow, KI 2002)

SemainesSemaines--22 0 0 33 66 99 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252

Cal

cC

alc

mie

(mg/

dL)

mie

(mg/

dL)

10.510.5

10.010.0

9.59.5

9.09.0

8.58.5

R=9.5 mg/dL (2.38 mmol/L)*R=9.5 mg/dL (2.38 mmol/L)*C=9.7 mg/dL (2.43 mmol/L)C=9.7 mg/dL (2.43 mmol/L)

R=9.4 mg/dL (2.35 mmol/L)R=9.4 mg/dL (2.35 mmol/L)C=9.3 mg/dL (2.33 mmol/L)C=9.3 mg/dL (2.33 mmol/L)

Renagel Renagel Calcium Calcium

* p = 0,002

Episodes dEpisodes dhypercalchypercalcmie mie 10.5 10.5 mg/dL mg/dL (2.63 mmol/L)(2.63 mmol/L)

%%

SemainesSemaines

--22 00 33 66 99 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 525200

55

1010

1515

2020

2525Renagel Renagel Calcium Calcium

*

* p

iPTHiPTH

SemainesSemaines

--22 0 0 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252

iPTH

(pg/

mL)

iPTH

(pg/

mL)

00

5050

100100

150150

200200

250250

300300

350350

400400

R = 232R = 232C = 200C = 200

R = 224R = 224C = 138C = 138

Renagel Renagel Calcium Calcium

P=0,1

CARE 2 CARE 2

Les chLes chlateurs calciques et nonlateurs calciques et non--calciques sontcalciques sont--ils comparables ?ils comparables ?

EfficacitTolrancePrixEffets osseuxEffets sur les calcifications vasculairesEffets sur la morbi-mortalit

les chlateurs calciques et non-calciques ne devraient pas tre prescrits dans les mmes conditions (ni aux mmes patients?)

Quand diminuer la balance Quand diminuer la balance vitaminocalcique ?vitaminocalcique ?

Calcmie

1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

Les caisses sont pleines

Calcmie

1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

Quand augmenter la balance Quand augmenter la balance vitaminocalcique ?vitaminocalcique ?

Les caisses sont vides

Calcmie

Calciumionis 1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

Quand maintenir la balance ?Quand maintenir la balance ?

CrditDbit

Calcmie

1,8

Setpoint

CaRVDR

2,2

3

2,6

0

PTH1000

200

600

RO

RO

SetSet--point haut: cinacalcetpoint haut: cinacalcet

Calcmie

Calciumionis 1,8

Setpoint

2,2

3

2,6

0

PTH1000

200

600

RO

RO

PTX: prudence !PTX: prudence !

Calcmie dpendante de lapport calcique

A lA lquilibre: stratquilibre: stratgies adaptgies adaptes aux es aux convictions et aux circonstancesconvictions et aux circonstances

Priorit aux vitamines D (natives actives): apports calciques (chlateurs et ou calcium

dialysat)

Priorit aux chlateurs non-calciques: apports vitamine D et/ou calcium dialysatPriorit aux chlateurs calciques: apports vitaminiques et/ou calcium dialysat

Une stratUne stratgie globale et individualisgie globale et individualiseePTH

et/ou ROPhosphat

mieCalcmie

basseCalcmienormale

Calcmie haute

basse basse > Vit D et ca Dial < calcium < calcium et vit D

basse normale > Vit D et ca Dial Chel. calc < vit D, chel non-cal

< calcium, chel. Non-cal

normale basse > Vit D et ca Dial > Vit D < calcium, stop chel

normale normale > Ca dial stable < calcium vit D

normale haute > chel. calc > Chel au choix

< cal vit D, chel non-cal

haute basse > Vit D > Vit D cinacalcet

haute normale > Vit D et Calcium > Vit D / calcium

cinacalcet

haute haute > Chel. Calc > Chel calc cinacalcet

Quelle place pour un chQuelle place pour un chlateur lateur calcique ?calcique ?

Chlation si hyperphosphatmie (quelle cible ?)On devrait utiliser un chlateur calcique pour payer les dettes: PTX ou PTX-like (cinacalcet) avec hypocalcmie: payer cash PTH et /ou marqueurs osseux levs: crdit

On ne devrait pas utiliser un chlateur calcique en cas dexcdents: PTH et/ou marqueurs osseux bas

On pourrait utiliser un chlateur calcique si les comptes sont lquilibre: PTH/marqueurs osseux dans la cible: ajuster vit D et ca dialysat

ConclusionConclusion

Le mtabolisme minral et osseux est probablement associ la morbi-mortalit des dialyss.Loptimisation des pratiques doit viser la normalisation des paramtres intermdiaires (PTH, PAL, calcmie, phosphatmie/mois)

effet bnfique sur la morbi-mortalit ? Fractures Calcifications vasculaires Mortalit cardio-vasculaire

Conclusion 2Conclusion 2La balance vitamino-calcique apparente doit tre mesure et individualise (dettes ou excdents)Cette gestion demande du temps, de lattention, une (des) stratgieLarsenal thrapeutique actuel et venir doit nous permettre de dfinir des stratgies adaptes: (calcium dialysat, chlateurs calciques et non

calciques, vitamines D, calcimimtiquesstratgie de dialyse, bisphosphonates)

Evolution 1994 Evolution 1994 2008 Tassin2008 TassinCa dialysat 1,70 1,45 1,5

Anne 1994 2004 2008

Caco3 25% 4% 14%

Gel Aluminium

46% 8% 1%

Vit D native 0 10% 95%

Vit D alfa 30% 35% 16%

Sevelamer 0% 34% 27%

FosRenol - - 9%

Mimpara - - 14%

PTH< 50 pg/ml

51% 10% 3%

PTH 50-150 29% 10% 21%

PTH 150-300 9% 40% 67%

PTH > 300 11% 40% 9%

Anne 1994 2004 2008

Dure EER

7h 10 6h 42 6h 18

Calcmie 2,50,1 2,410,1 2,240,1

Phospha 1,40,2 1,390,2 1,36 0,2

CaxP> 4,4

8,8% 13% 2%

Ca < 2,1 4% 4% 1%

Ca> 2,5 45% 19% 1%

Ph < 1,1 50% 25% 13%

Ph > 1,75 11% 18% 3%

Economies

Dettes Equilibre

Le bon et le mLe bon et le mchant calcium ?chant calcium ?

Ca++

Ca++

Ou des stratgies inadaptes ?

Quelques rQuelques rffrencesrences

Physiologie de la chlation calcique des phosphates

Philippe RieuService de Nphrologie-Transplantation

CNRS UMR 6198

CHU Reims

Phosphorus Intake1400 mg/d

Net Intestinalabsorption910 mg/d

Bone630 g

Plasma93 mg

Interstitium343 mg

210 mg/d

210 mg/d

ICF63 g

Feces : 490 mg /d Urinary excretion : 910 mg /d

60-70%

Phosphorus Intake1400 mg/d

Feces : 490 mg /d Urinary excretion < 910 mg /d

Net Intestinalabsorption910 mg/d

Bone630 g

Plasma93 mg

Interstitium343 mg

210 mg/d

210 mg/d

ICF63 g

60-70%

Balance phosphat et hyperphosphormie

Martinez I et al. Am J Kidney Dis 1997;29:496502

0

100+

909

980

89

707

960

69

505

940

49

303

920

29

101

9m

mol

/L

Creatinine clearance (mL/min)

0.75

1.00

1.25

1.50

Serum ionized calcium

Phosphorus

0.50

1. Absorption intestinale des phosphates

2. Chlation calcique des phosphates

3. Absorption intestinale du calcium

Physiologie de la chlation calcique des phosphates

1. Absorption intestinale des phosphates

2. Chlation calcique des phosphates

3. Absorption intestinale du calcium

Physiologie de la chlation calcique des phosphates

HPO42- / H2PO4-

absorption Intestinale

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

308 mg phosphate

Ramirez et al. 1986 Kidney int 30: 753

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

A jeun

Lavement N1(30 ml/min 4h)

Repas

Lavement N2(30 ml/min 3 h)

8 h

12 h

Fces 1

Fces 2

JS FordtranDallas

HPO42- / H2PO4-

absorption Intestinale

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

= 80 %Sujets sains

(calcitriol 48 pg/ml)

308 mg phosphate

Ramirez et al. 1986 Kidney int 30: 753

HPO42- / H2PO4-

absorption Intestinale

Bifteck (140g)Frites (100g)

Fromage (45g)

Feces

= 80 %Sujets sains

(calcitriol 48 pg/ml)

308 mg phosphate

= 60 %Sujets dialyss

(calcitriol 7 pg/ml)

Ramirez et al. 1986 Kidney int 30: 753

HPO42- / H2PO4-

absorption Intestinale

Bifteck (140g)Frites (100g)

Fromage (45g)

Feces

= 80 %Sujets sains

(calcitriol 48 pg/ml)

308 mg phosphate

= 60 %Sujets dialyss

(calcitriol 7 pg/ml)

= 86 %Sujets dialyss

(calcitriol 94 pg/ml)

Ramirez et al. 1986 Kidney int 30: 753

Duodnum

Jjunum

Ilon

Colon

2 Na?

Pi

Type IIb Na+ /Pi

Absorption intestinale du phosphate

HPO42- / H2PO4-

HPO42-

Absorption intestinale du phosphate

HPO42- / H2PO4-

0,32 0,64 0,92 1,28

0,3

0,6

0,9

Phosphate intake(mmol/kg/d)

Intestinal P absorption(mmol/kg/d)

R = 0,946P

?Pi

Type IIb Na+ /Pi

Absorption intestinale du phosphate

2Na+ HPO42-

Sodium dpendentSaturableVit D

2 Na

HPO42-

Feild et al 1999 BBRC 258: 578Hifiker et al 1998 PNAS 95: 14564

Immunohistochemicaldetection of the

Type IIb Na+ /Pi cotransporter

Low Pi dietHigh Pi diet

CholecalciferolControlHattenhauer et al, Am J Physiol, 1999, 277:G756

Duodnum

Jjunum

Ilon

Colon

?Pi

Type IIb Na+ /Pi

Absorption intestinale du phosphate

HPO42- / H2PO4-

2 Na

HPO42-

Absorption intestinale du phosphate

Kayne et al. 1993 JCI 91:915

Duodenum

jejunum

ilon

Chez le rat

Duodnum

Jjunum

Ilon

Colon

30%

30%

30%

?

HPO42- / H2PO4-

Absorption intestinale du phosphateChez le rat

Kayne et al. 1993 JCI 91:915Eto et al 2006 Drug Metab Pharmacokinet 21:217

Marks et al 2006 Exp Physiol 91:531

2 Na

HPO42-

Duodnum

Jjunum

Ilon

Colon

Absorption intestinale du phosphate

Kayne et al. 1993 JCI 91:915Eto et al 2006 Drug Metab Pharmacokinet 21:217

Marks et al 2006 Exp Physiol 91:531

60 % absorptiondu phosphate

1. Absorption intestinale des phosphates

2. Chlation calcique des phosphates

3. Absorption intestinale du calcium

Physiologie de la chlation calcique des phosphates

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

308 mg phosphate

2 Na?

Pi

Type IIb Na+ /Pi

HPO42- / H2PO4-

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

308 mg phosphate

2 Na?

Pi

Type IIb Na+ /Pi

HPO42- / H2PO4-

CaMgAlLa

Rsine

Bifteck (140g)Frites (100g)

Fromage (45g)

Fces

308 mg phosphate

2 Na?

Pi

Type IIb Na+ /Pi

HPO42- / H2PO4-

Ca

2 Na?

Pi

Type IIb Na+ /Pi

HPO42- / H2PO4-

Ca2 3 4 5 6 7 8

pH

100

80

60

40

20

Produit PxCaen %

pH = 5,5

Ca2+ + H2PO4- CaHPO4 + H+

2 3 4 5 6 7 8

pH

100

80

60

40

20

pH = 5,5

Ca2+ + H2PO4- CaHPO4 + H+

Produit PxCa

en %

2 3 4 5 6 7 8

100

80

60

40

20

Ca2+ + H2PO4- CaHPO4 + H+

320 mg Phosphate + 1500 mg Ca lmentQSP 600 ml eau

Sheikh et al. 1989 JCI 83: 66

Produit PxCaaprs 1 heure

en %

Carbonate de CalciumCaCO3 + H+ Ca2+ + HCO3-

pH

2 3 4 5 6 7 8

100

80

60

40

20

Ca2+ + H2PO4- CaHPO4 + H+

320 mg Phosphate + 1500 mg Ca lmentQSP 600 ml eau

Sheikh et al. 1989 JCI 83: 66

Produit PxCaaprs 1 heure

en %

Carbonate de CalciumCaCO3 + H+ Ca2+ + HCO3-

pHpH

100% 25% Solubilit CaC03

2 3 4 5 6 7 8

100

80

60

40

20

Produit PxCaaprs 1 heure

en %

Ca2+ + H2PO4- CaHPO4 + H+

Acetate de Calcium

Carbonate de Calcium

Ca(CH3COO-)2 Ca2+ + 2 CH3COO-

CaCO3 + H+ Ca2+ + HCO3-

320 mg Phosphate + 1500 mg Ca lmentQSP 600 ml eau

Sheikh et al. 1989 JCI 83: 66

pH

100% 100% Solubilit CaCH3COO

Ca2+ + H2PO4- CaHPO4 + H+

CaCO3 + H+

Ca2+ + HCO3-

Ca2+ + H2PO4- CaHPO4 + H+

Mesure du pH gastrique sur 24 h

Vallot et al 1988 Gastroenterol Clin Biol 12:610

2 Na?

Pi

Type IIb Na+ /Pi

HPO42- / H2PO4-

Actate de Calcium

Carbonate de Calcium

Ca(CH3COO-)2 Ca2+ + 2 CH3COO-

CaCO3 + H+ Ca2+ + HCO3-

La meilleure biodisponibilit du calcium de lactate de calcium est-elle associe une meilleure chlation

intestinale du phosphate ?

Pi

Pi

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 77 3 %Placebo

Sheikh et al. 1989 JCI 83: 66

N=6 sujets sains

345 mg phosphate

214 mg Ca lment

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 77 3 %Placebo

= 33 5 %Actatede Ca

Sheikh et al. 1989 JCI 83: 66

N=6 sujets sains

345 mg phosphate+ 1000 mg Ca lment

214 mg Ca lment

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 77 3 %Placebo

= 33 5 %Actatede Ca

= 43 5 %Carbonate

de Ca

p< 0,05

Sheikh et al. 1989 JCI 83: 66

N=6 sujets sains

345 mg phosphate+ 1000 mg Ca lment

214 mg Ca lment

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 52 9 %Placebo

Mai et al. 1989 Kidney int 36: 690

N=6 sujets HDCalcitriol < 10 pg/ml

346 mg phosphate

214 mg Ca lment

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 52 9 %Placebo

= 22 4 %Actatede Ca

Mai et al. 1989 Kidney int 36: 690

N=6 sujets HDCalcitriol < 10 pg/ml

346 mg phosphate+ 1000 mg Ca lment

214 mg Ca lment

HPO42- / H2PO4-

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 52 9 %Placebo

= 22 4 %Actatede Ca

= 40 6 %Carbonate

de Ca

p< 0,05

Mai et al. 1989 Kidney int 36: 690

N=6 sujets HDCalcitriol < 10 pg/ml

346 mg phosphate+ 1000 mg Ca lment

214 mg Ca lment

Ph2,08 0,53

1,51 0,39

1,99 0,62

1,34 0,41,2

1,4

1,6

1,8

2

2,2

2,4

2,6

Ca Ac 1,02 0,33 g/j CaC03 1,88 0,96 g/j

7 semaines 7 semaines

N=12

mM

Schaefer et al. 1991 NDT 6:170

Comparaison du CaCO3 et CaAc

Comparaison du CaCO3 et CaAc

Delmez, 1992 JASN 3:9620 patients pendant 6 mois

Hypercalcmie

Phosphormie

PTH

Ca lment g/j

8,7%

1,52 0,06

403 80

2,8 0,3

8,3%

1,71 0,06

454 74

1,4 0,1

Calcmie 2,54 0,02 2,49 0,02

CaCO3 CaAc

p

Ben Hamida, 1993 Nephron 63:258

Comparaison du CaCO3 et CaAc

28 patients pendant 6 mois

Hypercalcmie

Phosphormie

PTH

Ca lment g/j

8,2%

1,82 0,26

121 153

2,37 1,47

8%

1,73 0,23

122 69

1,24 0,52

Calcmie 2,47 0,11 2,5 0,10

CaCO3 CaAc

p

2 Na?

Pi

Type IIb Na+ /Pi

La meilleure biodisponibilit du calcium dans lactate de calcium est associe une meilleure chlation intestinale

du phosphate

Pi

Pi

HPO42- / H2PO4-

Actate de Calcium

Carbonate de Calcium

Ca(CH3COO-)2 Ca2+ + 2 CH3COO-

CaCO3 + H+ Ca2+ + HCO3-

La meilleure biodisponibilit du calcium de lactate de calcium est-elle associe une plus grande absorption du

calcium ?

Ca2+NCX1

Ca2+

Ca2+ Ca2+

Actate de Calcium

Carbonate de Calcium

Ca(CH3COO-)2 Ca2+ + 2 CH3COO-

CaCO3 + H+ Ca2+ + HCO3-

1. Absorption intestinale des phosphates

2. Chlation calcique des phosphates

3. Absorption intestinale du calcium

Physiologie de la chlation calcique des phosphates

Duodnum

Jjunum

Ilon

Colon

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5

Ca2+ Ca2+

Calbindin

Absorption intestinale du calcium

Duodnum

Jjunum

Ilon

Colon

Ca2+ Ca2+

Absorption intestinale du calcium

1. Ilon >> jjunum2. Non saturable3. Lent4. Concentration > 2-6 mM5. Calcitriol indpendant ?

Transport passif

Ca2+ Ca2+

Absorption intestinale du calcium

1. Ilon >> jjunum2. Non saturable3. Lent4. Concentration > 2-6 mM5. Calcitriol indpendant ?

Transport passif

Duodnum

Jjunum

Ilon

Colon

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5Calbindin

Absorption intestinale du calcium

1. Duodnum >> jjunum2. Saturable3. Rapide4. Faible concentration5. Calcitriol

Transport actif

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5Calbindin

Absorption intestinale du calcium

1. Duodnum >> jjunum2. Saturable3. Rapide4. Faible concentration5. Calcitriol

Transport actif

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5Calbindin

Absorption intestinale du calcium

1. Duodnum >> jjunum2. Saturable3. Rapide4. Faible concentration5. Calcitriol

Transport actif

Duodnum

Jjunum

Ilon

Colon

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5Calbindin

Absorption intestinale du calcium

1. Duodnum >> jjunum2. Saturable3. Rapide4. Faible concentration5. Calcitriol

Transport actif

Duodnum

Jjunum

Ilon

Colon

Ca2+ Ca2+

Absorption intestinale du calcium

1. Ilon >> jjunum2. Non saturable3. Lent4. Concentration > 2-6 mM5. Calcitriol

Transport passif

Claudin-2Claudin-12

Ca2+ Ca2+

Absorption intestinale du calciumTransport passif

Claudin-2Claudin-12

Fujita et al 2008 Mol Biol Cell 19:1912

1. Ilon >> jjunum2. Non saturable3. Lent4. Concentration > 2-6 mM5. Calcitriol

CaATPasePMCA1b

Ca2+NCX1

Ca2+

TRPV5

Ca2+ Ca2+

Calbindin

Absorption intestinale du calcium

Transport actif

Transport passif

[Calcitriol]Quantit Ca

ingre

Duodnum

Jjunum

Ilon

Colon

Absorption intestinale du calcium

8%

4%

88%

7%

17%

65%

4%

16%

80%

Rat Chien

< 10%

Marcus 1962 J Nutr 77:155Cramer 1959 Proc Soc Exp Biol Med 102: 514Cramer 1965 Can J Physiol Pharmacol 43:75

Duodnum

Jjunum

Ilon

Colon

Absorption intestinale du Ca et Pi

60 % absorptiondu phosphate

80 % absorptiondu Calcium

Ca2+

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 20 8 %Placebo

Sheikh et al. 1989 JCI 83: 66

N=6 sujets sains

345 mg phosphate

214 mg Ca lment

Ca2+

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 20 8 %Placebo

= 16 1 %Actatede Ca

= 20 2 %Carbonate

de Ca

Sheikh et al. 1989 JCI 83: 66

N=6 sujets sains

345 mg phosphate+ 1000 mg Ca lment

214 mg Ca lment

Ca2+

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 0 %Placebo

-28 mg

N=6 sujets HDCalcitriol < 10 pg/ml

Mai et al. 1989 Kidney int 36: 690

346 mg phosphate

201 mg Ca lment

Ca2+

absorption Intestinale

Bifteck (80g)Frites (100g)

Fromage (30g)

Fces

= 0 %Placebo

= 26 3 %Actatede Ca

= 30 4 %Carbonate

de Ca

NS

-28 mg

314 mg

355 mg

N=6 sujets HDCalcitriol < 10 pg/ml

Mai et al. 1989 Kidney int 36: 690

346 mg phosphate+ 1000 mg Ca lment

201 mg Ca lment

Ph2,08 0,53

1,51 0,39

1,99 0,62

1,34 0,41,2

1,4

1,6

1,8

2

2,2

2,4

2,6

Ca Ac 1,02 0,33 g/j CaC03 1,88 0,96 g/j

7 semaines 7 semaines

N=12

mM

Schaefer et al. 1991 NDT 6:170

Comparaison du CaCO3 et CaAc

Ca

Ph

2,36 0,21

2,53 0,19

2,19 0,19

2,08 0,53

1,51 0,39

1,99 0,62

1,34 0,41,2

1,4

1,6

1,8

2

2,2

2,4

2,6 2,53 0,19

Ca Ac 1,02 0,33 g/j CaC03 1,88 0,96 g/j

7 semaines 7 semaines

N=12

mM

Schaefer et al. 1991 NDT 6:170

Comparaison du CaCO3 et CaAc

Comparaison du CaCO3 et CaAc

Delmez, 1992 JASN 3:9620 patients pendant 6 mois

Hypercalcmie

Phosphormie

PTH

Ca lment g/j

8,7%

1,52 0,06

403 80

2,8 0,3

8,3%

1,71 0,06

454 74

1,4 0,1

Calcmie 2,54 0,02 2,49 0,02

CaCO3 CaAc

p

Ben Hamida, 1993 Nephron 63:258

Comparaison du CaCO3 et CaAc

28 patients pendant 6 mois

Hypercalcmie

Phosphormie

PTH

Ca lment g/j

8,2%

1,82 0,26

121 153

2,37 1,47

8%

1,73 0,23

122 69

1,24 0,52

Calcmie 2,47 0,11 2,5 0,10

CaCO3 CaAc

p

Clarkson et al. 1973 Kidney Int 3:258

Ca ingr-Ca fces

-Ca U

La balance calcique

Clarkson et al. 1973 Kidney Int 3:258

La balance calcique

Ca ingr-Ca fces

-Ca U

Clarkson et al. 1973 Kidney Int 3:258

La balance calcique

Ca ingr-Ca fces

-Ca U

1,2 2,4

Duodnum

Jjunum

Ilon

Colon

Absorptiondu phosphate

Absorptiondu Calcium

CaCO3CaAc

Sel de Ca

Physiologie de la chlation calcique des phosphates

Cardiovascular Calcification in Patients with ESRDImpact of Phosphate Binders

Wajeh Qunibi, MD, FACP

Professor of MedicineMedical Director of Dialysis Services

University of Texas Health Science Center

San Antonio, TX

Paris-France 1/21/2009

Mortality rate in Dialysis Patients

USRDS 2006

Year

Dea

ths

Per 1

00 P

atie

nt Y

ears

Corrected Serum Calcium (mg/dL)

=11.0

All-

Cau

se D

eath

Haz

ard

Rat

io

0.7

1.5

2

3

1

unadjustedcase-mixcase-mix & MICS

Serum Calcium

58,000 DaVita patients 2001-2003; Kalantar-Zadeh et al, ASN 2005 [unpublished]

K/DOQIrecommended

range

Serum Phosphorus (mg/dL)

=9

All-

Cau

se D

eath

Haz

ard

Rat

io

0.7

2

3

4

1

unadjustedcase-mixcase-mix & MICS

58,000 DaVita patients 2001-2003; Kalantar-Zadeh et al, ASN 2005 [unpublished]

Serum Phosphorus

K/DOQIrecommended range

Calcium*Phosphorus Product (mg2/dL2)

=90

All-

Cau

se D

eath

Haz

ard

Rat

io

0.7

2

4

7

1

unadjustedcase-mixcase-mix & MICS

58,000 DaVita patients 2001-2003; Kalantar-Zadeh et al, ASN 2005 [unpublished]

Calcium-Phosphorus ProductK/DOQI

recommended range

Serum Intact PTH (pg/mL)

=700

All

Cau

se D

eath

Haz

ard

Rat

io

0.8

1.5

2

1

unadjustedcase-mixcase-mix&MICS

intact PTH

58,000 DaVita patients 2001-2003; Kalantar-Zadeh et al, ASN 2005 [unpublished]

Should high PTH be ignored?

Adjusted relationship between serum calcium levels and all-cause mortality (HEMO Study)

In aggregate, these data question current KDOQI recommendations that call for maintaining serum calcium in the range of 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L). Attempts to achieve this lower target may have affected clinical practice through the curtailed use of calcium-based phosphate binders and vitamin D analogues, the latter of which may confer a survival benefit Wald R et al. Am J Kidney Dis 52:531-540, Sept 2008

Kalantar-Zadeh-2006

HEMO-2008

KDOQI-2003

Population Attributable Risk Percent

0.0%

5.0%

10.0%

15.0%

20.0%

AllMinerals

HighPTH> 60

HighCa

> 2.5

HighPO4> 1.6

AnemiaHb < 11

LowURR< 65

Block G, J Am Soc Neph 15: 2208-2218, 2004

> 5.0 > 10.0 > 600

Treatment with Phosphorus Binders in the First 90 Days is Independently Associated with Improved 1 Year Survival

Among Incident HD PatientsN = 10,044Treated = 3555Untreated = 5055

Hazard Risk = 0.7595% CI = 0.66 to 0.87P < 0.0001

Isakova et al. JASN Dec 2008

Percentage of Patients With Laboratory Values Within K/DOQI Guideline Range, by Country and Year

DOPPS I: 1996-2001-N = 3853DOPPS II: 2002-2004-N = 2246Only 23% to 28% fell within guideline for at least 3 measures and only 4.6% to 5.5% of patients were within range for all 4.Young et al. AJKD 44 (suppl 2): S34-S38, 2004

Phosphate Binders

Aluminum Hydroxide

Calcium-based phosphate binders (CBPB):Calcium AcetateCalcium Carbonate

Non-calcium, non-aluminum phosphate binders:Sevelamer HClSevelamer carbonateLanthanum Carbonate

Other investigational binders

Calcium Acetate: Comparison With CaCO3Calcium acetate binds 2x as much P as CaCO3 , yet contains half the elemental Ca.1

Phosphorous Binding by Calcium Acetate and Calcium Carbonate*1

Phosphorous Binding by Calcium Acetate and Calcium Carbonate*1

Source: 1Mai ML, Emmet M, Sheikh MS, et al. Calcium acetate, an effective phosphorous binder in patients with renal failure. Kidney International 1989; 36:690-695.

*Equivalent to 1 gram elemental calcium = 6 calcium acetate gelcaps; 4 tablets calcium carbonate tablets

Each 667 mg calcium acetate gelcap (167 mg elemental calcium) binds 18 mg P

Each 1000 mg calcium carbonate tablet (250 mg elemental calcium) binds 11 mg P

P

Meta-analysis of size of Hypercalcemic Effect of Calcium Carbonate versus Calcium Acetate

K/DOQI AJKD 42 (Suppl 4) : S74, 2003

100

pH 5pH 5

pH 3pH 3

pH 7pH 7

Ph

osp

hor

us

Ph

osp

hor

us

Rem

oved

Rem

oved

(%)

(%)

0

20

40

60

80

LanthanumLanthanumcarbonatecarbonate

CalciumCalciumcarbonatecarbonate

CalciumCalciumacetateacetate

AluminumAluminumhydroxidehydroxide

0

20

40

60

80

100

LanthanumLanthanumcarbonatecarbonate

CalciumCalciumcarbonatecarbonate

CalciumCalciumacetateacetate

AluminumAluminumhydroxidehydroxide

0

20

40

60

80

100

LanthanumLanthanumcarbonatecarbonate

CalciumCalciumcarbonatecarbonate

CalciumCalciumacetateacetate

AluminumAluminumhydroxidehydroxide

Damment SJP, Webster I. Adapted from abstract presented at Annual Meeting of the American Society of Nephrology;November 12-17, 2003; San Diego, Calif.

In Vitro Phosphorus Binding Across a Range of pH

Calcium acetate

Sevelamer hydrochloride

Time-average concentration (Cavg) wks 1- 8; 1.08 mg/dL difference, p = 0.0006

CARE Study: Weekly Mean Serum Phosphorus Levels

4.5

5

5.5

6

6.5

7

7.5

8

8.5

0 1 2 3 4 5 6 7 8

Treatment Week

Mea

n Se

rum

Pho

spho

rus

(mg/

dL)

Time average concentration (Cavg) wks 1-80.63 mg/dL difference; p < 0.0001

CARE Weekly Serum Calcium Levels

Calcium acetate

Sevelamer hydrochloride

8

8.5

9

9.5

10

10.5

11

11.5

12

0 1 2 3 4 5 6 7 8

Treatment Week

Seru

m C

alci

um (m

g/dL

)

Time average concentration (Cavg) wks 1-80.63 mg/dL difference; p < 0.0001

Time-average concentration (Cavg) wks 1-86.1 mg/dL difference; p = 0.022

40

45

50

55

60

65

70

75

0 1 2 3 4 5 6 7 8

Treatment Week

Ca

X P

Prod

uct (

mg2

/dL2

)

Calcium acetate

Sevelamer hydrochloride

CARE Study: Mean Weekly Ca X P Product

In Pooled Analysis of 10 RCT with 2501 patients, Serum P was Significantly Lower with CBPB than Sevelamer by 0.4 mg/dL (95% CI 0.15 to 0.6)

Tonelli et al. NDT 22:2856-2866, 2007

Serum Ca: 0.4 (CI 0.48 to 0.28)iPTH: Mean difference 7.0 to 95

Serum Ca x P: nonsignificantly lower with CBPBSerum HCO3: significantly lower with sevelamer

NKF-K/DOQI Guidelines1 for Treatment of Hyperphosphatemia in Stage 5 CKD

Reference: 1National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003; 42 (Suppl 3).

The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day (OPINION)

The total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day (OPINION)

Dose of Elemental Calcium From Calcium Acetate

5.01375Qunibi CARE-2

5.71796Qunibi-CARE

5.9986Hervas

5.11164Chertow

5.91265Bleyer

4.61400DAlmeida

5.8750Wallot

4.79957Almirall

4.671500Pflanz

6.211440Ring

5.571500Caeavaca

5.17620Moriniere

5.321235Ben Hamida

4.671020Schaefer

Phosphorus LevelElemental CalciumStudy

Treatment of Hyperphosphatemia with CBPBThe Link Between calcium load and Calcification

Treatment with CBPB is associated with excess gastrointestinal calcium absorption

Excess calcium load in contributes to progression of cardiovascular calcification by:

Transdifferentiation of VSMCs to osteoblast-like cells which in turn leads to cardiovascular calcification in patients with CKDHypercalcemiaOversuppression of PTH leading to ABD which will not be able to buffer excess calcium

CBPB, by contributing to cardiovascular calcification, increase the risk of death mainly from CVD

Observational Studies Linking VC with CaCO3

Serum P 6.0 mg/dLSerum P = 6.9 mg/dL vs. 6.3 mg/dL

CAC In Young dialysis Patients

0

Dos

e of

CaC

O3

1000

3000

4000

6000

2000

5000

Calcification

7000

No Calcification

Goodman et al NEJM 342: 1478-1483, 2000

Vascular Calcification and Dose of Elemental Calcium Intake From CaCO3

1

Vessel slices with ultrasound evidence of calcification

Ele

men

tal C

alci

um

In

take

(g/

day)

1.2

1.6

1.8

2.2

1.4

2.0

43210

2.4

VC evaluated by plain radiographsand ultrasoundof CCA, aorta, femoral and leg arteries in 120 HD patients. Calcificationscore 0-4 (# sites with VC)

Guerin et al. NDT 15: 1014-1021, 2000

Limitations: Observational (cannot establish causality)Small number of patientsRelied on prescribed rather than consumed amount of CaCO3

Median Percentage Change in Coronary And Aortic EBCT Calcium scores at 52 weeks

0

5

10

15

20

25

30

35M

edia

n P

erce

ntag

e C

han

ge

Calcium Sevelamer

25%

6%

P = 0.02

0

5

10

15

20

25

30

35

Med

ian

Per

cent

age

Ch

ange

Calcium Sevelamer

28%

5%

P = 0.02

Chertow et al KI: 62:245-253, 2002

SevelamerCalcium

Coronary Calcification Aorta Calcification

Percent Median Increase in CAC Scores in Patients With

Baseline Scores > 30

0

10

20

30

40

50

Per

cen

t M

edia

n I

ncr

ease

inC

AC

S

6-months

CBPB*Sevelamer

Block et al. KI 68:1815-1824, 2005

12-months 18-months

10%

26%

13%

41% 38%

52%

* Note: ~ 70% of CBPB group received CaCO3

P = 0.0599P = 0.0564P = 0.2971

LDL Levels at Baseline and at 52 weeks (TTG)

Study Week--22 00 1212 2424 5252

LD

L C

hol

este

rol (

mg/

dL

)

140140

120120

100100

8080

6060

SevelamerSevelamer

CalciumCalcium

S=102S=102C=102C=102

S=65S=65C=103C=103

Chertow GM, et al. The Treat to Goal study. Kidney Int Vol 62; 2002

S = 65

C = 103

LDL Levels at Baseline and at 12 Months (RIND)

0

20

40

60

80

100

120

140

LD

L L

evel

(m

g/dL

)

Baseline 52 weeks

72

81

P < 0.0001

7260

CBPB Sevelamer

Block et al. KI 68:1815-1824, 2005

Prevalent HD Patients Incident HD Patients

Correlation Analysis in The RIND Study

Factors correlating with change in CACS:AgeBaseline PTH levelsMean LDL cholesterol levelMean total cholesterol levelBaseline CAC score

Showed no correlation between dose of elemental calcium prescribed or episodes of hypercalcemia and CACS

Significant correlation between on treatment average LDL and total cholesterol and change in CACS

Block et al. KI 68:1815-1824, 2005

Calcium is an Integral Part of Atherosclerosis

Coronary Calcium by EBCT and Atherosclerotic Plaque by Histopathology

0 1 2 3 4 5 6 7 80

16

2

4

6

8

10

12

14

EBCT Coronary Calcium Score (Square root)

Ath

eros

cler

otic

Pla

que

Vol

ume

N=38R=0.90P

Calcium Acetate Renagel Evaluation study (CARE-2 study)

ObjectiveTest the hypothesis that, if LDL is intensively lowered by statins to equal levels in calcium acetate and sevelamer-treated patients, there will be no difference in progression of cardiovascular calcification

Prospective, multicenter, randomized, open-label, parallel-arm study

1:1 Randomization

CARE-2 Study Design

Washout

PO4 > 5.5LDL > 80

Washout

PO4 > 5.5LDL > 80

6 months 12 Months6 months 12 Months

calcium acetate

(667 mg)

+

Atorvastatin 20 mg/d

calcium acetate

(667 mg)

+

Atorvastatin 20 mg/d

Sevelamer HCL

(800 mg capsules)

+/-

Atorvastatin

Sevelamer HCL

(800 mg capsules)

+/-

Atorvastatin

2 6 weeks

Treatment

Treatment Goals:Serum P 3.5-5.5 mg/dLLDL level < 70 mg/dLEB

CT

Primary Endpoint:Change in EBCT-measured CAC scores at 1 yearSecondary Endpoints:Serum P, Ca, Ca x P product, HCO3, PTHLipid levels

EB

CT

EB

CT

CACS 30-7000

ASN 2006 (Poster)

CARE-2 Study Design

When the target serum P was reached, subjects with iPTH level > 300 pg/ml were given IV vitamin D during dialysis

Dose of vitamin D was started at the lowest and was titrated to achieve the goal iPTH level of 150-300 pg/ml

1Qunibi, WY et al. Poster. Presented at the American Society of Nephrology Renal Week. San Diego, CA. November 16, 2006.

CARE-2 Study Design

If adjusted serum Ca exceeded 10.2 mg/dL, IV vitamin D was discontinued for 1 week

If repeat serum Ca after 1 week remained >10.2 mg/dL, calcium acetate dose decreased by 1 gelcap per meal

Dialysate calcium concentration was maintained at 2.5 mEq/L throughout trial

1Qunibi, WY et al. Poster. Presented at the American Society of Nephrology Renal Week. San Diego, CA. November 16, 2006.

Mean Baseline and Monthly Serum LDL Levels By Treatment Group

50

60

70

80

90

100

110

120

0 30 60 90 120 150 180 240 300 360

Study Day

Mea

n L

DL

Calcium Acetate

Sevelamer

BaselineN 103 100Mean SD 1098 1440 969 1386Median 468 439 0.6

6-monthN 71 68Mean SD 1197 1413 996 1419Median 644 447 0.2Absolute increase

Mean SD 109 374 97 211Median 79 54 0.6Wilcoxon signed rank test*

CARE-2 Study Primary EndpointMedian % Change in CACS from Baseline

29%

20%

30%

14%

0%

5%

10%

15%

20%

25%

30%

35%

40%

6 Months 12 Months

Calcium Acetate Sevelamer

Med

ian

% C

han

ge

P = 0.4

P = 0.9

Qunibi et al. AJKD 51:952-965,June 2008

CARE-2 Study: Statistical Analysis

The protocol was designed as a noninferiority trialto demonstrate that treatment of hemodialysis patients with Calcium Acetate is not associated with greater progression of CAC than patients treated with Sevelamer when the LDL cholesterol concentration is lowered to less than 70 mg per deciliter

Statistical Methods

The primary outcome was the Day 360 to baseline ratio of total CAC scores, summarized within each study arm by the geometric mean (GM)

The study arms were then compared by the ratio of the two geometric means (Ratio of Ratios)

Total Agatston Score at Baseline and Month 12ITT Population

511.968617.058Day 360

0.856230.16728.855% Change from Day 02

0.154495.568126.358Change from Day 01

526.968691.158Day 360

439.0100468.0103Day 0

Median

0.93721.39671.3555Day 360/Day 0 Ratio2

411.499489.299Day 0

Geometric Mean

0.929556.86752.055% Change from Day 02

0.9799227.568228.058Change from Day 01

1115.6681296.958Day 360

968.51001098.3103Day 0

Mean

p-valueEBCTNEBCTN

SevelamerCalcium Acetate

Time Point or Parameter

1Absolute change was calculated for all subjects independent of the baseline value 2Calculated only in subjects with a EBCT baseline value > 0 (Zero baseline values are the primary source of missing ratios)

(Three Calcium acetate patients and 1 sevelamer patient had zero CACS)

0.85 0.99 1.16

1.090.710.47

1.270.55 0.84

1.150.920.74

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Coronary Artery

Total Aorta

Mitral Valve

Aortic Valve

A priori margin of non-inferiority

Calcium Acetate Better Sevelamer Better

Calcium Acetate to Sevelamer Ratio in Day 360/Day 0 Ratios of CAC Score

Qunibi et al. R = = 1.0Ca360/Ca0Sev360 /Sev0

AJKD 51:952-965,June 2008

0% 20% 40% 60% 80% 100%

12

6 Months

Calcium Acetate Sevelamer

Fishers Exact Test p-values for post hoc tests of superiority.

p = 0.41

p = 0.46

Per

cen

t of

Pat

ien

ts

Proportion of Subjects with > 15% Progression of CAC Among Subjects with Baseline CAC > 30

54%

47%

58%

64%12 Months

6 Months

Mean Values of Parameters of Mineral Metabolism During CARE-2 Study Period

Qunibi et al. AJKD June 2008

Percent of Patients with Serum iPTH at Goal of 150 300 pg/mL

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 30 60 90 120 150 180 210 240 270 300 330 360

Calcium AcetateSevelamer

% o

f Su

bje

cts

Study Day

P = 0.34

PTH < 150 pg/mL:Calcium Acetate 11%Sevelamer 9%

Potential Explanations for the Different Results of CARE-2 vs TTG and RIND Studies

Equal LDL levels

Lower total dose of elemental calcium used

Less suppression of PTH

Higher prevalence of diabetes

Higher prevalence of smoking

Percent Median Increase in CAC Scores At End of Study Period in HD Patients with Baseline CACS > 30

0

10

20

30

40

50

Perce

nt M

edian In

crea

se

in C

ACS

TTG Study

54%

25%

RIND Study CARE-2 Study

38%

29%30%

5%

70

60

P = 0.9

P = 0.0599

P = 0.02

Qunibi et al.ASN 2006 Poster

Chertow et al KI: 62:245-253, 2002

Block et al KI: 68:1815-1824, 2005

LDL Levels at End of Study

0

20

40

60

80

100

120

140

LDL L

evel (m

g/dL)

TTG RIND

10381

P < 0.0001

65 60

CBPB Sevelamer

CARE-2

P = NS

P < 0.0001

6862

Dose of Elemental Calcium (gram/day) from use of CBPB

0

TTG RIND CARE-2

Bin

der

Dos

e (g

m/

D)

1.375

1

1.5

2

2.5

3

2.3

1.2

1.72

Calcium Acetate

Calcium Carbonate

Percent Median Increase in CAC Scores At End of Study Period in HD Patients with Baseline CACS > 30

0

10

20

30

40

50

Perce

nt M

edian In

crea

se

in C

ACS

TTG Study

54%

25%

RIND Study CARE-2 Study

38%

29%30%

5%

70

60

P = 0.9

P = 0.0599

P = 0.02

Qunibi et al.AJKD 51:952-965, 2008

Chertow et al KI: 62:245-253, 2002

Block et al KI: 68:1815-1824, 2005

PTH Levels at Baseline and Study End

100

150

200

250

300

350

PTH

Lev

el ( p

g/m

L)

TTG

450

400

RIND CARE-2

500

503

CBPB Sevelamer

200

138

232

224

319

243

293 29

8

464

316

434

CBPB 57% 29% 11%Sevelamer 30% 18% 9%

PTH < 150:

Correlations between daily CaCO3 dosage (grams of elemental Ca) and AoCS or aortic PWV for patients with active bone and those with ABD

London et al. JASN May 14, 2008

Changes in CAC at 12 Months

Barreto et al. Nephron Clin Pract 110:c273-c283, 2008

Barreto et al. Nephron Clin Pract 110:c273-c283, 2008

Prospective Study that Compare the Effects of Calcium Acetate and Sevelamer on Progression of CAC in HD Patients

Mean CACS in Non-diabetic Predialysis Patients With Baseline CAC

0

100

200

300

400

500

600

700

Mea

n T

otal

CA

C S

core

Baseline 24-months

CKDHealthy controls

Russo et al. Am J Nephrol 27:152-158, 2007

Annualized Progression

CKD: N= 27 (GFR=34ml/min)Healthy: N = 6

800P < 0.01

P = NS

73 80

384

602

Serum Phosphorus was only variable associated with progression of CAC

41

276

Both Sevelamer and Calcium Carbonate Decrease CAC in Pre-dialysis CKD Patients

Russo et al. Kidney Int 72:1255-1261, 2007

Russo et al. Kidney Int 72:1255-1261, 2007

Effect of Calcium Carbonate on Vascular Calcification in Apolipoprotein E-/- Mice with Subtotal Nephrectomy

Phan et al. NDT; Dec 1-9, 2007

Did the age-related difference (> 65 vs. < 65 years) in mortality persist in this intent-to-treat data Analyses?

Pre-specified Secondary Analyses From DCOR Study

St. Peter et al. AJKD 51:445-454, March, 2008

Follow-up conducted by merging the DCOR analytical dataset with patients health care claims from CMSThe primary analyses censored patients at 90 days after study discontinuation This CMS-based analysis allows for an ITT evaluation and complete ascertainment of the primary endpoint (death from any cause)Found an interaction between age and treatment but the difference became nonsignificant after adjusting the p-value for the number

of interaction tests that were performed

$2.4 billion

$759 million

Annual cost for all dialysis patients in USA

$6734$18.45$2.053Sevelamer

$2168$5.94$0.663Calcium Acetate

Annual cost

Daily costCost/pillAverage Dose/meal

Cost Matters: Approximate Daily and Annual Cost of Calcium Acetate and Sevelamer

Dialysis population: 350,000

Conclusion-1

Mortality rate in CKD and dialysis patients is high

Abnormalities in mineral metabolism are associated with increased risk of death in these patients

Vascular calcification is common in CKD patients, starts early in the course of CKD, and progresses as renal function declines and during dialysis

Hyperphosphatemia is an important modifiable risk factor for CVC and death in patients with ESRD

Conclusion-II

Results of the CARE-2 study showed no significant difference in the progression of CVC at 1 year following equivalent lipid control in the calcium acetate and sevelamer treated groups

Significant reduction in LDL-C does not result in halting progression or inducing regression of CV calcification.

Multiple factors, both traditional and non-traditional are involved in progression of calcification in patients with ESRD

No apparent difference in the effect of phosphate binder class on all-cause or CV mortality

Thank You

Jrgen Floege. NDT 2008

Goldsmith and Covic. Int Urol Nephol 40:1009-1014, 2008