Vascular Calcification: Bones, Blood Vessels, and Outcomes

Ravi Thadhani, MD, MPH

Associate Professor of Medicine

Harvard Medical School

Massachusetts General Hospital

Disclosures: Grant Support from Abbott

Courtesy of Kevin Martin, MD

Calcified Plaque

Goodman WG et al, NEJM 2000

Schwarz et al, NDT

Plaque Morphology in ESRD

- Increased Media Thickness- Excess Calcification

Keelan et al, Circ 2000

London GM, JASN 2003

Okuno et al, AJKD 2007

DeLoach et al, NDT 2009

Aortic calcification and CVD events in Transplanted Patients

Haydar A et al, Kidney Int 2004

London GM, Kidney Int 2003

Klassen et al, JAMA 2002

Raggi P et al, Hypertension 2007

What has been linked with calcification?

• Ca• P• Ca X P• Fetuin• OPG• LDL• Matrix-Gla Protein• hsCRP• IL-6• TNF-

??

CAC and Minerals…

Frequent dialysis reduces need for P binders, but is this the mechanism of benefit?

Normally, mesenchymal stem cells differentiate to adipocytes, osteoblasts, chondrocytes, and vascular smooth muscle cells (VSMC)

Moe SM, JASN 2008

Kuro-o M et al, Nature 1997

Yumita et al, Tohuku J Exp Med 1996

Tsujikawa et al, Mol Endocrinol 2003

Tsujikawa H et al, Mol Endocrinol 2003

65%

70%

75%

80%

85%

90%

95%

100%

0 50 100 150 200 250 300 350Days

Surv

ival

Pro

babi

lity

(%

)

A/A A/C C/C

A

No. at risk

C/CC/AA/A

82327624

74725021

91530627

67923120

63221719

59420419

55120017

51719215

Log-Rank p=0.02165%

70%

75%

80%

85%

90%

95%

100%

0 50 100 150 200 250 300 350Days

Surv

ival

Pro

babi

lity

(%

)

A/A & A/C C/C

B

Log-Rank p=0.005

No. at risk

C/CA/A & A/C

823300

747271

679251

632236

594223

551217

517207

915333

65%

70%

75%

80%

85%

90%

95%

100%

0 50 100 150 200 250 300 350Days

Surv

ival

Pro

babi

lity

(%

)

A/A & A/C C/C

C

No. at risk

C/CA/A & CC

Log-Rank p=0.215

603231

562211

508194

473182

444170

411164

384154

643250

65%

70%

75%

80%

85%

90%

95%

100%

0 50 100 150 200 250 300 350Days

Surv

ival

Pro

babi

lity

(%

)

A/A & A/C C/C

D

No. at risk

C/CA/A & CC

Log-Rank p=0.007

22069

18560

17157

15954

15053

14053

13353

27283

+D Users - D Users

All Groups CEU, CHB, and JPT

+16%+21%

p=0.0045 p=0.0036

Friedman, Afkarian, et al, In Press

Rodriguez M et al, Kidney Int 2008

Cardus A et al, JBMR 2007

CAC and LVH tightly linked

Who Progresses?

What do the Statin Data tell us?

Fellström et al, NEJM 2009

55 yo F on HD for 8 years, dies of a CVA

IVST=1.4cm; EF 60%, Mod-Sev Concentric Hypertrophy

Circulation 2009

Some Ongoing Trials Examining Calcification in ESRD

• PRIMO I & II – Paricalcitol and LVH, MRI of Aorta Included• Cinacalcet + Low Dose Vitamin D (ADVANCE Trial)• P-Binders and CAC: Sevelamer, Phos-Lo, Fosrenol• Bisphosphonates and Calcification and BMD• Phosphate Control and Calcification

Conclusions

• Calcification and Outcomes linked?• Can Calcification be Modified?• What interventions accelerate/decelerate

calcification?• What Biomarkers do we follow?