Cardiovascular Disease in Chronic Renal Failure · Ticking Bomb of CVD in CKD Artery Lp(a) = lipoprotein (a); HDL-C = high-density lipoprotein cholesterol

Cardiovascular Disease in

Chronic Renal Failure

Antalya, October 18-22, 2017

Bengt C Fellström, MD, PhD

Professor of Nephrology

University Hospital

Uppsala

Sweden

USRDS

1000-fold

80 years

Mortality is massively increased in dialysis patients

as compared to the general population

Cardiovascular mortality: transplant patients

Age

(years)

An

nu

al

Mort

ali

ty (

%)

Foley et al AJKD 1998;32 (suppl 3) S112

0.01

0.1

1

1

0

25-34 35-44 45-54 55-64 65-74 75-84

Transplant

Control

Cardiovascular mortality by age group

Jardine A, Gaston R, Fellström B, Holdaas H. Lancet 378:1419-27; 2011

The cardiovascular burden that patients carry with them to transplantation .

Transplantation significantly reduces CV risk in these patients, it does not reduce to background population risk.

–CV risk > gen pop = cardiovascular risk increase as compared with background age adjusted risk. Stage = stage of renal career – CKD = chronic kidney disease;

–HD = haemodialysis; RTR = renal transplant recipient. Factors = stage specific risks – LVH = left ventricular hypertrophy; drugs = immunosuppressive agents.

…, and the development of

cardiovascular disease starts early :

Go A et al. N Engl J Med 2004;351:1296 - 1305

CVD1,120,295 adult

subjects in Kaiser

Permanente health

insurance plan in

Northern California

Median follow-up:

2.8 yrs

*

* MDRD equation

All-cause mortality

p < 0.0001

Cardiac death

p < 0.0001

Non-cardiovascular death

p = 0.0005

MACE

p = 0.0007

Non-fatal MI (NS)

Stroke (NS)

Creatinine (µmol/l)

Endpoint probabilities at baseline

creatinine levels

Pro

babili

ty

0

0.2

0.4

0.6

0.8

50 150 250 350 450 550

Fellström, Holdaas, JArdine, et al. Am J Transplant 2005; 5:1986-9

CVD in CRF

• Endothelial dysfunction

• Acelerated atherosclerosis

• Coronary heart disease

• Left Ventricular Hypertrophy

• Congestive Heart Failure

• Stroke

• Peripheral vascular disease

• Thrombo-embolic disease

Ticking Bomb of CVD in CKD

Artery

Lp(a) = lipoprotein (a); HDL-C = high-density lipoprotein cholesterol

AGEs = advanced glycosylation end products ; Ca x P = calcium-phosphorus product

Small dense LDL-C

Lp (a)

Low HDL-C

Oxidised LDL-C

Inflammation

Oxidant Stress

ROS, AGEs, AOPP

Malnutrition

Ca – P - PTH

Vascular calcification

Diabetes

Insulin resistance

Proteinuria

Renal dysfunction

HypertensionEndothelial

dysfunction

REACTIVE OXYGEN SPECIES

(ROS)

ATHEROSCLEROSIS

Endothelial

Cell

Smooth Muscle

Cell

ROS

ROS

ROSNO

L-

Arginine

BH4

ADMA

NOS

ROS

ROS

LDL-

Chol

Cell

Adhesion

Molecule

Receptor

Guanylyl

Cyclase PDGF-

AA

mRNA

ROS

GTP

cGMP

ROS SMC Proliferation

ECM Synthesis

PDGF-R

Monocyte

Scavang

er

Receptor

oxLDL

IL-1

PDGF

HLA-DR

Foam

Cell

0

,1

,2

,3

,4

,5

,6

,7

,8

,9

1

GS

SG

/GS

H

-10 0 10 20 30 40 50 60

CRP

Correlation between CRP and GSSG/GSH

0

100

200

300

400

500

600

700

800

S-c

rea

-10 0 10 20 30 40 50 60

CRP

Correlation between CRP and serum creatinine

CRP (mg/L)

GSS

G/G

SH

CRP (mg/L)

Ser

um c

reat

inin

e (m

mol

/L)

p= 0.0022

r= 0.50

p = 0.0008

r = 0.53

Relation of MACE with baseline hs CRP and Serum Albumin

Even

t rate

(%

)

16

14

12

10

8

6

hsCRP

Decile

0 2 4 6 8

p<0.0001

Even

t rate

(%

)

16

14

12

10

8

6

Albumin

Decile

0 2 4 6 8

p<0.0001

IL-6 Predicts Poor Outcome in ESRD

AJKD 2005

NDT 2004

NDT 2002

JASN 2006

Bologa et al. AJKD 1998

Oxidative stressInflammation

Retention of

uremic solutes

Decreased renal

function

Decreased clearance of

cytokines and AGEs

Sluggish innate

immune system

Priming of PMNL

Inability to respond

properly to danger

signals

Volume overload and

sympathetic overactivity

Infectious complications

Atherosclerosis

Endothelial

dysfunction

Yilmaz and Stenvinkel. In Press Clin Nephrol 2007

Peter Stenvinkel, MD, PhD

Inflammation in End Stage Renal Disease

- the Fire that Burns Within

Inflammation in CRF & CV effects

One of the strongest markers for CVD in CKD

Strong rel. to CV events in CRF & RTx

Driven by OS, imm-reactivity,

Inv. rel. to telomere shortening senescence

and apoptosis

Influence on other biomarkers ( LDL)

Influences statin effects in CKD

Risk factors for post-transplant

cardiovascular disease

Jardine A, Gaston R, Fellström B, Holdaas H. The Lancet 378:1419-27; 2011

CRP in renal transplant patients

Abedini, S. et al.

CJASN

2009;4:1246-1254

Hyperlipidaemia-

Dyslipidemia

Disturbances in Lipid Metabolism in ESRD

• serum levels of triglycerides, IDL,

VLDL, apo B and Lp(a)

• HDL

• Aggr. Small dense LDL particles

• reverse cholesterol transport

• lipoprotein oxidation,

carbamylation and transformation

by advanced glycation end-

products (AGEs)

Relative risk for all-cause mortality associated with plasma total cholesterol stratified by the presence or absence of inflammation and/or malnutrition in the Choices for Healthy

Outcomes in Caring for ESRD (CHOICE) study

Kwan, et al. Journal of the American Society of Nephrology. 18(4):1246-61, 2007.

Future Treatment of Dialysis patients?

How should the fire

be extinguished ?

Simplified flow schedule of uremia and its complications

Anti-inflammatory and other optionsPresent and future possibilities

Immunemodulation / Anti-Inflammation

Statin treatment

Immunosuppression

T-cells modulation

Vaccination

Cytokine inhibiiton

RAS inhibition

Anti-oxidation

NO-enhancement

Statins

ACEI

PPAR-g activators

Tocopherols

Heparin

Acetylcysteine

Sevelamer

Vitamin D

Aspirin and NSAID

• Thalidomide (TNF-blocker)

• Pentoxifylline (TNF-blocker)

• Etanercept (TNF-receptor blocker)

• Infliximab (TNF-antibodies)

• Anakinra (IL-1 receptor antagonist)

• Tocilizumab (Actemra )

( IL-6R Mo Ab )

• C5 / C3 blockade in the

future ?

Potential Pharmacological Strategies Using

Inflammation and Oxidative Stress as a Target


Immunemodulation / Anti-Inflammation

Statin treatment

Immunosuppression

T-cells modulation

Vaccination

Cytokine inhibiiton

RAS inhibition

Anti-oxidation

NO-enhancement

Statin Therapy Could Benefit Patients with

Kidney Disease at CVD Risk

Stabilisation of

atherosclerotic

plaques

Inhibition of

platelet function

Upregulation of

eNOS function

Reduction in

thrombosis

Decrease in the

hypertensive effects

of angiotensin II

Reduction in C-reactive

protein and inflammation

Reduction in LDL-C

Improvements in

endothelial function

Decrease in circulating

triglycerides

Increase in

circulating

HDL-C

Main action: lower endogenous

cholesterol production by inhibiting

3-hydroxy-3-methylglutaryl

coenzyme A (HMG Co-A) reductase

Statins also have pleiotropic effects

Statins

Ker. SA Fam Practice 2002: http://www.e-doc.co.za

Reductions in inflammatory marker CRP

8 weeks

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Mean %

change from

baseline in

CRP (%)

Rosuvastatin

Atorvastatin

Rosuvastatin

Atorvastatin

10 mg

16 weeks

20 mg

Comparison of rosuvastatin and atorvastatin in patients with type 2 diabetes

LDL-C = - 51%

LDL-C = - 39%

LDL-C = - 57%

LDL-C = - 46%

Atorvastatin reduces inflammation

within atherosclerotic plaques

0

0,5

1

1,5

2

2,5

3

3,5

4

Control AngII AngII +

Atv

Control TNF TNF + Atv

Ortego et al Atheroscl 1999:

147:253

Holdaas, Fellström, Jardine et al

Lancet 2003; 361:2024–2031

The ALERT trial

• A randomised, placebo controlled trial in 2102

renal transplant recipients

• 5 – 6 years follow-up, fluvastatin 40 – 80

mg/day versus placebo (Holdaas, Fellstrøm, Jardine et al. Lancet

2003:361:2024)

• The Alert core trial was extended by 2 years

during which time all patients were offered

fluvastatin 80 mg/day (Holdaas, Fellstrøm, Cole et al. Am J

Transplant 2005:5.2929)

7

Placebo

Fluvastatin

38%

6

5

4

3

2

1

P=0.031

Proportion

of patients

(%)

Years since randomisation

0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.00.5


1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.00.50

8

0


01.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.00.50


15

01.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

Placebo

Fluvastatin

0.50

35%

10

5

Primary Endpoint Cardiac Death

Definite MI Cardiac Death or Definite MI

Proportion

of patients

(%)

Proportion

of patients

(%)

Proportion

of patients

(%)

P=0.005

8

7Placebo

Fluvastatin

32%6

5

4

3

2

1

P=0.050

18

10

6

0

Placebo

Fluvastatin

17%P=0.139

12

14

16

8

4

2

1052

1050

1018

1009

972

974

929

930

878

885

819

791

17

14

1030

1031

1002

1008

971

973

935

938

882

844

18

16

1052

1050

1019

1022

983

991

945

957

900

917

842

821

17

15

1052

1050

1019

1022

983

991

945

957

900

917

842

821

17

15

1052

1051

Placebo

Fluvastatin

Placebo

Fluvastatin

Placebo

Fluvastatin

Placebo

Fluvastatin

Number at risk Number at risk

Number at risk Number at risk

A B

C D

Holdaas, Fellstrøm, Jardine et al Lancet 2003;362:2024

The ALERT extension trial

Holdaas, Fellström, Cole, Jardine et al et al. Am J Transplant 2005:5.2929

p=0.37

4D Study in Diabetic HemodialysisPatients: No Benefit of Statin

Therapy

4D=Die Deutsche Diabetes Dialyse Studie

No. at risk:

Placebo 636 532 383 252 136 51 19

Atorvastatin 619 515 378 252 136 58 29

Wanner C et al. N Engl J Med 2005; 353: 238–248

Cumulative incidence of primary endpoint (%)

Time (years)

Atorvastatin

Placebo60

50

40

30

20

10

0

60 1 2 3 4 5

Primary Endpoint :

CV death , non-fatal MI or stroke

AURORA study design

Matching placebo (n~1350)

Screening

6-monthly6 Final†

Patients (n~2750)Inclusion criteriaESRD, on hemodialysis for

≥3 months 50–80 yearsExclusion criteriaStatin within 6 monthsKidney transplant likely

within 1 yearCreatine kinase >3xULNALT >3xULNTSH >1.5xULN

–14 days1

02

64

Month:Visit:

Rosuvastatin 10 mg daily (n~1350)

33

125

Treatment

†Study medication was administered until 620 patients had experienced a major CV event

Randomization 1:1

Fellström BC, Jardine A, Schmieder R, Holdaas H et al. N Engl J Med 2009; 360: 1395–1407

Study Endpoints

• Primary Endpoint

– time to major CV event (CV death, non-fatal myocardial infarction [MI] or non-fatal stroke) adjudicated by blinded clinical endpoint committee


Placebo

AURORA: primary endpointKaplan-Meier estimate of time to

first major CV event

No. at risk:

Rosuvastatin 1390 1152 962 826 551 148

Placebo 1384 1163 952 809 534 153

Cumulative incidence of primary endpoint (%)

Years from randomization

Rosuvastatin

HR=0.96 (95% CI 0.84–1.11)P=0.59

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5


Smoking status

Primary endpointForest plot of predefined subgroups

0.90

0.84

0.23

0.87

0.71

<65≥65

Age (years)

NoYes

NoYes

Diabetes

NoYes

History of CVD

MaleFemale

Gender

0.5 0.75 1 1.25 1.5 1.75 2

Favors rosuvastatin Favors placebo

HR(95% CI) p value

Subgroup

127–146

Primary endpointForest plot of predefined subgroups (cont.)

†The three subgroups represent patients whose baseline values fall into tertiles 1, 2 or 3

LDL-C (mg/dL)

Hs-CRP (mg/L)

0.18

0.97

0.27

0.32

0.16

>80

>111

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Body mass index (kg/m2)

<7171–80

<2.9 2.9–8.5>8.5

<8383–111

<127

>146

<2323.0–26.6>26.6

0.5 0.75 1 1.25 1.5 1.75 2

Favors rosuvastatin Favors placebo

HR(95% CI) p value

Subgroup†

*

Baseline LDL-C as a risk factor according to hsCRP at 3 months

hsCRP <2.0 mg/L hsCRP ≥2.0 mg/L

LDL-C=low-density lipoprotein cholesterol; hsCRP=high-sensitivity C-reactive protein; HR=hazard ratio

Fellström BC et al. ISN-Nexus 2010, 15–18 April, Kyoto, Japan; poster S-10-3-9

0.8

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

Baseline LDL-C (mmol/L)

2 3 4 51

HR=1.53

p=0.014

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

Baseline LDL-C (mmol/L)

2 3 4 51

HR=0.83

p=0.015

Log

hazard

Major CV event in relation to post

randomization CRP

HR = 0.71p< 0.018

Fellström , Holdaas, Jardine, Schmieder, Zannad et al. ISN-Nexus 2010, Kyoto, Japan

CV death in relation to post

randomization CRP

HR=0.76

P=0.04

Relationship between hsCRP split points and HR for time to first major CV

event

hsCRP=high-sensitivity C-reactive protein; HR=hazard ratio; CV=cardiovascular

Fellström, Holdaas, Jardine, Schmieder, Zannad et al. ISN-Nexus 2010, 15–18 April, Kyoto, Japan

1.2

1.0

0.8

0.6

0.4

0.2

0

hsCRP split points (mg/L)

≥1.0 ≥2.0 ≥3.0 ≥4.0 ≥5.0

n=324

n=2168

p<0.018

n=618

n=1874

p<0.022 n=886

n=1606

p<0.023n=1107

n=1385

p<0.13

n=1203p<0.51

n=1289

<1.0 <2.0 <3.0 <4.0 <5.0

HR

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C,

Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano

M, Kasiske B, Walker R, Massy Z, Feldt-Rasmussen B, Krairittichai U,

Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Haas M, Grobbee

R, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham

M, Majoni W, Strony J, Musliner T, Grimm R, Pedersen T, Tobert J, Bray C, Knott

C, Collins R, on behalf of the SHARP Investigators.

Effects of lowering LDL-cholesterol with ezetimibe/simvastatin in patients with

chronic kidney disease: the Study of Heart and Renal Protection (SHARP).

The Lancet 2011 Jun 25;377(9784):2181-92.

0 1 2 3 4 5

Years of follow-up

0

5

10

15

20

25

Pro

po

rtio

n s

uff

erin

g ev

ent

(%) Risk ratio 0.83 (0.74 – 0.94)

Logrank 2P=0.0022

Placebo

Eze/simv

SHARP: Major Atherosclerotic Events

Anti-inflammatory treatment optionsPresent and future possibilities

Immunmodulering / Inflammationsdämpning

Statinbehandling

Immunosuppression

T-cells modulering

Vaccination

Cytokinhämning

RAS inhibition

Anti-oxidation

NO-enhancement

Semiquantitative estimation of influence by

immunosuppressive agents on CVD risk factors in

renal transplantation( 0 = neutral effect ; + , ++ , +++ = enhanced effect ; )

IS - drugs Hypertension Hyperlipidemia Diabetes Renal

Dysfunction

Cyclosporine ++ ++ + +

Tacrolimus + + ++ +

Sirolimus

/Everolimus

0 +++ 0 0

Corticosteroids + ++ +++ 0

Mycophenolate

mofetil

0 0 0 0

Monoclonal Ab 0 0 0 0

Fellström , Holdaas , Jardine : Cardiovascular Risk in RTx . Trends in Transplantation , 2009

Control RAPAMUNE

RAPAMUNE Prevents GVD in Monkeys

RE Morris

Et al

Sirolimus Protects Against Aortic Atherosclerosis

in Apo E Deficient Mice

Control Sirolimus 2 mg/kg

Everolimus reduces progression of intimal

thickening in HTxp=0.014

0.04 0.03

0.10

0.0

0.1

0.2

0.3

Max

imu

m i

nti

ma

l

thic

kn

ess

(m

m)

Everolimus

1.5 mg/day

(n=70)

Everolimus

3.0 mg/day

(n=69)

AZA

1–3 mg/kg/day

(n=72)

p=0.491 p=0.003

Proseek Multiplex CVD I 96x96 - Categories

Cardiovascular

Exploratory

Cardiovascular/

Inflammation

Inflammation

Proseek Multiplex CVD I 96x96 - Categories

–67

CA-125CCL20CCL3CCL4CSF-1CTSL1CXCL1CXCL-16ECPFS

GALHB-EGFIL-16IL-27AIL-4IL-6RAIL-8LOX-1mAmPPRLRAGES100A12/EN-RAGESCFTMTNF-R1TNF-R2TNFSF14/LIGHTTRAILTRANCEU-PARYKL-40/CHI3L1

CD40CD40L

CSTBCTSDCXCL-6FGF-23Gal-3GDF-15GHIL-18IL-1raIL-6KLK6MMP-12PAPPAPECAM-1/CD31PSGL-1RETNSELESPON1CASP-8IKBKG/IKK gammaSIRT2SRCTNFRSF10B/TRAIL 2

AGRPAMBeta-NGFCX3CL1Dkk-1EGFESM-1FABP4FASHGFhK11HSP 27LEPMBMCP-1Melusin/ITGB1BP2MMP-1MMP-10MMP-3MMP-7MPONPPBNT-pro-BNP

OPGPAR-1PDGF subunit BPlGFPTX3RENST2TFTIE2TMt-PAVEGF-AVEGF-D

Anti-inflammatory treatment optionsPresent and future possibilities


Statinbehandling

Immunosuppression

T-cell modulation

Vaccination

Cytokinhämning

RAS inhibition

Anti-oxidation

NO-enhancement

Immunological involvement in

atherosclerosis Tcells & Mac activity

10% T-cells in plaque

reactive to ox-LDL

Tregs downregulate

reactivityt

Tregs contribute to

imm. protection and

attenuation of plaque

inflammation

Antibody driven

protection

Dependence on T-cells

Use of anti CD 25

Tregs drop, protective

effect by Ab blunted

Vaccination against a-s

MoAb ox-LDL



Statinbehandling

Immunosuppression

T-cells modulering

Vaccination

Cytokinhämning

RAS inhibition

Anti-oxidation

NO-enhancement

Antibodies towards ox-LDL

Antibodies ox-LDL are protective

Vaccination towards ox-LDL in mice

– 50% reduction in atherosclerotic insult

Bojan Cercek, 1997 & Federico Calara, 1998

Jan Nilssons lab , Karolinska Institute, Stockholm

Immunological Targets in

Atherosclerosis

Immunol targets / ag

apoB100 sequences : p21, p 45 , p 210

Ox LDL

Ox PC

AGE , AOPP

Ox LDL , beta-OH –

Now entering into first vaccination studies in man

Lead by Jan Nilsson , Malmö

Zezina, Dimeny, Vessby, Fellström et al. Am J Nephrol 2002

Cut-off level for Ab-oxLDL < !255 l 255–3,533 > l 13,533 U/l

n (%) 30 (32.6%) 53 (57.6%) 9 (9.8%)

Graft loss due to

Chronic rejection 10% (3) 11% (6) 0

Acute rejectiona 20% (6) 6% (3) 0

Thrombosis 0 4% (2) 22% (2)

CHDc 37% (11) 13% (7) 11% (1)

Patient death 23% (7) 11% (6) 22% (2)

I nfluence of extreme Ab-oxLDL serum levels on the outcome of kidney transplantation.

and high but not significantly different incidence of graft loss due to acute rejection (p = 0.06).

Thirty patients (33%) had pre-transplant Ab-oxLDL levels < 256 U/l.

This group had higher frequency of CHD (p < 0.05)

High incidence of graft loss due to acute rejection (p = 0.06).

Antibodies Against Oxidised LDL

in Kidney Graft Recipients

IL-6R blockade ?

IL-1R blockade ?

TNFa blockade ?

Summary and Future Directions

• Uremic patients have a high morbitity & mortality in

Card-Vasc Disease (CKD)

• Uremia / CKD is associated with systemic inflammation

, which is a predictor of CVD

• Statins have a limited effect on CVD in advanced CKD

• Anti-inflammatory or cytokine inibiiton may turn out to

have beneficial effects , but needs to be shown.

• Documentation on the impact of complement

activation is pending.

• Future treatment with complement blockade may turn

out to be an option

Thank You

Questions or Comments

?

Cardiovascular Disease in Chronic Renal Failure · Ticking Bomb of CVD in CKD Artery Lp(a) = lipoprotein (a); HDL-C = high-density lipoprotein cholesterol

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