Factors associated with increased serum levels of cardiac troponins T and I in chronic haemodialysis patients: Chronic Haemodialysis And New Cardiac Markers Evaluation (CHANCE) study

Marie C. Iliou1,, Christine Fumeron4, Marie O. Benoit2, Philippe Tuppin5, Claire Le Courvoisier2, Victorio Menoyo Calonge4, Nicole Moatti2, Claude Buisson4 and Christian Jacquot3

1 Service de Réadaptation Cardiaque, 2 Service de Biochimie, 3 Service de Néphrologie et INSERM U430, Hôpital Broussais, 4 Association pour l'Utilisation du Rein Artificiel, and 5 Etablissement Français des Greffes, Paris, France



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Background. Serum concentrations of the cardiac troponins (cTn) T and I, specific markers of myocardial injury, are frequently elevated in haemodialysis patients. The clinical relevance of this is unclear. The aim of this study was to investigate factors associated with increased serum levels of cTn in haemodialysis patients.

Methods. We included in this cross-sectional study 258 chronic haemodialysis patients (150 men, age 60±15 years) without acute coronary symptoms. Clinical data, echocardiographic hypertrophy, biochemical status, and haemodialysis regimen were evaluated for each patient. Pre-dialysis serum cTnT (Elecsys, Roche), cTnI (Stratus and RXL, Dade–Berhing), and CK-MB (Stratus, Dade–Berhing) concentrations were determined. Logistic regression was the principal method of analysis.

Results. Pre-dialysis levels of cTnT >0.1 ng/ml (n=48, 18.6% of patients) were associated with age (P<0.001), diabetes (P<0.005), history of ischaemic heart disease (P<0.05), and left ventricular hypertrophy (P<0.05). In multivariate analysis, age odds ratio ((OR) 1.04), diabetes (OR 4.9), and indexed left ventricular mass (OR 1.01) were found to be independently associated with cTnT concentration above the threshold. Only six patients had cTnI-Stratus levels >0.6 ng/ml. cTnI-RXL levels >0.3 ng/ml (n=13, 5.0%) were associated with age (P=0.05) and hypercholesterolaemia (P<0.05). Only age (OR 1.06) remained associated in multivariate analysis.

Conclusion. Elevated baseline serum levels of cardiac troponins were associated with cardiovascular risk factors, history of ischaemic heart disease and left ventricular hypertrophy in asymptomatic chronic haemodialysis patients.

Keywords: cardiac markers; haemodialysis; left ventricular hypertrophy; renal disease; risk factors; troponin



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
The prevalence of ischaemic heart disease (IHD) in haemodialysis patients is 10–20 times higher than that in the general population, with 50% mortality due to cardiovascular disease. According to the US Renal Data System, 42% of patients undergoing haemodialysis have had a myocardial infarction or coronary revascularization. In addition, the rate of survival after myocardial infarction is much lower for haemodialysis patients than for the general population.

In non-uraemic patients with suspected myocardial damage the determination of myoglobin, CK-MB and troponins, has been shown to be reliable for early diagnosis and risk stratification [1]. In haemodialysis patients, the clinical symptoms of cardiac damage are difficult to diagnose and may be deceptive. In addition, high serum concentrations of myoglobin and creatine kinase MB (CK-MB) lack specificity [2]. For this population, it is unclear how high troponin levels should be interpreted. The value of troponin determination in myocardial ischaemia is discussed because conflicting evidence has been obtained concerning the diagnostic value of high levels [3,4]. There are at least two reasons for the debate in the literature: the populations studied are heterogeneous, and different methods have been used to determine troponin concentrations. The increase in serum troponin levels may be associated with possible subclinical myocardial injury (ischaemia due to coronary artery disease, left ventricular hypertrophy and/or fluctuations in blood volume) and/or abnormalities of troponins catabolism induced by renal failure and/or haemodialysis itself.

The aim of this study was to evaluate the factors associated with an increase in serum levels of cardiac troponins T and I in a large population of chronic haemodialysis patients.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Study protocol
We included all the asymptomatic patients aged over 18 years attending three Parisian haemodialysis centres between 12 and 26 April 1999, who had been treated by haemodialysis for more than 3 months (three sessions per week), and who gave informed consent and lacked exclusion criteria. The exclusion criteria were rhabdomyolysis, haemoglobin concentration <8 g/dl before the dialysis session, a traumatic or severe infectious episode during the 8 days before the study, myocardial infarction, angina pectoris or coronary revascularization during the 3 weeks preceding the start of the study, and refusal to participate.

Patients
The medical records of each patient, including those excluded from the study, were examined independently by a nephrologist and a cardiologist. Patients were classified as group I (with history of ischaemic heart disease) if they had (i) a prior myocardial infarction or coronary revascularization (by coronary artery by-pass graft surgery or percutaneous transluminal coronary angioplasty), or (ii) more than 70% stenosis and/or occlusion of at least one coronary artery if a coronary angiogram had been performed previously, or (iii) history of angina pectoris with ischaemia confirmed by exercise stress test or by at least two perfusion defects in stress–thallium scintigraphy and were treated with at least an anti-ischaemia drug. The others patients were classified as group II.

Diabetes was defined as fasting blood glucose level >126 mg/dl or treated with insulin or an oral anti-diabetic agent. Hypercholesterolaemia was defined as total cholesterol concentration >200 mg/dl or by a lipid-lowering drug regimen.

Echocardiography was carried out according to the recommendations of the American Society of Echocardiography, on a day on which the patient did not undergo dialysis, in the 3 months before or after sampling. Left ventricular hypertrophy was defined as an indexed left ventricular mass of at least 134 g/m2 in men and 110 g/m2 in women. Anuria was defined by urine volume <500 ml per day.

The duration of the dialysis session and the choice of membrane used were not modified for the study and were left to the discretion of the referring physician. Membranes were classified as high flux if they had an ultrafiltration coefficient of at least 20 ml/h/mmHg. Kt/V was calculated according to the 2nd Daugirdas rule.

Biochemical markers
Blood was collected in tubes under vacuum (from arteriovenous fistulae before heparin infusion) before the first and the second dialysis sessions of the week. Samples were centrifuged immediately after collection at 3500 r.p.m. (Centrifuge 4236 OSI) for 15 min, and sera and plasma were then frozen in aliquots at -80°C. Serum and plasma specimens were stored at -80°C for up to 4 weeks until the cardiac markers measurements had been made. BUN, serum creatinine, protein and potassium were determined using a Hitachi 911 analyser. Haemoglobin and haematocrit were determined using a Coulter MAXM analyser.

For determinations of cardiac markers, sera or plasma treated with lithium heparin were used according to manufacturers recommendations.

cTnT was determined on sera using the Elecsys system with Troponin T stat cardiac T reagents (both from Roche Diagnostics). In this third-generation immunoassay, the capture and detection antibodies show no cross reactivity with skeletal TnT for concentrations up to 1000 mg/ml (0.005%). This assay is an electrochemiluminescence immunoassay, or ‘ECLIA’. Its detection limit is 0.01 ng/ml and 0.1 ng/ml is recommended as a clinical threshold, above which damage to the myocardium can be assumed to have occurred. The coefficient of variation confidence value (CV) was 9% for 0.1 ng/ml.

cTnI was determined on plasma treated with lithium heparin using a two-site fluorimetric immunoassay (Stratus II, Dade Berhing), the analytical performance of which has also been characterized. Its detection limit is 0.3 ng/ml. The upper reference limit determined from clinical studies is 1.5 ng/ml for myocardial infarction and 0.6 ng/ml for unstable angina. The interassay CV is 8% at 1.5 ng/ml and 15% at 0.6 ng/ml.

cTnI was also determined using a new automated analyser (RXL-HM, Dade Berhing), with a lower detection limit (0.04 ng/ml). This method is a one-step enzyme immunoassay based on the ‘sandwich’ principle with the same antibody and area against the same epitopes as for the Stratus method. The sample is incubated with chromium dioxide particles coated with monoclonal antibody specific for the cardiac troponin I molecule and a specific monoclonal antibody conjugated with alkaline phosphatase (ALP) to form a particle/cardiac troponin/conjugate sandwich. The bound sandwich is then separated from unbound material and washed. ALP activity is then triggered and amplified. This process increases the sensitivity of the method, and the colour change measured is directly proportional to the concentration of cTnI in the patient's sample. The interassay CV was 4% for 1.5 ng/ml and 7% for 0.6 ng/ml. The results of these two assays for cTnI have been shown to be well correlated in a range from 0 to 45 ng/ml (r=0.998).

CK-MB mass was determined by fluorimetric enzyme immunoassay (Stratus II, Dade Berhing). The sensitivity of the assay is 0.4 ng/ml and the inter-assay CV is 6% at 5 ng/ml.

In our study, the thresholds used for the various markers were 0.1 ng/ml for cTnT and 0.6 ng/ml for cTnI Stratus. We adopted a threshold of 0.3 ng/ml for cTnI RXL as this assay is more sensitive and has a lower interassay CV than the cTnI Stratus assay. For CK-MB, a threshold of 3 ng/ml (upper limit of the normal range) was used.

In order to verify the validity of the assays, a second blood sample was collected before the second dialysis session on the same week.

Statistical analysis
Values were expressed as means±SD. We assessed baseline differences between groups I and II and groups with high or low serum levels cTn using the chi-square test and t-test for univariate analysis. A non-parametric test was also used to compare cTn levels between groups (Wilcoxon). Statistical significance was assumed for P values <0.05. Multiple logistic regression models using the backward selection procedure were used to identify independent significant factors associated with high pre-dialysis levels of cTn. Variables were included in multivariate analysis if P<0.1 in univariate analysis. Creatinine kinase and cTn concentrations were not included as predictive factors in multivariate analysis. OR were estimated with 95% confidence intervals (CI). Analyses were performed using SAS statistical software (SAS, Cary, NC).



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Patients
Two hundred and fifty-eight patients (58.1% men), with a mean age of 60.2±15.2 years (from 18 to 88 years), treated by haemodialysis for 7.6±7.2 years (0.3–27.7 years) were included in this study. Forty-four patients were excluded, due to absence (32 patients), refusal to participate (seven patients), severe anaemia (two patients), or recent start of dialysis (three patients). There was no significant difference in the demographic, metabolic, or cardiovascular characteristics of the included and excluded patients. The characteristics of the study population are described in Table 1Go: 19% of the patients were diabetic and 38% had hypercholesterolaemia. On echocardiography (n=246), 35.8% of patients were found to have left ventricular hypertrophy. The initial kidney disease was chronic primary glomerulonephritis in 23.3% of the patients, diabetic nephropathy in 15.1%, nephroangiosclerosis in 12.8%, chronic interstitial nephritis in 16.7%, polycystic kidney disease in 8.1%, a systemic autoimmune disease in 3.5%, unknown in 14.7%, and other diseases in 5.8% of patients.


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Table 1. Characteristics of the study population and in patients with (group I) or without (group II) a history of ischaemic heart disease

 
The mean duration of the dialysis session was 4.13±0.28 h. Twelve per cent of patients were treated by acetate-free biofiltration, the rest being treated by conventional bicarbonate haemodialysis. High-flux membranes were used in 68.2% of patients.

Patients with (group I) or without (group II) a history of ischaemic heart disease
Coronary angiography was carried out for 73 patients: 26 had no angiographically detectable disease, 47 had at least one stenosis of the coronary arteries (21 had single-vessel disease, 10 two-vessel disease, and 16 three-vessel disease).

Group I totalled 59 patients (22.9%) and group II 199 patients. The characteristics of these patients are presented in Table 1Go. Group I patients were significantly older than group II patients and had a higher indexed left ventricular mass. The prevalence of diabetes, hypercholesterolaemia, and left ventricular hypertrophy were significantly higher in group I than in group II. Groups I and II did not significantly differ in sex ratio, present smoking habits, length of time for which they had been treated by haemodialysis, initial nephropathy, haematocrit, membrane characteristics or Kt/V. Group I patients had significantly higher serum levels of CK-MB and cTnT than group II patients (Table 2Go)


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Table 2. Cardiac markers serum levels in all patients and in group I or group II patients

 

Cardiac markers before dialysis
Pre-dialysis serum levels from the first and second dialysis sessions are strongly correlated with correlation coefficient of 0.98, 0.91 and 0.90 (P<0.0001) for cTnT, cTnI RXL, and CK-MB respectively (Table 2Go). All the following results concern the first pre-dialysis samples.

Serum cTnT, cTnI Stratus, cTnI RXL and CK-MB levels above the thresholds defined in this study were observed in 18.6, 2.3, 5.03 and 7.4% of patients respectively. The maximum values for cTnT was 2.52 ng/ml, for cTnI Stratus 1.5 ng/ml, for cTnI RXL 1.8 ng/ml, and for CK-MB 9.7 ng/ml.

The predictive factors of a concentration of cTnT >0.1 ng/ml are shown in Table 3Go. Age, diabetes, left ventricular hypertrophy, a prior IHD, a history of coronary angioplasty, a low serum creatinine concentration before dialysis, and the interdialysis weight gain were all found to be significantly associated with a cTnT level >0.1 ng/ml in univariate analysis. Neither persistent hypertension nor haematocrit was associated with an increase in cTnT concentration. In multivariate analysis, age (OR 1.04, P<0.005), diabetes (OR 4.9, P<=0.0005), left ventricular hypertrophy (OR 1.01, P=0.05), and anuria (OR 0.25, P<=0.05) were independently associated with elevated levels of cTnT. Elevated cTnT concentrations were accompanied by significantly higher than normal levels of CK-MB and cTnI RXL (P<=0.005 and P<0.05 respectively). Thirty-five per cent of the patients with a cTnT level >0.1 ng/ml were IHD patients.


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Table 3. Factors associated with elevated cardiac troponin T concentration

 
None of the factors tested was found to be associated with a high cTnI Stratus level. Two of the six patients with a cTnI level >0.6 ng/ml were IHD patients.

The factors predicting cTnI RXL levels >0.3 ng/ml are shown in Table 4Go. Age, hypercholesterolaemia, low pre-dialysis serum creatinine concentration, and CK-MB levels >3 ng/ml were all found to be significantly associated with cTnI RXL levels >0.3 ng/ml in univariate analysis. Neither persistent hypertension nor haematocrit was found to be associated with an increase in cTnI RXL level. Only age (OR 1.06, P<=0.05) remained predictive of a cTnI RXL level >0.3 ng/ml in multivariate analysis. Fifteen per cent of the patients with a cTnI RXL level >0.3 ng/ml were IHD patients.


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Table 4. Factors associated with elevated cardiac troponin I RXL level.

 
Factors significantly associated with CK-MB >3 ng/ml were age, left ventricular mass index, and high pre-dialysis serum levels of cTnT and cTnI RXL. In multivariate analysis, only age was independently associated with high CK-MB levels.

Sex, initial kidney disease, length of time on haemodialysis treatment, and dialysis strategy were not associated with high concentration of either of these cardiac markers.

Left ventricular hypertrophy
Patients with cTnT and CK-MB higher than respective thresholds have a significantly higher indexed left ventricular mass than patients without elevations of these markers (Figure 1Go). For cTnI RXL, no difference was found in left ventricular masses. In addition, indexed left ventricular mass is an independent factor associated with high cardiac cTnT concentration.



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Fig. 1. Indexed left ventricular mass in patients with cardiac markers above (positive) or under the threshold (negative). Positive patients were >0.1 ng/ml for cTnT, >0.3 ng/ml for cTnI RXL, and >3 ng/ml for CK-MB.

 



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
This cross-sectional study was designed to evaluate the clinical and paraclinical factors associated with an increase in the concentrations of cardiac markers. A large population of non-selected chronic haemodialysis patients was studied, with characteristics typical of the patients treated in haemodialysis centres, including the prevalence of history of ischaemic heart disease identified according to strict criteria. The choice of membrane for dialysis was not random, but the clinical characteristics, extent of cardiac damage, and cTn levels before dialysis did not differ for patients undergoing dialysis with high- and low-flux membranes.

Before dialysis, 18% of our patients had a serum cTnT concentration >0.1 ng/ml, the upper limit of normal values obtained with second- and third-generation assays. Other studies [57] have reported frequencies of 20–53%. However, the populations studied differed, particularly in the prevalence of diabetes. Only six patients (2.3%) had a cTnI Stratus >0.6 ng/ml, the upper limit of the range of normal values according to previous studies. The small sample size precluded any statistical analysis. The new method of cTnI determination (cTnI RXL) has a much lower detection limit (0.04 ng/ml) than cTnI Stratus. In this study, the threshold separating high and low values for cTnI RXL was set arbitrarily at 0.3 ng/ml, although there are no studies evaluating the physiological and pathological significance of low values. The level of cTnI RXL was greater than 0.3 ng/ml in 5% of our patients. The difference between the results obtained with the two methods (Stratus and RXL) probably results from the higher sensitivity and reproducibility of determination by RXL for low concentrations of cTnI.

The observed disparities in increased levels of cardiac troponins T and I may be partly accounted for by some factors: differences in detection or release of complex forms, in half-life, and in catabolism pathways [4]. Furthermore, cTnT accounts for 8% of the ‘cytosolic pool’ [8] and cTnI for only 4% [9]. Cytosolic cTn T and cTn I are bound differently. Also, the transient membrane permeability changes that occur during myocardial cell injury may affect their release differently. If cTnT mRNA, but not cTnI mRNA, has been detected recently in haemodialysed patients with skeletal muscle disease [10], release of cTnT protein in serum have not been demonstrated so far in this situation. Furthermore, third-generation assay for cTnT does not detect skeletal muscle cTnT.

Age, diabetes, hypercholesterolaemia, known coronary artery disease, and interdialysis weight gain were found, in this study, to be associated with elevated serum concentrations of cTnT. Age and hypercholesterolaemia were found to be associated with elevated serum concentrations of cTnI. We found that age was an independent predictive factor of elevated concentrations of cTnT, cTnI RXL and CK-MB. It was also found to be an independent predictor of elevated concentrations of cTnT in the study of Ooi and House [5], in their analysis but only of the subgroup of patients excluding those with diabetes and coronary artery disease. Diabetes is associated with the development of microangiopathy and myocardial ischaemia, which may be clinically silent. In our study, diabetes was an independent predictive factor for high cTnT levels. Several other studies have reported similar findings [5,11,12]. Ooi and House [5] suggested that the increase in serum cTnT concentration in diabetics might be due to protein glycosylation, modifying the degradation of the molecule and/or inducing the re-expression of fetal genes. They suggested that a higher cut-off point should be used for diabetic haemodialysis patients.

In our study, neither the length of time on dialysis nor the initial kidney disease, even for diseases that progress slowly towards end-stage renal disease, was associated with high cTn levels. Serum concentrations of cTnT were significantly higher in anuric subjects than in subjects with diuresis. A similar, but non-significant trend was also observed for cTnI. Actually, little is known about the route of elimination of cTn, and furthermore the kinetics of decrease and the catabolic pathways of cTn in haemodialysed patients are not known. Willging et al. [13] reported rates of urinary clearance of less than 0.01 ml/min for cTnT and of less than 1.15 ml/min for cTnI in a patient without renal impairment following acute myocardial infarction. In chronic renal failure patients before haemodialysis, there seems to be a positive correlation between the serum concentrations of creatinine and cTn [14]. In contrast, in haemodialysis patients, as reported in this study and in that of Löwbeer et al. [15], there seems to be a negative relationship between the serum levels of cTn and creatinine. Indeed cardiovascular status is worse in old patients with decreased muscle mass.

One of the key elements of this study was the analysis of the association between left ventricular hypertrophy and high levels of the myocardial damage indicators. Left ventricular hypertrophy despite its relatively low prevalence in our study was associated with high levels of CK-MB and cTnT. It was more frequent in patients with known coronary artery disease and in those with the largest interdialysis weight gain. Our results are consistent with those of Löwbeer et al. [15], who demonstrated an association between left ventricular mass and serum concentrations of CK-MB and cTnT. No such association was found in the study of Tun et al. [16], involving the determination of cTnI by the Stratus method. The relationship between left ventricular hypertrophy and myocardial ischaemia is well established and based on several mechanisms (e.g. coronary artery disease, decrease in the perfusion of the sub-endocardial wall) [17].

It is well known that haemodialysis is associated with an overworking of the myocardium, the appearance of angina pectoris, or worsening of ischaemic heart disease. Elevated levels of CK-MB and cTn suggest myocardial injury whatever its cause, and may indicate a revaluation of clinical features, imaging data and treatment management. Martin et al. [18] studied patients with elevated cTnI and showed that all subjects had cardiac abnormalities demonstrated by echocardiography, nuclear imaging, or arteriography. Among these abnormalities, left ventricular hypertrophy, which contributes to myocardial ischaemia, was found to be a factor highly predictive of high serum levels of cardiac markers [15].

High levels of troponins may be caused not only by main coronary artery stenosis [19], but also by microvascular lesions or direct injury to myocardial cells (e.g. toxic, stretching, hypoxia, apoptosis) that are encountered in the cardiomyopathy of haemodialysis patients [20].

From a clinical point of view, elevated serum levels of cTn are observed in 5.0–20.0% of chronic haemodialysis patients without acute symptoms. It is probably due to a silent myocardial injury. Moreover, long-term prognostic value of cTnT is suggested in several studies [17,18].

Given the elevated serum levels of cTn in a high proportion of asymptomatic patients, interpretation of slightly elevated serum levels of cTn in a given haemodialysis patient with acute chest pain, needs to take baseline concentration into consideration. In a typical situation and according to the recent guidelines for management of acute coronary syndromes, a repeat ECG and cTn measurements should be obtained 6–12 h after the onset of symptoms and could help management strategy.

Very high serum levels of cTn with acute symptoms and/or ECG changes must be interpreted as a myocardial infarction, as in normal renal function patients.



   Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
This study shows that elevated cTn concentrations are observed in the basal state in a non-negligible percentage of chronic haemodialysis patients. This large population study supports previous data that suggested the cardiac origin of cTn. As cardiac diseases are the leading cause of morbidity and mortality in chronic haemodialysis patients, the determination of cTn may be a cost-effective marker for defining a population of patients at risk of cardiac events who might benefit from investigations and greater medical management.



   Acknowledgments
 
We would like to thank Roche Diagnostics France and Dade Behring Diagnostics France for providing immunoassays, and Sorin, Theradial, and Biodome for their technical assistance. We are indebted to the Biochemical Laboratory of AURA and the medical staff and nurses of the dialysis centres participating in this study for their substantial contribution.



   Notes
 
Correspondence and offprint requests to: Dr Marie Christine Iliou, Hôpital Broussais, 96 rue Didot, F-75014 Paris, France. Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 30. 8.00
Revision received 9. 2.01.