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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
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
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
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.
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
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)
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
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
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
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
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.
Amann K, et al. J Am Soc Nephrol 1988
Control
Hypertensive
Uremic
Cardiac Pathology in Hemodialysis Patients with Dilated Cardiomyopathy
Aoki, et al. Kidney Int 2005
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
Are there Serum Biomarkers that Predict Dialysis Patients with an Increased
Mortality and Cardiovascular Risk ?
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
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
Forest Plot of Primary Studies Evaluating An Elevated Troponin T > 0.1ng/mL and Cardiac Death in ESRD
Khan NA, et al. Circulation 2005
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%
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
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.
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
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
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
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)
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
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.
Correlation of Antemortem Serum CK, CK-MB, Troponin I, and Troponin T with Cardiac Pathology
Ooi DS, et al. Clin Chem 2000
Troponin T Elevations and MRI findings in Hemodialysis Patients
deFilippi CR, et al. Am J Cardiol 2007
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
Nature 1988
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
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.
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.
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
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
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
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
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
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
Ischemia triggers BNP expression in the human myocardium independent from mechanical stress
Möllmann H, et al. Int J Cardiol 2010
NT-pro-BNP & BNP are Equally Dependent on Renal Function for Their Clearance
Van Kimmenade RRJ, et al. J Am Coll Cardiol 2009
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
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.
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
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