Plasma elimination of cardiac troponin i in end-stage renal disease.

ABSTRACT

Background. We retrospectively compared the decline of cardiac troponin I after acute myocardial infarction (AMI) in patients with normal renal function and those with end-stage renal disease (ESRD) who were receiving hemodialysis.

Methods. We reviewed 257 cases with a discharge diagnosis of AMI or AMI plus ESRD; 222 were excluded due to inadequate data or evidence of ongoing myocardial necrosis. Decline of cardiac troponin I values was followed over a mean ([+ or -] SD) of 2.75 [+ or -] 1.2 days in patients with normal renal function and 2.7 [+ or -] 2.0 days in ESRD patients. Average apparent half-life and apparent elimination rate constant of troponin I were compared between groups.

Results. Of 35 patients with AMI, 16 had ESRD and were receiving hemodialysis, and 19 had normal renal function. Mean ([+ or -] SD) apparent half-lives of troponin I in the ESRD group and the group with normal renal function were 1.48 [+ or -] 0.77 days and 1.08 [+ or -] 0.63 days, respectively. The mean apparent elimination rate constants of cardiac troponin I were 0.64 [+ or -] 0.33 [days.sup.-1] in the ESRD group and 0.91 [+ or -] 0.55 [days.sup.-1] in the group with normal renal function.

Conclusion. The difference in apparent half-life and apparent elimination rate constant of cardiac troponin I between patients with normal renal function and those with ESRD is not statistically significant.

THE SIGNIFICANCE of an elevated cardiac troponin I level in the setting of ESRD has been a source of great controversy. Some schools of thought suggest that cardiac troponin I is falsely elevated in ESRD. (12) Others suggest that after an AMI, elevations of cardiac troponin I may be protracted in patients with ESRD who are receiving hemodialysis. (3)

Cardiac troponin I is a 24,000-dalton protein whose amino acid sequence is specific for cardiac muscle. (3) To date, there is no evidence of its translation from any other tissue in the body, making it a specific marker for myocardial necrosis. Conversely, cardiac troponin T has been found in regenerating skeletal muscle and in patients with ESRD without any objective evidence of coronary artery disease or myocardial necrosis. (46) The data involving cardiac troponin T is often erroneously applied to cardiac troponin I. Cardiac troponin I elevation has not been found in any situation other than myocardial necrosis. (5) However, recent evidence has shown abnormal cardiac troponin I levels in association with other acute illnesses that are subsequently found to be noncardiac. These findings do not exclude the possibility of injury or necrosis of small numbers of cardiac myocytes. (7) These acute illnesses, though noncardiac in nature, may serve as precipitants of myocardial necrosis. As a result, elevated level s of cardiac troponin I may be misinterpreted as being falsely positive, especially in the setting of ESRD.

The mechanisms of cardiac troponin I clearance have not been clearly elucidated. Given this uncertainty, it is not known whether the half-life and elimination rate constants of cardiac troponin I are affected by ESRD. There are many clinical situations involving renal failure and abnormally elevated levels of cardiac troponin I for which this knowledge is needed. The clinical scenario obscures the objective value of an abnormal cardiac troponin I measurement. Is an abnormal cardiac troponin I level indicative of an acute coronary syndrome? Alternatively, does an abnormal cardiac troponin I level represent a previous event, which may have already been addressed clinically, with delayed normalization of cardiac troponin I?

Our study was designed to directly compare the apparent elimination rate constant and the apparent half-life of abnormally elevated cardiac troponin I after myocardial infarction in patients with normal renal function and in those with ESRD who were receiving hemodialysis.

PATIENTS AND METHODS

Patients

Patients included in this study were from the Veterans Affairs Medical Center and from the Tulane University Hospital and Clinics, both of New Orleans, La. Given the study's retrospective nature, it was considered exempt research by our institutional review board. However, the study was reviewed and approved by the administration of both hospitals and the Department of Medicine. To preserve confidentiality, no patient identifiers are included in our report.

The study population was obtained by retrospectively enrolling two groups of patients based on discharge diagnoses. The first group of patients recruited had a single discharge diagnosis of AMI. The second group had two discharge diagnoses--AMI and ESRD. Patients in the group with ESRD were all receiving hemodialysis. Further review confirmed that all patients included in the study had had AMI. Patients were recruited retrospectively from the two medical facilities between December 1997 and December 1999.

Of the total 257 patients whose cases were reviewed from both groups, 208 had a discharge diagnosis of AMI, and 49 had a discharge diagnosis of AMI and ESRD. Inclusion criteria were as follows: age [greater than]18 years, peak troponin I level [greater than]2 ng/mL, documentation of times and dates of measured troponin I, and at least four declining troponin I values with no further evidence of myocardial necrosis. Cardiac troponin I levels with corresponding dates and times for each measurement were recorded. A minimum of four declining plasma troponin I values was used in an attempt to exclude the presence of another superimposed AMI. Also, the minimum of four declining troponin I values was used to improve the precision of modeling apparent plasma half-life and elimination rate constant.

The patients in the study did not have any subsequent acute coronary syndrome while hospitalized after the initial event on admission. Because of the trial's retrospective nature, it was impossible to obtain a cohort of patients with troponin I values measured at regular intervals. Of the 222 patients excluded from the study, 58 had inadequate documentation of the times and dates of troponin I acquisition, 71 had evidence of ongoing myocardial necrosis, and 93 lacked at least four declining troponin I values. After the application of the exclusion criteria, 35 patients remained eligible for inclusion in the study. The group with normal renal function contained 19 patients. Mean age ([+ or -] SD) was 64.5 [+ or -] 15 years, and 79% were men. The group with ESRD contained 16 patients. Mean age was 72.5 [+ or -] 11 years, and 75% were men (Table).

Data Analysis

The apparent half-life and elimination rate constant of troponin I in the two groups were obtained by using a one-compartment exponential model with WinNonlin kinetic software (Pharsight Corp, Mountainview, Calif). WinNonlin is an iterative least-squares exponential curve-fitting program. We assumed a model in which the release of troponin I from the myocardium during a myocardial infarction was analogous to an intravenous bolus of troponin I, which was then eliminated by a first-order process. Both one- and two-compartment models were fitted, but the more complex model did not significantly increase [gamma] values or reduce the residual sum of squares. All [gamma] values were [greater than]0.94.

The half-life and elimination rate constant are termed "apparent" because they do not strictly represent the elimination parameters. Processes of elimination and slow continuous release of troponin I into plasma from cardiac myocytes are occurring simultaneously. The apparent elimination rate constant is a product of the true elimination rate constant opposed by the transfer rate constant from the intracellular compartment of the myocardium to plasma. Unless active myocardial damage is occurring, as in the case of reinfarction, this transfer rate constant is assumed to be small relative to the elimination rate constant. The half-life, in units of days, is defined as the amount of time required for 50% of cardiac troponin I to be metabolized or the time required for a 50% reduction in the serum concentration of cardiac troponin I. The elimination rate constant, in units of [days.sup.-1] is defined as the fraction of cardiac troponin I being removed from plasma per unit of time.

The intervals of measurement of troponin I values after the peak were in units of days. The troponin I laboratory data for each patient had the date, hour, and minute of the sample's acquisition. Each patient had approximately five measured declining troponin I values, which were all given a time constant in units of days, starting with time zero. The declining troponin I values and their times of acquisition were entered as raw data, which allowed us to obtain the apparent half-life, apparent elimination rate constant, and nonlinear regressions.

Troponin I concentrations versus time curves were analyzed to obtain the apparent elimination rate constant and apparent half-life for each patient, using Prism Plus Graphics Software (Wind River Systems Inc, Alameda, Calif). The mean apparent elimination rate constant and apparent half-life for each group was calculated, compared using the unpaired t test, and expressed graphically (Figure).

Assay

Serum samples were obtained in collection tubes free of additives and were analyzed within 1 hour. The laboratories at each clinical site used the same assay to obtain troponin I results. The Dimension RxL clinical chemistry system was used to obtain the troponin I results via a heterogeneous immunoassay module (London Biotechnology Ltd, London, UK). The detection limit of troponin I is 0.4 ng/mL in both facilities.

The patients involved in the study with ESRD received dialysis in the named facilities. The filters used contained a modified cellulose acetate membrane (Terumo Corp, Tokyo, Japan), which permitted molecules weighing [less than]3,000 to 5,000 d to be removed. Troponin I is considered nondialyzable, with a molecular weight of 24,000 d.

Statistical Analysis

The variables being compared between the two groups included the apparent half-life and the apparent elimination rate constant. Within each group, the variables were expressed in terms of the mean and standard deviation. The unpaired t test was used to evaluate the statistical significance of the differences in the variables between the two groups. P [less than or equal to].05 was considered statistically significant. The statistical analysis was done using WinNonlin software.

RESULTS

A total of 35 patients enrolled in the retrospective study had the diagnosis of AMI. Nineteen had normal renal function, and 16 had ESRD and were receiving hemodialysis. Each of the patients was found to have an elevated troponin I value. The values were followed for a mean ([+ or -]SD) of 2.75 [+ or -] 1.2 days in the group with normal renal function and 2.7 [+ or -] 2.0 days in the group with ESRD. Given that the trial was retrospective, the intervals of cardiac troponin I measurement were random. The mean peak cardiac troponin I value in the group with normal renal function was 17.4 [+ or -] 28.0 ng/mL. The patients in the ESRD group had a mean peak cardiac troponin I value of 11.0 [+ or -] 13.0 ng/mL.

The cardiac troponin I values obtained after the peak value were all declining over the period of observation. The patients with normal renal function had a mean troponin I apparent half-life of 1.08 [+ or -] 0.63 days and a mean troponin I apparent elimination rate constant of 0.91 [+ or -] 0.55 [days.sup.-1]. The patients with ESRD had a mean troponin I apparent half-life of 1.48 [+ or -] 0.77 days and a mean troponin I apparent elimination rate constant of 0.64 [+ or -] 0.33 [days.sup.-1] The patients with ESRD had a marginally increased apparent half-life compared with the patients who had normal renal function. The unpaired t test revealed a P value of .1, which represents a statistically insignificant difference. The patients with ESRD also had an apparent elimination rate constant that was less than that of the patients with normal renal function. The unpaired t test revealed a P value of .1, representing a statistically insignificant difference (Table).

Graphic representation was made of the decline of troponin I for patients with normal renal function and patients with ESRD. The application of the two-compartment model to the data did not significantly alter curve fitting. A representative example, using a logarithmic scale, is shown (Figure).

DISCUSSION

Results of our study suggest that patients with ESRD who are receiving hemodialysis have an increased, though not statistically significant, apparent half-life and a smaller apparent elimination rate constant of cardiac troponin I than patients with normal renal function. This is likely due to the relatively small sample size used in our study or the strict inclusion criteria applied. Nevertheless, the data translate into a tendency for patients with ESRD to have a mildly prolonged decline in cardiac troponin I level. Cardiac troponin I has not been found to be elevated in any situation without the presence of some degree of myocardial necrosis.

Ironically, patients with renal failure have been found to have elevated levels of cardiac troponin T without any other evidence of myocardial necrosis. However, the clinical significance of the cardiac troponin T value should likely not be used to extrapolate that of cardiac troponin I. In the setting of ESRD requiring hemodialysis, elevations of cardiac troponin I should be assumed to be the result of myocardial necrosis. Given that our study showed no statistically significant difference between the half-lives and elimination rate constants of cardiac troponin I in patients with normal renal function and those with ESRD, an abnormal value should likely be interpreted as myocardial necrosis. Moreover, patients with ESRD have accelerated atherosclerosis, which reinforces our conclusion that abnormal cardiac troponin I values should not be dismissed as artifactual, due to the presence of ESRD.

References

(1.) Collinson PO: Troponin T or troponin I or CK-MB (or none?). Eur Heart J 1998; 19(suppl):N16-N24

(2.) Collinson PO, Hadcocks L, Foo AY, et al: Cardiac troponins in patients with renal dysfunction. Ann Clin Biochem 1998; 35:380-386

(3.) Wu AHB, Feng YJ: Biochemical differences between cTnT and cTnI and their significance for diagnosis of acute coronary syndromes. Eur Heart J 1998; 19:N25-N29

(4.) McLaurin MD, Apple FS, Voss EM, et al: Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle. clin Chem 1997; 43:976-982

(5.) Roppolo LP, Fitzgerald R, Dillow J, et al: A comparison of troponin T and troponin I as predictors of cardiac events in patients undergoing chronic dialysis at a veteran's hospital a pilot study J Am Coll Cardiol 1999; 34:448-454

(6.) Frankel WL, Herold DA, Ziegler TW, et al: Cardiac troponin T is elevated in asymptomatic patients with chronic renal failure. Am J Clin Pathol 1996; 106:118-123

(7.) Khan IA, Tun A, Wattanasauwan N, et al: Elevation of serum cardiac troponin I in noncardiac and cardiac diseases other than acute coronary syndromes. Am J Emerg Med 1999; 17:225-229

[Graph omitted]

TABLE.

Patient Characteristics and Results Diagnosis

                                           Diagnosis

                             AMI With Normal        AMI With
                             Renal Function           ESRD

No. patients                       19                  16
Mean age (yrs)              64.5 [+ or -] 15    72.5 [+ or -] 11
Sex, M/F (% M)                  15/4 (79)           12/4 (75)
Troponin I
 Peak level (ng/mL)         17.4 [+ or -] 28    11.0 [+ or -] 13
 Days measured              2.75 [+ or -] 1.2    2.7 [+ or -] 2.0
 Half-life (days)           1.08 [+ or -] 0.63  1.48 [+ or -] 0.77
 Elimination rate           0.91 [+ or -] 0.55  0.64 [+ or -] 0.33
  constant ([days.sup.-1])




                            P Value

No. patients                  N/A
Mean age (yrs)                N/A
Sex, M/F (% M)                N/A
Troponin I
 Peak level (ng/mL)           N/A
 Days measured                N/A
 Half-life (days)             .1
 Elimination rate             .1
  constant ([days.sup.-1])

Data are presented as mean values [+ or -] SD.

AMI = Acute myocardial infarction;

ESRD = end-stage renal disease;

N/A = not applicable;

M/F = male/female.

KEY POINTS

* End-stage renal disease results in a substantial escalation in the progression of coronary-artery disease.

* The cardiac troponins are novel markers for detecting myocardial necrosis, though their metabolism and clearance are not precisely defined.

* Controversy emerges regarding the cardiac troponins because cardiac troponin T has been found to be falsely elevated in patients with end-stage renal disease, and these data are often applied to cardiac troponin-I.

* Data involving cardiac troponin-I has not shown it to be falsely elevated in patients with end-stage renal disease.

* The apparent half-life and apparent elimination rate constant of cardiac troponin-I was not significantly different between patients with end-stage renal disease and patients with normal renal function.