Significance and Measurement of High-sensitivity Troponins I and T in Patients with Chronic Kidney Disease

    Authors

    Abstract

    Chronic kidney disease (CKD) is characterized by gradual progressive loss of all kidney functions over a period of time. One-fifth of men and one-quarter of women over the age of 65 suffer from CKD. Given the growing incidence of diabetes and hypertension, which are the main causes of this disease, CKD is becoming one of the major global public health issues. Cardiovascular diseases are the leading cause of death in people with CKD, primarily heart-related conditions such as ischemic heart disease and heart failure. High-sensitivity troponins (hs-cTnT, hs-cTnI) are crucial biomarkers used in the detection of cardiac pathology. They are mostly used in the detection of acute coronary syndrome, but elevated values can be also observed in several other conditions. Studies have shown that serum troponin levels are elevated in more than two-thirds of patients with CKD on dialysis, even in those without any cardiovascular pathology. The aim of this review was to examine the literature and to determine the reason for troponin increase in patients with CKD, and to establish whether there is a connection between their increase and the mortality rate. A literature search revealed that patients with end-stage renal disease (ESRD) are at especially high risk of cardiovascular morbidity and mortality. Studies have also found a strong association of high-sensitivity troponins with cardiovascular and all-cause mortality in those patients. On the other hand, even though the function of troponins is very well-known, little is known about their production and excretion from the body. The theory that troponins are excreted by the kidneys is becoming widely accepted in scientific circles. New studies, some of which are Croatian, have demonstrated the presence of troponins in urine, but further research is needed to determine whether it is possible to use troponins in urine as potential biomarkers for cardiovascular and kidney disease.

    Keywords

    chronic kidney disease, biomarkers, troponins, mortality, urine

    DOI

    https://doi.org/10.15836/ccar2022.3

    Full Text

    ## TROPONIN T Given the pandemic scale of the issue, the association between serum concentrations of troponin and CV morbidity and mortality in patients with CKD has been vigorously investigated over the last 20 years. In one of the initial studies conducted by Dierkes et al., 102 patients on dialysis were followed over the course of two years, and it was demonstrated that the group of 12 patients who had increased concentrations of cTnT, above 100 ng/L, had significantly higher mortality (>80%). ( 8 ) A group of 40 patients had cTnT concentrations above 40 ng/L, and 18 persons died in this group during the study period. All patients with undetectable cTnT survived the study period of two years. In conclusion, the sensitivity of elevated cTnT for the prediction of total mortality was 83% for concentrations above 100 ng/L and 45% for concentrations above 40 ng/L. The test specificity was 100%. A total of 33 patients developed some form of CVD during the follow-up period. No significant differences in cTnT concentration were observed in those patients who developed CVD in comparison with those who did not. Over the course of 15-month study, Deegan et al. reported deaths in 13 of 20 patients on dialysis with cTnT concentrations >100 ng/L and in 8 out of 53 patients with cTnT concentrations <100 ng/L. ( 9 ) Mallamaci et al. reported that initial cTnT concentrations during three-year follow-up were higher in patients who died in comparison with those who survived, and were also higher in patients who died of CVD in comparison with those who died of other diseases. ( 10 ) In a one-year follow-up of 94 patients on dialysis, Stolear et al. observed significant differences in survival rates, with those patients who had cTnT concentrations >100 ng/L having significantly poorer outcomes. ( 11 ) Newer studies are based on measuring hs-cTnT using fourth- and fifth-generation tests. Hassan et al. followed a cohort of 393 patients on dialysis for a period of one year. ( 12 ) Median hs-cTnT was 57 ng/L, with no significant difference between patients on peritoneal dialysis and those on hemodialysis. Total mortality and incidence of myocardial infarction increased along with increased hs-cTnT levels. It has been demonstrated that hs-cTnT is an independent outcome predictor (of death or fatal CVD), with an especially significant risk increase for hs-cTnT values above 49 ng/L. ( 13 ) ## TROPONIN I The results of studies conducted on cTnI are much more variable in comparison with studies on cTnT. Namely, some studies did not find an association between cTnI values and CV risk in a six-month follow-up period. ( 14 ) Other studies reported that new hs-cTnI had a similar level of precision in predicting CV risk as those that measure hs-cTnT. ( 15 ) According to one metanalysis, poorer predictivity of cTnI could be a consequence of inadequate test standardization. ( 16 ) Some sources state that hemodialysis could improve cTnI elimination and consequently influence its post-dialysis concentration and thus also its predictive potential. ( 2 ) In order to study the influence of hemodialysis on troponin concentrations, a pilot study was conducted based on measuring cTnT and cTnI concentrations in the dialysate of patients with anuria participating in a chronic hemodialysis program. ( 2 ) The median age in the study was 70 years. None of the participants suffered from heart failure. Troponin concentrations in all participants were measured according to a previously determined schedule. The first dialysate sample was taken half an hour after the start of the dialysis procedure, the second after 120 minutes, and the third after 180 minutes from the beginning of the procedure. cTnT was found in all dialysate samples, as opposed to cTnI, which was found in 53.3%, with higher cTnT concentrations in comparison with cTnI. The differences in troponin concentrations at the end of dialysis in comparison with average troponin T and I concentrations in the dialysate were not statistically significant. These results represent the first demonstration of the presence of troponins T and I in the dialysate of patients with anuria on hemodialysis. ( 2 ) Additionally, it was demonstrated that the concentration of troponin in the dialysate was stable during hemodialysis. The higher concentration of cTnT in comparison with cTnI might be explained by the binding of cTnI to the dialysis membrane. ( 17 ) ## Metabolism and excretion of troponin The structure and synthesis of troponins and the troponin complex as well as their circulation in the blood is well-established. However, not enough is known on the metabolism and excretion of troponin from the body. Troponin metabolism could potentially be the reason for higher troponin values in patients with CKD. A study by E. Michielsen found and described the degradation of troponins after irreversible cardiomyocyte damage. ( 18 ) Lancel et al. described the degradation of troponins within cardiomyocytes as a consequence of the action of proteases sensitive to cellular damage. ( 19 ) Other studies have claimed that the increase in intracellular calcium during ischemia and early myocardial reperfusion leads to the activation of calcium-dependent proteases such as calpain I and II, which subsequently degrade troponins. ( 20 ) Communal et al. pointed to enzymatic troponin degradation by caspase in vitro. ( 21 ) On the other hand, some sources have claimed that the reticuloendothelial system plays a key role in troponin metabolism. ( 22 ) ## The kidneys and troponin excretion Studies have been increasingly leaning towards the theory that the kidneys are the crucial organ for the elimination of troponin from the blood. Given the large molecular mass of intact troponins and the complexes in which they are released into the blood, it is unlikely that such large molecules would be excreted via the kidneys. ( 3 ) Based on the results of the abovementioned studies that demonstrated degradation of troponin into smaller fragments, it can be assumed that such significantly smaller products of degradation could be susceptible to excretion via the kidneys. ( 18 ) Pervan et al. determined the preliminary reference intervals for high-sensitivity troponin I (hs-cTnI) in the urine of healthy subjects. ( 1 ) The sample comprised 60 healthy subjects (30 men and 30 women) who were selected according to the following criteria: non-smokers between the ages of 25 and 65, body-mass index <30 kg/m 2 , absence of acute and chronic diseases, and absence of strenuous physical activity in the previous 7 days and night shit work in the past 30 days from the time the sample was collected. The study demonstrated the presence of troponin I in urine, and a preliminary 99 th percentile upper reference limit of the sampled group was determined. This value was 39.3 ng/L for men and 35.2 ng/L for women. This confirms the hypothesis that troponins are, at least in part, excreted via the kidneys in healthy individuals. ( 1 ) The theory that troponin is excreted via the kidneys is also supported by the fact that patients with ESRD have elevated troponin concentrations even without suspected CV pathology, as do children on dialysis. ( 2 , 23 ) It is thus important that diagnosis of ischemic heart disease in such patients include considering the clinical picture and dynamics of troponin over time, to avoid misdiagnosis of acute coronary syndrome (ACS). Fridén et al. used an animal model (rats) to determine that cTnT secretion via the kidneys is increased at low and stable concentrations in the blood, but when the concertation of cTnT is extremely elevated (for instance after myocardial infarction), extrarenal metabolism pathways become dominant. ( 24 ) This could explain why troponin concentration is elevated in the blood of patients with weakened renal function in the phase when they have not yet developed ACS or some other CV disease. The study by Ziebig et al. provided data on the elimination of troponin through urine that seem to corroborate the theory of V. Fridén, according to which troponin metabolism changes depending on the concentration in the blood. ( 25 ) Marute et al. demonstrated the presence of hs-cTnI in the urine of patients with myocardial damage. ( 26 ) Study participants were selected among patients with non-ST-elevation myocardial infarction (NSTEMI) and patients subjected to invasive cardiological procedures. The results showed that plasma hs-cTnI levels were significantly elevated in patients with NSTEMI and in those who underwent invasive procedures in comparison with healthy controls. In comparison with healthy controls, study subjects also had significantly elevated urine hs-cTnI values, with these values being 1000 to 10 000 times lower in comparison with plasma levels. The population of patients with diabetes, which is also reaching a pandemic scale, deserves special attention, as these patients comprise the majority of patients with ESRD, and it is thus necessary to systematically examine this complex interconnectedness of multiple organ systems, especially the influence of HbA 1c and troponin on final outcomes. ## Conclusion Given the global aging of the population and the continuously increasing incidence of chronic non-infectious diseases such as arterial hypertension and diabetes, we can expect a pandemic-level issue of increasing prevalence of CKD in everyday clinical practice. Although it is widely believed that patients in the end stages of kidney disease who are on dialysis die of kidney disease, the reality is different. Studies have clearly shown that CVDs are the leading cause of death in patients with CKD, especially those with ESRD. In most cases, these are sudden cardiac deaths with underlying ischemic heart disease and heart failure. Stroke and peripheral arterial disease are also common. It is indubitable that high-sensitivity troponin levels are elevated in patients with CKD and ESRD and that they are directly correlated with cardiovascular and total mortality, and thus with increased risk of a fatal outcome.

    Cardiologia Croatica
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    Significance and Measurement of High-sensitivity Troponins I and T in Patients with Chronic Kidney Disease

    Review Article
    Issue1-2
    Published
    Pages3-8
    PDF via DOIhttps://doi.org/10.15836/ccar2022.3
    chronic kidney disease
    biomarkers
    troponins
    mortality
    urine

    Authors

    Branko LozićORCIDSveučilište u Zagrebu, Medicinski fakultet, Zagreb, Hrvatska
    Điđi DelalićORCIDSveučilište u Zagrebu, Medicinski fakultet, Zagreb, Hrvatska
    Domagoj MarkovićORCIDKlinički bolnički centar, Split, Hrvatska
    Tomo SvagušaORCIDKlinička bolnica Dubrava, Hrvatska, Croatia
    Ingrid Prkačin*ORCIDSveučilište u Zagrebu, Medicinski fakultet, Zagreb, Hrvatska

    Abstract

    Chronic kidney disease (CKD) is characterized by gradual progressive loss of all kidney functions over a period of time. One-fifth of men and one-quarter of women over the age of 65 suffer from CKD. Given the growing incidence of diabetes and hypertension, which are the main causes of this disease, CKD is becoming one of the major global public health issues. Cardiovascular diseases are the leading cause of death in people with CKD, primarily heart-related conditions such as ischemic heart disease and heart failure. High-sensitivity troponins (hs-cTnT, hs-cTnI) are crucial biomarkers used in the detection of cardiac pathology. They are mostly used in the detection of acute coronary syndrome, but elevated values can be also observed in several other conditions. Studies have shown that serum troponin levels are elevated in more than two-thirds of patients with CKD on dialysis, even in those without any cardiovascular pathology. The aim of this review was to examine the literature and to determine the reason for troponin increase in patients with CKD, and to establish whether there is a connection between their increase and the mortality rate. A literature search revealed that patients with end-stage renal disease (ESRD) are at especially high risk of cardiovascular morbidity and mortality. Studies have also found a strong association of high-sensitivity troponins with cardiovascular and all-cause mortality in those patients. On the other hand, even though the function of troponins is very well-known, little is known about their production and excretion from the body. The theory that troponins are excreted by the kidneys is becoming widely accepted in scientific circles. New studies, some of which are Croatian, have demonstrated the presence of troponins in urine, but further research is needed to determine whether it is possible to use troponins in urine as potential biomarkers for cardiovascular and kidney disease.

    Full Text

    ## TROPONIN T Given the pandemic scale of the issue, the association between serum concentrations of troponin and CV morbidity and mortality in patients with CKD has been vigorously investigated over the last 20 years. In one of the initial studies conducted by Dierkes et al., 102 patients on dialysis were followed over the course of two years, and it was demonstrated that the group of 12 patients who had increased concentrations of cTnT, above 100 ng/L, had significantly higher mortality (>80%). ( 8 ) A group of 40 patients had cTnT concentrations above 40 ng/L, and 18 persons died in this group during the study period. All patients with undetectable cTnT survived the study period of two years. In conclusion, the sensitivity of elevated cTnT for the prediction of total mortality was 83% for concentrations above 100 ng/L and 45% for concentrations above 40 ng/L. The test specificity was 100%. A total of 33 patients developed some form of CVD during the follow-up period. No significant differences in cTnT concentration were observed in those patients who developed CVD in comparison with those who did not. Over the course of 15-month study, Deegan et al. reported deaths in 13 of 20 patients on dialysis with cTnT concentrations >100 ng/L and in 8 out of 53 patients with cTnT concentrations <100 ng/L. ( 9 ) Mallamaci et al. reported that initial cTnT concentrations during three-year follow-up were higher in patients who died in comparison with those who survived, and were also higher in patients who died of CVD in comparison with those who died of other diseases. ( 10 ) In a one-year follow-up of 94 patients on dialysis, Stolear et al. observed significant differences in survival rates, with those patients who had cTnT concentrations >100 ng/L having significantly poorer outcomes. ( 11 ) Newer studies are based on measuring hs-cTnT using fourth- and fifth-generation tests. Hassan et al. followed a cohort of 393 patients on dialysis for a period of one year. ( 12 ) Median hs-cTnT was 57 ng/L, with no significant difference between patients on peritoneal dialysis and those on hemodialysis. Total mortality and incidence of myocardial infarction increased along with increased hs-cTnT levels. It has been demonstrated that hs-cTnT is an independent outcome predictor (of death or fatal CVD), with an especially significant risk increase for hs-cTnT values above 49 ng/L. ( 13 ) ## TROPONIN I The results of studies conducted on cTnI are much more variable in comparison with studies on cTnT. Namely, some studies did not find an association between cTnI values and CV risk in a six-month follow-up period. ( 14 ) Other studies reported that new hs-cTnI had a similar level of precision in predicting CV risk as those that measure hs-cTnT. ( 15 ) According to one metanalysis, poorer predictivity of cTnI could be a consequence of inadequate test standardization. ( 16 ) Some sources state that hemodialysis could improve cTnI elimination and consequently influence its post-dialysis concentration and thus also its predictive potential. ( 2 ) In order to study the influence of hemodialysis on troponin concentrations, a pilot study was conducted based on measuring cTnT and cTnI concentrations in the dialysate of patients with anuria participating in a chronic hemodialysis program. ( 2 ) The median age in the study was 70 years. None of the participants suffered from heart failure. Troponin concentrations in all participants were measured according to a previously determined schedule. The first dialysate sample was taken half an hour after the start of the dialysis procedure, the second after 120 minutes, and the third after 180 minutes from the beginning of the procedure. cTnT was found in all dialysate samples, as opposed to cTnI, which was found in 53.3%, with higher cTnT concentrations in comparison with cTnI. The differences in troponin concentrations at the end of dialysis in comparison with average troponin T and I concentrations in the dialysate were not statistically significant. These results represent the first demonstration of the presence of troponins T and I in the dialysate of patients with anuria on hemodialysis. ( 2 ) Additionally, it was demonstrated that the concentration of troponin in the dialysate was stable during hemodialysis. The higher concentration of cTnT in comparison with cTnI might be explained by the binding of cTnI to the dialysis membrane. ( 17 ) ## Metabolism and excretion of troponin The structure and synthesis of troponins and the troponin complex as well as their circulation in the blood is well-established. However, not enough is known on the metabolism and excretion of troponin from the body. Troponin metabolism could potentially be the reason for higher troponin values in patients with CKD. A study by E. Michielsen found and described the degradation of troponins after irreversible cardiomyocyte damage. ( 18 ) Lancel et al. described the degradation of troponins within cardiomyocytes as a consequence of the action of proteases sensitive to cellular damage. ( 19 ) Other studies have claimed that the increase in intracellular calcium during ischemia and early myocardial reperfusion leads to the activation of calcium-dependent proteases such as calpain I and II, which subsequently degrade troponins. ( 20 ) Communal et al. pointed to enzymatic troponin degradation by caspase in vitro. ( 21 ) On the other hand, some sources have claimed that the reticuloendothelial system plays a key role in troponin metabolism. ( 22 ) ## The kidneys and troponin excretion Studies have been increasingly leaning towards the theory that the kidneys are the crucial organ for the elimination of troponin from the blood. Given the large molecular mass of intact troponins and the complexes in which they are released into the blood, it is unlikely that such large molecules would be excreted via the kidneys. ( 3 ) Based on the results of the abovementioned studies that demonstrated degradation of troponin into smaller fragments, it can be assumed that such significantly smaller products of degradation could be susceptible to excretion via the kidneys. ( 18 ) Pervan et al. determined the preliminary reference intervals for high-sensitivity troponin I (hs-cTnI) in the urine of healthy subjects. ( 1 ) The sample comprised 60 healthy subjects (30 men and 30 women) who were selected according to the following criteria: non-smokers between the ages of 25 and 65, body-mass index <30 kg/m 2 , absence of acute and chronic diseases, and absence of strenuous physical activity in the previous 7 days and night shit work in the past 30 days from the time the sample was collected. The study demonstrated the presence of troponin I in urine, and a preliminary 99 th percentile upper reference limit of the sampled group was determined. This value was 39.3 ng/L for men and 35.2 ng/L for women. This confirms the hypothesis that troponins are, at least in part, excreted via the kidneys in healthy individuals. ( 1 ) The theory that troponin is excreted via the kidneys is also supported by the fact that patients with ESRD have elevated troponin concentrations even without suspected CV pathology, as do children on dialysis. ( 2 , 23 ) It is thus important that diagnosis of ischemic heart disease in such patients include considering the clinical picture and dynamics of troponin over time, to avoid misdiagnosis of acute coronary syndrome (ACS). Fridén et al. used an animal model (rats) to determine that cTnT secretion via the kidneys is increased at low and stable concentrations in the blood, but when the concertation of cTnT is extremely elevated (for instance after myocardial infarction), extrarenal metabolism pathways become dominant. ( 24 ) This could explain why troponin concentration is elevated in the blood of patients with weakened renal function in the phase when they have not yet developed ACS or some other CV disease. The study by Ziebig et al. provided data on the elimination of troponin through urine that seem to corroborate the theory of V. Fridén, according to which troponin metabolism changes depending on the concentration in the blood. ( 25 ) Marute et al. demonstrated the presence of hs-cTnI in the urine of patients with myocardial damage. ( 26 ) Study participants were selected among patients with non-ST-elevation myocardial infarction (NSTEMI) and patients subjected to invasive cardiological procedures. The results showed that plasma hs-cTnI levels were significantly elevated in patients with NSTEMI and in those who underwent invasive procedures in comparison with healthy controls. In comparison with healthy controls, study subjects also had significantly elevated urine hs-cTnI values, with these values being 1000 to 10 000 times lower in comparison with plasma levels. The population of patients with diabetes, which is also reaching a pandemic scale, deserves special attention, as these patients comprise the majority of patients with ESRD, and it is thus necessary to systematically examine this complex interconnectedness of multiple organ systems, especially the influence of HbA 1c and troponin on final outcomes. ## Conclusion Given the global aging of the population and the continuously increasing incidence of chronic non-infectious diseases such as arterial hypertension and diabetes, we can expect a pandemic-level issue of increasing prevalence of CKD in everyday clinical practice. Although it is widely believed that patients in the end stages of kidney disease who are on dialysis die of kidney disease, the reality is different. Studies have clearly shown that CVDs are the leading cause of death in patients with CKD, especially those with ESRD. In most cases, these are sudden cardiac deaths with underlying ischemic heart disease and heart failure. Stroke and peripheral arterial disease are also common. It is indubitable that high-sensitivity troponin levels are elevated in patients with CKD and ESRD and that they are directly correlated with cardiovascular and total mortality, and thus with increased risk of a fatal outcome.