| Abstract|| |
Cardiac troponin T (cTnT) and I (cTnI) levels are considered as important diagnostic tools in acute coronary events. They could be of predictive value in hemodialysis (HD) patients. The aim of this study was to determine the prevalence of increased cTnI and cTnT in HD patients and their prognostic relevance to all-cause mortality. We measured cTnT and cTnI at baseline in 145 asymptomatic HD patients. We used three different cut-off criteria to define elevated cardiac troponin levels as follows: the 99 th percentile of a reference population, the lowest concentration to give a 10% imprecision [10% coefficient of variation (10% CV)] and the relative operating characteristic (ROC) curve-determined value optimized for diagnostic sensitivity and specificity for detection of myocardial injury (MI). These concentrations were 0.01 ng/mL, 0.03 ng/mL and 0.1 ng/mL for cTnT and 0.2 ng/mL, 0.6 ng/mL and 1 ng/mL for cTnI, respectively. Patients were followed for all-cause mortality (median follow-up 551 days). Kaplan-Meier survival curves, log-rank test and Cox models were employed to determine whether baseline cTnT and cTnI levels were predictive of mortality. Greater percentages of patients had an increased cTnT versus cTnI at each cut-off as follows: 99 th percentile, 90.3% versus 35.2%; 10% CV, 73.1% versus 2.1%; and ROC, 20.7% versus 0.7%. During follow-up, 40 patients died. Elevated cTnT levels above the ROC concentration were associated with increased mortality, although it was not significant after adjustment for other risk factors. Univariate and adjusted hazard ratios were 2.3 [confidence intervals (CI), 1.2-4.5; P = 0. 01] and 1.9 (CI, 0.9-3.9; P = 0.07). No differences were found for cTnI levels. Diabetes mellitus was also an independent predictor of mortality. There is a high prevalence of positive cTnT and cTnI in asymptomatic HD patients, with a greater number of patients having an increased cTnT. Elevated troponin T, but not cTnI, seems to be associated with poor prognosis.
|How to cite this article:|
Kalaji FR, Albitar S. Predictive value of cardiac troponin T and I in hemodialysis patients. Saudi J Kidney Dis Transpl 2012;23:939-45
|How to cite this URL:|
Kalaji FR, Albitar S. Predictive value of cardiac troponin T and I in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Aug 20];23:939-45. Available from: http://www.sjkdt.org/text.asp?2012/23/5/939/100868
| Introduction|| |
The presence of cardiovascular disease is an important predictor of mortality in patients with end-stage renal disease (ESRD), as it accounts for almost 50% of deaths.  Troponin is the biomarker of choice for detecting cardiac injury in patients with renal failure, including those with ESRD receiving long-term dialysis. , However, cardiac troponins are elevated in some patients with renal failure, even in the absence of clinically suspected ischemia.  The importance and significance of this elevation remains uncertain in this population. Several studies demonstrated that cardiac troponin T (cTnT) and/or cardiac troponin I (cTnI) are important predictors of long-term, all-cause mortality and cardiovascular mortality in these patients. ,,,,,,,, To explore the prevalence of elevated cTnT and cTnI and their prognostic relevance to all-cause mortality in asymptomatic hemodialysis (HD) patients, we conducted this prospective study.
| Materials and Methods|| |
This prospective cohort study comprised of 145 patients, treated by chronic intermittent HD, at two university teaching hospitals with established renal units. They were enrolled from June 2008 to November 2008.
All the patients had chronic kidney disease (CKD) stage V and were on maintenance hemodialysis. They were evaluated by history, ECG and review of their medical records to collect the relevant data (age, gender, weight, height, primary renal disease, duration of dialysis, smoking habits, past medical history and current medications). The adequacy of dialysis was assessed at study entry by calculating the dialysis dose (Kt/V). A Kt/V value of >1.2 is regarded as an indicator of adequacy of dialysis. The exclusion criteria were: age less than 18 years, recent acute coronary event within the previous month, undergoing dialysis for less than 30 days and refusal to participate.
Outcome end point
Patients were followed prospectively until January 1, 2010 for the end point: all-cause mortality. Survival was calculated from the date of blood draw until death or the end of the study period. The dates of death, transplantation or transfer to another dialysis facility were documented. At the end of the study, survivors were re-evaluated by ECG and history to detect any important clinical events during the follow-up period.
A pre-dialysis blood sample was taken for analysis of the following biochemical variables: blood count, glucose, albumin, creatinine and urea, and of the following risk-associated factors: cTnT, cTNI, C-reactive protein (CRP), total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein-cholesterol and triglycerides. The blood samples taken were centrifuged and the sera were stored frozen until analysis was performed.
Routine biochemical variables were measured by standardized methods on autoanalyzers at the start of the study. cTnT level was determined using the second-generation Elecsys Troponin T STAT immunoassay from Roche Diagnostics, on the Elecsys 1010 immunoassay analyzer. The detection limit of the assay was 0.01 ng/mL. cTnI was measured using an Immulite Troponin I kit from Siemens Medical Solutions Diagnostics with the Immulite analyzer. The sensitivity of the assay was 0.1 ng/mL.
Three different cut-off criteria were used to define elevated cardiac marker levels, as follows: the 99th percentile of a reference population, the lowest concentration to give a 10% imprecision [10% coefficient of variation (10% CV)] and the relative operating characteristic (ROC) curve-determined value optimized for diagnostic sensitivity and specificity for detection of MI. These concentrations were 0.01 ng/mL, 0.03 ng/mL and 0.1 ng/mL for cTnT and 0.2 ng/mL, 0.6 ng/mL and 1 ng/mL for cTnI, respectively. 
| Statistical Methods|| |
Continuous variables are reported as medians and interquartile ranges or as means and SDs. Exposure was computed from the date of determination of cardiac troponins until the date of death, with censoring for the first of the following: the end of the follow-up period, renal transplantation or transfer of patient to another dialysis center.
In a first analysis, differences at baseline were investigated between groups with elevated and normal cardiac troponins levels (according to each cut-off point) by means of the Mann-Whitney U test used for continuous variables and chi-square test for discrete variables. Variables were included in multivariate analysis if P was less than 0.1 in univariate analysis.
Survival curves were computed using the Kaplan-Meier method. Differences in survival between groups were analyzed using the logrank test. The Cox regression model was used to compare the predictive value of cTnT and cTnI. All tests were two-sided, and a probability value of 0.05 was considered to be significant. The SPSS software was used for statistical analyses.
| Results|| |
Clinical characteristics of the 145 patients are listed in [Table 1]. Laboratory variables are summarized in [Table 2]. A significant number of patients had elevated cTnT and cTnI regardless of the cut-off criteria chosen, with greater proportions of patients having increased cTnT relative to cTnI; specifically, 99th percentile, 90.3% versus 35.2%; 10% CV, 73.1% versus 2.1%; and ROC, 20.7% versus 0.7%, respectively.
Median follow-up was 551 days (range: 28- 582), with a total of 40 deaths (27.6%). Patient exposure was censored for renal transplantation (n: 2, 1.4%) or transfer to another dialysis center (n: 5, 3.4%).
In a crude analysis performed with the chi-square and Mann-Whitney U tests, no significant association could be detected between cTnI level (0.2 ng/mL) (the 99 th percentile cutoff) and age, smoking, baseline coronary artery disease (CAD), diabetes, time on dialysis, Kt/V, CRP levels or any of the lipids measured. In contrast, a significant association was noted with male sex and hypertension. The other cutpoints of cTnI (10% CV and ROC concentrations) could not be tested due to the insufficient number of patients above these levels.
On the other hand, cTnT significantly increased with age regardless of the cut-point chosen. There was no significant difference with regard to time on dialysis or baseline CAD, but an important association was noted between hypertension and cTnT at the 0.01 ng/mL and 0.03 ng/mL levels. When the cutpoint 0.1 ng/mL was tested, a significant association was detected with male sex, smoking, diabetes and HDL, and albumin and CRP levels.
In a univariate analysis, overall mortality was significantly greater in patients with elevated pre-dialysis serum cTnT at 0.03 ng/mL and 0.1 ng/mL cut-points than in patients with normal levels. No statistically significant difference was found for cTnT at the 99 th percentile cutpoint or for cTnI regardless of the selected cutoff value.
Cox proportional-hazards regression analysis was used to examine the baseline variables that were predictive of total mortality. Unadjusted for other risk factors for mortality, the risk of death was increased more than twofold, with elevated cTnT above the 0.1 ng/mL cut-point [Table 3]. An independent risk factor identified in the data was the presence of diabetes mellitus (HR, 2.9; 95% CI, 1.3-6.3; P = 0.007). Age, sex, time on dialysis, the presence of hypertension or CAD did not exhibit a significant effect on survival in this model.
|Table 3: Prognostic value of cTnT and cTnI levels at study entry for predicting all-cause mortality.|
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Adjustment was then made for baseline variables that were considered to be important predictors of mortality: age, time on dialysis, baseline diabetes and CAD. When these variables were included with cTnT in the analysis, cTnT did not exhibit a significant effect on survival [Table 3].
Kaplan-Meier survival curves for cTnT [Figure 1]A and cTnI [Figure 1]B based on increased and normal concentrations are shown in [Figure 1]. The difference in survival was statistically significant for cTnT (P = 0.037, log-rank test) but not significant for cTnI (P = 0.28, log-rank test).
|Figure 1: Kaplan-Meier survival curves by baseline troponin cut-offs, (A) cTnT using the 99th percentile 0.01 ng/mL, 10% CV 0.03 ng/mL and the ROC 0.1 ng/mL. (B) cTnI using the 99th percentile 0.2 ng/mL.|
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| Discussion|| |
This study confirms the high prevalence of elevated cardiac troponins in asymptomatic HD patients. In our population, only 14 patients (9.7%) and 94 patients (64.8%) had undetectable levels of cTnT and cTnI at baseline, respectively.
There is no definitive information about the etiologies of elevated troponin levels. These elevations could reflect silent myocardial necrosis, left ventricular hypertrophy, left ventricular systolic dysfunction, increased cardiac preload with myocardial stretch, microvascular disease, endothelial dysfunction, episodes of hypotension during dialysis or cardiac injury secondary to calcium and oxalate deposition.  Troponin elevations are unlikely owing to impaired renal clearance of troponin despite recent claims,  because the observation of elevated cTnT has been documented in patients with various degrees of renal failure and treatment modalities.  It has been suggested that elevated cTnT could come from muscle (skeletal isoform); however, second-generation assays do not cross-react with muscle troponin. Thus, in general, the troponin assay is considered very specific to cardiac muscle.  Our results substantiate the discordance between cTnT and cTnI elevations observed in several other studies. ,, Multiple hypotheses might explain the discrepancy between these two assays. First, there are differences in the structure, molecular weight, half-life and binding abilities of the two troponins. Second, the kinetics of release into the circulation after myocyte membrane permeability modifications can differ.  Third, cTn clearance from the circulation is different: cTnI, fast; cTnT, more stable. Once released into the circulation, TnI is susceptible to various biochemical modifications, including phosphorylation, oxidation and proteolysis. Proteolysis of TnT has been described to a lesser extent. Finally, dialysis may differentially affect serum levels of TnT and TnI. Regardless of the method of clearance or type of membrane used, TnI levels get decreased by up to 86% from pre- to post-dialysis;  however, mean TnT increased post-dialysis, possibly due to hemoconcentration. ,
We found that elevated versus normal cTnT defined by the ROC cut-off concentration (optimized for sensitivity and specificity for MI detection) was associated with increased risk of death, although it was not statistically significant after adjustment for other risk factors (age, time on dialysis and history of diabetes or CAD). This may be due to the high mortality among diabetic patients. When diabetes was not included in a multivariate Cox regression analysis, the risk of death remained increased more than two-fold with elevated cTnT above the 0.1 ng/mL level (HR, 2.2; 95% CI, 1.1-4.4; P = 0.02), but when diabetes (the other independent risk factor for mortality) was included in the model, cTnT did not exhibit a significant effect on survival (HR, 1.9; 95% CI, 0.9-3.9; P = 0.07). On the other hand, we did not find any prognostic value of cTnI for all-cause mortality regardless of the cut-off criteria chosen.
Previous studies with special emphasis on cTnT have demonstrated that high circulating troponin concentrations are associated with poor survival. ,,,,, Data concerning cTnI are thought to be less consistent and are more difficult to interpret, as no standardization between assays using different antibodies exists, whereas cTnT assays are available from only one manufacturer and are standardized to a single material. In a meta-analysis conducted by Khan et al,  they found that although individual studies generally showed an association between troponin I and long-term all-cause mortality, adjustment for other prognostic factors in these studies did not demonstrate an independent association between troponin I and long-term mortality.
In conclusion, based on the high prevalence of CAD in HD patients and the high mortality caused by this, and until precise recommendations can be reached, we see that HD patients, even if asymptomatic, might benefit from an evaluation, including annual or semiannual clinical, ECG and cTnT determination to risk stratify the patients and refer the high-risk group, including those with positive circulating cTnT, for further evaluation by stress echocardiography or other non-invasive cardiac tests.
| Acknowledgment|| |
The authors would like to acknowledge with gratitude Dr. Mahmoud Almalla for his grate assistance in this work as a whole, and especially in the laboratory section and literature search. The authors also gratefully appreciate Dr. Abdurrahman Alnashef for providing the immunoassays; Mahmoud Galo for technical assistance and the nephrologists, medical staff and nurses of the dialysis centers for their collaboration.
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Faiza Rawas Kalaji
Department of Internal Medicine, School of Medicine, University of Aleppo
[Table 1], [Table 2], [Table 3]