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Articles |
1
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, D-81675 Munich, Germany.
2
Dialysezentrum Ost, D-81671 Munich, Germany.
a Author for correspondence. Fax 49-89-4140-4875; e-mail baum{at}klinchem.med.tu-muenchen.de
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Abstract |
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Methods: We investigated time courses of cTnT and cTnI over 1 year and the clinical outcome over 2 years in 59 patients with end-stage renal failure undergoing chronic hemodialysis. At the start of the study, we divided the patients into two groups, group 1, without history of cardiac failure, and group 2, with history of cardiac failure, and looked for differences between the groups in later adverse outcome. cTnT was measured using the Enzymun® troponin T assay on an ES 700 analyzer (Roche). cTnI was measured on a Stratus® II analyzer (Dade Behring). Creatinine and blood urea nitrogen were measured on a Vitros® 950 IRC (Ortho).
Results: Dialysis acutely increased cTnT (P <0.01) and decreased cTnI (P <0.001) regardless of the dialysis membrane used. Although statistically not significant, cTnT but not cTnI was increased more frequently in group 2 than in group 1, in some cases over the whole study period. Five patients (8.5%) died of cardiac complications within 2 years; all of them had mostly increased cTnT and, in one or more samples, increased cTnI.
Conclusions: Dialysis alters measured cTnT and cTnI concentrations in serum. In patients suffering from end-stage renal failure, sporadic or persistently increased cTnT and cTnI appear to predict cardiac complications. Because of the effects of the dialysis procedure on troponin values, we recommend that blood be collected before dialysis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Various cTnI assays are available (12)(13). In patients with end-stage renal failure, cTnI is increased less frequently than cTnT (8). cTnI may be more specific for detection of myocardial injury than cTnT (14).
In our study, we measured cTnT with the second-generation assay and cTnI on a Stratus analyzer in multiple blood samples from 59 patients on chronic hemodialysis and compared the results with clinical outcomes 2 years later.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood was collected from the patients, after a 3-day interval of non-dialysis, at the onset of the study, and 4 weeks, 3 months, 6 months, and 1 year later. Each time, 10 mL blood was collected before and after dialysis and centrifuged within 1 h of collection. The serum samples were stored at -20 °C until analysis.
Follow-up examination was done 2 years later at the end of the observation period. The clinical examinations were made without knowledge of the troponin results.
cTnT was measured with the Enzymun® Troponin T on an ES 700 analyzer (both from Roche Diagnostics) according to the recommendations of the manufacturer. The upper reference limit was 0.1 µg/L. The reported intraassay and interassay imprecision (as CVs) in this range is 3% and 6%, respectively (11).
cTnI was measured on a Stratus® II analyzer
(Dade Behring) according to the recommendations of the manufacturer.
The results were considered pathological when concentrations were 
0.4
µg/L (15). The intraassay CV in this range is 13.6%, and
the interassay CV is 6.6% (12).
Creatinine and urea were measured on a Vitros® 950 IRC (Ortho Clinical Diagnostics). For statistical analysis, we used the Wilcoxon matched-pairs signed-rank test for comparing the values before and after dialyses, the Wilcoxon Mann–Whitney U-test for differences between groups 1 and 2, the Kruskal-Wallis test to compare the diagnoses, and the Spearman test for correlation. ROC curves and areas under the ROC curves were calculated for cTnT and cTnI.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Thus, cTnT was increased more frequently in postdialysis
samples (14% and 20% of pre- and postdialysis samples, respectively),
whereas the opposite was observed for cTnI (increased in 21% of
predialysis and 2% of postdialysis samples; Fig. 1
). No significant correlation between cTnT and cTnI was found
before (r = 0.139) or after dialysis (r
= 0.1754).
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Because of the effects of dialysis on cTnT and cTnI, we examined the membranes used for dialysis. Dialysis was done with the high-flux membrane Polysulfon in 29% of patients and with low-flux membranes in 76% (cellulose membrane in 22%, Hemeophan in 35.5%, and Cuprophan in 18.6%). cTnT was increased in 10% of patients before dialysis and in 14% after dialysis by high-flux membrane and in 0–29% of patients before and 3–37% after dialysis by low-flux membranes. Dialysis, regardless of membrane, decreased cTnI by up to 81–86%. These discrepancies in pre- and postdialysis cTnT and cTnI values indicate some influences of the dialysis procedure itself on the cTnT and cTnI values. To avoid discrepancies attributable to the dialysis procedure, we used only the results from the predialysis samples for further comparison.
The frequency of increases of cTnT and cTnI was not predictable based
on the underlying disease (Table 2
).
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results in patients with and without cardiac symptoms or
disease
The patients with cardiac symptoms or disease (group 2) were older
(67.3 ± 10.3 years) than those of group 1 (51 ± 11.2 years;
P <0.001), whereas the mean creatinine concentration before
dialysis was higher in group 1 (1034 ± 160 µmol/L) than in
group 2 (795 ± 164 µmol/L; P <0.001). The duration
of end-stage renal disease treated by dialysis did not differ
significantly.
In group 1 (non-cardiac), the mean cTnT concentration in all samples was 0.06 µg/L (range, <0.01–2.07 µg/L), and three individuals (10%) had increased cTnT values at some time. The mean cTnI was 0.2 µg/L (range, 0.0–1.1 µg/L), and cTnI was increased in 15 (48%) patients at some time.
In group 2 (cardiac), the mean cTnT was 0.07 µg/L (range,
<0.01–0.52 µg/L). Nine patients (32%) had increased values. For
cTnI, the mean value was 0.2 µg/L (range, 0.0–1.2 µg/L), and cTnI
was increased in 14 (50%) patients. The frequencies of increased
results per patient are shown in Fig. 2
. Significant differences between the two groups were found only
at the fourth time point, with higher cTnT in group 2 than in group 1.
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cardiac troponins and patient outcomes
Five (8.5%) patients died during or shortly after the study: From
group 2, one death was attributed to heart failure, one to sudden
cardiac death, one to myocardial infarction, and one to cardiac failure
in combination with a severe stenosis of the aortal valve. The fifth
patient was from group 1, and death was attributed to septicemia
following endocarditis. Four of the patients who died had increased
cTnT in two to four samples and increased cTnI in one or more samples
(Table 3
). Only the patient with endocarditis showed a progressive
increase of cTnT and cTnI during the study. The patient with severe
stenosis of the aortic valve consistently had cTnT concentrations
within the reference range, whereas cTnI was increased in three
of five samples (Table 3
).
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Two other patients (one from group 1 and one from group 2) developed
unstable angina with coronary vessel disease demonstrated by coronary
angiography. Both had troponin values within the reference
limits throughout the study (Table 3
).
We prepared ROC curves for cTnT and cTnI (Fig. 3
), using the values of the initial specimen before dialysis and
a composite endpoint of cardiac death or development of unstable angina
within 2 years after initial sampling. Using the recommended cutoff of
0.1 µg/L for cTnT, ROC analysis showed a sensitivity of 57% with an
specificity of 88%. For cTnI, the sensitivity and specificity were
57% and 67%, respectively, at 0.4 µg/L. The areas under the curves
were 0.703 for cTnT and 0.477 for cTnI. The difference between the
areas under the curves between cTnT and cTnI was not significant
(P = 0.213). Using the results of the other time points
(pre- and postdialysis samples), we obtained similar results without
significant differences between the areas under curve (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2% cross-reactivity with skeletal muscle troponin T, Hafner et
al. (8) found that up to 46% of all patients showed
increased values, whereas for cTnI, only 1.5% had increased values.
Using an improved cTnT assay with a cross-reactivity <0.01%, we found
increased cTnT values in 16.6% of all sera at a cutoff of 0.1 µg/L.
Similar results were obtained by McLaurin et al.
(16), who used the 0.2 µg/L cutoff, which was recommended
for patients with possible myopathy (11). For cTnI, the
cutoffs for discrimination differ much more. Fixing the cutoff at 0.8
µg/L, McLaurin et al. (16) found increased values in
4% of all serum samples. In contrast, using the cutoff of 0.4
µg/L, we found increased values in 12% of all serum samples. The
results obtained by Apple et al. (17) were similar, with
increased values in 18% of their serum samples. As shown in the Results, the correlation between cTnT and cTnI is poor. This is in agreement with Möckel et al. (18), who also found no significant correlation. This discrepancy may in part be attributable to differences in the precision at the lower end of the measuring range of the assays used. The imprecision of the cTnT assay in the lower end of the measuring range is better (6%) than that of the cTnI assay (13%). Another explanation may be the different effects of dialysis on cTnT and cTnI and the use of serum samples drawn before and after dialysis for comparison. cTnT is increased after dialysis because of concentration effects, whereas cTnI is decreased. Similar results have been described by others (19).
Because dialysis procedures use several different dialysis membranes, we first blamed the type of dialysis membranes for the differences between cTnT and cTnI. Two types of clearance (diffuse clearance and convective clearance) and two types of membranes (high-flux and low-flux membranes) can be differentiated (20). With high-flux membranes, diffuse clearance removes molecules up to 15 kDa, whereas with low-flux membranes, only molecules up to 5 kDa are removed. Convective clearance removes molecules up to a high molecular mass when high-flux membranes are used, but only molecules up to 9 kDa with low-flux membranes. In our study, one high-flux (Polysulfon) and three low-flux (Cuprophan, Hemeophan, and cellulose) membranes were used. We found no differences in cTnI removal attributable to the membrane type; therefore, clearance cannot be the reason for the reduced cTnI concentrations after dialysis (results not shown). It seems more likely that adsorption of cTnI onto the membrane may be the reason for the significant reduction after dialysis because free cTnI is hydrophobic and likely bind to other proteins and surfaces (21). Another explanation may be that modifications of the cTnI molecule by dialysis changes the epitope recognized by the cTnI antibody used in the assay, thus leading to false-negative results (21). Therefore, to achieve reliable values for clinical decision, it is necessary to take blood samples before dialysis. Only then can a correct comparison be carried out.
As shown in the ROC curve in Fig. 3
, when a major cardiac event or
cardiac death is used as the endpoint, the sensitivities of both cTnT
and cTnI are similar at their specific cutoffs, but the specificity is
better for cTnT. This may be explained by the higher imprecision of the
cTnI assay in the lower end of the measuring range in contrast to cTnT.
Our cutoff of 0.4 µg/L, which was recommended to detect patients with
minor myocardial injury (15), is quite similar to the lower
detection limit (0.36 µg/L) of the assay. In this range, the
imprecision is 13.6% (12). This may produce
false-positive as well as false-negative results and may explain why we
often found only one increased cTnI value per patient during
the year. In contrast, the imprecision of the cTnT assay is only 6% at
0.24 µg/L (11). Therefore, the results obtained by the
cTnT assay are more reliable then those obtained by the cTnI assay.
On the other hand, areas under the ROC curves indicate that CAD may not be the only reason for increased cTnT and cTnI values in our patients. Not only arteriosclerotic effects, but also nonarteriosclerotic effects (concentric and eccentric hypertrophy, water overload, myocardial fibrosis, decreased arterial compliance, intima-media hypertrophy) may lead to a decrease of myocardial blood flow, causing minimal ischemic lesions. This can lead to the release of small amounts of intracellular proteins such as troponin into the blood of hemodialyzed patients (22). This is in agreement with Frankel et al. (23), who showed that increased myocardial lengthening and congestive cardiomyopathy led to increases in cTnT in 18% of their patients.
For cTnI, the mean value and the number of patients with increased
values were similar in both groups. Only the number of samples with
increased cTnI per patient was higher in group 2 (Fig. 2
); the patients
in group 1 often had only one sample with an increased value. The mean
cTnT values for both groups were almost identical. However, the number
of patients with increased values was remarkably higher in group 2
(32%) than in group 1 (9%). In our population, nearly all patients
who died during the study had multiple cTnT values over the upper
reference limit, and all had one or more pathological cTnI values.
These findings are in agreement with those of Porter et al.
(24), whose patients with adverse cardiac outcomes all had
increased cTnT, with most having increased cTnI concentrations.
In another 1-year outcome study, Apple et al. (17) showed
similar results, but in that study, the patients who died were those
with the highest cTnT and cTnI values. We could not confirm this
because in our study, the amount of troponin did not correlate
with the outcome (Table 3
). None of the pathological values correlated
with acute cardiac symptoms, except for the patient with endocarditis.
But considering the pathological troponin values without acute signs of
myocardial injury, which often were followed by an adverse outcome
later, one must consider minor myocardial injury as the cause of the
release of the troponins from the myocardium. The cTnT discrimination
limit of 0.1 µg/L marks only minor myocardial injury (25);
for major cardiac events, the cutoff value is 0.4 µg/L. For cTnI, the
discrimination limit for myocardial infarction is 1.5 µg/L.
Ninety-seven percent of our cTnT values were<0.4 µg/L, and all cTnI
values were <1.5 µg/L, both indicating minor myocardial injury in
our patients.
The troponin concentrations of the patient with endocarditis were remarkable. Because isolated endocarditis does not cause the release of proteins from myocardial cells, the infection must have also affected the myocardium. Some studies have described pathological cTnT and cTnI values in patients with myocarditis (26). Unfortunately, no further examination such as myocardial biopsy was done in our patients to confirm this, but the remarkable increases in troponin (2.07 µg/L cTnT and 1.0 µg/L cTnI) support our assertion.
Other, noncardiac reasons for increases in the troponins, especially cTnT, have been suggested. It has been postulated that myopathic skeletal muscle produced by uremia reexpresses cTnT (16)(27). But Haller et al. (28) demonstrated in patients suffering from end-stage renal failure neither mRNA nor the cTnT protein itself. Therefore, the cTnT values in the blood of dialysis patients measured with the Enzymun cTnT assay do not seem to be of skeletal muscle origin.
In conclusion, sporadic or permanently increased values for cTnT and cTnI can be seen in patients suffering from end-stage renal failure and undergoing chronic hemodialysis. These increases are not always specific for acute CAD. In patients without signs of acute CAD, it seems rather to be an indicator for minor myocardial damage. The correlation between the troponins is poor. This can be explained by the different effects of dialysis on cTnT and cTnI concentrations or by the high imprecision of the cTnI assay in the lower end of the measuring range. Because of the different effects of dialysis on cTnT and cTnI values, we recommend that blood samples be collected before dialysis.
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Footnotes |
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References |
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