| Abstract|| |
Dialysis patients with troponin-I levels above the cut-off value diagnostic for acute myocardial event (AME) are sometimes labeled as having "renal cause" of elevated troponin-I. Patients with troponin-I levels above 0.0 ng/mL, but below the cut-off level for an AME, are reported to have increased risk for coronary heart disease and mortality. Single pre-dialysis blood samples were taken from 150 asymptomatic dialysis patients (on hemo- or peritoneal dialysis) for troponin-I, cardiac enzymes, C-reactive protein (CRP) and lipid parameters. Troponin-I was measured by a chemiluminescent microparticle immunoassay (CMIA), of which the cut-off value for AME was set at ≥0.4 ng/mL. Patients with troponin-I levels of 0.0 ng/mL, and those with levels between 0.1 and 0.3 ng/mL, were compared regarding their cardiovascular risk profile. None of the patients had troponin-I concentrations above the cut-off level diagnostic for an AME, with 85.3% of the patients having levels of 0.0 ng/mL. While there was no difference in the "traditional" risk factors such as age, body mass index, prevalence of diabetes mellitus, hypertension, total cholesterol and low-density lipoprotein cholesterol between patients with troponin-I levels of 0.1-0.3 ng/mL and those with levels of 0.0 ng/mL, CRP concentrations were higher in the former. In peritoneal dialysis patients, the weekly Kt/V was lower in the patients with troponin levels between 0.1 and 0.3 ng/mL. The findings should add strong support in settling the debate of whether or not in patients on dialysis, falsely elevated levels of troponin-I "commonly" occur. An increased level of CRP and lower Kt/V might add to the cardiovascular risk in patients with troponin-levels between 0.1 and 0.3 ng/mL.
|How to cite this article:|
Hussein MM, Mooij JM, Al Malki N, Demerdash TM, Mandourah AY. Troponin-I is not falsely elevated in asymptomatic dialysis patients. Saudi J Kidney Dis Transpl 2013;24:48-53
|How to cite this URL:|
Hussein MM, Mooij JM, Al Malki N, Demerdash TM, Mandourah AY. Troponin-I is not falsely elevated in asymptomatic dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2014 Sep 18];24:48-53. Available from: http://www.sjkdt.org/text.asp?2013/24/1/48/106240
| Introduction|| |
There is still some controversy existing regarding the significance of increased levels of cardiac troponins in patients with end-stage renal disease and those on dialysis, especially in the diagnosis of an acute ischemic myocardial event. Although it is well known for some time that cardiac troponin-T levels are frequently elevated in asymptomatic dialysis patients, many studies have established that this is much less the case for troponin-I. , Nevertheless, some respected medical educational services continue to publish statements that "elevations in serum troponins are commonly observed in dialysis patients, who do not have clinical evidence of myocardial damage,"  which might be interpreted as this being applicable in the same degree to both troponins. A reason for the controversy might be in the case of troponin-I, wherein it may be a lack of standardization of older assays, giving different cut-off values for diagnosing an acute myocardial ischemic event.  Because of this, even now, patients with end-stage renal disease who present with increased levels of troponin-I, above the level diagnostic for an acute myocardial ischemic event, are sometimes labeled as having "renal cause" of increased troponin-I.
In a previous study, using an older version of a microparticle enzyme immunoassay, none of 93 asymptomatic dialysis patients had troponin-I levels more than 2.0 ng/mL (the cut-off point for diagnosis of an acute myocardial infarction using the assay of that time); however, nine patients had increased troponin-I levels >0.0 ng/mL, but below 2.0 ng/mL. 
Newer versions of the assay have improved sensitivity and specificity, and the diagnostic level for an acute myocardial infarction has been set by the manufacturer to 0.3 ng/mL.  However, in our laboratory, after the introduction of the new version of the troponin-I assay in 2008, this cut-off point has been set at 0.4 ng/mL.
In view of the improved performance of the latest generation of tests, we repeated our study in the present dialysis population, both hemo- and peritoneal dialysis, to establish whether, and if at all to which degree, elevated blood levels of cardiac troponin-I are seen in asymptomatic dialysis patients. Other cardiac markers, including creatine kinase (CK), creatine kinase-MB (CK-MB), aspartate amino-transferase (AST) and lactate dehydrogenase (LDH) were also included in the study.
It has been reported that patients with troponin-I levels of ≥0.1 ng/mL, but less than the cut-off level for an acute myocardial event, have increased risk for cardiovascular and total mortality in the short- and long term, ,, and increased prevalence of coronary artery pathology. ,, Therefore, we compared some of the cardiovascular risk factors in these patients with those in patients having a troponin level of 0.0 ng/mL: age, gender, body mass index (BMI), prevalence of diabetes mellitus and hypertension, total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), very-low-density lipoprotein cholesterol (VLDL) and triglycerides, as well as C-reactive protein (CRP) as a non-traditional or "novel" cardiovascular risk marker.  The duration of dialysis (in months) and quality of dialysis as measured by Kt/V were also included in the comparison.
| Methods|| |
From all dialysis patients (hemo- and peritoneal dialysis; total n = 150) pre-dialysis blood samples for troponin-I, CK, CK-MB, AST and LDH, lipid parameters (total cholesterol, LDL, HDL, VLDL, triglycerides) and CRP were taken at one occasion.
From all the patients, the following parameters were recorded: age, gender, body mass index (BMI), dialysis modality (hemo- or peritoneal dialysis), presence of diabetes mellitus and/or hypertension, duration of dialysis (in months) and achieved quality of dialysis as measured by single-pool Kt/V in hemodialysis patients and weekly Kt/V in peritoneal dialysis patients. Patients with a recent history of an ischemic cardiac event (within three months) were excluded. Age was not taken as an exclusion criteria, as it is known that the cardiovascular risk in patients on dialysis is increased in all the age categories. 
Troponin-I levels were measured by a commercial chemiluminescent microparticle immunoassay (CMIA) (Architect stat Troponin-I ®, Abbott Laboratories, Abbott Park, IL, USA), for which the cut-off value for detection of myocardial infarction or ischemic damage is set by the manufacturer at 0.3 ng/mL.  In our laboratory, the cut-off point for myocardial infarction or ischemic damage has been kept at ≥0.4 ng/mL. To validate the specificity of the assay, troponin-I was also measured in 151 healthy blood donors. CK, CK-MB, AST, and LDH, total cholesterol, triglycerides, LDL, HDL, VLDL and CRP levels were measured by routine laboratory methods.
Differences between groups (hemo- and peritoneal dialysis patients, and patients with troponin-I levels of 0.0 ng/mL and those with levels of 0.1 up to 0.3 ng/mL) were analyzed with a non-parametric (Mann-Whitney test) test for continuous variables and with the Pearson chi-square test for discrete variables. The statistical program used was SPSS version 13 (SPSS Inc., Chicago, IL, USA). The level of significance was set at P <0.05.
| Results|| |
One hundred fifty patients were included in the study, of which 79 were males (52.7%) and 71 were females (47.3%). There were 122 patients on hemodialysis (81.3%) and 28 patients on peritoneal dialysis (18.7%). All patients were asymptomatic (no shortness of breath or chest pain on presentation) and none of the patients suffered an acute myocardial event during or just after the blood sampling.
The age of the patients ranged from seven to 102 years, with a mean of 57.0 ± 18.8 years. There was no significant difference in the age between hemo- and peritoneal dialysis patients. Of all patients, 66 (44%) were diabetics, with no significant difference between hemo- and peritoneal dialysis patients. However, hypertension, as defined by the use of antihypertensive agents, was more prevalent in peritoneal dialysis patients (71.3% in hemodialysis patients, while 100% in peritoneal dialysis patients; P = 0.001).
The troponin-I values in the whole group of 150 patients, as well as separately for hemo- and peritoneal dialysis patients, are given in [Table 1]. The results show that 85.3% of the asymptomatic dialysis patients had troponin-I levels of 0.0 ng/mL and 14.7% had levels between 0.1 and 0.3 ng/mL, but none had concentrations at or above the cut-off level (0.4 ng/mL), diagnostic for an acute myocardial ischemic event with the troponin-I assay used. There was no difference in these frequencies between hemo- and peritoneal dialysis patients. None of the healthy blood donors had troponin-I levels of ≥0.1 ng/mL. Six of the total group of 150 patients had increased CK levels (>200 U/L), four had increased CK-MB levels (>24 U/L), 17 had increased LDH levels (>243 U/L) and six showed elevated AST levels (>34 U/L).
In the group of 22 patients with troponin-I levels between 0.1 and 0.3 ng/mL, none had increased CK and CK-MB levels, but two had increased values of LDH and two showed elevated AST. The study also showed that there were no differences between the patients with troponin-I levels of 0.0 ng/mL and those with levels between 0.1 and 0.3 ng/mL in age, BMI, prevalence of diabetes mellitus and hypertension, duration of dialysis, Kt/V in hemodialysis patients as well as total cholesterol, LDL and HDL. Male gender was more common in the patients with troponin-I levels between 0.1 and 0.3 ng/mL. In those patients who were on peritoneal dialysis, the weekly Kt/V was lower compared with the group with troponin-I of 0.0 ng/mL. Surprisingly, the triglycerides and VLDL levels were lower in the patients with troponin-I levels between 0.1 and 0.3 ng/mL. However, the CRP levels were significantly higher in this group compared with patients with troponin-I levels of 0.0 ng/mL [Table 2].
|Table 2: Age, gender, body mass index (BMI), diabetes mellitus, hypertension, duration of dialysis, Kt/V, total cholesterol, LDL, HDL, triglycerides, VLDL and CRP levels in dialysis patients with troponin-I levels of 0.0 ng/mL and of 0.1–0.3 ng/mL.|
Click here to view
| Discussion|| |
The results indicate that in asymptomatic patients with end-stage renal disease (on hemo- or peritoneal dialysis), troponin-I is unlikely to be ≥0.4 ng/mL, which is the cut-off level for diagnosing a myocardial ischemic event by the assay used in the present study. The high specificity of the test was also confirmed in 151 healthy blood donors, none of which had values of ≥0.1 ng/mL.
In a review of 39 studies in 2004, Needham et al found in patients with chronic kidney disease (CKD) and on dialysis, a specificity of troponin-I in diagnosing an acute myocardial infarction of 97% (confidence interval: 93-99%).  Together with more recent findings, ,,,, the results of the present study, in our opinion, can considerably contribute to settle the debate whether or not in patients with end-stage renal disease falsely elevated levels of troponin-I, not related to an acute myocardial event, "commonly" occur.
As has been known for some time, this finding is clearly different compared with cardiac troponin-T, where detectable levels have been found in 30-94% ,, of the dialysis population and levels above the diagnostic level for an acute myocardial infarction in more than 25%.  Needham et al found for troponin-T, in the same review cited earlier, a specificity for the diagnosis of an acute myocardial infarction in dialysis patients of only 71%.  Recently, Hayashi et al reported that of 142 asymptomatic patients with end-stage renal disease but prior to starting dialysis, 23 (16%) had troponin-T levels above the diagnostic threshold of an acute myocardial infarction. 
As has been described in previous studies, , we also found in 14.7% of the patients troponin-I levels ≥0.1 ng/mL, but below the level diagnostic for an acute myocardial infarction (≥0.4 ng/mL). These levels in dialysis patients have been associated with increased mortality in the short- as well as the long term, ,, and also with coronary calcifications  and coronary artery disease. ,
In the present study, we found no correlation between increased troponin-I levels and some "traditional" risk factors for atherosclerosis (except male gender), such as LDL, age, BMI, prevalence of diabetes mellitus and hypertension. Surprisingly, there was even a negative correlation with triglycerides and VLDL levels. We have no explanation for this finding. None of these patients were on triglyceride-lowering drugs such as fenofibrate. A positive association was seen with CRP. We also found that the weekly Kt/V was lower in patients on peritoneal dialysis with increased troponin-I levels [Table 2].
These preliminary findings might therefore provide support for the importance of non-traditional ("novel") risk factors in the pathogenesis of coronary artery disease in dialysis patients, in particular inadequate dialysis, which is a well known indicator of poor outcome as well as inflammation, as reflected by the high level of CRP. ,,, Some of these studies have found an association of both troponin-I and CRP with prognosis  and angiographically defined coronary artery disease. 
In this study, we found that levels equal to or above 0.1 ng/mL, but below 0.4 ng/mL (the diagnostic cut-off for an acute AME), indicate that such patients are at increased risk for coronary heart disease and mortality, and that the findings of an increased level of CRP and inadequate dialysis adds to that risk. However, as elaborated by Stenvinkel et al, the effects of "traditional" and "novel" risk factors on morbidity and mortality in dialysis patients are complex and interrelated, and only large studies using innovative techniques might be able to unravel the pathogenesis.  Taken together, the present study should add strong support in settling the debate as to whether or not in patients on dialysis falsely elevated levels of troponin-I "commonly" occur.
| References|| |
|1.||Martin GS, Becker BN, Schulman G. Cardiac troponin-I accurately predicts myocardial injury in renal failure Nephrol Dial Transplant 1998;13/7:1709-12 |
|2.||Watnick S, Perazella MA. Cardiac troponins: utility in renal insufficiency and end-stage renal disease. Semin Dial 2002;15:66-70. |
|3.||Henrich WL, Serum cardiac enzymes in patients with renal failure. In: UpToDate, Basow DS, ed., UpToDate, Waltham MA, 2009. |
|4.||Khan NA, Hemmelgarn BR, Tonelli M, Thompson CR, Levin A. Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: A meta-analysis. Circulation 2005;112:3088-96. |
|5.||Hussein M, Mooij J, Roujouleh H, Al Shenawi O. Cardiac troponin-I and its prognostic significance in a dialysis population. Hemodial Int 2004;8:332-7. |
|6.||Package Insert. Architect STAT Troponin-I. Abbott Laboratories Diagnostics Division. Abbott Park, IL 60064, USA, 2008. |
|7.||Apple FS. Murakami MM. Pearce LA, Herzog CA. Predictive Value of Cardiac Troponin I and T for Subsequent Death in End-Stage Renal Disease. Circulation 2002;106:2941-5. |
|8.||Boulier A, Jaussent I, Terrier N, et al. Measurement of circulating troponin Ic enhances the prognostic value of C-reactive protein in haemodialysis patients. Nephrol Dial Transplant 2004;19:2313-8 |
|9.||Jung HH, Ma KR, Han H. Elevated concentrations of cardiac troponins are associated with severe coronary artery calcification in asymptomatic haemodialysis patients. Nephrol Dial Transplant 2004;19:3117-23. |
|10.||Zumrutdal A, Baltali M, Micozkadioglu H, et al. Determinants of coronary artery disease in nondiabetic hemodialysis patients: A matched case-control study. Ren Fail 2007;29:67-71. |
|11.||Katerinis I, Nguyen QV, Magnin JL, Descombes E. Cardiac findings in asymptomatic chronic hemodialysis patients with persistently elevated cardiac troponin I levels. Ren Fail 2008; 30:357-62. |
|12.||Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimbürger O, Massy Z. Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: How do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol 2008;3:505-21. |
|13.||Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998 (12 Suppl):S16-23. |
|14.||Needham DM, Shufelt KA, Tomlinson G, Scholey JW, Newton GE. Troponin I and T levels in renal failure patients without acute coronary syndrome: A systematic review of the literature. Can J Cardiol 2004;20:1212-8. |
|15.||Donnino MW, Karriem-Norwood V, Rivers EP, et al. Prevalence of elevated troponin I in end-stage renal disease patients receiving hemodialysis. Acad Emerg Med 2004;11:979-81. |
|16.||Buhaescu I, Izzedine H, Covic A. Cardiac troponins in renal failure - time for an optimistic consensus? Int J Clin Pract 2005;59: 1317-25. |
|17.||Roberts MA, MacMillan N, Hare DL, et al. Cardiac troponin levels in asymptomatic patients on the renal transplant waiting list. Nephrology (Carlton) 2006;11:471-6. |
|18.||Deléaval P, Descombes E, Magnin JL, Martin PY, Fellay G. Differences in cardiac troponin I and T levels measured in asymptomatic hemodialysis patients with last generation immunoassays. Nephrol Ther 2006;2:75-81. |
|19.||Brunet P, Oddoze C, Paganelli F, et al. Cardiac troponins I and T in hemodialysis patients without acute coronary syndrome. Int J Cardiol 2008;129:205-9. |
|20.||Stolear JC, Georges B, Shita A, Verbeelen D. The predictive value of cardiac troponin T measurements in subjects on regular haemodialysis. Nephrol Dial Transplant 1999;14: 1961-7. |
|21.||Deegan PB, Lafferty ME, Blumsohn A, Henderson IS, Mcgregor E. Prognostic value of troponin T in hemodialysis patients is independent of comorbidity. Kidney Int 2001;60: 2399-405. |
|22.||Mallamaci F, Zoccali C, Parlongo S, et al. Troponin is related to left ventricular mass and predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2002;40:68-75. |
|23.||deFilippi C, Wasserman S, Rosanio S, et al. Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis. JAMA 2003;290:353-9. |
|24.||Hayashi T, Obi Y, Kimura T, et al. Cardiac troponin T predicts occult coronary artery stenosis in patients with chronic kidney disease at the start of renal replacement therapy. Nephrol Dial Transplant 2008;23:2936-42. |
|25.||Tomiyama C, Higa A, Dalboni MA, et al. The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients. Nephrol Dial Transplant 2006;21: 2464-71. |
|26.||Spiegel DM, Raggi P, Smits G, Block GA. Factors associated with mortality in patients new to haemodialysis. Nephrol Dial Transplant 2007;22:3568-72. |
Magdi M Hussein
Head, Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, P.O. Box 1347, Taif
[Table 1], [Table 2]