Article, Cardiology

Interpreting troponin in renal disease: A narrative review for emergency clinicians

a b s t r a c t

Introduction: Patients with chronic kidney disease (CKD)/end stage renal disease (ESRD) can experience several severe complications, including acute coronary syndrome (ACS). While troponin is the biomarker of choice for evaluation of ACS, interpretation of troponin in CKD/ESRD can be challenging.

Objective: This narrative review evaluates Troponin elevation in patients with CKD/ESRD, pitfalls in the evaluation with troponin, and an approach to using troponin in these high-risk patients.

Discussion: Patients with CKD/ESRD are at greater risk for ACS and possess higher levels of circulating troponin. Relatedly, these patients often present atypically for ACS. Several pitfalls must be considered in the use of tropo- nin when evaluating for ACS. While troponin elevation in patients with CKD/ESRD is often considered to be due to underlying renal disease, this elevation has several etiologies including uremic skeletal myopathy, microinfarctions, left ventricular hypertrophy (LVH), decreased clearance, and unrecognized congestive heart failure (CHF). Utilizing troponin assays in this patient population requires a nuanced approach, as the sensitivity and specificity for Troponin testing in CKD varies. Concern for ACS with elevated troponin warrants treatment for ACS until proven otherwise, with consideration of atypical presentations along with other causes for Patient symptoms that may result in troponin elevation.

Conclusions: Patients with CKD/ESRD presenting with symptoms concerning for ACS are challenging. The utiliza- tion of troponin assays is important in this population given their high risk of ACS but requires an educated and nuanced approach.

Introduction

Acute coronary syndrome (ACS) is a cardiac emergency frequently encountered in the Emergency Department (ED) and encompasses the categories of ST-elevation myocardial infarction , non ST- elevation myocardial infarction (NSTEMI), and unstable angina [1-3]. NSTEMI is defined by the elevation in serum biomarkers of Myocardial necrosis (typically troponin in modern assays) without ST-elevation in patients with Ischemic symptoms [1,2]. According to the third and fourth universal definitions of myocardial infarction (MI), small amounts of myocardial injury with necrosis may be detected with use of cardiac troponin (cTn), which are also associated with congestive heart failure (CHF), renal failure, myocarditis, dysrhythmias, pulmonary embolism, critical illness, or otherwise uneventful percutaneous or sur- gical coronary procedures [1,2].

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.

E-mail addresses: [email protected] (B. Long), [email protected] (J.M. Bronner).

Chronic kidney disease (CKD) is a significant risk factor for ACS and predictor of cardiovascular mortality [4-7]. The condition is divided into stages 1 through 5 based on the patient’s Estimated glomerular filtration rate \(eGFR\) (Table 1) [7,8]. While these patients are at risk of many complications, they are at particularly high risk for ACS due to acceler- ated vascular disease and other comorbidities [4-7]. The prevalence of severe coronary stenosis among patients with CKD ranges from 38% to 63%, with most patients having multivessel disease [9,10]. The incidence of acute myocardial infarction (AMI) is over twice as high in patients with end stage renal disease and CKD compared to those with- out ESRD or CKD in patients presenting with chest pain to the ED [11-18]. Unfortunately, these patients also experience worse outcomes with ACS [19,20].

Low-level elevations in cTn correlate with higher risk for cardiovas- cular complications in patients with renal disease, and up to 70% of pa- tients with CKD demonstrate cTn elevation in the absence of ischemic symptoms [4-7,21]. Unfortunately, patients with CKD are also more likely to present in an atypical fashion [22-24]. Patients with CKD are less likely to present with chest pain and more likely to present with non-specific symptoms such as fatigue or generalized weakness

https://doi.org/10.1016/j.ajem.2019.11.041 0735-6757/

Table 1

Chronic kidney disease stages.

Stage Estimated glomerular filtration rate

>=90 mL/min/kg/1.73 m2 with kidney damage present such as albuminuria
  • b90 but >= 60 mL/min/kg/1.73 m2 with kidney damage present such as albuminuria
  • b60 but >= 30 mL/min/kg/1.73 m2
  • b30 but >= 15 mL/min/kg/1.73 m2
  • b15 mL/min/kg/1.73 m2 or undergoing dialysis Abbreviations: mL – millimeter, min – minute, kg – kilogram, m – meter.
  • [22-24]. Due to these factors including other underlying medical co- morbidities, atypical presentations, greater likelihood of troponin eleva-

    Table 2

    Etiologies of troponin elevation.

    General Specific

    Direct myocardial injury Cardiac contusion

    Cardiac ischemia from coronary thrombus cardiac transplantation

    Chemotherapy Myocarditis/pericarditis

    Procedure: ablation, biopsy, cardioversion, pacing

    Myocardial strain Chronic obstructive pulmonary disease Heart failure

    Pulmonary embolism Pulmonary hypertension

    tion, and high risk for ACS, patients with CKD present significant challenges to emergency clinicians. This narrative review evaluates cTn elevation in patients with CKD/ESRD, pitfalls in the evaluation with cTn, and an approach to using cTn in these high-risk patients.

    Methods

    Oxygen supply/demand

    mismatch

    Anemia

    Aortic dissection Cardiomyopathy Dysrhythmia Extreme exercise

    Hypertensive emergency Hypotension Hypovolemia

    This narrative review provides an evaluation of the use of cTn for ACS in patients with renal disease. The authors searched PubMed and Google Scholar for articles using a combination of the keywords “tropo- nin”, “renal”, “chronic kidney disease”. Authors evaluated case reports and series, retrospective and prospective studies, systematic reviews and meta-analyses, other narrative reviews, and guidelines evaluating cTn assays. Authors also reviewed supporting citations of included arti- cles. All generations of troponin assays were evaluated. The literature search was restricted to studies published in English, with focus on emergency medicine and Critical care literature. Authors decided which studies to include for the review by consensus. A total of 106 ar- ticles were selected for inclusion in this narrative review. As this is a nar- rative review, no pooling of data was completed.

    Discussion

    Cardiac troponin

    Cardiac troponin assays emerged as tools for diagnosis and progno- sis in ACS over 25 years ago [1-3,25,26]. These assays have replaced cre- atine kinase isoforms and are currently the assay of choice for ACS evaluation and prognostication [1-3]. Troponin is a subunit of the car- diac and skeletal myocytes which facilitates the activity of actin and my- osin, resulting in muscle contraction [27,28]. The troponin complex is attached to actin through troponin T, and troponin and myosin head in- teraction is inhibited by troponin I when insufficient calcium ions are present [27,28]. Troponin T and I are predominantly found in cardiac myocytes, and thus cardiac troponin T (cTnT) and I (cTnI) are the pri- mary biomarkers utilized for evaluation of myocardial injury, along with electrocardiogram (ECG) and imaging [1-3,25,26]. These markers are sensitive and specific for cardiac injury, and cTnT and cTnI possess a half-life approximating 2 h [27,28].

    Etiology of troponin elevation in renal disease

    As discussed, patients with renal disease commonly demonstrate el- evated cTn without electrocardiogram (ECG) or other clinical findings of myocardial injury, and cTnT is increased more commonly than cTnI in patients with renal failure [21,29-32]. High-sensitivity troponin (hsTn) is elevated at even greater proportions of patients with renal dis- ease [11,12,33]. One study including over 2400 patients with CKD found 81% had hsTn N 3 ng/L [33].

    There is no current consensus on utilizing distinct diagnostic criteria for AMI in patients with renal disease [1,2,34], and providers basing an elevated cTn value solely on the presence of CKD is a potential pitfall. While the renal system plays a role in the clearance of troponin, an

    Neurologic Hemorrhagic or ischemic stroke Seizure

    Systemic Burns

    Envenomation Environmental exposure Hypo-/hyperthyroidism Renal disease

    Sepsis

    systemic inflammation Toxic ingestion Trauma

    elevated cTn level in a patient with renal disease should not be ex- plained by reduced renal clearance alone [21,35-38]. Intact troponin molecules are approximately the size of albumin (66.5 kDa). While mol- ecules of this size are not typically cleared by the renal system, cardiac myocytes may release smaller troponin subunits than can be cleared by the kidneys [35-37]. Both larger and smaller cTn units can be mea- sured with laboratory assessment, and these smaller subunits may un- dergo renal excretion [21,38,39]. The renal reticuloendothelial system may also assist with clearance of smaller molecules [21,38,39]. Current data suggest the underlying cause of cTn elevation in patients with renal disease is not definitively known but likely has several etiologies including oxidative injury, myocyte death, normal cell turnover, in- creased cellular permeability, and protein fragmentation [35-37,40, 41]. Both Cardiac damage (uremic skeletal myopathy, microinfarctions, left ventricular hypertrophy, and congestive heart failure) and reduced clearance likely contribute to cTn elevation in patients with CKD [20,21, 36]. Table 2 depicts conditions associated with cTn elevation [42,43]. Lit- erature suggests this cTn elevation can assist with diagnosis of myocar- dial injury in CKD and with prognostication [2,20,21,36,37].

    Evidence concerning use of troponin in renal disease

    Several studies have evaluated use of cTn in patients with renal dis- ease. Much of this literature evaluates several generations of cTn assays [44-59]. While one study from 2010 including 284 patients with ERSD and ACS found a sensitivity and specificity over 95% for diagnosis of AMI using a third generation cTnT threshold of 0.35 ng/mL [44], the ma- jority of the literature suggests interpreting troponin assays of all gener- ations (including high-sensitivity) is fraught with challenges in patients with renal disease, especially first generation assays with specific- ity b 40% [45-59].

    In total, over 250 articles evaluate cTn testing in patients with renal disease. Unfortunately, much of this literature does not include patients diagnosed with CKD or ESRD based on official criteria; does not evaluate cTnI or cTnT; or has other faults including no gold standard, poor patient matching, varying definitions of renal disease, and no specified primary

    Table 3

    Literature evaluating troponin in renal disease.

    diagnosis of ACS

    Study Troponin Included Results

    1998 retrospective

    study [48]

    Second generation cTnT/cTnI

    85 patients with renal disease cTnT specificity 96% in those with CKD not on dialysis, 75% for those on

    HD b 1 year, and 46% for those on HD N 1 year

    cTnI specificity 96% in those with CKD not on dialysis

    1998 cohort study [96] cTnI 144 patients on HD cTnI N 0.03 ng/mL specificity 83% for cardiac condition

    HD did not alter cTnI levels 1998 cohort study [52] cTnI 155 patients on HD cTnI N 0.6 mcg/L specificity 81%, sensitivity 90% 2002 cohort study [55] cTnI 173 patients with CKD cTnI N 0.8 mcg/L specificity 91%, sensitivity 83%

    2003 retrospective

    study [50]

    Third generation cTnT/cTnI 31 patients on HD cTnT N 0.1 mcg/L specificity 42% and sensitivity 100% cTnI N 1.0 mcg/L specificity 100% and sensitivity 45%

    2003 cohort study [58] cTnT 695 patients cTnT N 0.1 mcg/L in those b 65 years and Cr N 1.5 mg/dL specificity 69%,

    sensitivity 43%

    cTnT N 0.1 mcg/L in those N 65 years and Cr N 1.5 mg/dL specificity 66%, sensitivity 52%

    2006 retrospective

    study [53]

    cTnI 467 patients cTnI N 0.5 mcg/L specificity 92%, sensitivity 70%

    2007 cohort study [56] cTnT 615 patients cTnT N 1.0 mcg/L in those b 70 years and Cr N 1.13 mg/dL PPV 59%

    cTnT N 1.0 mcg/L in those N 70 years and Cr N 1.13 mg/dL PPV 59%

    2007 cross-sectional

    study [57]

    2011 retrospective

    study [44]

    2011 prospective

    study [61]

    cTnT 46 patients on HD cTnT N 0.1 mcg/L specificity 85%, sensitivity 91% Third generation cTnT 284 patients with ESRD cTnT N 0.35 ng/L specificity 95%, sensitivity 97%

    hsTnT, hsTnI 836 patients hsTnT absolute change of 0.007 mcg/L specificity 93%, sensitivity 89% hsTnI absolute change of 0.020 mcg/L specificity 91%, sensitivity 93%

    2013 cross-sectional

    study [47]

    hsTnT 1514 patients, 382 with moderate to severe renal disease

    hsTnT N 0.014 mcg/L specificity 31%, sensitivity 74%

    2013 prospective

    study [51]

    2014 prospective

    study [54]

    2014 retrospective

    study [45]

    hsTnT 375 patients with CKD hsTnT N 35.8 ng/L specificity 86%, sensitivity 94%

    hsTnT N 14 ng/L specificity 54%, sensitivity 100% hsTnI, cTnT 1117 patients with CKD hsTnI N 0.0063 mcg/L specificity 53%, sensitivity 73%

    hsTnI N 0.0099 mcg/L specificity 48%, sensitivity 81%

    cTnT N 0.009 mcg/L specificity 37%, sensitivity 75%

    cTnT N 0.0194 mcg/L specificity 58%, sensitivity 71%

    cTnI 426 patients with CKD stages 3-5 cTnI N 0.5 mcg/L specificity 94%, sensitivity 43%

    cTnI N 0.11 mcg/L specificity 87%, sensitivity 64% cTnI elevated in 32%, with mortality 17% in those with CKD b stage 5, but 40% in those with CKD stage 5

    2014 meta-analysis

    [49]

    2015 prospective multicenter study [32]

    Multiple cTn assays and cutoffs

    7 cTn assays (3 sensitivity

    and 4 high-sensitivity)

    14 studies cTnT specificity 31-86%, sensitivity 71-100%

    cTnI specificity 48-100%, sensitivity 43-94%

    2813 patients, 447 with renal disease ROC for renal disease patients was 0.87-0.89 at initial presentation,

    0.91-0.95 at 3 h

    2015 retrospective

    study [62]

    2016 prospective

    study [59]

    2018 retrospective

    study [60]

    2018 prospective multicenter study [12]

    2018 prospective multicenter study [11]

    hsTn change by 50% 1054 patients 40% of patients had hsTn N 14 ng/mL 6.9%

    b70% specificity using hsTn change by 50%

    hsTnT 670 patients on HD Baseline hsTnT N 107.7 ng/L ROC 0.68, hsTnT relative change of 24% at 3 h

    ROC 0.90, hsTnT absolute change of 32.6 ng/L at 3 h ROC 0.88

    cTnI-Ultra assay 991 patients, 184 with renal failure cTnI-Ultra N 0.515 ng/dL specificity 42% and sensitivity 80.6% for renal

    disease

    hsTnT, hsTnI 3254 patients, 487 with renal disease hsTnT specificity 88.7%, sensitivity 100%

    hsTnI specificity 84.4%, sensitivity 98.6%

    hsTnI 4726 patients, 904 with renal disease hsTnI N 5 ng/L specificity 70.9%, sensitivity 98.9%

    Prevalence and Prognosis

    Study Troponin Included Results

    1998 prospective

    study [31]

    cTnI 56 patients with CKD cTnI elevated in 32%; all patients with elevated troponin had positive cardiac study

    Positive cTnI associated with mortality

    1999 cohort study [94] cTnT 94 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 15.49 for mortality

    2000 prospective

    study [98]

    cTnT, cTnI 59 patients on HD, with 566 samples HD increased cTnT (14% to 20%) and decreased cTnI (21% to 2%)

    2000 cohort study [93] cTnT 102 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 7.14 for mortality 2001 cohort study [91] cTnT 73 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 4.10 for mortality 2001 cohort study [92] cTnT 100 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 3.71 for mortality 2002 cohort study [89] cTnT 26 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 6.54 for mortality 2002 cohort study [90] cTnT 199 patients on dialysis cTnT N 0.098 mcg/L associated with HZ 2.39 for mortality

    2002 prospective

    study [19]

    cTnT, cTnI 733 patients with ESRD cTnT elevations associated with mortality, with RR 5.0 (univariate) and RR

    3.9 (adjusted)

    cTnI elevations associated with mortality, with RR 2.0 (univariate) and RR 2.1 (adjusted)

    2003 cohort study [88] cTnT 115 patients on dialysis cTnT N 0.01 mcg/L associated with HZ 2.66 for mortality

    2003 retrospective

    study [13]

    cTnT 224 patients on HD cTnT N 0.117 mcg/L associated with HZ 2.80 for mortality

    Table 3 (continued) Diagnosis of ACS

    Study Troponin Included Results

    2003 cohort study [73] cTnT, cTnI 258 patients on dialysis cTnT or cTnI N 0.1 mcg/L associated with HZ 1.83 for mortality 2003 cohort study [87] cTnI 137 patients on dialysis cTnI N 1 mcg/L associated with HZ 9.60 for mortality 2004 cohort study [85] cTnT 58 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 1.07 for mortality 2004 cohort study [86] cTnI 191 patients on dialysis cTnI N 0.03 mcg/L associated with HZ 3.90 for mortality

    2005 meta-analysis

    [63]

    cTnT 28 studies and 3931 patients cTnT N 0.1 ng/mL associated with increased mortality with RR 2.64

    2006 cohort study [84] cTnT 847 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 2.20 for mortality 2007 cohort study [83] cTnT 150 patients on dialysis cTnT N 0.106-0.569 mcg/L associated with HZ 3.39 for mortality

    2008 prospective

    study [97]

    2008 observational

    study [71]

    cTnT, cTnI 23 patients on HD HD may decrease cTnT and cTnI, but depends on the flux membranes used

    (low-flux membranes reduced cTnT by 37% and cTnT by 27%)

    cTnT, cTnI 31,586 patients with NSTEMI In moderate CKD, mortality increased with cTnI and cTnT elevation, OR 1.84

    In severe CKD, only major cTn elevations were correlated with increased mortality

    2008 cohort study [81] cTnT 230 patients on dialysis cTnT N 0.039 mcg/L associated with HZ 2.66 for mortality 2008 cohort study [82] cTnT, cTnI 109 patients on dialysis cTnT N 0.03 mcg/L associated with HZ 7.70 for mortality

    cTnI N 0.06 mcg/L associated with HZ 1.90 for mortality 2009 cohort study [80] cTnI 66 patients on dialysis cTnI N 0.2 mcg/L associated with HZ 5.90 for mortality

    2009 cohort study [64] cTnT, cTnI, hsTnT 32 patients with ESRD compared with

    501 healthy controls

    In patients with ESRD, 81% had elevated cTnT, 28% had elevated cTnI, and 100% had elevated hsTnT

    Patients with troponin elevation at risk for adverse event when compared to controls

    2010 prospective

    study [65]

    hsTnT 30 month follow up of patients on dialysis

    hsTnT detectable in all patients with cutoff 24.15 ng/L

    2010 cohort study [79] cTnT 50 patients on dialysis cTnT N 0.03 mcg/L associated with HZ 2.40 for mortality

    2011 prospective

    study [99]

    hsTnI 51 patients on HD with no cardiac symptoms

    hsTnI >= 0.035 ng/mL in 37%; of these, 79% were indeterminant range and 21% were diagnostic of AMI

    HD did not affect hsTnI results

    2011 cohort study [78] cTnT 109 patients on dialysis cTnT N 0.01 mcg/L associated with HZ 3.20 for mortality

    2012 prospective

    study [68]

    2012 randomized trial

    [70]

    Sensitive cTnI 51 patients on HD cTnI elevated in 51% of patients without symptoms

    45.1% of patients with cTnI elevation and history of CAD experienced a cardiac event within 2 years

    cTnT, cTnI 2179 patients with CKD cTn elevated in 59.2%

    cTn elevation associated with composite death or MI at 30 days with HZ 2.05 and 1 year with HZ 1.72

    2012 cohort study [72] Several cTn assays 11,340 patients admitted to the hospital Elevated cTn and CKD correlated with higher mortality 2012 cohort study [75] cTnT, cTnI 239 patients on dialysis cTnT N 0.067 mcg/L associated with HZ 6.01 for mortality

    cTnI N 0.022 mcg/L associated with HZ 2.87 for mortality 2012 cohort study [76] cTnT, cTnI 145 patients on dialysis cTnT N 0.1 mcg/L associated with HZ 1.90 for mortality

    cTnI N 0.2 mcg/L associated with HZ 1.60 for mortality 2012 cohort study [77] cTnT 103 patients on dialysis cTnT N 0.05 mcg/L associated with HZ 2.00 for mortality

    2012 prospective

    study [66]

    hsTnT 238 patients on HD hsTnT elevation correlated with mortality, HD decreased hsTnT by median 24%

    2013 cohort study [74] cTnI 206 patients on dialysis cTnI N 0.1 mcg/L associated with HZ 6.35 for mortality 2013 cohort study [95] cTnI 133 patients on dialysis cTnI N 0.06 mcg/L associated with HZ 2.57 for mortality 2013 cohort study [33] hsTnT 2464 patients with CKD hsTnT positive in 81% of patients, with reduced renal function correlated

    with greater increase in hsTnT

    2013 prospective

    study [69]

    cTnI 90 patients without cardiac symptoms, measurement before and after HD

    cTnI elevated in 34% before dialysis, which increased during HD

    Increase in cTnI associated with cardiovascular event, with HR 1.21 for every 10 ng/L increase

    2013 retrospective

    study [46]

    2014 prospective

    study [67]

    cTnI 293 patients with CKD cTnI elevated in 43.4% in those with non-ACS conditions

    hsTnT 393 patients on dialysis Elevation in hsTnT by every 25 ng/L associated with HR 1.10 for increased

    mortality

    2014 meta-analysis

    [49]

    Multiple cTn assays and cutoffs

    12 studies cTnT specificity and sensitivity for MACE during hospitalization 43% and 46%, within 6 months 45% and 72%, within 2 years 57% and 88%

    cTnI specificity and sensitivity for MACE during hospitalization 28% and 80%, within 6 months 27% and 83%, within 2 years 57% and 67%

    2014 meta-analysis

    [20]

    Multiple cTn assays and cut points

    98 studies including patients receiving dialysis

    cTnT pooled HR for all-cause mortality 3.0, cTnI pooled HR for all-cause mortality 2.7

    cTnT pooled HR for cardiovascular mortality 3.3, cTnI pooled HR for all-cause mortality 4.2

    Abbreviations: cTn – cardiac troponin, cTnT – cardiac troponin T, cTnI – cardiac troponin I, hsTn – high sensitivity troponin, HD – hemodialysis, HR – hazard ratio, CKD – chronic kidney disease, ACS – acute coronary syndrome, ng – nanograms, mcg – micrograms, L – liter, dL – deciliter, CAD – coronary artery disease, RR – relative risk, OR – odds ratio, AMI – acute myo- cardial infarction, ROC – receiver operating characteristic.

    outcome. Table 3 provides a detailed summary of the literature evaluat- ing cTn assays in renal disease. The highest quality literature was evalu- ated in a systematic review and meta-analysis from 2014 [49], which included 6 studies evaluating cTnT and 8 studies evaluating cTnI [19, 31,45,47,50-58]. This meta-analysis evaluated troponins of several

    generations, including sensitive and high-sensitivity assays [19,31,45, 47,50-58]. Sensitivity for diagnosis of ACS with cTnT was 71-100% and 43-94% for cTnI, while specificity was 31-86% for cTnT and 48-100% for cTnI (incorporating all troponin generations) [19,31,45, 47,49-58]. This meta-analysis demonstrated high heterogeneity

    concerning troponin assay generation, assay manufacturer, and assay cutoff, as well as study setting, populations, and ACS adjudication. Many of the studies also incorporated creatine kinase-MB for AMI diag- nosis [49]. Numbers of included patients ranged from 31 to 31,586 pa- tients [49]. One included study directly compared cTnT (Roche Elecsys) and cTnI (DPC Immulite), finding a cTnT threshold of 0.1 ug/L to possess a sensitivity and specificity of 100% and 42%, respectively, while a cTnI cutoff of 1.0 ug/L had a sensitivity and specificity of 45% and 100%, respectively [50].

    Studies have also evaluated cTn levels greater the 99th percentile for diagnosis of AMI in renal disease. A 2015 multicenter study evaluated 7 cTn assays (3 sensitive and 4 high-sensitivity assays) for diagnosis of AMI, with cTn positive in 45-80% of patients [32]. Study authors state sensitive and high-sensitivity cTn assays were able to diagnosis AMI, but overall accuracy decreased based on renal dysfunction. Using repeat assays over several hours improved diagnostic accuracy in patients with renal dysfunction [32].

    This study demonstrates the challenge of using the 99th percentile value for troponin value as a rule in test for diagnosis of AMI, as this 99th percentile is derived from an otherwise healthy population at large [1-3,32]. This 99th percentile depends upon the cTn assay gener- ation, assay cut-off, and institution. Many patients with CKD will dem- onstrate cTn measurements above the 99th percentile, with over 97% of patients in one study possessing an initial hsTnI over the 99th percen- tile [59]. Other studies have evaluated cTn thresholds for diagnosis of ACS, but these cutoffs are often arbitrarily chosen or retrospectively de- rived [11,12,20,47,60].

    high-sensitivity troponin Testing has also been evaluated [11,12,20, 47]. Literature suggests sensitivity ranges from 74% to 93%, and specific- ity ranges from 31% to 93%. Unfortunately, many studies utilize retro- spectively derived thersholds [47,51,54,61]. serial measurements of hsTn demonstrate higher sensitivity, but specificity remains inadequate [11,12,47,61,62]. One study evaluated absolute versus relative differ- ences of hsTn over 2 h and found absolute difference in hsTn to be more accurate for diagnosis of AMI, compared to using a relative differ- ence based on the Percentage change [61].

    Two recent studies from 2018 provide higher quality data compared with prior studies [11,12]. One of these studies found a hsTn b 5 ng/L at presentation placed 56% of patients at low risk for adverse cardiac out- come [11]. However, renal disease affected test performance. Of the in- cluded patients, 904 (19%) had renal disease defined as eGFR b 60 mL/ min/kg/1.73 m2, and 17% of these patients were risk stratified as low risk based on hsTn b 5 ng/L. Specificity was 70.9% for patients with renal disease, compared to 92.1% in those with no history of renal dis- ease [11]. A second 2018 study utilized a 0 and 1-hour hsTnT and hsTnI sample to risk stratify patients. Using this two-component testing strategy, authors found a sensitivity for rule out of 100% for patients with renal disease using hsTnT, compared to 99.2% for those without renal disease. Renal disease again affected the ability to rule in disease using hsTnT, as specificity was 88.7% for diagnosis in patients with renal disease, compared to 96.5% in those without. Using hsTnI, sensitiv- ity was 98.6% for rule out in patients with renal disease versus 98.5%, while specificity was 84.4% for those with renal disease and 91.7% for those without [12]. A significant portion of patients with renal disease fell into the intermediate category, defined as elevated troponin but no diagnosis of AMI, and were unable to be ruled out using the two sep- arate troponin measurements. The efficacy of the rule-out algorithm was much lower in patients with renal disease, approximately half. While patients without renal disease demonstrated a 92.5% event-free survival at 2 years, this decreased to 79% in patients with renal disease [12]. A 2015 retrospective study found a change in hsTn by 50% between two separate measurements was unable to improve specificity over 70%, and sensitivity was not sufficient to exclude AMI [62].

    These recent studies provide important data concerning the use of

    hsTn in patients with renal disease [11,12]. While two of the most re- cent studies by Miller-Hodges et al. and Twerenbold et al. used a hsTn

    threshold derived from patients with normal renal function, the low cut-off may be able to identify patients at low risk of ACS [11,12]. Unfor- tunately, the number of patients who can be definitively excluded based on this threshold is low, with 17% of patients in both studies categorized as low risk [11,12]. A significant proportion of patients were categorized in the intermediate category (43% and 47%, respectively) [11,12]. Mod- ifying the diagnostic cut-off did not improve the categorization of pa- tients from the intermediate to either low risk or high groups, and patients in the intermediate category still demonstrated high rates of Major adverse cardiac events [11,12].

    Troponin use for prognostication

    Elevation in cTn in patients with CKD is associated with poor short- term and long-term prognosis, whether the etiology of the cTn eleva- tion is ACS or another condition [20,49,63-99]. Many studies suggest el- evated cTn is associated with poor outcome, including higher mortality rates at 30 days and 1 year [63-99]. As the severity of renal disease in- creases with reduced eGFR, the risk of mortality also increases in pa- tients with ACS [33,69,71]. The risk of death in patients with eGFR 15-29 mL/min/kg/1.73 m2 is 3 times greater than patients without renal disease and 6 times greater for those with eGFR of b15 mL/min/ kg/1.73 m2 [4].

    A 2014 systematic review found a second generation cTnT assay threshold of 0.1 ug/L predicted major cardiac adverse event (MACE) during hospitalization with sensitivity and specificity of 43% and 46%, respectively; within 6 months 45% and 72%, respectively; and within 2 years 57% and 88%, respectively [49]. A second generation cTnI assay threshold of 0.6 ug/L demonstrated a sensitivity and specificity of 28% and 80%, respectively, to predict MACE during hospitalization, and a sensitivity and specificity of 27% and 83%, respectively, to predict MACE within 6 months. A second generation cTnI assay threshold of

    0.4 ug/L demonstrated a sensitivity and specificity of 57% and 67%, re- spectively, to predict MACE within 2 years [49]. Another systematic re- view evaluating patients with CKD on dialysis (including 98 studies and several generations of troponin assays) found elevated troponin was as- sociated with increased all-cause and cardiovascular mortality, with Hazard ratios (HZ) for all-cause mortality of 3.0 for cTnT and 2.7 for cTnI and cardiovascular mortality 3.3 for cTnT and 4.2 for cTnI [20]. High sensitivity assay elevation in patients with renal disease and dial- ysis demonstrates similar increased risk of mortality [65-67]. This in- creased risk is also present in those with CKD but not on dialysis, with one-meta-analysis (incorporating multiple generations of troponin as- says) finding a pooled HZ of 3.4 for all-cause mortality with a cTnT >= 0.01 ng/mL and a HZ of 1.7 for elevated cTnI [20].

    This increase in mortality is even present in patients without symp- toms and no suspicion of ACS, with close to a three-fold increase in mor- tality in those with an elevated cTn and renal disease, no matter the specific assay [20]. Due to this significant risk, CKD should be considered a coronary artery disease equivalent [72].

    Hemodialysis effects on Troponin assessment

    Hemodialysis can alter cTn measurements. Theoretically cTn levels may decrease due to dialysis clearance or increase due to hemoconcentration, and studies demonstrate conflicting data [96-99]. One study of 144 patients receiving laboratory assessment prior to and after hemodialysis demonstrated no change in cTnI [96]. Another study of 34 patients found decreases in cTnI and cTnT of 27% and 37%, respectively, after hemodialysis using a low-flux membrane [97], and another study of 59 patients found cTnT increased but cTnI decreased with hemodialysis [98]. There are several studies evaluating dialysis and hsTn. One prospective observational study found a median decrease of 10 ng/L with dialysis [66], while another found a median increase of 3 ng/L [69]. A third study found no change in hsTnI [99]. Further data are required in determining the pattern of cTn testing and hemodialysis.

    Diagnosis of AMI is still possible using the Clinical context and repeat cTn testing.

    Approach to renal disease and troponin evaluation

    Troponin is a key component in the diagnosis of acute MI [1,2]. cTn measurements are commonly elevated in patients with CKD, and ele- vated cTn is a marker for poor prognosis in these patients [20,21,32, 49]. Clinical judgment remains the foundation for the evaluation of pa- tients with CKD and elevated cTn, as the most common cause of signif- icantly elevated cTn in patients with CKD remains ACS [32]. Regarding the diagnosis of AMI, in patients with renal disease who present with signs or symptoms of ACS, a change in cTn values can be utilized to di- agnose AMI, which is supported by the American Heart Association, the Joint Task Force of the European Society of Cardiology, and the World Heart Federation [1-3,11,12,34,100]. Patients with an elevated initial CTn level should undergo repeat testing. An increase in cTn by 20% over the baseline value on a second measurement suggests a car- diac etiology, though there is a paucity of data that evaluates this crite- rion [1,2,34,100]. Using a change of 20% alone to exclude ACS in CKD is not recommended, as this can miss up to 12% of cases in patients with CKD [101]. An absolute change in cTn assay levels may be utilized based on the institution, rather than a percentage change [1,2]. The available data suggest cTnI may be more specific for myocardial injury in patients with renal disease, though clinic practice should not differ with use of cTnT or cTnI [1,2,30,34,100]. Current Consensus guidelines do not recommend one specific type of cTn assay over another (cTnT versus cTnI), and overall, data suggest similar results for diagnosis and prognosis of AMI in the setting of renal disease [1,2,20,30,34,49, 102-106]. Repeat cTn assessment is recommended with evaluation of the patient and ECG.

    If the subsequent cTn measurement is unchanged from the prior as- sessment but still elevated, this is more likely due to chronic myocardial injury, rather than an acute event. cTn testing with a rise and/or de- creasing pattern may be due to AMI or another condition such as vol- ume overload, heart failure, pulmonary embolism, aortic dissection, sepsis, and others [1,2,30,106]. This elevation should be taken into con- text of patient symptoms and ECG [1,2,34]. Patients with new ECG find- ings and ischemic symptoms should be admitted for further evaluation for AMI.

    In patients without ischemic symptoms and elevated cTn, consider- ation of other etiologies is needed, specifically evaluating for conditions from Table 2. Discussion with the patient’s primary care physician,

    Table 4

    Pitfalls and pearls in utilizing troponin in patients with renal disease. Pitfall Pearl

    nephrologist, and cardiologist is recommended if possible. While fur- ther data are needed regarding specific cut-offs dependent on the assay, patients may require admission for further evaluation of the un- derlying etiology. Table 4 lists pitfalls and pearls for emergency clini- cians in the evaluation of patients with CKD and use of cTn assays.

    Conclusion

    Troponin is the primary biomarker used in evaluation of ACS. While many patients with CKD demonstrate elevated cTn values, these pa- tients are high risk for ischemia and cardiac injury. Literature demon- strates a wide range of sensitivities and specificities regarding cTn use in ACS in patients with CKD. cTn may be elevated in patients with CKD at baseline, but an elevation in cTn in these patients confers higher risk of cardiovascular morbidity. Rather than relying on an isolated cTn value, clinicians should utilize the clinical situation with patient symptoms and ECG when assessing risk of ACS. Use of serial cTn testing is advised. It is important to consider other causes of elevated troponins in this patient population.

    Declaration of Competing Interest

    None.

    Acknowledgements

    CNB, JMB, BL, and AK conceived the idea for this manuscript, ob- tained permission for submission from Dr. White and Dr. Brady, and contributed substantially to the writing and editing of the review. This manuscript did not utilize any grants or funding, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible au- thorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

    References

    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third Universal Definition of Myocardial Infarction. J Am Coll Cardiol 2012:1581 9.
    2. Thygesen K, Alpert JS, Jaffe AS, et al. Executive Group on behalf of the Joint

      European Society of Cardiology (ESC)/American College of Cardiology (ACC)/ American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of

      Assuming an elevated cTn in

      CKD/ESRD does not represent ACS.

      Assuming an elevated cTn is solely due to decreased renal clearance.

    3. Failure to obtain an initial and repeat cTn measurement.
    4. Failure to consider other etiologies of cTn elevation.
    5. Not all patients with renal disease have

      elevated cTn, and elevated cTn represents higher risk of Cardiovascular complications and poor prognosis.

      Intact cTn is not predominantly renally cleared, though smaller subunits may undergo renal excretion. There are multiple etiologies for cTn elevation in renal disease.

    6. Repeat cTn measurements in these patients is vital, as acute rise in the appropriate clinical context is suggestive of ACS.
    7. While ACS is the most common cause of significantly elevated cTn, patients with CKD are at risk for other diagnoses that may elevate cTn, including pulmonary embolism, heart failure, severe dysrhythmia, aortic dissection, sepsis, and others.

      Myocardial Infarction (2018). Circulation. 2018 Nov 13;138(20):e618-e651.

      Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-69.

    8. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, car- diovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.
    9. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351: 1285-95.
    10. Marenzi G, Cabiati A, Assanelli E. Chronic kidney disease in acute coronary syn- dromes. World J Nephrol 2012;1(5):134-45.
    11. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for devel- opment of cardiovascular disease: a statement from the American Heart Associa- tion Councils on Kidney in Cardiovascular Disease, high blood pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension 2003;42: 1050-65.
    12. Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80(1):17-28.
    13. Manske CL, Thomas W, Wang Y, Wilson RF. Screening diabetic transplant candi-

      Abbreviations: cTn – cardiac troponin, ACS – acute coronary syndrome, CKD – chronic kid- ney disease, ESRD – end stage renal disease.

      dates for coronary artery disease: identification of a low risk subgroup. Kidney Int 1993;44:617-21.

      Herzog CA, Marwick TH, Pheley AM, et al. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080-90.

    14. Miller-Hodges E, Anand A, Shah ASV, et al. High-sensitivity cardiac troponin and the risk stratification of patients with Renal impairment presenting with suspected acute coronary syndrome. Circulation 2018 Jan 30;137(5):425-35.
    15. Twerenbold R, Badertscher P, Boeddinghaus J, et al. 0/1-Hour triage algorithm for myocardial infarction in patients with renal dysfunction. Circulation 2018 Jan 30; 137(5):436-51.
    16. deFilippi C, Wasserman S, Rosanio S, et al. Cardiac troponin T and C-reactive pro- tein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in pa- tients undergoing long-term hemodialysis. JAMA 2003;290(3):353-9.
    17. 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(9):2936-42.
    18. Charytan D, Kuntz RE, Mauri L, DeFilippi C. Distribution of coronary artery disease and relation to mortality in asymptomatic hemodialysis patients. Am J Kidney Dis 2007;49(3):409-16.
    19. Chonchol M, Whittle J, Desbien A, et al. Chronic kidney disease is associated with angiographic coronary artery disease. Am J Nephrol 2008;28(2):354-60.
    20. Ohtake T, Kobayashi S, Moriya H, et al. High prevalence of occult coronary artery stenosis in patients with chronic kidney disease at the initiation of renal replace- ment therapy: an Angiographic examination. J Am Soc Nephrol 2005;16(4): 1141-8.
    21. Kawai H, Sarai M, Motoyama S, et al. Coronary plaque characteristics in patients with mild chronic kidney disease. Analysis by 320-row area detector computed to- mography. Circ J 2012;76(6):1436-41.
    22. Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of cardiac tropo- nin I and T for subsequent death in end-stage renal disease. Circulation 2002 Dec 3;106(23):2941-5.
    23. Michos ED, Wilson LM, Yeh HC, et al. Prognostic value of cardiac troponin in pa- tients with chronic kidney disease without Suspected acute coronary syndrome: a systematic review and meta-analysis. Ann Intern Med 2014;161:491-501.
    24. Freda BJ, Tang WH, Van Lente F, et al. cardiac troponins in renal insufficiency: re- view and clinical implications. J Am Coll Cardiol 2002;40:2065-71.
    25. Cai Q, Mukku VK, Ahmad M. Coronary Artery Disease in Patients with Chronic Kid- ney Disease: A Clinical Update. Curr Cardiol Rev 2013 Nov;9(4):331-9.
    26. Aronow WS, Ahn C, Mercando AD, Epstein S. Prevalence of coronary artery disease, complex ventricular arrhythmias, and Silent myocardial ischemia and incidence of new coronary events in older persons with chronic renal insufficiency and with normal renal function. Am J Cardiol 2000;86:1142-3.
    27. Nakamura S, Uzu T, Inenaga T, Kimura G. Prediction of coronary artery disease and cardiac events using electrocardiographic changes during hemodialysis. Am J Kid- ney Dis 2000;36:592-9.
    28. Gupta S, de Lemos JA. Use and misuse of cardiac troponins in clinical practice. Prog Cardiovasc Dis 2007;50:151-65.
    29. Garg P, Morris P, Fazlanie AL, et al. Cardiac biomarkers of acute coronary syndrome: from history to high-sensitivity cardiac troponin. Intern Emerg Med 2017;12(2): 147-55.
    30. Ooi DS, Isotalo PA. Veinot JP (2000) Correlation of antemortem serum creatine ki- nase, creatine kinase-MB, troponin I, and troponin T with cardiac pathology. Clin Chem 2000;46:338-44.
    31. Takeda S, Yamashita A, Maeda K, Maeda Y. Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature 2003;424:35-41.
    32. Robitaille R, Lafrance JP, Leblanc M. Altered laboratory findings associated with end-stage renal disease. Semin Dial 2006;19(5):373-80.
    33. 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 Jun;43(6 Pt 1): 976-82.
    34. Martin GS, Becker BN, Schulman G. cardiac troponin-I accurately predicts myocar- dial injury in renal failure. Nephrol Dial Transplant 1998 Jul;13(7):1709-12.
    35. Twerenbold R, Wildi K, Jaeger C, et al. Optimal Cutoff Levels of More Sensitive Car- diac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction. Circulation 2015;131(23):2041-50.
    36. Dubin RF, Li Y, He J, et al. Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC). BMC Nephrol 2013 Oct;22(14):229.
    37. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus document on prac- tical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Con- sensus Documents. J Am Coll Cardiol 2012;60:2427-63.
    38. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med 2005;142:786-91.
    39. Kanderian AS, Francis GS. Cardiac troponins and chronic kidney disease. Kidney Int 2006;69:1112-4.
    40. Wang AY, Lai KN. Use of cardiac biomarkers in end-stage renal disease. J Am Soc Nephrol 2008;19:1643-52.
    41. Fredericks S, Chang R, Gregson H, et al. Circulating cardiac troponin-T in patients before and after renal transplantation. Clin Chim Acta 2001;310:199-203.
    42. Diris JH, Hackeng CM, Kooman JP, et al. Impaired renal clearance explains elevated troponin T fragments in hemodialysis patients. Circulation 2004;109:23-5.
    43. Kajimoto H, Kai H, Aoki H, et al. Inhibition of eNOS phosphorylation mediates en- dothelial dysfunction in renal failure: new effect of asymmetric dimethylarginine. Kidney Int 2012;81(8):762-8.
    44. Del Vecchio L, Locatelli F, Carini M. What we know about oxidative stress in pa- tients with chronic kidney disease on dialysis–clinical effects, potential treatment, and prevention. Semin Dial 2011;24(1):56-64.
    45. Parikh RH, Seliger SL, deFilippi CR. Use and interpretation of high sensitivity cardiac troponins in patients with chronic kidney disease with and without acute myocar- dial infarction. Clin Biochem 2015;48:247-53.
    46. Dikow R, Hardt SE. The uremic myocardium and ischemic tolerance: a world of dif-

      ference. Circulation 2012;125:1215-6.

      Ryu DR, Park JT, Chung JH, et al. A more appropriate cardiac troponin T level that can predict outcomes in end-stage renal disease patients with acute coronary syn- drome. Yonsei Med J 2011;52(4):595-602.

    47. Flores-Solis LM, Hernandez-Dominguez JL. Cardiac troponin I in patients with chronic kidney disease stage 3 to 5 in conditions other than acute coronary syn- drome. Clin Lab 2014;60:281-90.
    48. Chen S, Huang C, Wu B, et al. Cardiac troponin I in non-acute coronary syndrome patients with chronic kidney disease. PLoS One 2013;8:e82752.
    49. Pfortmueller CA, Funk GC, Marti G, et al. Diagnostic performance of high- sensitive troponin T in patients with renal insufficiency. Am J Cardiol 2013; 112:1968-72.
    50. Willging S, Keller F, Steinbach G. Specificity of cardiac troponins I and T in renal dis- ease. Clin Chem Lab Med 1998;36:87-92.
    51. Stacy SR, Suarez-Cuervo C, Berger Z, et al. Role of troponin in patients with chronic kidney disease and suspected acute coronary syndrome: a systematic review. Ann Intern Med 2014;161(7):502-12.
    52. Fehr T, Knoflach A, Ammann P, et al. Differential use of cardiac troponin T versus I in hemodialysis patients. Clin Nephrol 2003;59:35-9.
    53. Chenevier-Gobeaux C, Meune C, Freund Y, et al. Influence of age and renal function on high-sensitivity cardiac troponin T diagnostic accuracy for the diagnosis of acute myocardial infarction. Am J Cardiol 2013;111(12):1701-7.
    54. Bhagavan NV, Goldstein AP, Honda SA, et al. Role of cardiac troponin I in the eval- uation of myocardial injury. J Clin Lab Anal 1998;12:276-9.
    55. Flores LM, Hernandez Dominguez JL, Otero A, et al. Cardiac troponin I determina- tion in patients with chronic renal failure. Neffologia 2006;26:107-12.
    56. Haaf P, Reichlin T, Twerenbold R, et al. Risk stratification in patients with acute chest pain using three high-sensitivity cardiac troponin assays. Eur Heart J 2014; 35:365-75.
    57. Ikeda J, Zenimoto M, Kita M, Mori M. Usefulness of cardiac troponin I in patients with acute myocardial infarction. Rinsho Byori 2002;50:982-6.
    58. Alcalai R, Planer D, Culhaoglu A, et al. Acute coronary syndrome vs nonspecific tro- ponin elevation: Clinical predictors and survival analysis. Arch Intern Med 2007; 167:276-81.
    59. Sukonthasam A, Ponglopisit S. Diagnostic level of cardiac troponin T in patients with chronic renal dysfunction, a pilot study. J Med Assoc Thai 2007;90:1749-58.
    60. Noeller TP, Meldon SW, Peacock WF, et al. Troponin T in elders with suspected acute coronary syndromes. Am J Emerg Med 2003;21:293-7.
    61. Huang HL, Zhu S, Wang WQ, et al. Diagnosis of acute myocardial infarction in he- modialysis patients with high-sensitivity cardiac troponin T assay. Arch Pathol Lab Med 2016 Jan;140(1):75-80.
    62. Soerio AM, Gualandro DM, Bossa AS, et al. Sensitive troponin I assay in patients with chest pain – association with Significant coronary lesions with or without renal failure. Arq Bras Cardiol 2018;110(1):68-73.
    63. Reichlin T, Irfan A, Twerenbold R, et al. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarc- tion. Circulation 2011;124(2):136-45.
    64. Sajeev JK, New G, Roberts L, et al. High sensitivity troponin: Does the 50% delta change alter clinical outcomes in chest pain presentations to the emergency room? Int J Cardiol 2015 Apr;1(184):170-4.
    65. Khan NA, Hemmelgarn BR, Tonelli M, et al. Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: a meta-analysis. Cir- culation 2005;112:3088-96.
    66. Jacobs LH, van de Kerkhof J, Mingels AM, et al. Haemodialysis patients longitu- dinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem 2009;46(Pt 4): 283-90.
    67. McGill D, Talaulikar G, Potter JM, et al. Over time, high sensitivity TnT replaces NT- proBNP as the most powerful predictor of death in patients with dialysis- dependent chronic renal failure. Clin Chim Acta 2010;411(13-14):936-9.
    68. Wolley M, Stewart R, Curry E, et al. Variation in and Prognostic importance of tro- ponin T measured using a high-sensitivity assay in clinically stable haemodialysis patients. Clin Kidney J 2012;6(4):402-9.
    69. Hassan HC, Howlin K, Jefferys A, et al. High-sensitivity troponin as a predictor of cardiac events and mortality in the stable dialysis population. Clin Chem 2014;60 (2):389-98.
    70. Gaiki MR, DeVita MV, Michelis MF, et al. Troponin I as a prognostic marker of car- diac events in asymptomatic hemodialysis patients using a sensitive troponin I assay. Int Urol Nephrol 2012;44(6):1841-5.
    71. Assa S, Gansevoort RT, Westerhuis R, et al. Determinants and prognostic signifi- cance of an intra-dialysis rise of cardiac troponin I measured by sensitive assay in hemodialysis patients. Clin Res Cardiol 2013;102(6):439-45.
    72. Acharji S, Baber U, Mehran R, et al. Prognostic significance of elevated baseline tro- ponin in patients with acute coronary syndromes and chronic kidney disease treated with different antithrombotic regiments: a substudy from the ACUITY trial. Circ Cardiovasc Interv 2012;5:157-65.
    73. Melloni C, Alexander KP, Milford-Beland S, et al. Crusade Investigators. Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syn- dromes and chronic kidney disease. Clin Cardiol 2008;31(3):125-9.
    74. Tonelli M, Muntner P, Lloyd A, et al. Alberta Kidney Disease Network. Risk of coro- nary events in people with chronic kidney disease compared with those with dia- betes: a population-level cohort study. Lancet 2012;380:807-14.
    75. Iliou MC, Fumeron C, Benoit MO, et al. Prognostic value of cardiac markers in ESRD: Chronic Hemodialysis and New Cardiac Markers Evaluation (CHANCE) study. Am J Kidney Dis 2003;42:513-23.
    76. Geerse DA, van Berkel M, Vogels S, et al. Moderate elevations of high-sensitivity cardiac troponin I and B-type natriuretic peptide in chronic hemodialysis patients are associated with mortality. Clin Chem Lab Med 2013;51:1321-8.
    77. Artunc F, Mueller C, Breidthardt T, et al. Sensitive troponins–which suits better for hemodialysis patients? Associated factors and prediction of mortality. PLoS One 2012;7:e47610.
    78. Kalaji FR, Albitar S. Predictive value of cardiac troponin T and I in hemodialysis pa- tients. Saudi J Kidney Dis Transpl 2012;23:939-45.
    79. Holden RM, Beseau D, Booth SL, et al. FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients. Hemodial Int 2012;16:53-8.
    80. Hallen J, Madsen L, Ladefoged S, et al. Incremental value of a combination of cardiac troponin T, N-terminal pro-brain natriuretic peptide and C-reactive protein for pre- diction of mortality in end-stage renal disease. Scand J Urol Nephrol 2011;45: 151-8.
    81. Codognotto M, Piccoli A, Zaninotto M, et al. Effect of a dialysis session on the prog- nostic values of NT-proBNP, troponins, endothelial damage and inflammation bio- markers. J Nephrol 2010;23:465-71.
    82. Kang EW, Na HJ, Hong SM, Shin SK, Kang SW, Choi KH, et al. Prognostic value of el- evated cardiac troponin I in ESRD patients with sepsis. Nephrol Dial Transplant 2009;24:1568-73.
    83. Hocher B, Kalk P, Godes M, et al. Gender-dependent impact of risk factors for car- diovascular and non-cardiovascular mortality in end-stage renal disease patients on haemodialysis. Kidney Blood Press Res 2008;31:360-6.
    84. Helleskov Madsen L, Ladefoged S, Hildebrandt P, Atar D. Comparison of four differ- ent cardiac troponin assays in patients with end-stage renal disease on chronic haemodialysis. Acute Card Care 2008;10:173-80.
    85. Satyan S, Light RP, Agarwal R. Relationships of N-terminal pro-B natriuretic peptide and cardiac troponin T to left ventricular mass and function and mortality in asymptomatic hemodialysis patients. Am J Kidney Dis 2007;50:1009-19.
    86. Havekes B, van Manen JG, Krediet RT, et al. NECOSAD Study Group. Serum troponin T concentration as a predictor of mortality in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 2006;47:823-9.
    87. Fernandez-Reyes MJ, Mon C, Heras M, et al. Predictive value of troponin T levels for ischemic heart disease and mortality in patients on hemodialysis. J Nephrol 2004; 17:721-7.
    88. Boulier A, Jaussent I, Terrier N, et al. Measurement of circulating troponin Ic en- hances the prognostic value of C-reactive protein in haemodialysis patients. Nephrol Dial Transplant 2004;19:2313-8.
    89. Farkouh ME, Robbins MJ, Zafar MU, et al. Association between Troponin I levels and mortality in stable hemodialysis patients. Am J Med 2003;114:224-6.
    90. Lowbeer C, Stenvinkel P, Pecoits-Filho R, et al. Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality. J Intern Med 2003;253:153-60.
    91. Lowbeer C, Gutierrez A, Gustafsson SA, et al. Elevated cardiac troponin T in perito- neal dialysis patients is associated with CRP and predicts all-cause mortality and cardiac death. Nephrol Dial Transplant 2002;17:2178-83.
    92. 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.
    93. Deegan PB, Lafferty ME, Blumsohn A, et al. Prognostic value of troponin T in hemo- dialysis patients is independent of comorbidity. Kidney Int 2001;60:2399-405.
    94. Ishii J, Nomura M, Okuma T, Minagawa T, Naruse H, Mori Y, et al. Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis. Clin Chim Acta 2001;312:69-79.
    95. Dierkes J, Domrose U, Westphal S, et al. Cardiac troponin T predicts mortality in pa- tients with end-stage renal disease. Circulation 2000;102:1964-9.
    96. 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.
    97. Alam A, Palumbo A, Mucsi I, et al. Elevated troponin I levels but not low grade chronic inflammation is associated with cardiac-specific mortality in stable hemo- dialysis patients. BMC Nephrol 2013;14:247.
    98. Tun A, Khan IA, Win MT, et al. Specificity of cardiac troponin I and creatine kinase- MB isoenzyme in asymptomatic long-term hemodialysis patients and effect of he- modialysis on these cardiac markers. Cardiology 1998;90(4):280-5.
    99. Lippi G, Tessitore N, Montagnana M, et al. Influence of sampling time and ultrafil- tration coefficient of the dialysis membrane on cardiac troponin I and T. Arch Pathol Lab Med 2008;132(1):72-6.
    100. Wayand D, Baum H, Schatzle G, et al. Cardiac troponin T and I in end-stage renal failure. Clin Chem 2000;46(9):1345-50.
    101. Kumar N, Michelis MF, DeVita MV, et al. Troponin I levels in asymptomatic patients on haemodialysis using a high-sensitivity assay. Nephrol Dial Transplant 2011;26 (2):665-70.
    102. Amsterdam EZ, Wenger NK, Peterson ED, et al. 2014 AHA/ACC guideline for the management of patients with non-ST elevation acute coronary syndromes. J Am Coll Cardiol 2014;64:e139-228.
    103. Bjurman C, Larsson M, Johanson P, et al. Small changes in troponin T levels are common in patients with Non-ST-segment elevation myocardial infarction and are linked to higher mortality. J Am Coll Cardiol 2013;62(14):1231-8.
    104. Haller C, Stevanovich A, Katus HA. Are cardiac troponins reliable serodiagnostic markers of cardiac ischaemia in end-stage renal disease? Nephrol Dial Transplant 1996;11(6):941-4.
    105. Adams 3rd JE, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation 1993;88(1):101-6.
    106. Hafner G, Thome-Kromer B, Schaube J, et al. Cardiac troponins in serum in chronic renal failure. Clin Chem 1994;40(9):1790-1.
    107. Frankel WL, Herold DA, Ziegler TW, Fitzgerald RL. Cardiac troponin T is elevated in asymptomatic patients with chronic renal failure. Am J Clin Pathol 1996;106(1): 118-23.
    108. McCullough PA, Nowak RM, Foreback C, et al. Performance of multiple cardiac bio- markers measured in the emergency department in patients with chronic kidney disease and chest pain. Acad Emerg Med 2002;9(12):1389-96.

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