Transcript Estimated GFR : definition, uses and implications

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
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
Rates of death and cardiovascular events
rise as renal function declines
11.36
4.76
1.08
2.11
10
3.65
11.29
20
14.14
21.8
30
0.76
Age-standardised rate
per 100 person years
36.6
Death from any cause
Cardiovascular events
40
0
>60
45-59
30-44
15-29
Estimated GFR (ml/min/1.73 m2)
Go et al et al. NEJM 2004 23: 351(13): 1296-1305
<15
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
CRISIS : survival
Cause of death (ONS)
%
Cardiovascular Mortality Rates are
Higher among Dialysis Patients
Annual mortality (%)
100
10
1
Dialysis: male
Dialysis: female
0.1
General
population: male
General
population:
female
0.01
0.001
25-34
35-44
45-54
55-64
65-74
Age
Adapted from Levey AS et al. Am J Kidney Dis 1998; 32: 853-906.
75-84
>85
Cumulative incidence (%)
4D Study: Primary composite endpoint
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
60
50
40
30
Placebo
Atorvastatin 20 mg
20
10
0
0
Placebo
636
Atorvastatin 619
1
532
515
2
3
4
Years from Randomization
383
378
252
252
5
5.5 years
136
51
29
136
58
19
Wanner et al NEJM 2005;353:238-48.
Cardiovascular Disease in CKD :
Multifactorial Pathogenesis
Elevated PTH/
2°HPT
Duration of
dialysis
Oxidative
stress
Dyslipidemia
Exogenous
vitamin
D/deficit
Hypertension
Cardiovascular
Disease
Diabetes
Mellitus
Chronic
inflammation
Hyperphosphatemia
Genetics
Exogenous Ca
intake
Smoking
Increased
homocysteine
levels
Elevated Ca ×
P product
Traditional risk factors
Non 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 SCD
 SCD is usually the 1st cardiac event that a patient
will suffer
 80% have abnormal coronary arteries
 Risk is > 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
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
70
60
50
event
rate per
1000 yrs
40
30
20
CKD
10
0
General
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
Prevalence of Left Ventricular Hypertrophy in
Relation to Creatinine Clearance
n = 246
Prevalence of LVH (%)
80
70
p <0.003 (trend
analysis)
60
50
40
30
20
10
0
50-75
25-50
<25
Creatinine clearance (mL/min)
Patients with diabetes = 24%
Adapted from Levin A et al. Am J Kidney Dis 1999; 34: 125-34.
Dialysis
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 arteries
Pre-contrast
Post-contrast
Khogali and Townend NEJM 2002;347:1584
Arterial Medial Calcification
in ESRD
London GM, et al. Nephrol Dial Transplant. 2003;18:1731-1740
Prevalence of Vascular
Calcification in CKD
Patients New to Dialysis and Established Patients
100%
***
83%
80%
Stage 3-4 CKD
60%
**
57%
*
40%
40%
20%
0%
Russo et al
*Russo et al AJKD 2004 (CrCl =33 ml/min)
**Spiegel D et al. Hemod Internat 2004: 8:265
***Chertow et al KI 2002
RIND
TTG
Probability of All-Cause Survival
According to Calcification Status
Probability of Survival
1.00
Calcification Score: 0
Calcification Score: 1
0.75
Calcification Score: 2
0.50
Calcification Score: 3
0.25
Calcification Score: 4
0.00
0
20
40
60
Duration of Follow-Up (Months)
*Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001)
Source: Blacher A, et al. Hypertension:938-942, October 2001
80
Augmentation index : Applanation
Tonometry
Aortic Augmentation Index (%) =
(AIx)
∆P
PP
x 100
Importance of phosphate
Serum Phosphorus and Mortality
in Hemodialysis Patients
Relative Risk of Death*
2.5
2
2.03
n = 40,538
P < 0.0001
1.68
1.50
1.42
1.5
1.25
1.08
1.00
1.00
3-4
4-5
1
0.5
0
<3
5-6
6-7
7-8
8-9
>9
Serum Phosphorous Concentration (mg/dL)
*Multivariable Adjusted
Block 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
PO4 <1.01
N=1213
PO4 1.02 – 1.16
PO4 1.17-1.33
PO4 ≥1.34
All
P value
N=318
N=300
N=293
N=302
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
Baseline phosphate and survival
Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH
Mean follow-up 4.3 years
Phosphate <1.01
Phosphate 1.02-1.16
Phosphate 1.17-1.33
Phosphate >1.33
Hazard ratio 1.8
P = 0.04
n=946
n=810
n=624
n=375
n=136
12mth time-average PO4 survival
Adjusted for eGFR, Age, Gender, Hb, Diabetes, CVD, proteinuria, PTH
Mean follow-up 3.6 years
Phosphate <1.01
Phosphate
<1.01
Phosphate
1.02-1.16
Phosphate
1.02-1.16
Phosphate
1.17-1.34
Phosphate
1.17-1.34
Phosphate
>1.34
Phosphate >1.34
Hazard ratio 2.59
Hazard ratio 2.12
P = 0.006
P = 0.01
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
Above target
1.9 (0.9-4.0) P = 0.08
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 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 < 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
Mild
Moderate
Severe
0-10
10-100
101-300
>300
3.2%
4.8%
1.1%
0.5%
P-Spline plot relating adjusted odds ratio
of CAC ≥ 100 and serum phosphorus
4
3.5
3
2.5
AOR
2
1.5
1
0.5
0
3
3.2
3.4
3.6
3.8
4
4.2
4.4
4.6
4.8
Phosphorus (mg/dL)
AOR, with 95% confidence intervals. Adjusted for all variables
except calcium-phosphorus product and diastolic blood pressure
5
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
Parathyroid
Skeleton
Pi
Small bowel
Possibly
inhibits
mineralization
1,25D
FGF23 inhibits PTH
mRNA transcription and
protein secretion
Stimulates
Reduces Ca and Pi
absorption in small bowel
FGF-23
Possibly
stimulates
+ Klotho
 1,25D
Inhibits
1α-hydroxylase
1α(OH)D3
Kuro-o. Keynote lecture from ERA-EDTA 2008, ASN 2008
Adapted from: Emmett M, et al. Kidney International 2008;73:3–5
Phosphaturia
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
52 Vitamin D naïve haemodialysis patients (>90% ‘deficient’)
Mean PTH 345pg/ml ± 37 (245)
Mean 25(OH)D 14.2 ± 1 (13.5)
London GM et al JASN 2007: 18;613-620 (latitude 48o)
Vitamin D levels assoc with
arterial function
London GM et al JASN 2007: 18;613-620 (latitude 48o)
Studies of intervention for
vascular calcification
Median percentage change
Treat-to-Goal Study : Prevalent
haemodialysis patients
40%
35%
Sevelamer
Calcium
30%
28%*
25%*
25%
20%
15%
10%
6%
5%
5%
0%
Coronary
*Within treatment P<0.0001;
between treatment groups P=0.02
Aorta
Chertow et al. Kidney Int. 2002
ADVANCE :Study Endpoints
• Percentage changePrimary
from baseline
in CAC score at week 52
Endpoint
•
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 > 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.
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.
Percent Change in Total Coronary Artery
Calcification Score (CAC) – Agatston
Median % Change (P10, P90) in CAC
Primary
Analysis
Cinacalcet
Control group
(n=115)
(n=119)
p-value
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.
Percent Change in Total Coronary Artery
Calcification Score (CAC) - Agatston
Geometric Mean % Change (95% CI) in
CAC
Analysis
adjusted for
Control
Cinacalcet
p-value
baseline
group
(n=115)
(n=119)
phosphorus
Supportive
analysis (as planned in the protocol) using a generalised linear model to adjust for the baseline imbalance in phosphorous levels
between treatment groups.
26 (16, 36)
42 (31, 54)
0.031
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
Cumulative Incidence of
All-Cause Mortality
0.6
RR 0.91 (0.77-1.08), p = 0.30
0.5
n=2103
0.4
0.3
0.2
Calcium
Sevelamer
0.1
0.0
0
1
2
3
Time in Study (Years)
4
Suki et al, Kidney Int 2007;72:1130-1137
Cumulative Incidence of All-Cause Mortality
DCOR : All-Cause Mortality in
Patients ≥ 65 years
0.8
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)]
0.7
0.6
0.5
0.4
↓ 22%
p = 0.03
0.3
0.2
Calcium
Sevelamer
0.1
0.0
0
No. at Risk
Calcium
556
Sevelamer 585
1
2
3
Time on Study (Years)
366
381
245
253
98
99
4
Final KDIGO Grading of
Recommendations
Grade for
Strength of
Recommendation
Level 1
Level 2
Strength
Strong
Weak
Wording
“We
recommend…
should”
“We suggest…
might”
Grade for
Quality of
Evidence
Quality of
Evidence
A
High
B
Moderate
C
Low
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
Normal
Normal
2.1-2.4
Calcium
range range mmol/l
0.9-1.5
0.9-1.5
1.1-1.8
Phosphate mmol/l mmol/l mmol/l
<3.6
<3.6
<
4.3
Ca x P
mmol/l mmo/l/ mmol/l
3.9-7.7
7.7-12.1
16.5-33
PTH
pmol/l pmol/l pmol/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 CKDMBD 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 CKDMBD