Ischemia-Modified Albumin Predicts Mortality in ESRD

Ischemia-Modified Albumin Predicts Mortality in ESRD Rajan Sharma, MD, David C. Gaze, PhD, Denis Pellerin, MD, Rajnikant L. Mehta, MSc, Helen Gregson, BSc, Christopher P. Streather, FRCP, Paul O. Collinson, FRCPath, and Stephen J.D. Brecker, MD ● Background: The primary study aim is to determine whether ischemia-modified albumin (IMA) levels predict mortality in patients with end-stage renal disease (ESRD). The secondary aim is to determine characteristics of patients with elevated IMA levels. Methods: A prospective observational study of 114 renal transplantation candidates was performed. All underwent coronary angiography and dobutamine stress echocardiography. The primary end point is total mortality. Results: During a follow-up period of 2.25 ⴞ 0.71 years, there were 18 deaths; 10 were cardiac related. Diabetes, severe coronary artery disease, positive dobutamine stress echocardiography result, cardiac troponin T (cTnT) level, IMA level, left ventricular (LV) end-systolic diameter, LV ejection fraction, left atrial size, and mitral peak velocity of early filling (E)/early diastolic velocity (Ea) ratio all predicted mortality. The receiver operating characteristic area under the curve for mortality prediction was similar for IMA and cTnT levels. An IMA level of 95 KU/L or greater (n ⴝ 46) predicted mortality with a sensitivity of 76% and specificity of 74%. cTnT level of 0.06 ng/mL or greater (>0.06 ␮g/L; n ⴝ 51) predicted mortality with a sensitivity of 75% and specificity of 72%. Thirty-eight patients (33%) had both IMA and cTnT levels elevated. With multivariate analysis, a positive dobutamine stress echocardiography result (P ⴝ 0.003), combined elevated IMA and cTnT levels (P ⴝ 0.005), and E/Ea ratio (P ⴝ 0.009) were independent prognostic factors. IMA and cTnT levels alone were not independent predictors of mortality. Patients with an elevated IMA level had a significantly larger LV size, decreased LV systolic function, and greater E/Ea ratio compared with those without an increased level. Conclusion: IMA level predicts mortality in patients with ESRD. Patients with elevated levels have larger LV size, decreased systolic function, and greater estimated LV filling pressures. Am J Kidney Dis 47:493-502. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Ischemia-modified albumin; end-stage renal disease (ESRD); renal transplantation candidate; mortality; risk stratification.

S

EVERAL BIOMARKERS have been identified that predict cardiac and total mortality in patients with end-stage renal disease (ESRD). These include cardiac troponin,1,2 natriuretic peptides,3,4 high-sensitivity C-reactive protein,5,6 and asymmetrical dimethylarginine.7 It has not been established whether targeted intervention to patients based on biomarker findings improves outcome. Nevertheless, given that cardiac disease remains the leading cause of mortality in patients with ESRD,8 the identification of new prognostic factors in these patients is important. Ischemiamodified albumin (IMA) is a novel biomarker of acute ischemia with high sensitivity, but moderate specificity.9,10 It has not been studied in patients with ESRD. In this single-center, prospective, observational study of 114 renal transplantation candidates, we hypothesized that baseline IMA levels may predict both cardiac disease and mortality in patients with ESRD. During a 2-year follow-up period, the primary end point was total mortality. IMA level was compared with other markers of adverse outcome in patients with ESRD. The optimal IMA level that predicted mortality was determined. We then investigated cardiac structural and functional characteristics of patients

with elevated baseline IMA levels. All patients underwent coronary angiography, dobutamine stress echocardiography (DSE), and determination of levels of baseline biochemical markers. Informed consent was obtained, and the study had full ethical approval. METHODS

Population Between January 2002 and December 2003, a total of 114 consecutive patients referred for renal transplantation evaluation at St George’s Hospital, London, UK, were studied

From the Departments of Cardiology, Chemical Pathology, and Renal Medicine, St George’s Hospital; The Heart Hospital, London; and the Department of Medical Statistics, Southampton General Hospital, Southampton, UK. Received October 24, 2005; accepted in revised form November 29, 2005. Originally published online as doi:10.1053/j.ajkd.2005.11.026 on January 24, 2006. Support: None. Potential conflict of interest: None. Address reprint requests to Rajan Sharma, MD, Department of Cardiology, E Level East Wing, Mailpoint 46, Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, UK. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4703-0016$32.00/0 doi:10.1053/j.ajkd.2005.11.026

American Journal of Kidney Diseases, Vol 47, No 3 (March), 2006: pp 493-502

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494

prospectively. Exclusion criteria were age younger than 18 years, severe aortic stenosis, unstable angina, and inability to consent. Clinicians reporting echocardiographic and coronary angiographic data were blinded to biochemical data. Echocardiography and coronary angiography results were used to determine suitability for renal transplantation and whether revascularization was required.

Transthoracic Echocardiography The General Electric Vingmed System 7 (Horten, Norway) was used. For those on dialysis therapy, studies were performed 16 to 24 hours postdialysis, when patients were most likely to be closest to their euvolemic state.11,12 Left ventricular (LV) end-diastolic diameter, LV end-systolic diameter, and interventricular and LV posterior wall thickness at end-diastole were measured from parasternal M-mode recordings of the left ventricle, with the cursor at the tips of the mitral valve leaflets. LV end-systolic and end-diastolic volumes were determined by using a modified biplane Simpson rule and the standard formula applied to give LV ejection fraction. Measurements were averaged over 3 cardiac cycles. LV mass was calculated according to Devereux and Reichek.13 This was corrected for body surface area to give LV mass index. Transmitral inflow was recorded by using pulsed-wave Doppler recordings at the mitral valve leaflet tips in the apical 4-chamber view. Peak velocity of early filling (E), peak velocity of atrial filling (A), E/A ratio, and E deceleration time were measured. Flow propagation velocity (Vp) was determined from color M-mode in apical 4-chamber view. From pulsed-wave real-time tissue Doppler images obtained in the 4-chamber view, peak systolic and early diastolic (Ea) velocities were measured. The sample volume was placed at the lateral mitral annulus. LV filling pressure was estimated from E/Ea and E/Vp ratios.14

Dobutamine Stress Echocardiography Images were acquired in parasternal long- and short-axis and apical 2-, 3-, and 4-chamber views at baseline and during stepwise infusion of dobutamine, administered according to a protocol based on 3-minute stages of 5, 10, 20, 30, and 40 ␮g/kg/min. Atropine was administered up to a total of 1.0 mg intravenously if target heart rate was not achieved. Blood pressure and 12-lead electrocardiograms were recorded at each infusion stage. Baseline, low-dose (heart rate, 10 to 15 beats/min greater than baseline), peak, and recovery (10 minutes after drug infusion was terminated) stage images were stored and analyzed in digital quad screen format. The test was stopped if: (1) target heart rate was achieved ([220 ⫺ age] ⫻ 0.85), (2) ST depression greater than 2 mm occurred, (3) significant tachyarrhythmia (sustained supraventricular tachycardia or ⬎ 3-beat run of ventricular tachycardia) occurred, (4) symptomatic severe hypotension occurred, or (5) blood pressure exceeded 240 mm Hg systolic or 140 mm Hg diastolic. All images were reported off-line by 2 experienced observers blinded to the rest of the study. Qualitative analysis was performed with the left ventricle divided into a 17-segment model. Regional wall motion was described as hyperkinetic, normal, hypokinetic, akinetic, and dyskinetic. Results were classified as a normal response with an overall increase in wall

SHARMA ET AL

motion or abnormal response. An abnormal response was described by the occurrence under stress of hypokinesia, akinesia, or dyskinesia in 1 or more resting normal segments and/or worsening of wall motion in 1 or more resting hypokinetic segments.15 Resting and peak wall motion index scores were calculated. The level of agreement between the 2 sonographers was ␬ ⫽ 0.82. Consensus was obtained in discordant cases. There were 6 discordant cases, and agreement was reached after discussion between the 2 observers.

Sample Acquisition Whole-blood venous samples were collected at the time of DSE. Samples were allowed to clot and were centrifuged at 3,000 rpm for 10 minutes. Serum was decanted and frozen until analysis.

Cardiac Troponin T Assay Cardiac troponin T (cTnT) was measured by using the third-generation TROP T STAT assay on an Elecsys 2010 electrochemiluminescent immunoassay system (Roche Diagnostics, Lewes, East Sussex, UK).16 The assay detection limit was less than 0.01 ng/mL (⬍0.01 ␮g/L). Total assay coefficients of variation were 5.5% at 0.32 ng/mL (0.32 ␮g/L) and 5.4% at 6.0 ng/mL (6.0 ␮g/L). The corresponding concentration with a 10% coefficient of variation was 0.03 ng/mL (0.03 ␮g/L). The receiver operating characteristic curve medical decision cutoff value for myocardial infarction is 0.05 ng/mL (0.05 ␮g/L).17 The 99th percentile is 0.01 ng/mL (0.01 ␮g/L).

Ischemia-Modified Albumin Serum IMA was measured by means of the albumin cobalt-binding (ACB) test on a Cobas MIRA PLUS instrument (ABX Diagnostics, London, UK). The first-generation ACB test has been validated and described previously.18,19 We used a second-generation ACB test, and in our laboratory, assay coefficients of variation were 5.1% in the range of 56.67 to 66.57 KU/L and 3.1% in the range of 147.17 to 158.03 KU/L. According to the manufacturer, the IMA upper limit of normal is 85 KU/L, determined from the 95th percentile of 283 apparently healthy individuals.

Estimated Glomerular Filtration Rate In patients with residual urine production (n ⫽ 70), estimated glomerular filtration rate (GFR) was calculated by using the Cockcroft-Gault equation: GFR ⫽ (140 ⫺ age) ⫻ lean body weight (kg)/72 ⫻ stable serum creatinine (␮mol/L) ⫻ (0.85 for females).

Coronary Angiography Coronary angiograms were interpreted blindly by 2 experienced observers and consensus was obtained for disagreement. Level of agreement was ␬ ⫽ 0.85. The stenosis severity of each epicardial artery was assessed visually and graded as follows: normal, mild (⬍50% luminal narrowing), moderate (50% to 70% luminal narrowing), and significant (⬎70% luminal narrowing). Severe coronary artery disease (CAD) is defined as luminal stenosis greater than 70% in 1 or more epicardial artery.

ISCHEMIA-MODIFIED ALBUMIN IN ESRD

Statistical Analysis

495 Table 1. Baseline Characteristics

Continuous variables are expressed as mean ⫾ 1 SD, and differences between groups were determined by using unpaired t-test. Categorical variables were compared by using chi-square analysis or Fisher exact test. Pearson correlation coefficient was calculated for the correlation of continuous variables with IMA level. The optimal IMA cutoff value to predict mortality was determined from receiver operating characteristic analysis. The area under the curve was calculated and compared with cTnT level. Stepwise multivariate logistic regression analysis was used to determine independent predictors of mortality. Long-term survival related to cTnT and IMA levels was analyzed in a Kaplan-Meier model. Log-rank test was used to evaluate differences between Kaplan-Meier curves. All statistical tests were 2 tailed, with P less than 0.05 to indicate statistical significance. The level of agreement between 2 observers was analyzed by using ␬ statistics. The SPSS statistics package (SPSS Inc, version 12; Chicago, IL) was used.

Follow-Up Follow-up of clinical status was obtained by review of inpatient and outpatient medical records and telephone calls to the transplantation unit. The primary end point is all-cause mortality.

RESULTS

Baseline Characteristics Of 117 renal transplantation candidates screened, 1 patient was excluded for severe aortic stenosis, 2 patients refused to consent for the study. Thus, 114 patients were enrolled. Baseline characteristics are listed in Table 1. Diabetes (40%) was the leading cause of renal failure and 55% were on dialysis therapy. Eighty-one patients (71%) had residual urine production. Mean estimated GFR was 16 ⫾ 9 mL/min (0.27 ⫾ 0.15 mL/s). Thirtyfour patients (30%) had severe CAD and 23 patients (20%) had impaired LV function (LV ejection fraction ⬍ 50%), but none had severe impairment (LV ejection fraction ⬍ 30%). Medication use included aspirin in 51 patients (45%), ␤-blockers in 40 patients (35%), angiotensinconverting enzyme inhibitors in 53 patients (46%), statins in 58 patients (51%), erythropoietin in 60 patients (53%), and diuretics in 49 patients (44%). Medication was not adjusted in relation to DSE or coronary angiogram results. Follow-Up Mean follow-up was 2.25 ⫾ 0.71 years (range, 0.19 to 3.27 years). Thirty-eight patients received a renal transplant, and 7 patients were taken off the transplant list. There were 18 deaths,

Age (y) Sex Men Women Ethnicity White Asian Afro-Carribean Chinese Other Serum creatinine (mg/dL) Serum hemoglobin (g/dL) Cholesterol (mg/dL) cTnT (ng/mL) IMA (KU/L) Serum albumin (g/dL) ESRD cause Diabetes Glomerulonephritis Hypertension Adult polycystic kidney disease Obstructive uropathy Other Dialysis modality Predialysis Hemodialysis Peritoneal dialysis Dialysis time (mo) Previous transplant Cardiac symptoms NYHA class 1 NYHA class 2 NYHA classes 3 and 4 Diabetes Type 1 Type 2 Hypertension Increased cholesterol Smoker Preexisting cardiac disease Ischemic heart disease Heart failure Positive DSE result Severe CAD

52 ⫾ 12 (44-76) 76 (67) 38 (33) 51 (45) 27 (24) 33 (29) 2 1 6.9 ⫾ 3.1 (2.9-15.0) 10.2 ⫾ 1.6 (8-14) 189 ⫾ 70 (54-580) 0.08 ⫾ 0.05 (0-1.08) 88 ⫾ 29 (39-164) 3.6 ⫾ 0.7 (2.1-4.4) 46 (40) 24 (21) 14 (12) 13 (11) 10 (9) 7 (5) 48 (42) 43 (38) 23 (20) 2.73 ⫾ 2.19 (0-11) 13 (11) 52 (46) 35 (31) 17 (15) 0 (0) 46 (40) 20 26 105 (92) 59 (52) 14 (12) 12 (11) 10 (8) 35 (31) 34 (30)

NOTE. Values expressed as mean ⫾ 1 SD (range) or number (percent). To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4; hemoglobin and albumin in g/dL to g/L, multiply by 10; cholesterol in mg/dL to mmol/L, multiply by 0.02586; cTnT in ng/mL to ␮g/L, multiply by 1. Abbreviation: NYHA, New York Heart Association.

10 of which were cardiac related. Mean time to death was 0.97 ⫾ 0.45 years (range, 0.19 to 3.15 years). Eight patients underwent coronary artery bypass surgery, and 11 patients underwent percutaneous intervention. The decision for revascular-

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ization was driven by DSE and coronary angiogram results. Comparison Between Survivors and Nonsurvivors Differences between survivors and nonsurvivors are listed in Table 2. Nonsurvivors were

older and a significantly greater proportion had diabetes, severe CAD, and a positive DSE result. Baseline cTnT and IMA levels were significantly greater in nonsurvivors. LV cavity dimensions were larger, systolic function was lower, left atrial (LA) size was larger, and estimated LV filling pressures were greater in nonsurvivors.

Table 2. Comparison of Survivors and Nonsurvivors Parameter

Survivors

Nonsurvivors

P*

Cardiac Mortality

P†

No. of patients Age (y) Male Female Smoker Hypertension Increased cholesterol Diabetes Positive family history Cardiac symptoms NYHA class 1 NYHA class 2 Past history ischemic heart disease Past history heart failure Previous renal transplant Dialysis Dialysis time (mo) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cholesterol (mg/dL) Hemoglobin (g/dL) Creatinine (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Albumin (g/dL) cTnT (ng/mL) IMA (KU/L) LV end-systolic diameter (cm) LV end-systolic volume (cm)3 LV end-diastolic diameter (cm) LV end-diastolic volume (cm)3 LV fractional shortening (%) LV ejection fraction (%) LV mass index (g/m2) LA size (cm) E/Ea ratio E/Vp ratio Positive DSE result Severe CAD

96 (88) 50 ⫾ 13 66 (61) 30 (31) 10 (11) 90 (92) 50 (44) 31 (33) 10 (11) 44 (46) 30 (31) 14 (15) 7 (8) 6 (7) 9 (11) 56 (58) 2.58 ⫾ 1.26 25 ⫾ 16 145 ⫾ 18 76 ⫾ 11 189 ⫾ 48 11.2 ⫾ 1.4 6.6 ⫾ 3.1 9.4 ⫾ 1.0 5.4 ⫾ 1.2 3.7 ⫾ 1.5 0.07 ⫾ 0.04 83 ⫾ 26 2.8 ⫾ 0.8 34 ⫾ 22 4.7 ⫾ 0.9 105 ⫾ 43 39 ⫾ 10 68 ⫾ 13 132 ⫾ 18 3.8 ⫾ 0.6 11.2 ⫾ 4.2 2.02 ⫾ 0.72 25 (26) 24 (23)

18 (16) 59 ⫾ 12 10 (55) 8 (44) 4 (22) 15 (83) 9 (50) 15 (83) 5 (27) 8 (44) 5 (28) 3 (17) 5 (28) 4 (23) 4 (22) 10 (55) 2.85 ⫾ 1.66 24 ⫾ 10 148 ⫾ 10 83 ⫾ 9 174 ⫾ 45 11.7 ⫾ 1.3 7.3 ⫾ 2.7 9.5 ⫾ 0.9 5.2 ⫾ 1.1 3.4 ⫾ 1.9 0.16 ⫾ 0.08 102 ⫾ 25 3.7 ⫾ 0.9 64 ⫾ 22 5.7 ⫾ 1.2 147 ⫾ 46 27 ⫾ 10 52 ⫾ 14 154 ⫾ 11 4.4 ⫾ 0.7 19.1 ⫾ 8.2 2.56 ⫾ 0.78 10 (55) 10 (55)

0.05 0.69 0.61 0.57 0.88 0.71 ⬍0.001 0.35 0.63 0.52 0.51 0.05 0.07 0.11 0.74 0.26 0.89 0.66 0.49 0.32 0.68 0.35 0.74 0.86 0.37 0.02 0.02 0.008 0.004 0.007 0.01 0.005 0.006 0.05 0.02 0.009 0.04 0.01 0.02

10 (9) 57 ⫾ 4 5 (50) 4 (40) 2 (20) 8 (80) 6 (60) 9 (90) 3 (30) 5 (50) 2 (20) 1 (10) 4 (40) 3 (30) 2 (20) 6 (60) 2.83 ⫾ 0.26 23 ⫾ 11 150 ⫾ 18 82 ⫾ 11 175 ⫾ 43 11.5 ⫾ 1.4 6.9 ⫾ 2.5 9.7 ⫾ 0.5 5.2 ⫾ 1.1 3.3 ⫾ 1.4 0.14 ⫾ 0.07 101 ⫾ 38 3.7 ⫾ 0.6 66 ⫾ 27 5.6 ⫾ 0.6 144 ⫾ 74 29 ⫾ 78 51 ⫾ 16 158 ⫾ 18 4.3 ⫾ 0.6 18.6 ⫾ 9.1 2.61 ⫾ 0.72 8 (80) 9 (80)

0.05 0.91 0.74 0.78 0.92 0.37 ⬍0.001 0.41 0.51 0.44 0.81 0.03 0.03 0.63 0.32 0.37 0.88 0.38 0.79 0.37 0.52 0.44 0.22 0.85 0.32 0.03 0.03 0.001 0.002 0.001 0.009 0.004 0.001 0.05 0.03 0.008 0.03 0.005 0.007

NOTE. Values expressed as number (percent) or mean ⫾ 1 SD unless noted otherwise. To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4; hemoglobin and albumin in g/dL to g/L, multiply by 10; cholesterol in mg/dL to mmol/L, multiply by 0.02586; cTnT in ng/mL to ␮g/L, multiply by 1; calcium in mg/dL to mmol/L, multiply by 0.2495; phosphate in mg/dL to mmol/L, multiply by 0.3229. *Comparison of survivors and nonsurvivors. †Comparison of survivors and mortality from cardiac causes.

ISCHEMIA-MODIFIED ALBUMIN IN ESRD

497

cTnT

1.00

1.00

.75

.75

.50

.50

.25

.25

Sensitivity

Sensitivity

IMA

0.00 0.00

.25

.50

.75

1.00

0.00 0.00

.25

.50

.75

1 - Specificity

1 - Specificity

Diagonal segments are produced by ties.

Diagonal segments are produced by ties.

1.00

AUC = 0.76 (95% CI 0.59, 0.94)

AUC = 0.82 (95% CI 0.64, 0.99)

P = 0.05

P = 0.02

Optimal IMA concentration to predict mortality is

Optimal cTnT concentration to predict mortality is

95 KU/L (sensitivity 76%, specificity 74%)

0.06 ng/mL (sensitivity 75%, specificity 72%)

Fig 1. Receiver operating characteristic curves for baseline IMA and cTnT concentrations that predict mortality. Abbreviation: AUC, area under the curve. To covert cTnT in ng/mL to ␮g/L, multiply by 1.

Sex and the proportion on dialysis therapy were similar in the 2 groups. Comparison of IMA and cTnT Levels to Predict Mortality Figure 1 shows receiver operating characteristic analysis for IMA and cTnT levels to predict mortality. Area under the curve comparison showed both markers had high, but similar, predictive accuracy (P ⫽ 0.83). The optimal biomarker concentrations to predict mortality were determined from receiver operating characteristic curves. IMA level of 95 KU/L or greater, seen in 46 patients (40%), predicted mortality with a sensitivity of 76% and specificity of 74%. cTnT level of 0.06 ng/mL or greater (ⱖ0.06 ␮g/L), seen in 51 patients (45%), predicted mortality with a sensitivity of 75% and specificity of 72%. Figure 2 shows Kaplan-Meier survival curves for both cTnT and IMA according to these cutoff values. Thirty-eight patients (33%) had both elevated IMA and cTnT levels.

Predictors of Mortality Table 3 shows logistic regression analysis for predictors of mortality. In univariate analysis, diabetes, severe CAD, positive DSE result, cTnT level, IMA level, LV end-systolic diameter, LV ejection fraction, LA size, and E/Ea ratio all predicted mortality. In multivariate analysis, a positive DSE result (odds ratio [OR], 8.11; 95% confidence interval [CI], 5.12 to 9.67; P ⫽ 0.003), combined elevated IMA and cTnT levels (OR, 7.12; 95% CI, 4.14 to 10.12; P ⫽ 0.005), and E/Ea ratio (OR, 6.21; 95% CI, 4.95 to 8.11; P ⫽ 0.009) were found to be independent prognostic factors. IMA and cTnT levels alone were not independent predictors of mortality. Characteristics of Patients With Elevated Baseline IMA Levels Cumulative mortalities during the follow-up period for patients with and without increased IMA levels were 79% and 96%, respectively. Table 4 lists differences in patients with and

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IMA (p = 0.02)

cTnT (p = 0.001)

Survival Survival Functions

Survival 1.1

1.1

1.0

IMA < 95 KU/L

1.0

cTnTcTnT cTnT > 0.06 <<0.06 µg/L 0.06µg/L ng/mL

.9 .9

cTnT > 0.06 ng/mL

.8

.7

.8

IMA > 95KU/L

.7

.6 0.0

.5

1.0

1.5

2.0

2.5

3.0

3.5

Follow Up Time (Years)

0.0

.5

1.0

1.5

2.0

2.5

3.0

3.5

Follow Up Time (Years)

Fig 2. Kaplan-Meier survival curves according to IMA and cTnT concentrations. To covert cTnT in ng/mL to ␮g/L, multiply by 1.

without baseline IMA levels of 95 KU/L or greater. Those with elevated IMA levels had significantly greater LA and LV cavity size, significantly decreased LV systolic function, and greater estimated LV filling pressures. Age, cTnT level, medication, and proportions on dialysis therapy, with diabetes, with severe CAD, with a positive DSE result, and undergoing revascularization were similar in the 2 groups. When correlation coefficients were calculated for IMA with continuous variables, there was a significant positive correlation with LV end-systolic diameter (r ⫽ 0.39; P ⫽ 0.04) and E/Ea ratio (r ⫽ 0.41; P ⫽ 0.05) and a negative correlation with LV ejection fraction (r ⫽ ⫺0.44; P ⫽ 0.02) and albumin level (r ⫽ ⫺0.38; P ⫽ 0.04). There was no correlation with age or cTnT level. DISCUSSION

This is the first study to investigate IMA levels in patients with ESRD. We found that IMA level is a marker of mortality in a group of renal transplantation candidates. The predictive accuracy was similar to that of cTnT level. By using multivariate analysis, cTnT and IMA levels were

not independent predictors of mortality. However, combined elevated IMA and cTnT levels independently predicted mortality when tested with clinical, echocardiographic, and angiographic parameters. We determined the optimal cutoff value for IMA to predict prognosis as 95 KU/L. This is greater than the IMA cutoff value suggested for ischemia diagnosis (85 KU/L). Patients with IMA levels of 95 KU/L or greater had larger LA and LV size, more decreased LV systolic function, and greater estimated LV filling pressures than those with IMA levels less than 95 KU/L. Age and proportions on dialysis therapy and with diabetes, severe CAD, and inducible ischemia were similar in the 2 groups. There was a negative correlation between IMA and albumin levels. Additional studies are required to determine whether baseline albumin level affects quantitative IMA level. In this study, albumin levels were not significantly different in survivors and nonsurvivors and patients with and without elevated IMA levels. Therefore, we do not believe the observed differences in IMA levels between survivors and nonsurvivors can be explained by significant differences in baseline albumin levels.

ISCHEMIA-MODIFIED ALBUMIN IN ESRD

499

Table 3. Univariate and Multivariate Logistic Regression Analysis to Determine Predictors of Mortality

Univariate predictors Age Sex Dialysis Diabetes cTnT IMA LV end-systolic diameter (cm) LV end-diastolic diameter (cm) LV ejection fraction (%) LA size (cm) E/Ea ratio LV mass index Positive DSE result Severe CAD Elevated IMA and cTnT Multivariate predictors Positive DSE result Elevated IMA and cTnT E/Ea ratio

OR for Prediction of Mortality (95% CI)

P

0.07 (0.01-0.18) 0.25 (0.12-0.51) 3.34 (2.12-5.58) 6.24 (3.32-8.18) 7.14 (5.71-10.22) 6.91 (3.11-7.19)

0.79 0.61 0.07 0.01 0.004 0.04

5.68 (2.21-7.22)

0.02

2.99 (1.63-5.11) 6.99 (3.21-8.75) 5.32 (2.14-7.34) 7.12 (3.44-8.12) 0.08 (0.02-1.21) 9.16 (4.45-11.95) 6.91 (2.18-12.11) 7.81 (2.16-12.11)

0.08 0.008 0.02 0.002 0.77 0.001 0.009 0.002

8.11 (5.12-9.67) 7.12 (4.14-10.12) 6.21 (4.95-8.11)

0.003 0.005 0.009

The patients studied, namely renal transplantation candidates, represented a lower risk group than previously studied; patients with ESRD on dialysis therapy. This reflects current referral practice for renal transplantation. Only a third had severe CAD, 81% had normal LV systolic function, none had an LV ejection fraction less than 30%, and a large proportion were not on dialysis therapy. However, the use of biomarkers to assess risk in patients with ESRD is highly relevant for patients referred for transplantation. IMA is a marker of ischemia. The N-terminus of albumin becomes damaged under conditions of ischemia, resulting in IMA. IMA is unable to bind metals at the N-terminus. In the ACB test, a known amount of cobalt is added to the serum sample. Unbound cobalt is measured spectrophotometrically and is proportional to the amount of IMA in the sample. Serum IMA concentrations increase acutely after percutaneous coronary intervention9 and in patients with spontaneous ischemia.20,21 Its exact role in the risk stratification of patients with acute chest pain has yet to be defined. The recommended cutoff value for ischemia diagnosis is 85 KU/L. Sensitivity is high, but specificity is low. Serum concentrations are

elevated in patients with skeletal muscle ischemia and should be interpreted with caution in patients with peripheral vascular disease.22 IMA has not been investigated previously in patients with ESRD. Several biomarkers have been proposed for risk stratification in patients with ESRD. Although their ultimate role in the management of patients with renal failure has yet to be established, they identify a high-risk group that may benefit from therapeutic intervention. cTnT level is elevated in a proportion of patients with ESRD and is associated with worse survival.1,2 Reasons for this have yet to be determined. Potential mechanisms include CAD,23 microinfarctions, myocarditis, or arrhythmia. Natriuretic peptide and high-sensitivity C-reactive protein levels predict poorer outcome in patients with ESRD.3-5 A brain natriuretic peptide cutoff concentration of 390 ng/L has been shown to predict mortality in hemodialysis patients.3 Apple et al6 proposed a multibiomarker model incorporating cTnT, N-terminal pro-B-type natriuetic peptide, and high-sensitivity C-reactive protein levels for risk stratification in patients with ESRD. Increased cTnT and high-sensitivity C-reactive protein levels independently predicted death in 399 hemodialysis patients during a 2-year period. Tertile analysis for N-terminal pro-B-type natriuretic peptide also showed a prognostic value at a high cutoff value. Levels of symmetrical dimethylarginine, a nitric oxidase inhibitor linked to atherosclerosis and endothelial dysfunction, are increased in hemodialysis patients and predict mortality.7 This study suggests that IMA is an additional biomarker to predict outcome in patients with ESRD. Although IMA and cTnT levels alone were not independent predictors of mortality, this study shows that a combination of elevated IMA and cTnT levels independently predicts outcome, along with E/Ea ratio and a positive DSE result. Such a combined biochemical marker model may be used in the future to evaluate cardiac risk in potential renal transplantation candidates. Using an IMA cutoff value of 95 KU/L, 46 patients with ESRD (40%) had elevated baseline levels. This represents the optimal IMA level for mortality prediction in this study. These patients had significantly increased LA and LV cavity size, decreased systolic function, and greater estimated LV filling pressures. The mechanism

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SHARMA ET AL Table 4. Characteristics of Patients With and Without an Elevated Baseline IMA Level of 95 U/mL or Greater

Age (y) Dialysis Creatinine (mg/dL) GFR (mL/min) Diabetes Past history heart failure Past history ischemic heart disease NYHA class Positive DSE result Severe CAD Hemoglobin (g/dL) cTnT (ng/mL) Albumin (g/dL) LV end-systolic diameter (cm) LV end-diastolic diameter (cm) LV fractional shortening (%) LV end-systolic volume (mL) LV end-diastolic volume (mL) LV ejection fraction (%) Peak systolic velocity (m/s) E/Ea ratio E/Vp ratio LA size (cm) LV mass index (g/m2)

IMA ⱖ 95 KU/L (n ⫽ 46)

IMA ⬍ 95 KU/L (n ⫽ 68)

P

52.7 ⫾ 13.8 26 (57) 6.7 ⫾ 2.9 17 ⫾ 12 21 (45) 5 (11) 5 (13) 1.9 ⫾ 0.5 15 (33) 14 (31) 11.4 ⫾ 1.8 0.09 ⫾ 0.05 3.4 ⫾ 1.8 3.1 ⫾ 0.9 5.1 ⫾ 0.9 35.1 ⫾ 11.2 46 ⫾ 24 121 ⫾ 41 60 ⫾ 22 0.07 ⫾ 0.02 16.5 ⫾ 8.1 2.2 ⫾ 0.7 4.3 ⫾ 2.4 152.3 ⫾ 31.6

49.6 ⫾ 11.2 40 (58) 6.5 ⫾ 1.8 19 ⫾ 10 25 (37) 5 (7) 7 (10) 1.6 ⫾ 0.6 20 (29) 20 (29) 10.8 ⫾ 1.1 0.07 ⫾ 0.04 3.7 ⫾ 1.5 2.6 ⫾ 0.8 4.5 ⫾ 1.0 39.6 ⫾ 11.7 28 ⫾ 16 94 ⫾ 26 69 ⫾ 15 0.09 ⫾ 0.02 11.9 ⫾ 4.3 1.8 ⫾ 0.6 3.9 ⫾ 2.4 159.1 ⫾ 54.3

0.68 0.84 0.58 0.39 0.42 0.88 0.87 0.16 0.39 0.33 0.32 0.11 0.22 0.04 0.02 0.05 0.03 0.05 0.05 0.02 0.05 0.07 0.04 0.62

NOTE. To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4; hemoglobin and albumin in g/dL to g/L, multiply by 10; cTnT in ng/mL to ␮g/L, multiply by 1; GFR in mL/min to mL/s, multiply by 0.01667. Abbreviation: NYHA, New York Heart Association.

for this remains unclear. There was no association with severe CAD or a positive DSE result. The proportions on dialysis therapy and mean GFRs were similar in those with and without increased IMA levels. This suggests that increased IMA levels are genuine markers of cardiac damage in patients with renal failure and not simply a false-positive result related to impaired renal excretion. Although high IMA levels may reflect low-grade ischemia, cTnT level was not significantly increased in this group. This indicates that increased levels do not represent significant myocardial necrosis. ACB test results are influenced by ischemia, with or without irreversible myocardial necrosis.19 IMA level previously was studied primarily for the detection of myocardial ischemia. However, increased IMA levels have been reported because of gastrointestinal and skeletal muscle ischemia.24,25 Modification of albumin during ischemia may be caused by hypoxia, free radical damage, or acidosis. All these processes may be occurring in patients with renal disease as a result of tissue oxidative

stress. Increased IMA levels in patients with ESRD therefore may reflect skeletal muscle, gastrointestinal, and renal ischemia, as well as cardiac ischemia. However, cTnT level is a very sensitive marker for myocardial necrosis and not generalized ischemia in other organs. This may be a reason that IMA level adds incremental prognostic information to cTnT level in patients with ESRD. Additional studies are required to verify this hypothesis. The decreased survival in patients with increased IMA levels is explained, at least in part, by the increased LV cavity size and decreased systolic function because both are predictors of mortality in patients on dialysis therapy26,27 and after renal transplantation.28 The observed greater LA size and E/Ea ratio in those with elevated IMA levels, suggestive of increased LV filling pressure, is associated with greater mortality in nonuremic patients.29 E/Ea ratio is an independent prognostic factor in this study. Main study limitations are the small sample size and short follow-up. Larger scale studies are

ISCHEMIA-MODIFIED ALBUMIN IN ESRD

required to validate our findings and show any incremental prognostic information that IMA level provides over existing risk-stratification tools in patients with ESRD. In conclusion, IMA level predicts mortality in patients with ESRD. Using a cutoff IMA value of 95 KU/L, patients with elevated levels had larger LA and LV cavity size, decreased LV systolic function, and greater estimated LV filling pressures than those in whom levels were not increased. These findings suggest that IMA is a genuine biomarker of mortality and cardiac damage in patients with ESRD. REFERENCES 1. Dierkes J, Domrose U, Westphal S, et al: Cardiac troponin T predicts mortality in patients with end-stage renal disease. Circulation 102:1964-1969, 2000 2. Apple FS, Murakami MM, Pearce LA, Herzog CA: Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease. Circulation 106:2941-2945, 2002 3. Goto T, Takase H, Toriyama T, et al: Increased circulating levels of natriuretic peptides predict future cardiac event in patients with chronic hemodialysis. Nephron 92:610-615, 2002 4. Naganuma T, Sugimura K, Wada S, et al: The prognostic role of brain natriuretic peptides in hemodialysis patients. Am J Nephrol 22:437-444, 2002 5. Yeun JY, Levine RA, Mantadilok V, Kaysen GA: C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 35:469476, 2000 6. Apple FS, Murakami MM, Pearce LA, Herzog CA: Multi-biomarker risk stratification of N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T and I in end-stage renal disease for all-cause death. Clin Chem 50:2279-2285, 2004 7. Zoccali C, Bode-Boger S, Mallamaci F, et al: Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end stage renal disease: A prospective study. Lancet 358:2113-2117, 2001 8. US Renal Data System: Causes of death. Am J Kidney Dis 32:S81-S88, 1998 (suppl 2) 9. Sinha MK, Gaze DC, Tippins JR, Collinson PO, Kaski JC: Ischemia modified albumin is a sensitive marker of myocardial ischemia after percutaneous coronary intervention. Circulation 107:2403-2405, 2003 10. Pollack C, Peackock W, Summers R, et al: Ischemiamodified albumin is useful in risk stratification of emergency department chest pain patients. Acad Emerg Med 10:555-556, 2003 11. London GM, Fabiani F, Marchais SJ, et al: Uremic cardiomyopathy: An inadequate left ventricular hypertrophy. Kidney Int 31:973-980, 1987 12. Harnett JD, Murphy B, Collingwood P, Purchase L, Kent G, Parfrey PS: The reliability and validity of echocar-

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