Cardiovascular disease and vascular calcification in CKD

1
Cardiovascular disease and vascular calcification
in CKD

• Professor Philip A Kalra
• Consultant and Honorary Professor of Nephrology
• Salford Royal Hospital and University of
  Manchester, UK

2
Key topics

• Epidemiology of CVS risk
• In dialysis patients
• Non-dialysis CKD
• SCD
• Non-traditional CVS risk factors
• Cardiac structural changes
• CKD-MBD importance of phosphate

3
Rates of death and cardiovascular events rise as
renal function declines
Death from any cause
Cardiovascular events
Age-standardised rate per 100 person years
Estimated GFR (ml/min/1.73 m2)
Go et al et al. NEJM 2004 23 351(13) 1296-1305
4
Chronic Renal Insufficiency Standards
Implementation Study(CRISIS)

• Mean age 65 yrs
• eGFR 31 ml/min
• Diabetes 32
• CVS disease (baseline) 47
• 1325 patients with mean FU of 34 months

5
CRISIS survival
6
Cause of death (ONS)

7
Cardiovascular Mortality Rates are Higher among
Dialysis Patients
100
10
1
Dialysis male
Dialysis female
0.1
General population male
0.01
General population female
0.001
Adapted from Levey AS et al. Am J Kidney Dis
1998 32 853-906.
8
4D Study Primary composite endpoint
Relative Risk Reduction 8 (95 CI -23,
10, P0.37)
60
N1255 HD pts with type 2 diabetes Cardiac death,
non-fatal MI or stroke Mean follow-up 4 years
50
40
Cumulative incidence ()
30
Placebo
20
Atorvastatin 20 mg
10
0
1
2
3
4
5
0
5.5 years
Years from Randomization
Placebo 636 532
383 252 136
51 29 Atorvastatin 619
515 378 252
136 58 19
Wanner et al NEJM 2005353238-48.
9
Cardiovascular Disease in CKD Multifactorial
Pathogenesis
Duration of dialysis
Elevated PTH/ 2HPT
Oxidative stress
Dyslipidemia
Exogenous vitamin D/deficit
Hypertension
CardiovascularDisease
Chronicinflammation
Diabetes Mellitus
Genetics
Hyperphos-phatemia
Exogenous Ca intake
Smoking
Elevated Ca P product
Increased homocysteine levels
10
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

11
Epidemiology of SCD general population

• 1 in every 1000 deaths thought to be due to SCD
• SCD is usually the 1st cardiac event that a
  patient will suffer
• 80 have abnormal coronary arteries
• Risk is gt in immediate post-MI period
• Poor LV function (particularly due to ischemic
  cardiomyopathy) and a documented history of
  significant ventricular arrhythmia, are the
  strongest predictors of SCD

12
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

13
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 gt for HD than PD patients during 1st
  6 months of dialysis, but equalises thereafter

CKD
Dialysis
General
14
Karnik JA et al (Kidney International
200160350-357) 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

15
CVS risk factors in CKD

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

16
Prevalence of Left Ventricular Hypertrophy in
Relation to Creatinine Clearance
n 246
p lt0.003 (trend analysis)
Patients with diabetes 24
Adapted from Levin A et al. Am J Kidney Dis 1999
34 125-34.
17
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18
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19
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

20
Calcification of the coronary arteries
Post-contrast
Pre-contrast
Khogali and Townend NEJM 20023471584
21
Arterial Medial Calcification in ESRD
London GM, et al. Nephrol Dial Transplant.
2003181731-1740
22
Prevalence of Vascular Calcification in CKD
Patients New to Dialysis and Established Patients


Stage 3-4 CKD

Russo et al AJKD 2004 (CrCl 33
ml/min) Spiegel D et al. Hemod Internat 2004
8265 Chertow et al KI 2002
23
Probability of All-Cause Survival According to
Calcification Status
Calcification Score 0
Calcification Score 1
Calcification Score 2
Probability of Survival
Calcification Score 3
Calcification Score 4
Duration of Follow-Up (Months)
Comparison Between Curves Was Highly Significant
(x242.66, Plt0.0001)Source Blacher A, et al.
Hypertension938-942, October 2001
24
Augmentation index Applanation Tonometry

Aortic Augmentation Index () ?P x
100 (AIx)
PP
25
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26
Importance of phosphate
27
Serum Phosphorus and Mortality in Hemodialysis
Patients
28
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

29
Baseline demographics
N1213 All PO4 lt1.01 N318 PO4 1.02 1.16 N300 PO4 1.17-1.33 N293 PO4 1.34 N302 P 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) lt0.0001
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) lt0.0001
Hb 124 (18) 135 (18) 125 (16) 123 (14) 114 (17) lt0.0001
eGFR 31.6 (15) 40 (14) 34 (13) 31 (14) 20 (11) lt0.0001
Proteinuria 1.1 (1.8) 0.5 (0.7) 0.8 (1.2) 0.9 (1.2) 2.1 (2.7) lt0.0001
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
30
Baseline phosphate and survival
Adjusted for eGFR, Age, Gender, Hb, Diabetes,
CVD, proteinuria, PTH Mean follow-up 4.3 years
Phosphate lt1.01 Phosphate 1.02-1.16 Phosphate
1.17-1.33 Phosphate gt1.33
Hazard ratio 1.8 P 0.04
n946 n810 n624 n375
n136
31
12mth time-average PO4 survival
Adjusted for eGFR, Age, Gender, Hb, Diabetes,
CVD, proteinuria, PTH Mean follow-up 3.6 years
Phosphate lt1.01 Phosphate 1.02-1.16 Phosphate
1.17-1.34 Phosphate gt1.34
Phosphate lt1.01 Phosphate 1.02-1.16 Phosphate
1.17-1.34 Phosphate gt1.34
Hazard ratio 2.59 P 0.006
Hazard ratio 2.12 P 0.01
n810 n622 n375
n136
32
Survival according to previous KDOQI phosphate
guidelines

Below Target In Target Above Target
Hazard ratio In target 1.9 (0.9-4.0) P
0.08 Above target 2.6 (1.1-6.2) P 0.03
33
Phosphate general population
34
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

35
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

36
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, p0.0018)

37
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 data
• Mean age 25.2 years
• mean phosphate 3.6 mg/dl, calcium 9.5 mg/dl
• Mean eGFR 116.6 ml/min/1.73m2
• 0.2 with eGFR lt 60 ml/min/1.73m2

38
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 gt300 0.5

39
P-Spline plot relating adjusted odds ratio of CAC
100 and serum phosphorus
AOR, with 95 confidence intervals. Adjusted for
all variables except calcium-phosphorus product
and diastolic blood pressure
40
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

41
FGF-23/Klotho New players in CKD-MBD
Kuro-o. Keynote lecture from ERA-EDTA 2008, ASN
2008
Adapted from Emmett M, et al. Kidney
International 20087335
42
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
43
Temporal aspects of mineral disorders in
progressive CKD and post transplantation
Wolf JASN 2010
44
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)

45
Vitamin D levels very low in dialysis patients
52 Vitamin D naïve haemodialysis patients (gt90
deficient) Mean PTH 345pg/ml 37 (245) Mean
25(OH)D 14.2 1 (13.5)
London GM et al JASN 2007 18613-620 (latitude
48o)
46
Vitamin D levels assoc with arterial function
London GM et al JASN 2007 18613-620 (latitude
48o)
47
Studies of intervention for vascular calcification
48
Treat-to-Goal Study Prevalent haemodialysis
patients
Sevelamer
Calcium


Median percentage change
Within treatment Plt0.0001 between treatment
groups P0.02
Chertow et al. Kidney Int. 2002
49
ADVANCE Study Endpoints
Primary Endpoint

• Percentage change from baseline in CAC score at
  week 52

Secondary Endpoints

• Percentage change from baseline in CAC score at
  week 52

Secondary Endpoints

• 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 gt 15
  progression of CAC at week 52
• Safety

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.
50
Patient characteristics

• 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

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.
51
Percent Change in Total Coronary Artery
Calcification Score (CAC) Agatston
Primary Analysis Median Change (P10, P90) in CAC Median Change (P10, P90) in CAC Median Change (P10, P90) in CAC
Primary Analysis Cinacalcet (n115) Control group (n119) p-value
Primary Analysis 24 (-22, 119) 31 (-9, 179) 0.073
Primary analysis based on a generalised
Cochran-Mantel-Haenszel test on ranks
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.
52
Percent Change in Total Coronary Artery
Calcification Score (CAC) - Agatston
Analysis adjusted for baseline phosphorus Geometric Mean Change (95 CI) in CAC Geometric Mean Change (95 CI) in CAC Geometric Mean Change (95 CI) in CAC
Analysis adjusted for baseline phosphorus Cinacalcet (n115) Control group (n119) p-value
Analysis adjusted for baseline phosphorus 26 (16, 36) 42 (31, 54) 0.031
Supportive analysis (as planned in the protocol)
using a generalised linear model to adjust for
the baseline imbalance in phosphorous levels
between treatment groups.
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.
53
Does reducing vascular calcification translate
into survival benefit?
54
DCOR study Primary Endpoint
0.6
RR 0.91 (0.77-1.08), p 0.30
0.5
n2103
0.4
Cumulative Incidence of All-Cause Mortality
0.3
0.2
Calcium
0.1
Sevelamer
0.0
1
2
3
4
0
Time in Study (Years)
Suki et al, Kidney Int 2007721130-1137
55
DCOR All-Cause Mortality in Patients 65 years
Sevelamer therapy resulted in a statistically
significant reduction in the relative risk for
all-cause mortality in pre-specified subset RR
0.78 (0.62-0.97)
Cumulative Incidence of All-Cause Mortality
? 22 p 0.03
Time on Study (Years)
No. at Risk
Calcium
556 366
245 98
Sevelamer
585 381
253 99
56
Final KDIGO Grading of Recommendations
Grading Options 1A, 1B, 1C, 1D, 2A, 2B, 2D, 2D,
not graded
57
KDOQI Mineral and PTH targets
Stage 3 Stage 4 Stage 5
Calcium Normal range Normal range 2.1-2.4 mmol/l
Phosphate 0.9-1.5 mmol/l 0.9-1.5 mmol/l 1.1-1.8 mmol/l
Ca x P lt3.6 mmol/l lt3.6 mmo/l/ lt 4.3 mmol/l
PTH 3.9-7.7 pmol/l 7.7-12.1 pmol/l 16.5-33 pmol/l
National Kidney Foundation. Am J Kidney Dis
200342S1-S202
58
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).

59
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