Serum troponin T measurement in patients with chronic renal impairment predicts survival and vascular disease: a 2 year prospective study

Grahame N. I. Wood1, Brian Keevil2, Jaya Gupta1, Robert Foley1, Abdalla Bubtana3, Garry McDowell2 and Peter Ackrill3

1 Department of Renal Medicine, Salford Royal Hospitals NHS Trust and 2 Department of Clinical Biochemistry and 3 Department of Renal Medicine, South Manchester University Hospital NHS Trust, Manchester, UK

Correspondence and offprint requests to: Dr G. N. I. Wood, Renal Unit, Eccles Old Road, Salford M6 8HD, UK. Email: Grahame.Wood{at}srht.nhs.uk



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Cardiovascular mortality in end-stage renal failure patients is high and early risk stratification in these patients may aid clinical management improving outcomes. Cardiac troponin T (cTnT) is a component of the cardiac myocyte which is released into the circulation following myocardial necrosis. It has been shown to be of prognostic significance in patients with unstable angina. The role of cTnT in patients with renal disease remains unclear. The aim of this investigation, therefore, was to assess the prognostic significance of cTnT in chronic renal impairment patients, pre-dialysis.

Methods. Ninety-six patients with chronic renal impairment were followed prospectively after cTnT determination by a quantitative laboratory method. The clinical outcomes after 2 years were determined. The measured cTnT values were correlated with biochemical parameters and clinical end-points.

Results. A cut-off of 0.1 ng/ml was used in assessing the prognostic significance of cTnT. Twenty-five patients had a cTnT >0.1 ng/ml, whilst 71 had a cTnT <=0.1 ng/ml. Twenty-one patients died during the follow-up period. Eleven of these had elevated cTnT at entry into the study. Death rate in the patients with cTnT >0.1 ng/ml was 42% compared with 14% in those with levels below the cut-off. Thirty-three patients died or had a vascular event. The rate of death or a vascular event in the elevated group was 64% compared with 24% in those with levels below the cut-off. At the end of the study, 23 patients were treated by continuous ambulatory peritoneal dialysis, 29 by haemodialysis, 22 had functioning renal transplants and one patient was not on renal replacement therapy. Factors that were found to significantly affect cTnT were diabetes, age and urea. cTnT was found to be a significant predictor of survival in these patients. Patients with high cTnT values were more likely to end up on haemodialysis. No relation of renal function to cTnT level was found.

Conclusions. These results show that in patients with renal impairment, the measurement of cTnT prior to commencing renal replacement is a significant independent predictor of survival. cTnT did show potential as a prognostic test to stratify patients with a high cardiovascular risk and may enable intensive risk factor modification in this patient group. This may be of further use in selection of patients’ suitability for renal transplantation.

Keywords: cardiovascular; pre-dialysis; prognosis; renal failure; troponin T.



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Technical and pharmacological advancements have enabled the quality of life of patients with severe renal failure to be improved significantly. Despite improved techniques and increased access to renal replacement, the long-term prospects for such patients is still burdened by a high cardiovascular morbidity and mortality [1].

Cardiovascular mortality in end-stage renal disease (ESRD) patients is 10–20 times higher than in the general population [1]. Cardiovascular disease, including ischaemic heart disease, angina, congestive cardiac failure (CCF) and stroke, is the leading cause of death in this population. It is noted that there is a high death rate and cardiovascular system (CVS) event rate in the first year of commencing regular dialysis. With the age of patients being accepted onto dialysis rising and a higher proportion of patients with diabetes, this is likely to become a significantly greater problem.

Risk factors for the development of CVS disease in the general population are well known and defined [2,3]. The significance of the same in patients with chronic renal impairment and ESRD is less clear [4]. Even accounting for traditional risk factors, the observed rates of CVS disease are higher in both chronic renal impairment (CRI) and patients receiving renal replacement [4,5]. This suggests either other pro-atherogenic factors are in place or the same factors are of more significance in these groups. Intensive risk factor modification in the period prior to commencing regular dialysis may improve long-term outcome. Unselected screening for occult vascular disease in all patients with diminished renal function is neither safe nor practical [6]. However, if patients could be stratified according to risk, a more directed focus could be used. Additionally, knowledge of likely long-term outcomes may influence patient and physician decisions with respect to planning of future renal transplantation.

Troponin T (39 kDa) is part of the troponin–tropomyosin complex along with troponins C and I. With myocardial necrosis, the troponins exhibit a biphasic release pattern due to the release of both free cytosolic and structurally bound molecules [7]. This along with cardiac specificity of troponin T makes it an important prognostic indicator in patients presenting with chest pain. It has been shown that cardiac troponin T (cTnT) is particularly useful for risk stratification in patients with unstable angina. In these patients, its presence is associated with increased mortality even in the absence of a myocardial infarction (MI) [8]. Therefore, it is thought that patients can be classified as having ‘minor myocardial damage’ (MMD) [9]. It has been shown that cTnT is superior to creatine kinase (CK) and creatine kinase-MB (CK-MB) activity for the detection of MMD [10].

In unstable angina, elevated levels are not only strongly related to long-term risk of death from cardiac survival, but also shown to be independent from and additive to other clinical indicators of risk. Since myoglobin, CK and CK-MB are frequently elevated in CRI patients, a cardiac-specific marker may be advantageous. The observation of elevated cTnT has been observed in patients with various degrees of renal failure and treatment modalities. The cause and significance has so far been speculative. The role of cTnT in ESRD patients as a prognostic and diagnostic tool in both acute coronary syndromes and long-term follow-up remains somewhat inconclusive [11,12].

The aim of this study was to further investigate the relation of cTnT to renal impairment and the long-term prognostic value of cTnT measurement in a group of patients with established renal impairment likely to require renal replacement therapy.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
The study setting was a university teaching hospital with an established renal unit. Ninety-six patients with a serum creatinine >500 µmol/l, attending the pre-dialysis clinic, were selected. These patients had advanced renal disease but had not yet started renal replacement therapy, although they were thought to be suitable candidates for future dialysis. Most patients were taking antihypertensive medication aiming to achieve therapeutic targets of 140/80 mmHg. All patients were receiving dietary advice with protein restriction to prevent or defer the need for renal replacement.

A blood sample was taken from these patients for cTnT measurement by a quantitative laboratory method. Baseline data on each patient were recorded. After the initial cTnT measurement, any subsequent CVS events or deaths over the subsequent 2 years were noted. Survival was calculated from the time of the determination of the serum cTnT until death or the end of the 2 year period. The clinical state of the patients at 2 years was determined by chart review. Cardiovascular events were defined as: MI, newly diagnosed angina, new onset cardiac failure, coronary artery bypass surgery, coronary angioplasty with or without stent placement, new onset of claudication, femoro-popliteal bypass surgery or angioplasty, transient ischaemic attack and cerebrovascular event. To determine the influence of cTnT on outcome, the patients were divided into high and low cTnT groups with a cut-off of 0.1 ng/ml.

Laboratory methods
The blood samples taken for cTnT measurement were centrifuged and the serum was stored frozen until analysis was performed.

Determination of serum cTnT was performed on the Elecsys 1010 system (Roche Diagnostics, East Sussex, UK) using the Roche diagnostics troponin T kit, based on electrochemiluminescence immunoassay technology, according to manufacturer’s instructions. The total coefficient of variation for the assay was 5.8% at 0.47 ng/ml and 5.4% at 2.63 ng/ml. The limit of detection was 0.01 ng/ml (a level of >0.1 ng/ml was considered positive for myocardial necrosis).

Statistics
The results are expressed as means ± SEM. Kaplan–Meier analysis was performed to show differences in cumulative survival between the two groups (elevated and normal cTnT levels). The effect of different parameters, selected a priori, on survival was calculated using Cox’s regression analysis. Factors influencing cTnT values were assessed by logistic regression. All statistics were performed with the SPSS package release version 10.1.0.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient demographics by cTnT category and aetiology of CRI are shown in Table 1. For statistical analysis, patients were grouped into those with a cTnT <=0.1 and >0.1 ng/ml.


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Table 1. Baseline characteristicsa

 
Twenty-five patients had an elevated cTnT (>0.1 ng/ml), whilst 71 had a value below the cut-off (<=0.1 ng/ml). Mean age of those with cTnT determination >0.1 ng/ml was 59.0 ± 2.7 years and those with cTnT <=0.1 ng/ml was 50.3 years ± 1.6 years.

Twenty-one patients died during the follow-up period and their details are presented in Table 3. Eleven of these had elevated cTnT at entry into the study. At the end of the study, 41 patients had been treated by continuous ambulatory peritoneal dialysis (CAPD), 33 had been treated by haemodialysis, 32 received renal transplants and one was not on renal replacement therapy.


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Table 3. Causes of death in patients with high and low cTnT measurements

 
Kaplan–Meier survival analysis is shown in Figure 1, using a cut-off point of 0.1 ng/ml for cTnT. A significant difference in survival time or time to cardiac event was noted between the two cTnT groups ({chi}2 = 10.73, df = 1; P = 0.001). In addition, Kaplan–Meier analysis was conducted with survival time only (Figure 2). Again using a cTnT cut-off point of 0.1 ng/ml, a significant difference in survival time was noted between the two groups ({chi}2 = 9.82, df = 1; P = 0.002).



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Fig. 1. Kaplan–Meier analysis for survival or CVS event over a 2 year period (1, cTnT < 0.1 ng/ml; 2, cTnT > 0.1 ng/ml).

 


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Fig. 2. Kaplan–Meier analysis for survival over a 2 year period (1, cTnT < 0.1 ng/ml; 2, cTnT > 0.1 ng/ml).

 
Logistic regression analysis of troponin T showed no relation with age, serum urea, serum creatinine or calculated creatinine clearance. Logistic regression analysis also did not show any significant correlation between troponin T and the presence of diabetes mellitus or the presence of a cardiovascular history.

Survival was also analysed with a Cox’s regression analysis. Survival time was significantly influenced by two parameters, cTnT and cardiovascular history. The presence of diabetes mellitus did not exhibit a significant effect on survival or time to cardiac event in this model. When age and sex were included with cTnT in the analysis, cTnT still exhibited a significant effect on survival (Table 2).


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Table 2. Cox regression analysisa

 


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The prevalence, aetiology and clinical significance of raised serum cTnT in patients with renal dysfunction are not well defined. cTnT has been shown to be a good prognostic indicator in patients with acute coronary syndromes in the absence of renal disease. Studies have shown elevated cTnT levels to be associated with subsequent MI and death [8]. Their measurement has been shown to be of both diagnostic and prognostic use. The prognostic value of cTnT is particularly evident in patients with unstable angina pectoris, the risk of cardiac death or MI being linked to the maximal value of cTnT [10]. These findings enable the patient management to be improved by fast tracking of high-risk patients to earlier investigation and treatment.

Laboratory cTnT measurement of 0.05 ng/ml is the upper reference level in healthy blood donors and a value of <0.05 ng/ml can be used clinically to exclude MI. A value of >0.05 ng/ml is thought to indicate a moderate risk. Lindahl et al. [10] found that a cTnT value of >0.06 ng/nl was associated with a 12.8% incidence of MI. The GUSTO trial [13] found that in patients with suspected MI, a cTnT value >0.1 ng/ml was associated with increased mortality at 30 days. Present local laboratory guidelines suggest that a cTnT value of >0.1 ng/ml represents myocardial damage. Hence, this was used as the cut-off point between positive and negative cTnT in this study.

Although troponins are known to be better markers than CK-MB and other presently used cardiac markers, there has been debate as to whether troponin T or troponin I is the more superior marker [10]. George and Singh [14] found that cTnT shows poor specificity in ESRD, whereas cTnI maintained a high sensitivity and specificity. They suggested that the poor specificity of cTnT may be due to variable expression in extracardiac tissues. However, several other studies have shown troponin T to be the better marker [15]. Collinson [8] also demonstrated that current assay performance for cTnT is better than that for cTnI and direct comparison of cTnT with cTnI suggests a better outcome prediction for cTnT. cTnT assays are available from only one manufacturer and are standardized to a single material, whereas multiple cTnI assays are available. False positive TNTI have been reported [16]. Although there is some degree of correlation between assays, there are significant proportional biases between results. This means that depending on the test used, clinicians may arrive at different diagnostic conclusions for the same TnI value depending on the assay used. Therefore, in this study we chose to investigate the usefulness of cTnT as a prognostic tool.

The use of troponins as diagnostic markers for acute MI in patients with renal impairment has been unclear because of the high prevalence of elevated cTnT levels found in this patient population. It has been hypothesized that haemodialysis patients may have elevated cTnT levels because of volume overload causing myocardial stretch and subsequent cTnT leakage, though this has subsequently been rejected by Frankel et al. [11]. Findings shown here concur with this as all cTnT measurements were taken before regular dialysis treatment or transplantation.

In this study, cTnT was found to be a significant independent predictor of 2 year mortality (P < 0.05). When age and sex were included in the Cox’s regression analysis, the relationship between cTnT and survival still held. The results showed that the proportion of patients who died in the cTnT >0.1 ng/ml group was almost four times greater than that in the cTnT <=0.1 ng/ml group (54 vs 14%). This is comparable with haemodialysis patients studied by Stolear et al. [17] who also found a similar difference in death rate between the two groups.

A number of studies have looked at the long-term prognostic value of cTnT in ESRD patients and in many of these the follow-up period was <=12 months [9,17--19]. There are surprisingly very few short-term or even cross-sectional studies of troponins in renal impairment, renal transplant or peritoneal dialysis patients. There are a number of factors that lead to difficulty in their interpretation. A feature is that the data are predominantly from patients being treated by haemodialysis. Such patients are a small cohort of the spectrum of renal disease and may lead to selection bias. Patients in these studies may have been treated for prolonged and variable times by haemodialysis. This is a group of patients where cardiovascular risk factors are common and ischaemic heart disease deaths may have already removed those most at risk, weakening the predictive value of any variable. The exclusion of patients at high risk from the outset is also likely to influence the conclusion [9]. Perhaps, these and other factors explain why other short-term studies have demonstrated a varied predictive value in troponin measurement. Our study in pre-dialysis patients shows cTnT to be predictive of mortality and CVS events and its value is independent of age, previous CVS history and presence of diabetes. This is somewhat surprising given the high incidence of ischaemic heart disease in the endemic population. Interestingly, a similar pattern has recently been observed by a group in Dundee [20], showing cTnT to be of prognostic value independent of other comorbidity in haemodialysis patients.

This work is not without its limitations. Evaluation of left ventricular function has not been made. Use of echocardiography would have enabled more precise correlation of clinical and biochemical markers, further validating the theory of the higher cTnT arising from concomitant CVS disease in CRI patients.

The selection of patients from a pre-dialysis clinic setting might have influenced the results. Many patients presenting with acute and acute on chronic renal failure were admitted to the hospital and commenced dialysis. These were not included in this study. Patients with renal impairment but not planned to receive renal replacement were seen elsewhere. Again, these patients were excluded from the study. It would seem likely that excluding these groups would underestimate the CVS risk. These groups should be included in future evaluations. The predictive value of cTnT in those patients with lesser or stable renal function is not known. The patient cohort studied here had advanced renal impairment; previous work has shown that many CVS risk factors are present even before these levels are reached. It would be surprising if similar findings were not made and enable detailed and accurate assessment of more CVS risk, broadening the scope for screening, risk factor modification and intervention.

This study demonstrates that measurement of serum cTnT in patients with renal impairment is a significant predictor of subsequent mortality. The predominant causes of patient death, as they progress to needing renal replacement, are noted to be cardiovascular in nature. The same cTnT measurement was also a good predictor of death or CVS event in this group. The value of the test held even when other significant CVS risk factors were considered by Cox’s proportional hazards analysis. No relationship between renal function and cTnT level was found. These results suggest that the cause of raised cTnT in patients with renal disease is not related to their deranged renal function per se, but to concomitant CVS disease already present in a high-risk group. The clinical utility of cTnT measurement is 2-fold. Firstly, earlier identification of patients at high CVS risk enables appropriate primary and secondary preventive strategies to be implemented. The need for such a strategy must be highlighted, as often coronary artery disease is asymptomatic. And secondly, realistic awareness of likely long-term prognosis would be an invaluable tool when patients and their physicians plan suitability and timing of renal transplantation. Further study of cTnT as a prognostic tool in a larger sample, over a longer period of time is needed. This may add to the accuracy of cTnT in different patient groups.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 5.02
Accepted in revised form: 21. 2.03