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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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Page 1: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 2: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 3: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 4: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 5: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 6: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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)

Page 7: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 8: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 9: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 10: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 11: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 12: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Amann K, et al. J Am Soc Nephrol 1988

Control

Hypertensive

Uremic

Page 13: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Cardiac Pathology in Hemodialysis Patients with Dilated Cardiomyopathy

Aoki, et al. Kidney Int 2005

Page 14: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 15: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Are there Serum Biomarkers that Predict Dialysis Patients with an Increased

Mortality and Cardiovascular Risk ?

Page 16: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 17: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 18: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Forest Plot of Primary Studies Evaluating An Elevated Troponin T > 0.1ng/mL and Cardiac Death in ESRD

Khan NA, et al. Circulation 2005

Page 19: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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%

Page 20: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 21: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 22: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 23: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 24: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 25: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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)

Page 26: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 27: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 28: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Correlation of Antemortem Serum CK, CK-MB, Troponin I, and Troponin T with Cardiac Pathology

Ooi DS, et al. Clin Chem 2000

Page 29: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Troponin T Elevations and MRI findings in Hemodialysis Patients

deFilippi CR, et al. Am J Cardiol 2007

Page 30: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 31: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

Nature 1988

Page 32: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 33: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 34: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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.

Page 35: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 36: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 37: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 38: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 39: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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

Page 40: Novel Predictors of Cardiovascular Mortality in Dialysis ... · Novel Predictors of Cardiovascular Mortality in Dialysis Patients Angela Yee-Moon WANG, MD, PhD . Department of Medicine

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