cardiovascular disease and vascular calcification in ckd professor philip a kalra consultant and...

Cardiovascular disease and Cardiovascular disease and vascular calcification in CKD vascular calcification in CKD

Professor Philip A KalraConsultant and Honorary Professor of

Nephrology Salford Royal Hospital and University of

Manchester, UK

Key topicsKey topicsEpidemiology of CVS risk

– In dialysis patients– Non-dialysis CKD– SCD

Non-traditional CVS risk factors– Cardiac structural changes– CKD-MBD : importance of phosphate

Rates of death and cardiovascular events Rates of death and cardiovascular events

rise as renal function declinesrise as renal function declines

1.0

8 4.7

6

11

.36

14

.14

21

.8

36

.6

0.7

6

11

.29

3.6

5

2.1

1

0

10

20

30

40

>60 45-59 30-44 15-29 <15

Ag

e-st

and

ard

ised

rat

e p

er 1

00 p

erso

n y

ears

Death from any cause

Cardiovascular events

Go et al et al. NEJM 2004 23: 351(13): 1296-1305

Estimated GFR (ml/min/1.73 m2)

Chronic Renal Insufficiency Standards Implementation Study

(CRISIS)

Mean age 65 yrseGFR 31 ml/minDiabetes 32%CVS disease (baseline) 47%

1325 patients with mean FU of 34 months

CRISIS : survival

Cause of death (ONS)

%

25-34 35-44 45-54 55-64 65-74 75-84 >85

Age

Ann

ual m

orta

lity

(%)

Adapted from Levey AS et al. Am J Kidney Dis 1998; 32: 853-906.

Cardiovascular Mortality Rates are Cardiovascular Mortality Rates are Higher among Dialysis Patients Higher among Dialysis Patients

General population: maleGeneral population: female

Dialysis: maleDialysis: female

10

100

1

0.01

0.1

0.001

Placebo 636 532 383 252 136 51 29 Atorvastatin 619 515 378 252 136 58 19

Relative Risk Reduction 8 % (95 % CI: -23%, +10%, P=0.37)N=1255 HD pts with type 2 diabetes

Cardiac death, non-fatal MI or stroke

Mean follow-up 4 years

Cum

ulat

ive

inci

denc

e (%

)

0

10

20

30

40

50

60

1 2 3 4 50 5.5 years

PlaceboAtorvastatin 20 mg

Years from Randomization

Wanner et al NEJM 2005;353:238-48.

4D Study: Primary composite endpoint

Cardiovascular Disease in CKD :Cardiovascular Disease in CKD : Multifactorial PathogenesisMultifactorial Pathogenesis

CardiovascularCardiovascularDiseaseDisease

Chronicinflammation

Exogenous vitamin D/deficit

Oxidative stress

Duration of dialysis

Elevated PTH/ 2°HPT

Hypertension

Dyslipidemia

Diabetes Mellitus

Genetics

Increased homocysteine

levels

Elevated Ca × P product

Exogenous Ca intake

Hyperphos-phatemia

Smoking

Traditional risk factorsNon Traditional risk factors

Definition of Sudden Cardiac Death (SCD)

Sudden cardiac death is the unexpected natural death from a cardiac cause within one hour of the onset of symptoms in a person not known to have a condition that is potentially fatal

Epidemiology of SCD : general population

1 in every 1000 deaths thought to be due to SCDSCD is usually the 1st cardiac event that a patient

will suffer80% have abnormal coronary arteriesRisk is > in immediate post-MI periodPoor LV function (particularly due to ischemic

cardiomyopathy) and a documented history of significant ventricular arrhythmia, are the strongest predictors of SCD

Mechanism of SCD : general population

Myocardial infarction and poor left ventricular function both lead to risk of re-entrant ventricular tachycardia (VT) :– MI : by post-infarction scarring– LV failure : by abnormal fibrotic myocardial

remodelling

These areas of abnormal tissue may still contain functioning myocytes, but the surrounding scar tissue is thought to cause bundle branch block, and predispose to subsequent re-entrant tachycardia

Epidemiology of SCD : CKD populations

CKD stages 3-5 (not dialysis) SCD risk ↑ by HR of 1.1 for every 10ml/min decline in eGFR

Event rate 0.8% per yr in non-dialysis CKD

In non-diabetic dialysis patients, rate is 7% in 1st yr of RRT

SCD risk is > for HD than PD patients during 1st 6 months of dialysis, but equalises thereafter

0

10

20

30

40

50

60

70

eventrate per1000 yrs

General

CKD

Dialysis

Karnik JA et al (Kidney International 2001:60:350-357) : Characteristics

associated with arrest on haemodialysis

– Monday or Tuesday (greatest risk last 12 hrs before dialysis)

– Low potassium dialysate– Older age– Diabetic– Catheter for access

CVS risk factors in CKD

Cardiac structural changes – LVH and CCF CAD Vascular calcification/arterial stiffness Phosphate Vitamin D deficiency Anaemia Metabolic changes Inflammation

0

10

20

30

40

50

60

70

80

50-75 25-50 <25 Dialysis

Creatinine clearance (mL/min)

Pre

vale

nce o

f L

VH

(%

)

p <0.003 (trend analysis)

Prevalence of Left Ventricular Hypertrophy in Prevalence of Left Ventricular Hypertrophy in Relation to Creatinine ClearanceRelation to Creatinine Clearance

Patients with diabetes = 24%Adapted from Levin A et al. Am J Kidney Dis 1999; 34: 125-34.

n = 246

Intra-dialytic myocardial ischaemia

C McIntyre and colleagues (Derby, UK) :

Haemodialysis induces reversible intra-dialytic myocardial stunning

↑stunning associated with greater propensity to arrhythmia

↑stunning associated with worse mortality Some relationship between endotoxaemia and

myocardial ischaemia

Calcification of the coronary arteriesCalcification of the coronary arteries

Khogali and Townend NEJM 2002;347:1584

Pre-contrast Post-contrast

Arterial Medial Calcification Arterial Medial Calcification in ESRDin ESRD

London GM, et al. London GM, et al. Nephrol Dial TransplantNephrol Dial Transplant. 2003;18:1731-1740. 2003;18:1731-1740

Patients New to Dialysis and Established PatientsPatients New to Dialysis and Established Patients

Prevalence of Vascular Prevalence of Vascular Calcification in CKDCalcification in CKD

40%

57%

83%

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

40%

57%

83%

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002

*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002

*

**

***

Stage 3-4 CKD

Probability of All-Cause Survival Probability of All-Cause Survival According to Calcification StatusAccording to Calcification Status

*Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001)Source: Blacher A, et al. Hypertension:938-942, October 2001*Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001)Source: Blacher A, et al. Hypertension:938-942, October 2001

Pro

bab

ility

of

Su

rviv

alP

rob

abili

ty o

f S

urv

ival

0.000.00

0.250.25

0.500.50

0.750.75

1.001.00

Duration of Follow-Up (Months)Duration of Follow-Up (Months)

00 2020 4040 6060 8080

Calcification Score: 0Calcification Score: 0





Augmentation index : Applanation Tonometry

Aortic Augmentation Index (%) = ∆P x 100 (AIx) PP

Importance of phosphate

Serum Phosphorus and Mortality Serum Phosphorus and Mortality in Hemodialysis Patientsin Hemodialysis Patients

1.501.50

1.001.00 1.001.001.081.08

1.251.25

1.421.42

1.681.68

2.032.03

00

0.50.5

11

1.51.5

22

2.52.5

<3<3 3-43-4 4-54-5 5-65-6 6-76-7 7-87-8 8-98-9 >9>9

Serum Phosphorous Concentration (mg/dL)Serum Phosphorous Concentration (mg/dL)

Rel

ativ

e R

isk

of

Dea

th*

Rel

ativ

e R

isk

of

Dea

th*

n = 40,538n = 40,538P < 0.0001P < 0.0001

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

CRISIS study : analysis of serum phosphate (Eddington H et al, CJASN

2010)

1213 patients Baseline demographics – Phosphate divided

into quartiles

Cox regression Baseline phosphate and survival Time-averaged phosphate and survival

Baseline demographics

N=1213 All PO4 <1.01

N=318

PO4 1.02 – 1.16

N=300

PO4 1.17-1.33

N=293

PO4 ≥1.34

N=302P value

Age 64.2 (13.9) 64 (14) 65 (14) 65 (14) 62 (14) 0.037

Female sex

429 (35.4%) 76 (24%) 109 (36%) 124 (42%) 120 (40%) <0.0001

Calcium 2.29 (0.14) 2.29 (0.13) 2.29 (0.19) 2.30 (0.13) 2.28 (0.19) ns

PTH 89 (86) 58 (42) 77 62) 86 (77) 135 (124) <0.0001

Hb 124 (18) 135 (18) 125 (16) 123 (14) 114 (17) <0.0001

eGFR 31.6 (15) 40 (14) 34 (13) 31 (14) 20 (11) <0.0001

Proteinuria 1.1 (1.8) 0.5 (0.7) 0.8 (1.2) 0.9 (1.2) 2.1 (2.7) <0.0001

CVD 380 (31%) 99 (31%) 109 (36%) 99 (34%) 73 (24%) 0.009

DM 385(32%) 84 (27%) 89 (29%) 90 (29%) 122 (40%) 0.002

Phosphate <1.01

Phosphate 1.02-1.16

Phosphate 1.17-1.33

Phosphate >1.33

Baseline phosphate and survival

Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH

Mean follow-up 4.3 years

Hazard ratio 1.8

P = 0.04

n=946 n=810 n=624 n=375 n=136

12mth time-average PO4 survival

Phosphate <1.01

Phosphate 1.02-1.16

Phosphate 1.17-1.34

Phosphate >1.34

Hazard ratio 2.12

P = 0.01

Phosphate <1.01

Phosphate 1.02-1.16

Phosphate 1.17-1.34

Phosphate >1.34

Hazard ratio 2.59

P = 0.006

Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH

Mean follow-up 3.6 years

n=810 n=622 n=375 n=136

Survival according to previous KDOQI phosphate guidelines

Below Target

In Target

Above Target

Hazard ratio:In target 1.9 (0.9-4.0) P = 0.08Above target 2.6 (1.1-6.2) P = 0.03

Phosphate : general population

CARDIA (Coronary artery risk development in young adults)

Prospective multi-centre observational study of CVS disease development in fit young adults (age 18-30 yrs)

1985-86 in 4 US regions (Birmingham, Alabama; Chicago, Illinois; Minneapolis,Minnesota; Oakland, California)

5113 participants

CARDIA (Coronary artery risk development in young adults)

Various baseline variables assessed

LVMI assessed by echocardiography 5 years after entry

Coronary artery calcification assessed by CT scan 15 years later

Left ventricular hypertrophy (LVH) : Foley RN et al Kid Blood Press Res

2009; 32(1):37-44

4005 of 5113 participants underwent echocardiography

Baseline data Mean age 25 years Mean phosphate 3.7 mg/dl eGFR 118.5 ml/min/1.73m2

Results

Each SD of baseline phosphate above the mean was associated with ↑presence of LVH 5 years later (AOR 1.301, p=0.0018)

Coronary artery calcification (CAC) : Foley RN et al J Am Soc Neph

2009; 20(2): 397-404

3015 of 5113 participants underwent CT at 15 years

Baseline dataMean age 25.2 years mean phosphate 3.6 mg/dl, calcium 9.5 mg/dlMean eGFR 116.6 ml/min/1.73m2

0.2% with eGFR < 60 ml/min/1.73m2

Coronary artery calcification (CAC) : Foley RN et al J Am Soc Neph

2009; 20(2): 397-404

Year 15 CAC scores

Minimal 0-10 3.2%Mild 10-100 4.8%Moderate 101-300 1.1%Severe >300 0.5%

P-Spline plot relating adjusted odds ratio

of CAC ≥ 100 and serum phosphorus

0

0.5

1

1.5

2

2.5

3

3.5

4

3 3.2 3.4 3.6 3.8 4 4.2 4.4 4.6 4.8 5

Phosphorus (mg/dL)

AOR

AOR, with 95% confidence intervals. Adjusted for all variablesAOR, with 95% confidence intervals. Adjusted for all variables except calcium-phosphorus product and diastolic blood pressureexcept calcium-phosphorus product and diastolic blood pressure

Studies of phosphate in general population : conclusions

Phosphate levels even at the upper end of normal range appear to be a risk factor for :

Coronary artery calcification (surrogate of coronary atherosclerosis)

Left ventricular hypertrophy

? Pathogenetic effect or association

FGF-23/Klotho: New players in CKD-MBD

Adapted from: Emmett M, et al. Kidney International 2008;73:3–5

Kuro-o. Keynote lecture from ERA-EDTA 2008, ASN 2008

Pi

1,25DSmall bowel

Reduces Ca and Pi absorption in small bowel

1,25D

1α(OH)D3

Inhibits 1α-hydroxylase

FGF-23

Parathyroid

Possibly stimulates

Phosphaturia

+ Klotho

Stimulates

Skeleton

Possibly inhibits

mineralizationFGF23 inhibits PTH

mRNA transcription and protein secretion

Kidney

Haemodialysis patients within the highest range of FGF-23 levels had nearly 6x greater risk of death

Gutierrez OM et al; N Engl J Med 2008 :359; 584-592

Temporal aspects of mineral disorders in progressive CKD and post transplantation

Wolf JASN 2010

How might FGF-23 be associated with CVS risk?

↑ FGF-23 associated with ↓vitamin D, CKD progression and mortality in CKD

↑ FGF-23 associated with ↑ LVH (Gutierrez OM et al, Circulation 2009; 119 : 2545-2552)

↑ FGF-23 associated with ↑ ADMA (asymmetric di-methyl arginine; an inhibitor of NO synthase)

↑ FGF-23 associated with ↓ flow-mediated dilatation (FMD) in CKD patients (Yilmaz MI et al, Kidney Int, 2010; 78 : 679-685)

Vitamin D levels very low in dialysis patients

London GM et al JASN 2007: 18;613-620 (latitude 48o)

52 Vitamin D naïve haemodialysis patients (>90% ‘deficient’)

Mean PTH 345pg/ml ± 37 (245)

Mean 25(OH)D 14.2 ± 1 (13.5)

Vitamin D levels assoc with arterial function

London GM et al JASN 2007: 18;613-620 (latitude 48o)

Studies of intervention for vascular calcification

6% 5%

25%28%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Coronary Aorta

SevelamerSevelamerCalcium Calcium

**

Treat-to-Goal Study : Prevalent haemodialysis patients

*Within treatment P<0.0001; *Within treatment P<0.0001; between treatment groups P=0.02between treatment groups P=0.02 ChertowChertow et al. et al. Kidney IntKidney Int. 2002. 2002

Med

ian

per

cen

tag

e ch

ang

eM

edia

n p

erce

nta

ge

chan

ge

• Percentage change from baseline in CAC score at week 52

•Absolute change in CAC score at week 52

•Absolute and percentage change from baseline in– Aortic calcification at week 52

– Aortic valve calcification at week 52

– Laboratory parameters at end of study (weeks 44 through 52)

•Proportion of patients achieving > 15% progression of CAC at week 52

•Safety

Secondary Endpoints•Percentage change from baseline in CAC score at week 52

Primary Endpoint

Secondary Endpoints

ADVANCE :Study Endpoints

Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, 2010.Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

• 737 patients were screened and 360 were randomized, 180 to each group.– Mean (SD) age was 61.5 (12.7) years, 58% were

male and 24% were black– Median (P10, P90) time on hemodialysis was 36.7

(9.5, 107.0) months.

• The efficacy analysis included 235 subjects: – 115 assigned to cinacalcet plus low dose vitamin D – 120 assigned to flexible doses of vitamin D sterols

Patient characteristics


Primary Analysis

Median % Change (P10, P90) in CAC

Cinacalcet(n=115)

Control group(n=119)

p-value

24 (-22, 119) 31 (-9, 179) 0.073Primary analysis based on a generalised Cochran-Mantel-Haenszel test on ranks

Percent Change in Total Coronary Artery Calcification Score (CAC) – Agatston


Supportive analysis (as planned in the protocol) using a generalised linear model to adjust for the baseline imbalance in phosphorous levels between treatment groups.

Analysis adjusted for

baseline phosphorus

Geometric Mean % Change (95% CI) in CAC

Cinacalcet(n=115)

Control group

(n=119)

p-value

26 (16, 36) 42 (31, 54) 0.031

Percent Change in Total Coronary Artery Calcification Score (CAC) - Agatston


Does reducing vascular calcification translate into

survival benefit?

DCOR study: Primary Endpoint

Time in Study (Years)

Cum

ulat

ive

Inci

denc

e of

A

ll-C

ause

Mor

talit

y

1 2 3 400.0

0.1

0.2

0.3

0.4

0.5

0.6

SevelamerCalcium

RR 0.91 (0.77-1.08), p = 0.30

n=2103

Suki et al, Kidney Int 2007;72:1130-1137

Time on Study (Years)Time on Study (Years)

Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

yC

um

ula

tive

In

cid

en

ce o

f A

ll-C

ause

Mo

rtal

ity

No. at RiskNo. at RiskCalciumCalciumSevelamerSevelamer

556 366 245 98 556 366 245 98 585 381 253 99 585 381 253 99

00 11 22 33 44

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

SevelamerSevelamerCalciumCalcium

Sevelamer therapy resulted in Sevelamer therapy resulted in

a statistically significant a statistically significant reduction in the relative risk reduction in the relative risk

for all-cause mortality in for all-cause mortality in pre-specified subsetpre-specified subset[RR 0.78 (0.62-0.97)][RR 0.78 (0.62-0.97)]

Sevelamer therapy resulted in Sevelamer therapy resulted in

a statistically significant a statistically significant reduction in the relative risk reduction in the relative risk

for all-cause mortality in for all-cause mortality in pre-specified subsetpre-specified subset[RR 0.78 (0.62-0.97)][RR 0.78 (0.62-0.97)]

↓ ↓ 22%22% p = 0.03p = 0.03

DCOR : All-Cause Mortality in Patients ≥ 65 years

Final KDIGO Grading of Recommendations

Grade for Strength of

Recommendation Strength Wording

Grade for Quality of Evidence

Quality of Evidence

A High Level 1 Strong “We recommend…

should” B Moderate

C Low Level 2 Weak “We suggest… might”

D Very low

Grading Options: 1A, 1B, 1C, 1D, 2A, 2B, 2D, 2D, & “not graded”

KDOQI Mineral and PTH targets

Stage 3 Stage 4 Stage 5

Calcium Normal range

Normal range

2.1-2.4mmol/l

Phosphate 0.9-1.5mmol/l

0.9-1.5mmol/l

1.1-1.8mmol/l

Ca x P <3.6 mmol/l

<3.6 mmo/l/

< 4.3 mmol/l

PTH 3.9-7.7pmol/l

7.7-12.1pmol/l

16.5-33pmol/l

National Kidney Foundation. Am J Kidney Dis 2003;42:S1-S202

Diagnosis of CKD-MBD: Vascular Calcification

3.3.1. In patients with CKD Stages 3-5D, we suggest a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification, and an echocardiogram can be used to detect the presence or absence of valvular calcification, as reasonable alternatives to computed tomography (CT)-based imaging (2C).

3.3.2. We suggest that patients with CKD Stages 3-5D with known vascular/valvular calcification be considered at highest cardiovascular risk (2A). It is reasonable to use this information to guide management of CKD-MBD (not graded).

Summary Patients with CKD are at high CVS risk and CKD-

MBD is a major contributor Observational data show the importance of several

factors (low vitamin D, ↑ Phosphate, ? ↑ Calcium dose, ↑ PTH)

Early phosphate rise seems to be important in earlier CKD and even in the general population (relevance of FGF-23?)

Interventional studies suggest that calcification can be slowed

Further interventional studies (eg EVOLVE) are necessary to guide optimal treatment in CKD-MBD

cardiovascular disease and vascular calcification in ckd professor philip a kalra consultant and...

Documents

risk of

survival slide

general ckd dialysis

fatal slide

tachycardia slide

dialysis scd risk

access slide

importance of phosphate