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Value of Troponin T as a Screening Test for Left Ventricular Hypertrophy in CKD
Editorial Value of Troponin T as a Screening Test for Left Ventricular Hypertrophy in CKD Related Article, p 701
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ardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) stages 4-5.1 The excessive CVD risk in these patients arises from substantially elevated frequencies of coronary artery disease, heart failure, cardiac hypertrophy, and cardiomyopathy. Therefore, discovering which serum biomarkers can be used to profile CVD risk and identify patients at highest risk of early mortality is an important research goal. The cardiac form of troponin T (cTnT) is a biomarker that already is used extensively in the general population to establish the diagnosis and prognosis of acute coronary heart disease. Substantial progress has been made regarding the underlying biology of cTnT and its long-term prognostic value in both the general population and patients with various clinical conditions, including dialysis patients. In patients with uremia, cTnT levels increase in serum due to the diminished clearance capacity of the kidneys. Although this accumulation occurs in tandem with other biomarkers, such as brain and atrial natriuretic peptides, cTnT has remarkable associations with left ventricular (LV) mass and function and predicts all-cause and CVD mortality in clinically stable dialysis patients who do not have a clinical diagnosis of heart failure.2 In hemodialysis patients with no CVD symptoms, cTnT levels increase in step with LV mass, echoing the decline in LV systolic function.2 These changes likely occur because of subtle myocardial cell ischemia facilitated by the interstitial fibrosis in the uremic myocardium. The resulting myocardial cell hypoxia allows myocardial cell proteins, including cTnT, to leak into systemic circulation. Biologically speaking, cTnT reflects more than just LV mass and function: its plasma concentration denotes levels of myocardial cell distress. Wang et al3 have described how cTnT could be informative in asymptomatic peritoneal dialysis patients, showing that plasma cTnT level has strong prognostic potential for outcomes in this patient population. In this issue of AJKD, Mishra et al4 report on the relationship between cTnT level and cardiac alterations in a large cohort of patients with CKD stages 2-4 who did not have clinical signs of heart failure and confirm previous observations in dialysis patients.5 The authors found cTnT level to be associated strongly with LV hypertrophy (LVH) and to a minor degree with LV systolic dysfunction. The study’s crosssectional design is well suited to studying the diagnosAm J Kidney Dis. 2013;61(5):689-691
tic value of cTnT level for LVH, but it is inherently inadequate to test the prognostic value of this biomarker. In studies by other investigators performed in patients with CKD with type 2 diabetes who were not on dialysis therapy, cTnT level predicted progression to chronic kidney failure beyond established risk factors,6 which suggests a link between cardiac injury and the development of chronic kidney failure, a hypothesis supported by experimental data in the rat.7 Thus, cTnT level is an intriguing indicator of ongoing cardiac disease, as well as a predictor of the evolution of CKD. Therefore, studies focusing on the diagnostic and prognostic value of cTnT level represent a worthwhile clinical research effort. Validating a novel biomarker in clinical medicine demands a phased analytical approach. Early-phase studies should demonstrate that the biomarker under investigation reflects the severity of a given clinical condition and provides information on the disease above and beyond what traditional biomarkers provide. Midphase studies should investigate how much the additional information provided by the new biomarker affects the decisions of clinicians in the context of screening and diagnosis, which represent 2 distinct areas of clinical and public health research. A diagnostic test is used to establish the presence/absence of a given disease in symptomatic individuals, whereas a screening test is applied to identify those who could be affected by the disease of interest in a preclinical stage (asymptomatic individuals). Results of a screening test for the identification or exclusion of a given disease should be confirmed by a gold-standard diagnostic test. The study by Mishra et al4 investigated the predictive value of cTnT for screening for functional and anatomical LV alterations in patients with CKD without clinical heart failure by focusing on sensitivity and specificity, in other words, 2 fixed characteristics of diagnostic test performance that are fully independent of disease frequency.8 However, for screening purposes, positive and negaAddress correspondence to Francesca Mallamaci, MD, CNRIBIM and Nephrology, Dialysis and Transplantation Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, c/o EUROLINE di Barillà Francesca-Via Vallone Petrara 55-57, CAP: 89124, Reggio Calabria, Italy. E-mail: [email protected] © 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.02.352 689
Mallamaci and Tripepi
Posive Predicve Value (%)
100 80 60
Prevalence of LVH (%)
40 100 60
eGFR (ml/min/1.73 m2)
20 70 60 50 40 30 20
Cardiac Troponin T Figure 1. Positive predictive values for left ventricular hypertrophy (LVH) of cardiac tropnin T (cTnT; cut-off: 90th percentile), LVH prevalence and estimated glomerular filtration rate (eGFR), based on cTnT levels. Abbreviation: Q, quartile.
tive predictive values of cTnT also should be given because these 2 indexes take into account the prevalence of the disease,8 a fundamental issue in any screening program. The positive predictive value is the proportion of patients with a positive test result who have the disease of interest, whereas the negative predictive value is the proportion of patients with a negative test result who are disease free. Given that positive and negative predictive values depend on the prevalence of the disease in the population studied, these indicators cannot be considered as fixed characteristics of a test. To better clarify the potential role of cTnT as a screening test, we compiled 3 graphs from the data reported by Mishra et al4 in their first table. These graphs show cTnT’s positive predictive value (see upper panel in Fig 1) for LVH (cutoff, 90th percentile) as a function of estimated glomerular filtration rate (eGFR), LVH prevalence, and cTnT level (Fig 1). The positive predictive value of cTnT increases in close parallel with the reduction in eGFR, which indicates that the level of kidney function has a crucial role in the interpretation of the predictive value of cTnT level 690
to identify LVH in patients with CKD. The increasing positive predictive value of cTnT level in patients with progressively lower eGFRs depends on the fact that the proportion of patients with LVH increases as kidney function deteriorates (Fig 1). The prevalence of LVH was 20% in patients with an average eGFR of 51 mL/min/1.73 m2, but reached 74% in those with an average eGFR of 33 mL/min/1.73 m2. Of note, in patients with a marked reduction in eGFR (mean, 33 ⫾ 14 [standard deviation] mL/min/1.73 m2), the positive predictive value of cTnT level for LVH was 89% and almost identical to that reported in hemodialysis patients, 87%.5 In this context, the authors’ conclusion that “the utility of cTnT for screening patients with CKD for cardiac structural and functional abnormalities is limited” should be mitigated to say that the positive predictive value of cTnT level for LVH becomes stronger with lower kidney function. In contrast, the negative predictive value of cTnT level for excluding patients with systolic dysfunction (ie, ejection fraction ⬍45%) was affected little by level of kidney function, the negative predictive value of cTnT being 96% in patients with relatively high eGFRs (51 mL/min/1.73 m2) and 86% in those with relatively low eGFRs (33 mL/min/1.73 m2). This large well-conducted study by Mishra et al4 shows that cTnT has potential diagnostic value for the identification of LVH in patients with CKD stages 2-4. Whether cTnT level will be useful in the context of clinical decision making needs to be formally investigated in a randomized, controlled clinical trial. Francesca Mallamaci, MD Giovanni Tripepi, PhD CNR-IBIM Reggio di Calabria, Italy
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. 2. 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. 3. Wang AY, Lam CW, Wang M, et al. Prognostic value of cardiac troponin T is independent of inflammation, residual renal function, and cardiac hypertrophy and dysfunction in peritoneal dialysis patients. Clin Chem. 2007;53:882-889. 4. Mishra RK, Li Y, DeFilippi C, et al. Association of cardiac troponin T with left ventricular structure and function in CKD. Am J Kidney Dis. 2013;61(5):701-709. Am J Kidney Dis. 2013;61(5):689-691
Editorial 5. Mallamaci F, Zoccali C, Parlongo S, et al; Cardiovascular Risk Extended Evaluation in Dialysis Investigators. Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients. Kidney Int. 2002;62(5):1884-1890. 6. Desai AS, Toto R, Jarolim P, et al. Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD. Am J Kidney Dis. 2011;58:717-728.
Am J Kidney Dis. 2013;61(5):689-691
7. van Dokkum RP, Eijkelkamp WB, Kluppel AC, et al. Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. J Am Soc Nephrol. 2004;15:3103-3010. 8. van Stralen KJ, Stel VS, Reitsma JB, Dekker FW, Zoccali C, Jager KJ. Diagnostic methods I: sensitivity, specificity, and other measures of accuracy. Kidney Int. 2009;75:1257-1263.
691
C
ardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) stages 4-5.1 The excessive CVD risk in these patients arises from substantially elevated frequencies of coronary artery disease, heart failure, cardiac hypertrophy, and cardiomyopathy. Therefore, discovering which serum biomarkers can be used to profile CVD risk and identify patients at highest risk of early mortality is an important research goal. The cardiac form of troponin T (cTnT) is a biomarker that already is used extensively in the general population to establish the diagnosis and prognosis of acute coronary heart disease. Substantial progress has been made regarding the underlying biology of cTnT and its long-term prognostic value in both the general population and patients with various clinical conditions, including dialysis patients. In patients with uremia, cTnT levels increase in serum due to the diminished clearance capacity of the kidneys. Although this accumulation occurs in tandem with other biomarkers, such as brain and atrial natriuretic peptides, cTnT has remarkable associations with left ventricular (LV) mass and function and predicts all-cause and CVD mortality in clinically stable dialysis patients who do not have a clinical diagnosis of heart failure.2 In hemodialysis patients with no CVD symptoms, cTnT levels increase in step with LV mass, echoing the decline in LV systolic function.2 These changes likely occur because of subtle myocardial cell ischemia facilitated by the interstitial fibrosis in the uremic myocardium. The resulting myocardial cell hypoxia allows myocardial cell proteins, including cTnT, to leak into systemic circulation. Biologically speaking, cTnT reflects more than just LV mass and function: its plasma concentration denotes levels of myocardial cell distress. Wang et al3 have described how cTnT could be informative in asymptomatic peritoneal dialysis patients, showing that plasma cTnT level has strong prognostic potential for outcomes in this patient population. In this issue of AJKD, Mishra et al4 report on the relationship between cTnT level and cardiac alterations in a large cohort of patients with CKD stages 2-4 who did not have clinical signs of heart failure and confirm previous observations in dialysis patients.5 The authors found cTnT level to be associated strongly with LV hypertrophy (LVH) and to a minor degree with LV systolic dysfunction. The study’s crosssectional design is well suited to studying the diagnosAm J Kidney Dis. 2013;61(5):689-691
tic value of cTnT level for LVH, but it is inherently inadequate to test the prognostic value of this biomarker. In studies by other investigators performed in patients with CKD with type 2 diabetes who were not on dialysis therapy, cTnT level predicted progression to chronic kidney failure beyond established risk factors,6 which suggests a link between cardiac injury and the development of chronic kidney failure, a hypothesis supported by experimental data in the rat.7 Thus, cTnT level is an intriguing indicator of ongoing cardiac disease, as well as a predictor of the evolution of CKD. Therefore, studies focusing on the diagnostic and prognostic value of cTnT level represent a worthwhile clinical research effort. Validating a novel biomarker in clinical medicine demands a phased analytical approach. Early-phase studies should demonstrate that the biomarker under investigation reflects the severity of a given clinical condition and provides information on the disease above and beyond what traditional biomarkers provide. Midphase studies should investigate how much the additional information provided by the new biomarker affects the decisions of clinicians in the context of screening and diagnosis, which represent 2 distinct areas of clinical and public health research. A diagnostic test is used to establish the presence/absence of a given disease in symptomatic individuals, whereas a screening test is applied to identify those who could be affected by the disease of interest in a preclinical stage (asymptomatic individuals). Results of a screening test for the identification or exclusion of a given disease should be confirmed by a gold-standard diagnostic test. The study by Mishra et al4 investigated the predictive value of cTnT for screening for functional and anatomical LV alterations in patients with CKD without clinical heart failure by focusing on sensitivity and specificity, in other words, 2 fixed characteristics of diagnostic test performance that are fully independent of disease frequency.8 However, for screening purposes, positive and negaAddress correspondence to Francesca Mallamaci, MD, CNRIBIM and Nephrology, Dialysis and Transplantation Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, c/o EUROLINE di Barillà Francesca-Via Vallone Petrara 55-57, CAP: 89124, Reggio Calabria, Italy. E-mail: [email protected] © 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.02.352 689
Mallamaci and Tripepi
Posive Predicve Value (%)
100 80 60
Prevalence of LVH (%)
40 100 60
eGFR (ml/min/1.73 m2)
20 70 60 50 40 30 20
Cardiac Troponin T Figure 1. Positive predictive values for left ventricular hypertrophy (LVH) of cardiac tropnin T (cTnT; cut-off: 90th percentile), LVH prevalence and estimated glomerular filtration rate (eGFR), based on cTnT levels. Abbreviation: Q, quartile.
tive predictive values of cTnT also should be given because these 2 indexes take into account the prevalence of the disease,8 a fundamental issue in any screening program. The positive predictive value is the proportion of patients with a positive test result who have the disease of interest, whereas the negative predictive value is the proportion of patients with a negative test result who are disease free. Given that positive and negative predictive values depend on the prevalence of the disease in the population studied, these indicators cannot be considered as fixed characteristics of a test. To better clarify the potential role of cTnT as a screening test, we compiled 3 graphs from the data reported by Mishra et al4 in their first table. These graphs show cTnT’s positive predictive value (see upper panel in Fig 1) for LVH (cutoff, 90th percentile) as a function of estimated glomerular filtration rate (eGFR), LVH prevalence, and cTnT level (Fig 1). The positive predictive value of cTnT increases in close parallel with the reduction in eGFR, which indicates that the level of kidney function has a crucial role in the interpretation of the predictive value of cTnT level 690
to identify LVH in patients with CKD. The increasing positive predictive value of cTnT level in patients with progressively lower eGFRs depends on the fact that the proportion of patients with LVH increases as kidney function deteriorates (Fig 1). The prevalence of LVH was 20% in patients with an average eGFR of 51 mL/min/1.73 m2, but reached 74% in those with an average eGFR of 33 mL/min/1.73 m2. Of note, in patients with a marked reduction in eGFR (mean, 33 ⫾ 14 [standard deviation] mL/min/1.73 m2), the positive predictive value of cTnT level for LVH was 89% and almost identical to that reported in hemodialysis patients, 87%.5 In this context, the authors’ conclusion that “the utility of cTnT for screening patients with CKD for cardiac structural and functional abnormalities is limited” should be mitigated to say that the positive predictive value of cTnT level for LVH becomes stronger with lower kidney function. In contrast, the negative predictive value of cTnT level for excluding patients with systolic dysfunction (ie, ejection fraction ⬍45%) was affected little by level of kidney function, the negative predictive value of cTnT being 96% in patients with relatively high eGFRs (51 mL/min/1.73 m2) and 86% in those with relatively low eGFRs (33 mL/min/1.73 m2). This large well-conducted study by Mishra et al4 shows that cTnT has potential diagnostic value for the identification of LVH in patients with CKD stages 2-4. Whether cTnT level will be useful in the context of clinical decision making needs to be formally investigated in a randomized, controlled clinical trial. Francesca Mallamaci, MD Giovanni Tripepi, PhD CNR-IBIM Reggio di Calabria, Italy
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305. 2. 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. 3. Wang AY, Lam CW, Wang M, et al. Prognostic value of cardiac troponin T is independent of inflammation, residual renal function, and cardiac hypertrophy and dysfunction in peritoneal dialysis patients. Clin Chem. 2007;53:882-889. 4. Mishra RK, Li Y, DeFilippi C, et al. Association of cardiac troponin T with left ventricular structure and function in CKD. Am J Kidney Dis. 2013;61(5):701-709. Am J Kidney Dis. 2013;61(5):689-691
Editorial 5. Mallamaci F, Zoccali C, Parlongo S, et al; Cardiovascular Risk Extended Evaluation in Dialysis Investigators. Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients. Kidney Int. 2002;62(5):1884-1890. 6. Desai AS, Toto R, Jarolim P, et al. Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD. Am J Kidney Dis. 2011;58:717-728.
Am J Kidney Dis. 2013;61(5):689-691
7. van Dokkum RP, Eijkelkamp WB, Kluppel AC, et al. Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. J Am Soc Nephrol. 2004;15:3103-3010. 8. van Stralen KJ, Stel VS, Reitsma JB, Dekker FW, Zoccali C, Jager KJ. Diagnostic methods I: sensitivity, specificity, and other measures of accuracy. Kidney Int. 2009;75:1257-1263.
691