The predictive value of cardiac troponin T measurements in subjects on regular haemodialysis

Jean Claude Stolear1, Bernard Georges1, Ali Shita2 and Dierik Verbeelen3

1 Departments of Nephrology and 2 Cardiology, Institut Medico-Chirurgical de Tournai, Tournai, Belgium and 3 Section of Nephrology, Department of Medicine, Academisch Ziekenhuis, Vrije Universiteit Brussel, Belgium

Correspondence and offprint requests to: J. Cl. Stolear, Service de Nephrologie, IMCHO Tournai, 80, chaussée de St Amand, B-7500 Tournai, Belgium.



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Cardiac troponin T (cTnT) is a subunit of the cardiac actin–myosin complex, which leaks into the circulation when myocardial necrosis is present. Detection of cTnT is associated with a poor outcome in patients with unstable angina, and is a useful tool for risk stratification. The value of cTnT determination in patients with renal failure has been questioned, and the specificity of cTnT in this particular group has not been established.

Methods. In the present study, 94 patients at a single centre were followed prospectively after three determinations of cTNT, at 1-month intervals. The outcome after 12 months was chosen as the end-point. cTnT was measured using both a quantitative chemiluminiscence immunoassay and a qualitative rapid bedside immunoassay on a test strip. The maximum of three measurements was used and was correlated with different parameters and outcome. The following statistical tests were performed: Kaplan–Meier analysis, Cox's proportional regression analysis for measuring survival and logistic regression for analysing factors influencing cTnT.

Results. Forty seven of the 94 patients had a positive cTnT by test strip defined as >0.10 ng/ml. Twenty four patients died in the follow-up period (14 from cardiovascular causes). Twenty of the 24 non-survivors had an increased cTnT by test strip and 23 had increased cTnT by laboratory immunoassay. The outcome analysed by a Cox's proportional regression analysis showed that the factors which influenced survival significantly were cTnT, the presence of ischaemic heart disease, C-reactive protein (CRP) and pre-albumin. A logistic multivariate analysis revealed that age and CRP significantly influenced cTnT. A good correlation was found between cTnT determined by test strip and in the laboratory.

Conclusion. cTnT is elevated in a large number of patients on regular haemodialysis and is a significant independent predictor of outcome. Increased cTnT is significantly predicted by age and CRP.

Keywords: cardiac troponin T; renal disease; survival



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Mortality in patients with end-stage renal disease (ESRD) remains high. According to the US renal data system 1997 annual data report, the gross mortality of patients on dialysis still exceeds 20% of the prevalent population per year. In the category of patients aged between 65 and 74 years, it averages 31.3 and in those >75 years it is 45.5 per 100 patients per year. Fifty per cent of the patients die because of a cardiovascular problem. Infection is responsible for some 16% of total mortality [1]. Mortality is very high in the US, but also in other regions of the world. In Japan, a country with a large dialysis population, including a lot of young patients on dialysis, the gross mortality in 1994 was still ~10% per year [2]. Although there seems to be some improvement in survival rate in the population with ESRD, the life expectancy is <25% of that expected in a control population [3]. Several factors have been shown to have an impact on patient survival. First, patient characteristics, such as age, race and gender determine survival [4,5]. Secondly, a number of co-morbid conditions, which are more difficult to delineate, can influence survival significantly. Examples of some of these conditions include kidney disease, especially diabetes mellitus, peripheral and cerebral vascular disease, the presence of heart failure and of neoplasia, and impaired functional status [46]. In addition, a number of biochemical determinations may have a prognostic value. C-reactive protein (CRP) is an acute phase protein. It is increased in several inflammatory diseases, including atherosclerosis [7]. Its prognostic value has been examined in dialysis patients by different authors since it is elevated in a large number of dialysis patients [8,9]. Studies examining short-term survival (6 months) or long-term survival (7 years) have shown that parameters that reflect nutritional status, especially serum albumin and pre-albumin, are strong predictors of outcome [8,1013]. Lastly, the adequacy of dialysis has been shown to have an effect on survival, since patients receiving a dose of dialysis >65% of urea removal rate do better than those who receive less [10].

Cardiac troponin T (cTnT) is a subunit of the cardiac actin–myosin complex, which leaks into the circulation in cases of myocardial damage, and its detection has been used as a sensitive marker of myocardial necrosis. In patients with unstable angina, its presence is associated with increased mortality even in the absence of a myocardial infarction [14]. It is therefore considered a useful tool for risk stratification in patients with unstable angina [1518]. Up to 73% of patients on dialysis have cTnT determinations above the normal range [1921]. Two studies could not correlate the presence of cTnT with any clinical finding [19,20]. In another study, examining 30 patients on dialysis, 10 had a positive cTnT determination. In the positive group, four died and three had a diagnosis of coronary artery disease. In the negative group, only one patient died [21]. Since the value of cTnT determinations in patients with renal failure is not clearly established, we have undertaken the present study, with the aim of examining the prognostic value of cTnT in patients on regular haemodialysis.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The haemodialysis unit of IMC Tournai is an in-hospital dialysis facility of a regional hospital. A total of 94 patients were followed prospectively, after determination of cTnT. Three pre-dialysis samples at 1-month intervals were taken. cTnT was measured with both a semi-quantitative bedside method and a quantitative laboratory method. The peak value of three measurements was used for calculation. The purpose of the study was to correlate the measurements of cTnT with outcome and with other patient characteristics and measurements. The following characteristics and measurements were noted: age at the time of the study and age at the start of renal replacement therapy (RRT), time on RRT, gender, kidney disease, diabetes, body weight, mean fluid removal during dialysis, presence of malignancy, systolic and diastolic blood pressure before and after dialysis, and the presence of auricular fibrillation (detected by ECG). The following biochemical parameters were also included in the analysis: haematocrit, CRP, pre-albumin and dialysis adequacy measured by Kt/V. Any drugs taken by the patients for ischaemic cardiac disease were noted, as well as the cause of death and patients who developed acute myocardial infarction. For those patients who died at home, sudden death was considered. Survival was calculated from the time of the first cTnT determination until death or the end of a 12-month period.

Measurement of cTnT
Bedside semi-quantitative determination of cTnT was carried out with a rapid immunoassay. cTnT was measured with TROP T RA (Boehringer Mannheim). This cTnT whole-blood rapid assay was performed by adding 150 µl of whole blood via a packaged syringe directly to the application well of the test device. The cTnT in the blood forms a sandwich complex with a capture antibody labelled with biotin and a signal antibody labelled with gold particles, on a test strip. The complex migrates to the reading zone and is concentrated by binding to streptavidin immobilized on the test strip to produce a red line within 20 min if the cTnT concentration is >0.2 ng/ml, i.e. a positive result. Each test provides a second line to serve as a positive control. The presence of one line represents a correctly performed negative test (control line), while the presence of two lines represents a positive test.

Laboratory quantitative serum cTnT immunoassay
Determination of serum cTnT was performed on the Elecsys 2010 system (Boehringer Mannheim) using the electrochemiluminiscence immunoassay (ECLIA). The minimum detection limit was 0.01 ng/ml; a level of >0.10 ng/ml was considered positive. The test is based on the sandwich principle. In the first incubation, using 15 µl of sample, a biotinylated monoclonal troponin T-specific antibody and a monoclonal troponin T-specific antibody labelled with a ruthenium complex react to form a sandwich complex. In the second incubation, after the addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin. The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell. Application of a voltage to the electrode then induces chemiluminiscent emission which is measured by a photomultipier.

CRP
CRP was measured using a precipitation method with the Tina-Quant Boehringer Mannheim test. Normal values are <5 mg/l and the detection limit is 3 mg/l. The coefficient of variation (CV) of the method is 4.2% in the 5 mg/l range and 2.0% in the 10 mg/l range. Pre-albumin was measured with an immunoprecipitation method, using Bayer-Technicon reagents. Serum is pre-diluted 1/25 and 4% polyethylene glycol is used for precipitation. Normal values range between 0.1 and 0.4 g/l. The CV of the method varies between 3 and 8%.

Adequacy of dialysis
Adequacy of dialysis was measured by the Kt/V formula, calculated from the monthly pre- and post-dialysis blood urea levels using a formal single compartment model. The vascular score was determined by scoring the following vascular problems: peripheral vascular disease or amputation, cerebrovascular disease and history of myocardial infarction. The maximum score was 3, the minimum 0.

Statistics
The results are expressed as mean±SEM. The Spearman rank correlation test was used for univariate analysis. Kaplan–Meier survival analysis was performed and differences in survival between groups were calculated with a log rank test. The effects of different parameters that may influence survival were analysed with Cox's regression model. Factors influencing cTnT high/normal values were analysed with logistic regression. All statistics were performed with the SPSS package.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The mean age at the start of RRT was 58.6±1.5 years and at the start of the study 62.9±1.4 years. Mean time on dialysis was 52.4±5.4 months. Fifty five patients were male and 39 female. The following kidney diseases were noted: diabetes 17, vascular renal disease 17, primary renal disease (including glomerulonephritis, polycystic kidney disease and interstitial nephritis) 38, neoplasia three and other or unknown one. Forty seven patients had a cTnT determination >0.10 ng/ml and an equal number had a cTnT <=0.10 ng/ml. During the 12 months following cTnT measurements, 24 patients died (16 male/8 female). Their cause of death was: vascular or sudden death in 14, infection in three, cachexia in four and miscellaneous in three (Table 1Go). In the survivors, there were two patients who developed acute myocardial infarction after 3 and 5 months of follow-up, respectively. Both had increased cTnT. Twenty nine patients with ischaemic heart disease were treated with either nitrates, calcium channel blockers, ß-blocking drugs or a combination. Of those 29 patients, cTnT was >0.10 ng/ml in 20. Fourteen patients with a history of ischaemic heart disease died during the study. Patients with a high cTnT were older (age 56.8±2.1 vs 67.5±2.9 years; P=0.0003), and more often male (high: 40 male/20 female; low: 15 male/19 female). Diabetes could not discriminate between high and low cTnT. Irregular rhythm was observed in 12 patients, 10 of whom had a high cTnT. However, only one of those patients died. CRP was elevated in 20 out of the 24 (86%) patients who died, while in those who survived, it was elevated in 27 out of 70 (38%).


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Table 1. Causes of death in patients with high and low cTnT measurements
 
Kaplan–Meier survival analysis is shown in Figure 1Go, using a cut-off point of 0.1 ng/ml. A significant difference in survival is noted between low and high cTnT groups as measured by laboratory immunoassay ({chi}2=8.721; P=0.0031). Survival was also analysed with a Cox's proportional hazards model. Survival time was significantly influenced by three parameters, namely cTnT measured by the bedside test, pre-albumin and the presence of ischaemic heart disease (Table 2Go). CRP did not reach the P <0.05 level. Other factors entered into the model which did not show statistical significance are age, gender, vascular co-morbidity, renal disease, Kt/V and haematocrit. The results are shown in Table 3Go.



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Fig. 1. Kaplan–Meier survival analysis during a 12 month period of patients according to their cTnT: >0.1 ng/ml ({square}) and >=0.1 ng/ml ({circ}). There were 47 patients in each group.

 

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Table 2. Results of Cox's proportional hazards analysis, using survival time as the dependent variable: variables in the equation
 

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Table 3. Results of Cox's proportional hazards analysis, using survival time as the dependent variable: variables not in the equation [residual {chi}2=9.91 with 9 df (P=0.3579)]
 
A logistic multivariate analysis showed that only two factors were correlated with the high/low laboratory determination of cTnT, namely CRP and age (Tables 4 and 5GoGo). Parameters that showed no statistical relationship were Kt/V, haematocrit, pre-albumin and vascular status (Table 6Go).


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Table 4. Results of the logistic regression with dependent cTnT, using a cut-off value of 0.10 ng/ml: variables in the equation
 

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Table 5. Model if a term is removed, based on conditional parameter estimates
 

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Table 6. Results of the logistic regression with dependent cTnT: variables not in the equation [residual {chi}2 4.188 with 3 df (P=0.2418)]
 
A positive cTnT bedside test was observed in 50 patients. In 41 patients, the test was positive at the first determination. In nine other patients, the cTnT bedside test was positive at the second and/or third determination. Twenty two of the 24 patients who died during that period had a positive test. Two out of the 44 patients with a negative test died during this period ({chi}2=19.162; P=0.0001). There was a significant correlation between the laboratory and bedside cTnT measurements (r=0.815; P=0.001).



   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The aim of the present study was to examine the value of both bedside and laboratory cTnT tests in predicting the 1 year outcome of patients on regular dialysis. A laboratory cTnT measurement <0.06 ng/ml is the upper reference level in healthy blood donors. In different categories of patients at risk, a value <0.06 ng/ml corresponds to a low risk profile. In a cohort of patients with unstable angina, a laboratory cTnT value >0.06 ng/ml was associated with an incidence of 12.8% of fatal or non-fatal myocardial infarction [22]. In patients with suspected myocardial infarction, a cTnT value >0.10 ng/ml was a powerful independent predictor of 30-day mortality [16,23]. In patients with acute chest pain, the presence of a positive bedside cTnT measurement was associated with a 25.8 greater relative risk of mortality at 30 days, whereas in the negative group, the risk of myocardial infarction was 0.3%. Patients with an increased cTnT but without myocardial infarction (>0.20 ng/ml) had a similar prognosis to patients with myocardial infarction [26]. Hamm et al. [16] showed that patients who were admitted to the emergency room with acute chest pain could have a negative cTnT test on admission, but a positive test on retesting 4 h later. We also used three consecutive measurements. Performing multiple testing in a population with cardiac symptoms increased the number of patients with a positive cTnT test from 44 to 79%. In patients with a negative test, a fatal or non-fatal event was recorded in 1.1% of cases. In the same study, it was shown that the relative risk of developing a fatal or non fatal myocardial infarction was 25.8 in the group with a positive test. Therefore multiple testing was performed in the present study. Twenty eight per cent of positive patients had a positive test on the second or third evaluation but not on the first one.

In studies performed in patients with unstable angina or ECG characteristics of coronary disease, some 20–25% of the patients with a positive cTnT test develop a significant cardiac event. Studies in patients with renal disease have shown less convincing results. In a study including 16 patients with diabetes on RRT, 12 had a laboratory cTnT >0.20 ng/ml. In the following year, four cardiac events were noted in this group. It was concluded from this study that cTnT lacks specificity in renal patients [19]. A survey of patients on different modes of RRT showed that cTnT is elevated in 71% of patients on regular haemodialysis, 57% of patients on peritoneal dialysis and 30% of patients with renal failure not yet on RRT. In those patients, no particular cardiac event was noted [20]. In the GUSTO IIa study, also evaluating cardiac patients, subjects with a serum creatinine >2.5 mg/dl were excluded, because there was a discrepancy between cTnI and cTnT [23]. Nevertheless, when patients with a discrepant result for cTnT and cTnI were analysed separately, it appeared that a positive cTnT was associated with increased mortality even in the absence of increased cTnI. In this study, we clearly show that the presence of an increased cTnT is associated with an increased mortality risk. Both Kaplan–Meier survival analysis and the Cox's proportional regression analysis confirm the predictive value of cTnT.

The cause of increased cTnT in renal patients is not clear. In early studies, using first generation tests, the cTnT assay lacked specificity. It has been suggested that the older tests may cross-react with muscle proteins. The second generation tests are considered to be very specific for the cardiac muscle troponin. Truncal muscle biopsies of patients with ESRD could not show the presence of cTnT nor its mRNA expression [2427].

In the present study, we examined 94 patients on RRT, of whom 29 were treated for ischaemic heart disease, but without acute cardiac complaints at the time of study and irrespective of their age. A high proportion of the 94 patients studied showed a positive result for both laboratory and bedside cTnT. When 0.10 ng/ml is used as the cut-off value, 50% of the patients have a positive test. Only two patients developed a myocardial infarction during follow-up and both had an elevated cTnT. Patients treated for ischaemic heart disease had a cTnT value >0.10 ng/ml more frequently than patients without treatment. The absence of signs or complaints suggesting acute myocardial infarction at the time of blood sampling and the high proportion of patients with ischaemic heart disease suggests that some degree of myocardial injury must occur. The fact that an increase of cTnT is noted after cross-clamp release of patients undergoing coronary bypass surgery in the absence of myocardial infarction is an additional argument for this hypothesis [28].

In another non-cardiac population, namely patients with sepsis, the mortality was 83% in patients with a positive cTnT, compared with 38% in patients with normal values, again indicating that a positive cTnT value may have a prognostic significance in a non-cardiac population [29]. The high mortality rate, observed during the 1-year follow-up, indicates that the cTnT test reflects more than a false-positive laboratory finding in patients on regular dialysis. In a meta-analysis examining the prognostic value of cTnT and cTnI in unstable angina, it was shown that both markers have equivalent sensitivity and specificity for diagnosing myocardial infarction (63 and 90%, respectively) and for cardiac death [18]. A more recent study [23] evaluating the relative value of cTnT and cTnI in acute coronary syndromes demonstrated that cTnT provided more information than cTnI for predicting mortality. In patients with positive cTnT and negative cTnI, five out of 60 died within a period of 30 days, while none of eight patients with a positive cTnI and a negative cTnT died. In this study, we did not evaluate cTnI and we therefore cannot comment on the suggestion that cTnI is more specific for detecting myocardial infarction in patients with renal failure. However, in a recent study, Martin et al. showed that in renal patients with a suspected myocardial infarction cTnI was positive in 18 out of 54 patients. Twelve of those patients had a documented myocardial infarction. The sensitivity and the specificity of cTnI was 94 and 100%, respectively, compared with 44 and 56% for creatinine kinase MB [30].

A multivariate logistic regression model was applied to examine the different factors that may cause a positive cTnT. We observed that only two parameters were associated with an increased concentration of cTnT, namely older age and CRP levels. There was no relationship with other parameters that may influence cardiac state, e.g. auricular fibrillation, ischaemic heart disease, vascular co-morbidity, gender, haematocrit, dialysis adequacy (Kt/V) and pre-albumin. In our patients with auricular fibrillation, cTnT was elevated, but outcome in this category of patients was good. The relationship between CRP and troponin could be explained by activation of coagulation. Three main mechanisms help to explain the relationship between CRP and coagulation. Previous or ongoing infection can activate the acute phase response which is correlated with the activation of the coagulation cascade. Atherosclerosis is accompanied by an increased synthesis of interleukins. Interleukin-6 is particularly associated with recruitment of macrophages and monocytes into atherosclerotic plaques. CRP can induce the expression of a membrane glycoprotein in monocytes which is important for the initiation of coagulation. An indirect argument is the finding of a beneficial effect of aspirin on the occurrence of a first myocardial infarction in patients with increased CRP [3133]. In a non-renal population of patients with angina and both a positive CRP and cTnT test, a higher mortality was noted than in patients with negative cTnT and/or CRP measurement, indicating that the presence of increased CRP in this population worsens their prognosis [31,32]. Even in subjects without unfavourable coronary risk factors, the finding of an increased CRP was shown to be an important determinant of myocardial infarction and ischaemic stroke [33].

Recently, Owen and Lowrie [8] could not correlate increased levels of CRP with fatal outcome over a short time period. In the present study, increased CRP is linked to a bad outcome, since 20 out of 24 patients (83%) with a high CRP died, while only 38% (27/70) of the survivors had an increased value. In a more recent study, cardiovascular mortality was significantly higher in patients with increased CRP levels, and multivariate analysis showed that both age and CRP were independent predictors of outcome [9]. Differences in the parameters studied and in the patient population and management could explain the differences in CRP values between the study of Owen and Lowrie and others [9].

Outcome in our patients was also significantly associated with pre-albumin. There is now good evidence that nutritional status is a main determinant of survival in renal patients. Pre-albumin has been claimed to be the best nutritional predictor in patients on RRT and was therefore included in this analysis [11]. It is a protein with a rapid turnover, and is strongly correlated with other nutritional markers. Nutritional status depends on the intake of proteins and inflammatory state of the patient. In both renal and non-renal patients, it has been shown that the presence of low-grade inflammation, which can be detected by increased serum CRP levels, is inversely related to serum albumin, illustrating the effect of inflammation on nutritional state. The present findings also indicate that inflammation has a double negative impact on survival. It enhances the activation of coagulation, which results in an increased ratio of vascular accidents, and it induces malnutrition by both loss of appetite and defective protein synthesis [13].

In the present study, we only report extensively the analysis of laboratory cTnT values. However, there is a very good correlation between the laboratory and bedside cTnT determinations.

The exact cause of increased cTnT in our patients needs to be clarified further. At present, we speculate that it is caused by damage to myocardial tissue due to uraemia, possibly aggravated by chronic inflammation.

Determination of cTnT could be helpful in understanding the causes of high mortality in patients with ESRD, since it could be an aid in risk stratification and selecting patients who could benefit from more invasive cardiac investigation and treatment.



   Acknowledgments
 
R. Anica and M. Gregory, Boehringer Mannheim Diagnostica (now Roche NV), Belgium provided the cTnT testing material.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 24.11.98
Accepted in revised form: 9. 4.99