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
Calcification Score: 1Calcification Score: 1
Calcification Score: 2Calcification Score: 2
Calcification Score: 3Calcification Score: 3
Calcification Score: 4Calcification Score: 4
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
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.
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
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.
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
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.
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