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Novel Predictors of Cardiovascular Mortality in Dialysis Patients
Angela Yee-Moon WANG, MD, PhD Department of Medicine
Queen Mary Hospital University of Hong Kong
Hong Kong
Berlin Dialysis Seminar 2011
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Cardiovascular Mortality in ESRD Patients
CV death = 43.7%
USRDS 2009
39.1%
50.8%
10.2%
Cardiovascular Non-cardiovascular unknown
de Jager DJ, et al. JAMA 2009
Incident dialysis patients (n=123,407) from ERA-EDTA registry between 1st Jan1994 and 1st Jan 2007, FU mean of 1.8 ± 1.1 yrs
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Prevalence of Cardiovascular Disease in ESRD Patients Starting Dialysis Therapy
0 20 40 60 80
Left ventricular hypertrophy
Left ventricular dilatation
Systolic dysfunction
Coronary Artery Disease
Angina
Cardiac failure
%Foley RN, et al. Kidney Int 1995
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Prevalence of Heart Failure in Dialysis Population
Author, year HD/PD N I or P Prevalence
Harnett, 1999 HD + PD 432 I 31
Stack, 2001 HD + PD 4024 I 36
Wang, 2002 PD 246 P 38
Cheung, 2004 HD 1846 P 40
Couchard, 2008 PD HD
1530 9285
I I
34 28
I, incident; P, prevalent; HD, hemodialysis; PD, peritoneal dialysis; N, number
Wang AY, et al. Am J Kidney Dis 2011.
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Prevalence of De-novo or Recurrent Heart Failure in Relation to Baseline Heart Status in Dialysis Patients
0
10
20
30
40
50
60
70
80
No baseline HF(N=134)
Baseline HF (n=86)
% o
f pa
tient
s
HF No HF
Wang AY, et al. J Am Soc Nephrol 2007
27.6%
61.6%
0
10
20
30
40
50
60
70
80
No baseline HF(N=299)
Baseline HF(n=134)
% o
f pat
ients
HF No HF
Harnett JD, et al. Kidney Int 1995
25%
56%
PD patients HD + PD patients
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Heart Failure Increased Risk of Early Death (within 90 days of Dialysis Initiation) in Dialysis Patients
Soucie JM, et al. J Am Soc Nephrol 1996
Factor Level OR (95% CI) Age 45-64
65-74 75+
2.1 (1.4, 3.3) 4.3 (2.8, 6.6) 5.0 (3.2, 7.8)
Gender Male 1.6 (1.3, 1.9) Albumin (g/L) 35-40
31-34 10-30
1.4 (0.9, 2.2) 2.4 (1.5, 3.7) 4.4 (2.8, 6.9)
Heart failure Yes 1.5 (1.2, 1.9) Myocardial infarction by age level <45
45-64 65-74 75+
8.8 (4.2, 18.6) 1.4 (0.8, 2.4) 1.2 (0.8, 1.9) 1.0 (0.6, 1.6)
Hypertension Yes 0.7 (0.6, 0.9)
Smoking Yes 1.3 (1.0, 1.7) Activity impairment Severe 2.3 (1.4, 3.6)
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Baseline History of Heart Failure Increased Long Term Mortality Risk in Dialysis Patients
Harnett JD, et al. Kidney Int 1995 Wang AY, et al. Clin JASN 2011
HD + PD PD
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Risk Factors Predicting Heart Failure in Dialysis Patients
P HR (95% CI)
Hemoglobin (1 g/dl ↑) 0.064 0.87 (0.76, 1.01)
Serum albumin (1 g/L ↑) 0.014 0.94 (0.89, 0.99)
Diabetes mellitus 0.115 1.46 (0.91, 2.35)
Systolic blood pressure (1 mmHg ↑) < 0.001 1.03 (1.01, 1.04)
Atherosclerotic vascular disease 0.026 1.75 (1.07, 2.87)
LV mass index (1 g/m2.7 ↑) 0.050 1.006 (1.000, 1.011)
Ejection fraction (1 % ↑) 0.014 0.97 (0.94, 0.99)
Wang AY, et al. Kidney Int 2006
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Causes of Cardiovascular Death in Dialysis Patients
USRDS 2009
Cause of death N (%)
Total number 115
Cardiovascular 64 (55.7)
- IHD/AMI 10 (8.7)
- Heart failure 5 (4.3)
- Arrhythmia 1 (0.9)
- CVA 14 (12.2)
- Sudden cardiac death 28 (24.3)
- Peripheral vascular disease 4 (3.5)
Non-cardiovascular 51 (44.3)
Wang AY, et al. Hypertension 2010
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Wang AY, et al. Hypertension 2010
cTnT ≤ 0.01 µg/L
cTnT between 0.01 – 0.99 µg/L
cTnT ≥ 0.1 µg/L
P=0.001
Systolic Dysfunction Predicts Sudden Cardiac Death in ESRD Patients
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Incremental Value of E/Em ratio (a non-invasive marker of Left Ventricular Filling Pressure) in Predicting
Mortality of Dialysis Patients
Wang AY, et al. Hypertension 2008
Lower tertile: E/Em ratio ≤ 14.43; Middle tertile: E/Em ratio 14.43 - 21.73; Upper tertile: E/Em ratio ≥ 21.73.
E/Em ratio, early mitral inflow velocity to peak mitral annulus velocity ratio.
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Amann K, et al. J Am Soc Nephrol 1988
Control
Hypertensive
Uremic
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Cardiac Pathology in Hemodialysis Patients with Dilated Cardiomyopathy
Aoki, et al. Kidney Int 2005
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Risk Factors for Cardiac Hypertrophy and Fibrosis
Old Age
Diabetes
Anemia
Hypertension Extra-cellular
volume expansion
Hyperphosphatemia
Uremic milieu Left ventricular
hypertrophy
Arterial stiffening
Inflammation
Sympathetic Overactivity
Asymmetric dimethyl arginine
Renin-angiotensin system
Local growth factors Myocardial ischemia Vitamin D
deficiency
Hyperparathyroidism
Hypoalbumin
FGF-23
Vascular calcification
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Are there Serum Biomarkers that Predict Dialysis Patients with an Increased
Mortality and Cardiovascular Risk ?
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Korff S et al, Heart, 2006; Wu A et al, Clin Chem 1998; Katrukha A et al, Clin Chem 1997
Circulating forms Free cTnT (37kDa) is the major cTnT circulating form
•Cardiac TnI is highly susceptible to proteolysis and enzymatic modification
•Degradation occurs both in-vitro and in-vivo
•Multiple circulating cTnI forms are described:
Free and complexed forms Proteolysed forms Complexed or not to heparin Phosphorylated forms
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Prevalence of Troponin T Elevation in CKD Patients without Acute Myocardial Ischemia
Author CKD (No.) Prevalence of elevated cTnT
Ooi, 1998 174 HD 28.7% > 0.1ng/mL, 10.3% > 0.2ng/mL
Dierkes, 2000 102 HD 83% > 0.01ng/mL, 38% > 0.04ng/mL
Degan, 2001 73 HD 27.4% > 0.1ng/mL
Apple, 2002 733 HD 53% > 0.03ng/mL, 20% > 0.1ng/mL
deFilippi, 2003 224 HD 25.4% > 0.029ng/mL
Goicoechea, 2004 128 CKD 3-5 15.6% > 0.1ng/mL
Abbas, 2005 222 CKD 3-5 43% ≥ 0.01ng/mL, 18% ≥ 0.07ng/mL
Havekes, 2006 847 HD + PD 33.2% > 0.04ng/mL, 11% ≥ 0.1ng/mL
Sommerer, 2007 134 HD 39.6% > 0.03ng/mL
Wang, 2007 238 PD 67.6% > 0.01ngmL, 32.8% 0.01 – 0.099ng/mL, 34.9% ≥ 0.1ng/mL
Hickson, 2008 644 on Txp wait list
61% > 0.01ng/mL, 20% 0.04 – 0.09ng/mL, 13% ≥ 0.1ng/mL
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Forest Plot of Primary Studies Evaluating An Elevated Troponin T > 0.1ng/mL and Cardiac Death in ESRD
Khan NA, et al. Circulation 2005
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Serial Increased Cardiac Troponin T Predicts Mortality and Cardiovascular Event in Asymptomatic Hemodialysis Patients
Roberts MA, et al. Ann Clin Biochem 2009
Five serial measurements N=81
All 5 samples no cTnT+ (≥ 0.04ng/mL) 35%
1-4 samples cTnT + 24%
All 5 samples cTnT + 41%
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Kaplan Meier Estimates in relation to All-Cause Mortality and Fatal or Non-Fatal Cardiovascular Events in Peritoneal
Dialysis Patients
cTnT < 0.01ng/mL
cTnT 0.01 – 0.099ng/mL
cTnT ≥ 0.1ng/mL
cTnT < 0.01ng/mL
cTnT 0.01 – 0.099ng/mL
cTnT ≥ 0.1ng/mL
P<0.001 P<0.001
Wang AY, et al. Clin Chem 2007
All-cause mortality Cardiovascular Event
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Factors Associated with An Elevated Cardiac Troponin T
Initial Plasma Troponin T level, µg/L P-value for
Trend <0.01 (n=77) 0.01 – 0.099 (n=78)b
≥0.10 (n=83)
Age (years) 52.1 ± 12.4 57.0 ± 11.0 57.9 ± 10.6 0.001 Male (%) 40.3 50.0 62.7 0.005 Positive smoking history (%) 26.0 37.2 47.0 0.006 Diabetes (%) 13.0 29.5 48.2 <0.001 Coronary artery disease (%) 6.5 23.1 30.1 <0.001 AVD (%) 6.5 21.8 39.8 <0.001 Dialysis duration (months) 23 (14, 40) 26 (13, 57) 40 (16, 60) 0.003 Total weekly Kt/V 1.94 ± 0.39 1.81 ± 0.45 1.68 ± 0.45 <0.001 Total weekly CrCl (L/wk per
1.73m2) 67.1 ± 25.0 56.5 ± 21.9 49.2 ± 15.3 <0.001
% with no RRF 13.0 38.5 62.7 <0.001
Wang AY, et al. Clin Chem 2007
AVD, atherosclerotic vascular disease; RRF, residual renal function.
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Initial Plasma Troponin T level, µg/L P-value for
Trend <0.01 (n=77) 0.01 – 0.099 (n=78)
≥0.10 (n=83)
Hemoglobin (g/dL) 9.9 ± 1.7 9.2 ± 1.7 8.8 ± 1.6 <0.001
Serum albumin (g/L) 29.4 ± 5.4 28.6 ± 5.1 26.5 ± 4.4 <0.001
C-reactive protein (mg/L) 1.3 (0.7, 4.0) 4.3 (0.6, 13.7) 5.3 (1.4, 16.4) <0.001
Systolic blood pressure (mmHg)
143 ± 17 147 ± 17 149 ± 19 0.020
Left ventricular mass index (g/m2)
172 ± 47 236 ± 81 263 ± 90 <0.001
% patients with LVEF < 40% 0 2.6 16.3 <0.001
Factors Associated with An Elevated Cardiac Troponin T
Wang AY, et al. Clin Chem 2007
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Multivariable Cox Regression Analysis for Different Outcomes
Adjusted HR (95% confidence intervals), P-value
All-cause mortality (n=70) a
Cardiovascular death (n=44) b
Fatal and non-fatal CVEs (n=129) c
CRP (mg/L) 1.02 (1.01, 1.04), 0.006 1.02 (1.00, 1.04), 0.019 1.00 (0.99, 1.02), 0.93
Residual GFR (ml/min per 1.73m2)
0.64 (0.50, 0.81), <0.001 0.61 (0.45, 0.83), 0.002 0.86 (0.76, 0.97), 0.017
LVMi (g/m2) 1.003 (1.000, 1.006), 0.072
1.003 (0.999, 1.007), 0.15 1.004 (1.002, 1.006), 0.001
LV EF (%) 0.97 (0.94, 1.00), 0.039 0.99 (0.95, 1.02), 0.41 0.97 (0.94, 0.99), 0.003
Cardiac troponin T (ng/mL)
4.43 (1.87, 10.45), 0.001 4.12 (1.29, 13.17), 0.017 3.59 (1.48, 8.70), 0.005
a Including age, background coronary artery disease. b Including age, background coronary artery disease, diabetes. c Including age, gender, background coronary artery disease, diabetes, duration of dialysis, hemoglobin. Clin Chem 2007
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Predictive value of Cardiac Troponin T, CRP and Other Risk Predictors in PD Patients: ROC curve analysis with AUCs
All-cause mortality CV death Fatal and non-fatal CV events
Model 1: cardiac troponin T .774 (.706-.841) .720 (.638-.802) .711 (.645-.776)
Model 2: hs-CRP .691 (.619-.763) .668 (.584-.752) .593 (.519-.666)
Model 3: echocardiographic parameters
.691 (.614-.768) .657 (.561-.752) .713 (.646-.780)
Model 4: age, gender, clinical and biochemical and echo parameters
.813 (.748-.877) .800 (.726-.874) .769 (.708 -.830)
Model 5: model 4 + hs-CRP .812 (.746-.877) .795 (.718-.872) .758 (.697-.820)
Model 6: model 4 + cardiac troponin T
.832 (.669-.894) .810 (.739-.883) .780 (.720-.840)
Model 7: model 4 + cardiac troponin T + hs-CRP
.828 (.764-.891) .810 (.735-.884) .779 (.719-.838)
Wang AY, et al. Clin Chem 2007; 53(5): 882-889
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Troponin T Enhances the Prognostic Value of LV Systolic Function and Hypertrophy for Heart Failure in ESRD Patients
cTnT > median, LV EF ≤ 50%
cTnT > median, LV EF > 50% cTnT ≤ median, LV EF ≤ 50%
cTnT ≤ median, LV EF > 50%
P<0.0001
Wang AY, et al. Kidney Int 2006
cTnT > 0.06ng/mL, LV EF > 50%
cTnT ≤ 0.06ng/mL, LV EF ≤ 50%
cTnT > 0.06ng/mL, LV EF ≤ 50%
P
0.034
0.398
<0.001
Adjusted HR (95% CI)*
1.88 (1.05 -3.38)
1.42 (0.63 – 3.19)
3.10 (1.71 – 5.63) vs cTnT ≤ 0.06ng/mL, LV EF > 50% (ref group), *adjusting for age, gender, diabetes, serum albumin, systolic BP, atherosclerotic vascular disease.
TnT > 0.06µg/L, LVMi < median TnT ≤ 0.06µg/L, LVMi ≥ median TnT >0.06µg/L, LVMi ≥ median vs cTnT ≤0.06ng/ml, LVMi < median
P 0.097 0.148 0.003
Adjusted HR 1.91 (0.89, 4.10) 1.72 (0.83, 3.58) 2.68 (1.39, 5.19)
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Wang AY, et al. Hypertension 2010.
cTnT ≤ 0.01 µg/L
cTnT between 0.01 – 0.99 µg/L
cTnT ≥ 0.1 µg/L
P=0.001
Cardiac Troponin T Predicts Sudden Cardiac Death in Dialysis Patients
Variable Shrinkage corrected HR (95% CI) P-value
Systolic BP (1mmHg) 1.05 (1.02 – 1.08) 0.0031
Diastolic BP (1mmHg) 0.92 (0.87 – 0.97) 0.0033
Erythropoietin use 0.44 (0.18 – 1.06) 0.066
Diabetes mellitus 0.48 (0.20 – 1.15) 0.10
Cardiac troponin T (0.1µg/L) 1.14 (1.01 – 1.31) 0.031
Valvular calcification 1.90 (0.83 – 4.32) 0.13
LV ejection fraction (1%) 0.94 (0.89 – 0.98) 0.004
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Cardiac Troponin T is Related to Extent of Coronary Atherosclerosis in ESRD Patients
deFilippi CR, et al. JAMA 2003
Quartiles of cTnT level P for trend cTnT, ng/mL <0.029
(n=16) 0.029-0.064
(n=19) 0.065-0.116
(n=18) ≥0.116 (n=14)
Multivessel CAD, %
0 25 50 62 <0.001
CAD index > 48, %
0 21 22 29 0.048
CAD, coronary artery disease.
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Correlation of Antemortem Serum CK, CK-MB, Troponin I, and Troponin T with Cardiac Pathology
Ooi DS, et al. Clin Chem 2000
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Troponin T Elevations and MRI findings in Hemodialysis Patients
deFilippi CR, et al. Am J Cardiol 2007
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Cardiac Troponin T Circulates in the Free Intact Form in Patients with Kidney Failure
Fahie-Wilson MN, et al. Clin Chem 2006
PD HD
ACS Serum with Tn extract
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Nature 1988
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BNP Secreted Mainly from the Left Ventricle in Response to Wall Stress and in Proportion to the Severity of LV Dysfunction
Yasue H, et al. Circulation 1994
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Prognostic value of BNP in ESRD Patients
Author J, yr Subjects
Inclusion criteria
FU (Mos)
Outcome and Hazard ratios (95% CI)
Zoccali JASN, 2001
212 HD & 34 PD
LVEF > 35% and no history of HF
26 ± 10 Death - 1.62 (1.20 – 2.17) for 1 unit ↑ in log-BNP* CV death – T3 vs T1, 6.72 (2.44 – 18.54)*
Cataliotti Mayo Clin Proc, 2001
112 ESRD
No HF or LVSD
26 ± 10 CV death (P<0.001)
Naganuma AJN, 2002 164 HD Non-selective
36 Cardiac death – Q4 vs Q1, 51.9 (6.5 – 416.3)
Goto Nephron, 2002
53 HD Non-selective
11.3 ± 0.3
CV events (P<0.0001)
Wang AY, et al. J Am Soc Nephrol 2008
HD, hemodialysis; PD, peritoneal dialysis; CV, cardiovascular; HF, heart failure, LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction.
*Independent of LV mass and ejection fraction.
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Prognostic value of NT-pro-BNP in ESRD Author J, yr Subjects, N FU Mos Outcome & Hazard ratios (95% CI)
Apple Clin Chem 2004 399 HD 24 Death: Upper tertile >18692pg/mL ↑ mortality
Wang JASN 2007 240 PD 36 Q4 vs Q1: Death – 4.97 (1.35 – 18.28)* CV death – 7.50 (1.36 – 41.39)* CV events – 9.10 (2.46 – 33.67)*
Madsen KI 2007 190 HD 24 Death - Pre-HD: ln NT-pro-BNP, 1.42 (1.10-1.82)* Post-HD: Ln NT-pro-BNP, 1.52 (1.18–1.96)*
Sommerer Nephron Clin Pract 2007
134 HD 36 Composite endpoint of death and CV events - 3.2 (1.70 – 6.02)
Satyan AJKD 2007 150 HD 24 Death – Q4 vs Q1: 4.03 (1.31 – 12.40) CV mortality – Q4 vs Q1: 8.54 (1.04 – 69.98)
Sharma Heart 2007 50 HD & 29 PD
2.25 ± 0.71 yrs
Mortality - 5.57 (3.14 - 8.21) [univariate analysis]
Winkler EHJ 2008 1255 T2DM HD
4 yrs Q4 vs Q1: Stroke – 4.1 (2.0-8.4), Sudden death – 2.0 (1.2 – 3.3), CVE – 2.0 (1.5-2.7), mortality – 2.1 (1.6 – 2.7)
Paniagua NDT 2010 753 PD & HD
16 Mortality – 1.006 (1.001-1.011) every 1000pg/ml ↑ CV mortality – 1.010 (1.004-1.006) every 1000pg/mL ↑
Wang AY, et al. J Am Soc Nephrol 2008 *Independent of LV mass & ejection fraction.
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Change in NT-pro-BNP and Risk of Sudden Death, Stroke, Myocardial Infarction and All-cause Mortality in
Diabetic Dialysis Patients
Winkler K, et al. Eur Heart J 2008
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Wang AY, et al. Hypertension 2010
cTnT ≤ 0.01 µg/L
cTnT between 0.01 – 0.99 µg/L
cTnT ≥ 0.1 µg/L
P=0.001
NT-pro-BNP and Sudden Cardiac Death in PD Patients
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ROC Curves of NT-pro-BNP, Cardiac Troponin T and hs-CRP in Predicting (A) Systolic Dysfunction and (B) Severe LV
Hypertrophy in Dialysis Patients
AUCs (95% CIs) NT-proBNP 0.802 (0.732 – 0.872)
cTnT 0.765 (0.687 – 0.843)
hs-CRP 0.600 (0.508 – 0.692)
NT-pro-BNP cTnT
hs-CRP
hs-CRP
NT-pro-BNP
cTnT
AUCs (95% CIs) NT-pro-BNP 0.785 (0.726 – 0.844)
cTnT 0.713 (0.645 – 0.780)
hs-CRP 0.634 (0.562 – 0.706)
A B
Wang AY, et al. Nephrol Dial Transplant 2009
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Biomarkers Best Cutoff Sensitivity (%)
Specificity (%)
PPV (%) NPV (%)
Severe LV hypertrophy (LVMi ≥ upper tertile, 247.8g/m2) (n=77)
- NT-pro-BNP 8862 pg/mL 76.6 79.1 64.8 87.1
- cTnT 0.01 ng/mL 92.2 49.0 47.7 92.6
Systolic dysfunction (EF ≤ 45%) (n=38)
- NT-pro-BNP 7468 pg/mL 84.2 64.6 32.0 95.4
- cTnT 0.07 ng/mL 76.3 64.1 29.6 93.2
Predictive Value of cTnT and NT-pro-BNP for Severe LV Hypertrophy and Systolic Dysfunction in Dialysis
Patients
Wang AY, et al. Nephrol Dial Transplant 2009
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Wang AY, et al. J Am Soc Nephrol 2007
Baseline NT-pro-BNP in Patients with and without Subsequent Circulatory Congestion with Stratification for LV
Function
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Relationship between NT-pro-BNP and Hydration Status is related to Pre-existing LV Dysfunction
David S, et al. Nephrol Dial Transplant 2007
Post-dialytic hydration status: low range (LR) - ECW/BW < median high-range (HR) - ECW/BW > median
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Ischemia triggers BNP expression in the human myocardium independent from mechanical stress
Möllmann H, et al. Int J Cardiol 2010
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NT-pro-BNP & BNP are Equally Dependent on Renal Function for Their Clearance
Van Kimmenade RRJ, et al. J Am Coll Cardiol 2009
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LV End-Diastolic Wall Stress is a Strong Determinant of BNP in Heart Failure Patients
with CKD and ESRD
Niizuma S, et al. Clin Chem 2009
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Conclusions Cardiac troponin T and BNP/NT-pro-BNP are powerful
predictors of adverse cardiovascular outcomes in dialysis patients and provide important additional prognostic value beyond that of LV hypertrophy and systolic dysfunction.
Cardiac troponin T elevation appears a useful marker in reflecting myocardial injury/pathology while elevated BNP/NT-pro-BNP is a useful marker of increased LV wall stress secondary to LV hypertrophy and dysfunction, extracellular volume overload or myocardial ischemia.
Their testing is a valuable adjunct to echocardiography in assessing cardiovascular status of dialysis patients.
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HK Peritoneal Dialysis Study Collaborative Research Team
Prof Jean Woo, Center of Nutritional Studies,
PWH, CUHK Prof Christopher Wai-Kei Lam and Dr Iris HS
Chan, Chemical Pathology, PWH, CUHK
Dr Mei Wang, Medicine, QMH, HKU
Dr Lui Siu-Fai, Medicine, PWH, CUHK
Prof John Sanderson, Cardiology, PWH, CUHK
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Thank You for Your Kind Attention
- Hong Kong Health Service Research Fund - Hong Kong Society of Nephrology Research Grants
- Hong Kong Research Grant Council - Baxter Extramural Grant Program
Acknowledgement