AFECTACION CARDIOVASCULAR CKD-MBD

Mariano Rodriguez

Unidad de Investigacion, Servicio de Nefrologia.

Hospital Univ. Reina Sofía (IMIBIC). Fundación Nefrologica-Red Renal

PROYECTO PROMETEO.

Alcalá de Henares, Oct 2011

Chronic kidney disease­mineral and bone disorder

Laboratory abnormaiHies

evo FRACTURES MORTALITY

Vascular calcification

Bone abnormalities

Calcification score-Survival• Probality of all-cause survival according to calcification score. Comparison

(log-rank test) between curves was highly significant ( Chi D =42.66 ; P<0.0001).

Calcification score : 0

0.25

0.50

0.75

1

0

0 20 40 60 80

Calcification score : 1

Calcification score : 2

Calcification score : 3

Calcification score : 4

Duration of follow-up (months)

Prob

ality

of s

urvi

val

Blacher et al Hypertension 2001

(n=37)

(n=12)

(n=13)

(N=14)

(n=34)

¡;¡ Non-calcified > 0.75 ·s: ... P<0.001 :S 0.50 "' ~ Arterial medial calcification "' :S 0.25 os P<0.01 y - 0.00 X2=44.3; p<0.00001 Arterial i ntim al calcification <t

o 25 50 75 100

¡;¡ >

1.00 Non-calcified -~ P<0.001 :S 0.75 Arterial medial calcificationa "' ... os 0.50 :S P<0.01 u

"' os > 0.25 Arterial intim al calcification o

"O 0.00 X2=34.9; p<0.0001 ...

os u o 25 50

Months 75 100

London GM. et al. Nephrol Dial Transplant 2003;18:1731·4 o.

Datos clínicos y aproximaciones terapeuticas -Ca-P-PTH-Vit D-FGF23-Klotho

Mecanismos de calcificación-P-se puede reparar el vaso calcificado?

Oialysis Therapies

Mild Hyperphosphatemia and IVIortality in Hemodialysis Patients

Alberto Rod riguez-Benot et al Am J Kidney Dis 46:68-77, 2005.

ro >

-~ ::S VI Q.l

Table 4. Multivariated Risk Ratios for Mortality

RR 5% Cl 95% Cl Significance

Phosphate 1.30 1.14 1.49 0.00 (unadjusted)

Adjusted Risk Ratios Phosphate (1 mg/dl) 1.26 1.09 1.47 0.02

.._.-------------~-,.._.,,.._...,. ______ ,.~etes, hemoglobin level, albumin level, nPCR, Kt/V, serum calcium, level, andPTHievel.

JAMA. 2011;305(11):1119-1127

Of 8380 citations identified in the original search, 47 cohort studies (N=327 644 patients) met the inclusion criteria.

S. Phosphorus

S. PTH

5 covariates: age, race, time on dialysis] [or estimated glomerular filtration rate), CV disease, and diabetes.

<5 covariates

S. Calcium

S. Phosphorus

S. PTH

S. Calcium

In individuals not yet requiring dialysis, the risk of all cause mortality for each 1-mg/dL increaseIn P (RR, 1.29) was similar to that observed in individuals requiring Dialysis (RR, 1.17)(P = .22).

No evidence of an association between serum calcium and all-cause mortality was found in either individuals with earlier stages of chronic kidney disease (RR, 1.02) or those requiring dialysis (RR, 1.09) P=.63

Bone Disease :Impact on Soft Tissue Calcification

PTH (pg/ml)

http://www.kidney-international.org original article © 2009 1 nternati onal Society of Nephrology

see commentary on page 931

Chronic kidney disease, hypovitaminosis D, and mortality in the United States Rajnish Mehrotra 1'

2, Dulcíe A. Kermah3

, Isidro B. Saluskl. Myles S. Wolf. Ravi l. Thadhani5, Yi-Wen

Chiu 1'6

, David Martins3, Sharon G. Adler1

'2 and Keith C. Norris2

'3

Table 21 Adjusted hazards ratios for the relationship between serum 25-hydroxy vitamin O levels and aH-cause mortality in participants with chronic kidney disease from the Third National Health and Nutrition Examination Survey cohort

Models adjusted fo r

Demograph icsa Demographics and cardiovascular risk factorsb Demographics, cardiovascular risk factors, and laboratory an d socioecon omic vari ablesc

Total events

1123 989 848

> 30 ng/ml

Reference Reference Reference

1.52 (1.18, 1.96) 1.60 (1.22,2.10) 1.56 (1.12,2.1 8)

Table 3 1 Adjusted hazards ratios for the relationship between serum 25-hydroxy vitamin O levels and cardiovascular and non­cardiovascular mortality in the Third National Health and Nutrition Examination Survey cohort

Models adjusted for

Cardjoyg.m¡Jqc moctality Demog raph icsa Demographics an d cardiovascular risk factorsb Demographics, cardiovascular risk factors, and laboratory and socioeconomic variablesc

Non-cacdiovasr:u/ac mocta/ity Demograph icsa Demographics and cardiovascular risk factorsb Demographics, cardiovascular risk factors, and laboratory and socioeconomic variablesc

Total events

588 518 444

535 4 71 404

Vitamin Da

> 30ng/ml

Reference 1.19 (0.94, 1.5 ) 1.51 (1.01,2.28) Reference 1.21 (0.93, 1. ) 1.51 (0.96,2.38) Reference 1.19 (0.91, 1. 7) 1.49 (0.94,2.36)

Reference 1.17 (0.93, 1.4 Reference 1.22 (0.96, 1.5 Reference 1.17 (0.88, 1.55)

A

10

B

10

"

~h 1o aldtnol

" " Wonths

" JO

21

f i&llltl. kapfan-MIIi• An~ ofSUMv&!Ao:onfn¡ eo tM l1pt ofYibmin OThtrapy.

...... JS ••

..... " 40

P.JneiA shO'o\'$ tht swvwal of ~ticnrs rreatcdwilh ei1her paric;~tltol or ("Al· C1trtoJwM rtctNfd tht nrnt tllm~ f<Jr tflt duutr.onof tlw folow-up. hntl 8 1hows the survival o( patierY.s who s.-Mtched from calcitnol !o parical~l or fromp¡ritflkhol ro gkt-:r!oldvnng 1he follow·vpptrlod. Tht t.mt o( ~~td~

in¡ wu~pro)jmate!y900days ~et tt!e in'l:i.ation « di~lyus for b()lh ¡rou~. P \'&!~ were <akulated wilh the-11-se oft~~&·ratlk test.

ILI ______ o_'"-'·_·•_N_A_L_A_ft·_r •_c_L_E _____ ___JII

Survival ofPatients Undergoing Hemodialysis with ParicalcitOI or Calcitriol Therapy

M1ng Ttng. M.(>., Myles. Wo!f, M.O., M.M.$c., €dmvnd lowri~. M.(> .. Norma Of1thun. Ph.O.,J Mi<-h~el L~•rus., M.O.,

and l<;av, Th;aQh;ani. M.O., M.P.H.

Even alter Adjustment of Serum Minerals, VDR Activation

was still independently associated with improved survival

N En!ll J Med. 2003

Association of Activated Vitamin D Treatment and Mortality in Chronic Kidney Disease Csaba P. Kovesrl:v. MD: Shahram Ahma~adeh, MD;]ohn E. Anderson, MD; Kamyar Kalantar-Zadeh, MD Arch lnternMed. 2008;168(4):39(-403

All -·-Age~70 y -· Age>70 y -·--White race -·--Black race -·

Diabetes mellitus No diabetes mellitus

ASCVD No ASCVD

eGFR ~ 30 ml/min/1.73 m2 eGFR > 30 ml/min/1.73 m2

Calcium level~9.1 mg/dl Calcium level>9.1 mg/dl

Phosphorus level~4.0 md/dl Phosphorus level>4.0 md/dl

PTH level ~ 1 03 pg/ml PTH level > 1 03 pg/ml

Albumin leve 1~ 3. 6 g/dl Albumin leve 1> 3. 6 g/dl

He moglobin leve 1~ 12 pg/ce 11 He moglobin leve 1> 12 pg/ce 11

o:o

-·----· --· -· -·---·----· -·---· --· -· --· -·----· -· -·--Favors

Calcitriol

10

Favors N o Calcitriol

Ad ju sted In ci dance Rate Ratio

P

PROXIMAL TUBULE

LUMEN

FGFR FGF23P

↓1α(OH)asa mRNA

NPT2a,c

NPT2a,c

↓1α(OH)2D3

↓P

KLOTHO

↑1α(OH)2D3

↑ P

↑ 24 (OH)asa

PTH

FGF23 null

Hyperphosphatemia

High calcitriol levels

Calcification

FGF23 null

Heart

Kidney

FGF-23 in patients with end-stage renal disease on hemodialysis YASUO IMANISID, Kidney lnternalional, Vol. 65 (2004), pp. 1943-1946

107 ~---------------------------, r= 0.544. Pe:: 0.0001

r = O .446. P e:: 0.0001

1~~~--~~~~~--~~~~

10 102 103

Serum intae:t PTH. pglmL

FGF23 predice mortalidad …incluso ajustando por P

Preguntas:-FGF23 es nocivo??-FGF23 refleja un largo historial de P alto.- FGF23 refleja otras alteraciones CKD MBD además del P elevado

FGF-23 and Mortality in CKD. Isakova et al. JAMA 2011

Myles Wolf…J Am Soc Nephrol 22: 956–966, 2011

Mortality Allograft Loss

Years Years

% %

Fibroblast Growth Factor 23 and Left Ventricular H ypertrophy in Chronic Kidney Disease

Orlando M. Gutiérrez, MD, MMSc; James L. Januzzi, MD; Tamara Isakova, MD; (Circulation. 2009;119:2545-2552.) Karen Laliberte, RN, MS; Kelsey Smith, BA; Gina Collerone, AS; Ammar Sarwar, MD;

Udo Hoffmann, MD; Erin Coglianese, MD; Robert Christenson, PhD; Thomas J. Wang, MD, MPH Christopher deFilippi, MD; Myles Wolf, MD, MMSc

ARTICLE Annals of lnternal Medicine

The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study Benjamin D. Parker, MD; Leon J. Schurgers, PhD; Vincent M. Brandenburg, MD; Robert H. Christenson, PhD; Cees Vermeer, PhD; Markus Ketteler, MD; Michael G. Shlipak, MD, MPH; 1\1\ary A. Whooley, MD; and Joachim H. lx, MD, MAS

Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community Majd A.I. Mirza a, Anders Larssona, Lars Lind a, Tobias E. Larsson a,b,:+:

Atherosclerosis 205 ( 2009) 385-390

↑ Phosphate

Cardiovascular disease

+Mortality

↓1,25 (OH)2 D3

↑FGF23

↑ PTH

Membrane Klotho

Klotho , /

transport / FGFR-1 signaling

Soluble Klotho

, __ -, ,. - - - --'t

'

FGF-23

lntracellular

............................ ~····· ·· · ···· · · ···········. ',,; ; e CYP2781 - . : ... _ ' :

¡_ Gene transcription l • Pi transport ...................................................... •

Figure 21 The fibroblast growth factor (FGF)-23 receptor. In light blue, FGF receptor type-1 (FGFR-1 }. In dark blue, left-sided mem brane-boun d Klotho; right-sided soluble, shed Klotho. The red hexagon depicts FGF-23. FGF-23 signal transduction is established when Klotho and FGFR-1 colocalize (left side}. lt is unknown whether signal transduction can occur by soluble Klotho (right side}. In the kidney, signaling leads to down­regulation of CYP27B 1 and retrieval of phosphate transporters in the proximal tu bu le (figure provided by J H oenderop, Departm ent of Physiology, University Medica/ Center N ijm egen, The N etherlands}.

Vervloet MG, Larsson TE. Fi broblast growth factor-23 and Klotho in eh ron ic kidney disease. Kidney inter., Suppl. 2011; 1: 130 135.

•

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Ming Chang Hu/t~ Mingjun Shi/ Jianning Zhang/ Henry Quiñones/ Carolyn Griffith/ Makoto Kuro-o/§ and Orson W. Moe*tll

J A m S oc Nephrol 22: 124-136, 2011. <

D

~

::; 25 B o 20

~ 15 S2 tD 1!:' 5

~ o

"ii 1rMKI prot~ln jfmolsl 5 10 5o 25 o z

•

.... -ti 1

., .. 1 1

Normal Stige1 Stage2 ~3

C.K.Ostage

2 3 4

-Ol

30€ .!1 ~

20":. 1 ...

tO ~ 2 ....... "~ - ~ n E Stage-4 StlgeS :J

A 400

~ e 3oo .! 'fi l5 ~ -(,) Q. 200 E "' .2 E ~ o. 100 u-5

o Pi (mM) 1 2

Kl (nM) O

D 35 • .U

'2 30

"'E 25 .,. _ a~ 20

" "" 15 ·- o Q.E 10 a 5 o

Pi(mM) 1 2 -Kl (nM) o

...

1 2

0 .4

.. 21 1 2 -0.4

Na•.<fependent

ESTUDIOS PROSPECTIVOS ( progresión de la CV)

1-Estudios clínicos han mostrado que control del P con Sevelamer y también con lantano disminuyen la progresión de la CV.

2- ADVANCE sugiere que Calcimimeticos retrasan la progresión de la CV

Calcificación Vascular ≈ Mortalidad vascular ??

FRENAR CALCIFICACIÓN:

• Eliminar factores que estimulen la calcificación

• Intervenir sobre los mecanismos celulares

• Favorecer la reparación -reabsorción de calcificación -restitución (reparación) del tejido

-

Calcimimetico PTH

Ca P

Se puede controlar el hiperperatiroidismo y además disminuir el Ca y el P

Que pasa con las calcificaciones vasculares??

FIGURE 5

(A) Sham (B) 5/6 Nx + vehicle (C) 5/6 Nx + R-568 (1.5mg/kg)

(E) 5/6 Nx + Calcitriol (F) 5/6 Nx + Calcitriol

+ R-568 (1.5 mg/kg)

(C) 5/6 Nx + R-568 (3 mg/kg)Lopez I et alJ Am Soc Nephrol 17: 795–804, 2006

Mendoza et al, Calcified Tissue International (2010)

aP<0.05 vs AMG 1 µM

0

0.5

1.0

1.5

2.0

2.5

3.0

AMG 0.1 µMControl AMG 0.5 µM AMG 1 µM

mR

NA

MG

P/G

AP

DH

Calcimimetico estimula la expresion de MGP

*

Mendoza et al (en AJP)

0 2 4 6 8 10 12 14 1 2 3 4 5 6 7 14 21 28TIME (DAYS)

Sacrifice

High Phosphorus Diet (P = 1.2%)

Normal Phosphorus Diet (P = 0.6 %)

(5/6Nx)

Sacrifice

Time 0

Calcitriol / 48h AMG-641 / 48h

CTR CTR CTR CTR CTR CTR CTR

Are calcifications reversible?

Calcitriol / 48h AMG-641 / 48h

Sacrifice

Am J Physiol Renal Physiol. 2009 Mar 25. [Epub ahead of print] PubMed PMID: 19321594.

Lopez I

CTR AMG-641Vehicle

Time 0

Am J Physiol Renal Physiol. 2009 Lopez I

ADVANCE

A randomizeD VAscular calcificatioN study to evaluate the effects of CinacalcEt

HIPOTESISUn régimen de tratamiento que incluya cinacalcet y dosis bajas de análogos de vitamina D atenuará la progresión de la calcificación de la arteria coronaria (CAC) durante un año, en comparación con el tratamiento convencional*, en pacientes sometidos a hemodiálisis tratados con o sin quelantes de fósforo cálcicos.

PTH Ca

Ca x P P

Resultados

Cambio porcentual en la puntuación total de la calcificación de la arteria coronaria (CAC)

Análisis primario basado en una prueba generalizada de Cochran-Mantel-Haenszel sobre rangos.Análisis complementario (según lo establecido en el protocolo) utilizando un modelo lineal generalizado para ajustar según el desequilibrio basal en los niveles de fósforo entre los grupos de tratamiento.

Mediana de las diferencias según tratamiento, todos los puntos

Mediana (IC 95%) de la de la diferencia del tratamiento ajustado por grupos (cambio % en la calcificación)

Puntuación de Agatston Puntuación del volumen

Favorable para el grupo cinacalcet

Favorable para el grupo control

Arteria coronaria total

Aorta torácica

Válvula aórtica

Válvula mitral

FRENAR CALCIFICACIÓN:

• Eliminar factores que estimulen la calcificación

• Intervenir sobre los mecanismos celulares

• Favorecer la reparación -reabsorción de calcificación -restitución (reparación) del tejido

-

VASCULAR CALCIFICATION (vascular ossification). Essential elements:

- Cells (Bone forming cells: osteoblasts)

- Molecular mediators (osteogenic proteins)

Bone forming cells (osteoblasts)

CalcificationMolecular mediators (osteogenic proteins)

(Cbfa-1) VSMC

Pathogenic factors of Vascular Calcification particularly relevant in uremia:

-Phosphate -Calcium-Calcitriol

-Inflammation-↓Fetuin-Uremic toxins-Dyslipemia AGETime on DialysisDiabetes

PTH –Bone remodeling

FGF23

Sham 5/6 Nx 5/6 NxCalcitriol*

2.5

5.0

7.5

10.0

12.5

15.0

mg/gCALCIUM in AORTA

High Phosphorus (1.2%) Diet

*

5/6 Nx

Normal P(0.6%) Diet

(*)Calcitriol (40 ng/kg/day) (15 days)

5/6 NxCalcitriol*

Phosphate is a key factor in vascular calcification associated to vitamin D administration

Pathogenic factors of Vascular Calcification particularly relevant in uremia:

-Phosphate -Calcium-Calcitriol

-Inflammation-↓Fetuin-Uremic toxins-Dyslipemia AGETime on DialysisDiabetes

PTH –Bone remodeling

FGF23 (Cbfa-1) VSMC

(Cbfa-1) VSMC

NaP

P

PxCa: nanocristals

Inflammation –Cytokines

Ox. Stress

Ox. Stress ?

2hrs after ral load of P (1.2g)

None Klotho pep Klotho pep + TNFaTNFa

0

20

40

60

80

100

PD 2 PD 26 PD 42

RO

S a

ctiv

ity

(%

)

0

20

40

60

80

100

PD 2 PD 26 PD 42

*

*

Figure 6

Soluble klotho decreases oxidative stress in senescent endothelial cells

(work submitted)

*

*

*

Ap

op

tosi

s (%

)

VSMC

SM22α

P

XCbfa 1

(Cbfa-1)

VSMC

OSTEOBLAST

P

OSTEOBLAST

Methylation(Gene Silencing)

P

Cbfa 1

SM22α

X

High phosphate induces methylation of SM22α promoter

SM22α protein

Cbfa1 binding activity

Von kossa

SM22α promoter methylation

Control P P +Procaine (1mM)

(methylation inhibitor)

Inhibition of Methylation prevents Calcification

Montes de Oca J Bone Miner Res 2010 25(9):1996-2005.

methylation of the SM22α promoter causes calcification (independent of phosphate )

S-Adenosyl Methionine (a methylating agent)

SM22α promoter methylation

PSAMeControl

PSAMeControl

PSAMeControl

Cbfa1 mRNA

Ca µg/mg

Outcomes of SiRNA knockdown of SM22α on Cbfa1 expression in HASMCs

SM22α mRNA

Cbfa1 mRNA

Control

Control

SiRNA SM22α

SiRNA SM22α

Control SiRNA SM22α

Control SiRNA SM22α

SM22α protein

Cbfa1 binding activity

50 100 150 2001,25D (pmol/L)

0.3

0.4

0.5

0.6

0.7

Carotid intima media thickness

50 100 150 2001,25D (pmol/L)

0.00.5

2.02.53.0

Log calcification score +1

1.01.5

hs-CRP (mg/L)

50 100 150 200

1,25D (pmol/L)

0

10

20

40

30

Controls No calcification

Calcification present

0

10

20

30

40

50

60

hs-

CR

P le

vels

(m

g/L

)

0.4

1.35

15.3

p<0.0001

p=0.003

50

The effect of vitamin D derivatives on vascular calcification in uremic rats treated with LPS Guerrero F,1 Montes de Oca A,1 Aguilera-Tejero E,1 Zafra R, 2 Rodríguez M,3 López I1

5/6Nx, High P diet (P:0.9%, Ca:0.8%)LPS daily -Calcitriol(1,25D3)= 80ng/kg (3/week)-Paricalcitol(19-nor) = 240ng/kg (3/week)

A)

B)

a,b

a,c

a

a p<0.05 vs Controlb p<0.05 vs P 3.3 mMc p<0.05 vs P+TNF

VSMCs (ug/mg protein)

Control P 3.3 mM P+TNF P+TNF+PCT

P+TNF+CTR

a,b

0

2

4

6

8

a

a,b

a,b

a,c

Calcium content

Rat Aortic Rings (mg/g protein)

a

b,c

a

a p<0.05 vs Controlb p<0.05 vs P 3.3 mMc p<0.05 vs P+TNF

c

0

3

6

mRNA BMP2/ bactin

5

4

2

1

Control P 3.3 mM P+TNF P+TNF+PCT

P+TNF+CTR

The effect of vitamin D derivatives on vascular calcification in uremic rats treated with LPS Guerrero F,1 Montes de Oca A,1 Aguilera-Tejero E,1 Zafra R, 2 Rodríguez M,3 López I1

Gracias