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Troponin T as a Predictor of End-Stage Renal Disease and All-Cause Death in African Americans and Whites From Hypertensive Families

Published:October 19, 2015DOI:https://doi.org/10.1016/j.mayocp.2015.08.016

      Abstract

      Objective

      To evaluate cardiac troponin T (cTnT) as a predictor of end-stage renal disease (ESRD) and death in a cohort of African American and white community-dwelling adults with hypertensive families.

      Patients and Methods

      A total of 3050 participants (whites from Rochester, Minnesota; African Americans from Jackson, Mississippi) of the Genetic Epidemiology Network of Arteriopathy study were followed from baseline examination (June 1, 1996, through August 31, 2000) through January 22, 2010. Cox proportional hazards regression models were used to examine the association of cTnT with ESRD and death after adjusting for traditional risk factors.

      Results

      Cohort demographic characteristics and measurements included 1395 whites (45.7%), 2174 hypertensive (71.3%), 992 estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2 (32.5%), 1574 high-sensitivity C-reactive protein level of greater than 3 mg/L (51.6%), and 66 abnormal cTnT level of 0.01 ng/mL or higher (2.2%). The estimated cumulative incidence of ESRD at 10 years was 27.4% among those with abnormal cTnT levels compared with 1.3% for those with normal levels. Similarly, the estimated cumulative incidence of death at 10 years was 47% among those with abnormal cTnT compared with 7.3% among those with normal cTnT. Abnormal cTnT levels were strongly associated with ESRD and death. This effect was attenuated but was still highly significant after adjustment for demographic characteristics, estimated glomerular filtration rate, and traditional risk factors for ESRD (unadjusted hazard ratio [HR], 23.91; 95% CI, 12.9-44.2; adjusted HR, 2.81; 95% CI, 1.3-5.9) and death (unadjusted HR, 8.43; 95% CI, 6.0-11.9; adjusted HR, 3.46; 95% CI, 2.3-5.1).

      Conclusion

      Cardiac troponin T makes an independent contribution to the prediction of ESRD and all-cause death in community-dwelling individuals beyond traditional risk markers. Further studies may be needed to determine whether cTnT screening in individuals with hypertension or in a subset of hypertensive individuals would help identify those at risk of ESRD and all-cause death.

      Abbreviations and Acronyms:

      cTnT (cardiac troponin T), eGFR (estimated glomerular filtration rate), ESRD (end-stage renal disease), GENOA (Genetic Epidemiology Network of Arteriopathy), HR (hazard ratio), hsCRP (high-sensitivity C-reactive protein)
      Hypertension is a priority health condition,

      Healthy People 2020. Heart Disease and Stroke 2020 Objectives: Hypertension. Vol 2014. U.S. Department of Health and Human Services. Available at www.healthypeople.gov. Accessed September 29, 2015.

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      Hypertensive adults have up to a 4-fold increase in cardiovascular disease–related deaths, with disproportionate rates seen in racial and ethnic minorities.
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      Temporal trends in the population attributable risk for cardiovascular disease: the Atherosclerosis Risk in Communities Study.
      Hypertension-related morbidity extends to kidney disease, comprising one of the most common causes of end-stage renal disease (ESRD), a condition affecting approximately 600,000 people and costing nearly $50 billion in public and private funds in the United States.
      • de Jager D.J.
      • Grootendorst D.C.
      • Jager K.J.
      • et al.
      Cardiovascular and noncardiovascular mortality among patients starting dialysis.
      U.S. Renal Data System
      USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States.
      Persons with hypertension represent a high-risk population for the development of ESRD and death, likely because of the interplay of other cardiovascular diseases and associated morbidity. Recently published guidelines by the American College of Physicians
      • Qaseem A.
      • Hopkins Jr., R.H.
      • Sweet D.E.
      • Starkey M.
      • Shekelle P.
      Clinical Guidelines Committee of the American College of Physicians. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians.
      suggest that screening for chronic kidney disease stages 1 to 3 is not clearly beneficial in the general population despite the increased risk of adverse cardiovascular and renal outcomes in these patients.
      • Brantsma A.H.
      • Bakker S.J.
      • Hillege H.L.
      • de Zeeuw D.
      • de Jong P.E.
      • Gansevoort R.T.
      PREVEND Study Group. Cardiovascular and renal outcome in subjects with K/DOQI stage 1-3 chronic kidney disease: the importance of urinary albumin excretion.
      Instead, it may be more beneficial to identify the higher-risk patients who need close monitoring for ESRD and other comorbid events. Identification of risk markers that improve risk assessment for death and the prediction of ESRD may be more cost-effective, improve medical decision making, and help target interventions at those who will clearly benefit.
      Cardiac troponin T (cTnT) is a sensitive and specific biomarker for myocyte injury in the setting of acute coronary syndrome.
      • Jaffe A.S.
      Troponin—past, present, and future.
      In the general population, minimally elevated cTnT levels as measured with the standard, readily-available assay are rare in individuals without chronic conditions such as heart failure, left ventricular hypertrophy, chronic kidney disease, or diabetes mellitus.
      • Wallace T.W.
      • Abdullah S.M.
      • Drazner M.H.
      • et al.
      Prevalence and determinants of troponin T elevation in the general population.
      • Michos E.D.
      • Wilson L.M.
      • Yeh H.C.
      • et al.
      Prognostic value of cardiac troponin in patients with chronic kidney disease without suspected acute coronary syndrome: a systematic review.
      • Jeremias A.
      • Gibson C.M.
      Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded.
      However, minimally elevated cTnT levels in asymptomatic older individuals and in patients with chronic kidney failure are associated with all-cause death.
      • Michos E.D.
      • Wilson L.M.
      • Yeh H.C.
      • et al.
      Prognostic value of cardiac troponin in patients with chronic kidney disease without suspected acute coronary syndrome: a systematic review.
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      • Daniels L.B.
      • Laughlin G.A.
      • Clopton P.
      • Maisel A.S.
      • Barrett-Connor E.
      Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study.
      • Mishra R.K.
      • Li Y.
      • DeFilippi C.
      • et al.
      CRIC Study Investigators
      Association of cardiac troponin T with left ventricular structure and function in CKD.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update: a report from the american heart association.
      • Goicoechea M.
      • Garca de Vinuesa S.
      • Gómez-Campderá F.
      • et al.
      Clinical significance of cardiac troponin T levels in chronic kidney disease patients: predictive value for cardiovascular risk.
      • Hickson L.J.
      • Cosio F.G.
      • El-Zoghby Z.M.
      • et al.
      Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T.
      • Hickson L.J.
      • El-Zoghby Z.M.
      • Lorenz E.C.
      • Stegall M.D.
      • Jaffe A.S.
      • Cosio F.G.
      Patient survival after kidney transplantation: relationship to pretransplant cardiac troponin T levels.
      • Keddis M.T.
      • El-Zoghby Z.M.
      • El Ters M.
      • et al.
      Cardiac troponin T before and after kidney transplantation: determinants and implications for posttransplant survival.
      Whether cTnT can distinguish those at the highest risk of ESRD in addition to death is less clear. To address this question, we used the Genetic Epidemiology Network of Arteriopathy (GENOA) multiethnic cohort study of hypertensive families sampled from the community. We tested the hypothesis that cTnT would predict death and ESRD independent of traditional cardiovascular risk factors and kidney function.

      Patients and Methods

       Design Overview

      The study design is a prospective cohort study of individuals from hypertensive families. The association of baseline cTnT with subsequent ESRD or all-cause death was assessed.

       Setting and Participants

       GENOA Cohort

      Study participants were members of sibships enrolled in the GENOA study designed to identify genetic determinants of hypertension in multiple racial groups.
      • Daniels P.R.
      • Kardia S.L.
      • Hanis C.L.
      • et al.
      Genetic Epidemiology Network of Arteriopathy study
      Familial aggregation of hypertension treatment and control in the Genetic Epidemiology Network of Arteriopathy (GENOA) study.
      FBPP Investigators
      Multi-center genetic study of hypertension: the Family Blood Pressure Program (FBPP).
      The sibships from the GENOA study were ascertained on the basis of 2 or more members of the sibships having primary hypertension diagnosed before the age of 60. In Rochester, Minnesota, a Mayo Clinic diagnostic index was used to identify all non-Hispanic white residents of Olmsted County with a diagnosis of essential hypertension made before the age of 60, who were then recruited for enrollment. In Jackson, Mississippi, individuals were recruited through hypertensive probands from the Atherosclerosis Risk in Communities cohort, a probability sample of 45- to 64-year-old non-Hispanic black or African American residents of that community.
      The ARIC Investigators
      The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives.
      All siblings of individuals recruited from these cohorts were invited to participate in the GENOA study. Sibships in which the index sibling was known to have a cause of secondary hypertension (eg, renal artery stenosis) including severely impaired kidney function (eg, serum creatinine level≥2.0 mg/dL) were not recruited. All available members of the recruited sibships, including normotensive siblings, were invited to the initial (baseline) study visit conducted from June 1, 1996, through August 31, 2000. Participants were excluded if they lacked stored serum samples or had kidney failure at their baseline visit. This study was approved by the Mayo Clinic Institutional Review Board and the institutional review board of the University of Mississippi Medical Center.

       Cohort Baseline Assessment

      The initial GENOA study visit involved the administration of a questionnaire enquiring about personal medical history, comorbid conditions, and family history; blood pressure measurement; and blood drawn for measurements of serum glucose, lipids (total cholesterol, high-density lipoprotein cholesterol, triglycerides), and creatinine. Hypertension was confirmed if a previous diagnosis and prescription antihypertensive medication were reported or if the average systolic blood pressure or diastolic blood pressure was 140 mm Hg or higher or 90 mm Hg or higher, respectively. Diabetes was diagnosed if the individual reported treatment with insulin or oral hypoglycemic agents or the fasting serum glucose concentration was 126 mg/dL or higher. Serum creatinine measurements were obtained with a standardized enzymatic assay.
      • Rule A.D.
      • Bailey K.R.
      • Lieske J.C.
      • Peyser P.A.
      • Turner S.T.
      Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease.
      The estimated glomerular filtration rate (eGFR) at the baseline examination was calculated using the Modification of Diet in Renal Disease Study equation.
      • Murata K.
      • Baumann N.A.
      • Saenger A.K.
      • Larson T.S.
      • Rule A.D.
      • Lieske J.C.
      Relative performance of the MDRD and CKD-EPI equations for estimating glomerular filtration rate among patients with varied clinical presentations.
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.
      The eGFR was also calculated using the CKD-EPI 2009 equation,
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
      A new equation to estimate glomerular filtration rate.
      but it led to no meaningful difference in the study findings compared with using the Modification of Diet in Renal Disease Study equation and was thus not reported. Cardiac troponin T and high-sensitivity C-reactive protein (hsCRP) levels were measured in stored serum samples from the baseline examination (June 1996 to August 2000) in Rochester. The cTnT level was measured by means of immunoassay methods on Roche e-modulers using an electrochemiluminescent immunoassay (Roche Diagnostics) in the Central Clinical Laboratory at Mayo Clinic in Rochester. The limit of detection for this assay is less than 0.01 ng/mL, which is also the 99th percentile of the upper reference range.
      • Apple F.S.
      • Parvin C.A.
      • Buechler K.F.
      • Christenson R.H.
      • Wu A.H.
      • Jaffe A.S.
      Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction.
      • Apple F.S.
      • Quist H.E.
      • Doyle P.J.
      • Otto A.P.
      • Murakami M.M.
      Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations.
      The 10% coefficient of variation for this assay is 0.035 ng/mL. In our laboratory, the coefficient of variation is 18% at the limit of detection. The hsCRP level was measured with the Roche Cobas 6000, latex-enhanced immunoturbidimetric assay (Roche Diagnostics).

       Outcomes and Follow-Up

      The primary outcome measures were all-cause death and ESRD. Vital status and death date were obtained using Accurint (www.accurint.com). For study participants who were deceased as of January 22, 2010, death certificates were obtained to verify death and to determine the primary cause of death. Primary causes of death were grouped into the following categories: malignancy, cardiac, sepsis/infection, pulmonary, cerebrovascular, trauma, renal, and unknown/other. End-stage renal disease events (ie, initiation of maintenance dialysis therapy or kidney transplantation) as of May 2008 were determined in 2010 via a query conducted in the United States Renal Data System, a comprehensive national database which collects, analyzes, and distributes information about ESRD in the United States (www.usrds.org).

       Statistical Analyses

      Because 98% of cTnT values were undetectable, they were stratified into 2 categories: normal (undetectable; <0.01 ng/mL) and abnormal (detectable; ≥0.01 ng/mL).
      • Wallace T.W.
      • Abdullah S.M.
      • Drazner M.H.
      • et al.
      Prevalence and determinants of troponin T elevation in the general population.
      • Hickson L.J.
      • Cosio F.G.
      • El-Zoghby Z.M.
      • et al.
      Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T.
      • Hickson L.J.
      • El-Zoghby Z.M.
      • Lorenz E.C.
      • Stegall M.D.
      • Jaffe A.S.
      • Cosio F.G.
      Patient survival after kidney transplantation: relationship to pretransplant cardiac troponin T levels.
      • Hamm C.W.
      • Giannitsis E.
      • Katus H.A.
      Cardiac troponin elevations in patients without acute coronary syndrome.
      Both hsCRP and triglyceride levels were assessed as continuous variables, and measurements were log-transformed due to skewness. The hsCRP level was also analyzed as a categorical variable with 2 categories: low to average risk (≤3 mg/L) and high risk (>3 mg/L).
      • Haverkate F.
      • Thompson S.G.
      • Pyke S.D.
      • Gallimore J.R.
      • Pepys M.B.
      Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
      • Rebuzzi A.G.
      • Quaranta G.
      • Liuzzo G.
      • et al.
      Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris.
      Demographic and clinical variables were compared between abnormal and normal cTnT groups using the 2-sample rank sum test for quantitative variables and the chi-square test for categorical variables. Cumulative rates of all-cause death and kidney failure (ESRD) events were estimated using the Kaplan-Meier method, and log-rank tests were used for group comparisons. Cox proportional hazards regression models were used to examine the association between cTnT and all-cause death (or ESRD) in univariable and multivariable models. Multivariable regression models were used to adjust for potential confounding variables. Age, sex, race, diabetes, hypertension, low-density lipoprotein cholesterol level, cigarette smoking, history of myocardial infarction, hsCRP level, and eGFR were evaluated as covariates in multivariable models.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      • Larson M.G.
      • Massaro J.M.
      • Vasan R.S.
      Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study.
      • Bash L.D.
      • Astor B.C.
      • Coresh J.
      Risk of incident ESRD: a comprehensive look at cardiovascular risk factors and 17 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) Study.
      Because of the limited number of ESRD events, the number of covariates used in multivariable models for predicting ESRD was restricted. Event times were defined as the time elapsed from study entry to the time of death or ESRD. Individuals free of death events were censored at the time of death survey, that is, January 22, 2010. Individuals free of ESRD events were censored at the time of death or at the time of most recent United States Renal Data System ESRD survey data availability (2-year reporting delay), that is, May 2008. For both outcomes, the presence of an interaction between the eGFR and the cTnT level was tested using a likelihood ratio test comparing nested Cox proportional hazards models (with vs without interaction). The C statistic was used to assess the effect of cTnT in different models. The results were expressed as hazard ratios (HRs) with 95% CIs. A secondary analysis for ESRD was conducted using the regression method of Fine and Gray
      • Fine J.P.
      • Gray J.G.
      A proportional hazards model for the subdistribution of a competing risk.
      to obtain the subdistribution HR for ESRD. This method accounts for individuals who died before the occurrence of ESRD (competing risk). Individuals lost to follow-up before ESRD or death were censored. Individuals who died before the occurrence of ESRD remained in the risk set with an adjusted weight. All analyses were performed using SAS version 9.3 (SAS Institute).

      Results

       Baseline Characteristics

      Of 3431 participants of the GENOA study, only 3050 comprised the final study cohort because of exclusions for the following: lack of stored serum samples available for both cTnT and hsCRP measurements (n=361); kidney failure based on documented ESRD before the baseline examination (n=8) or eGFR less than 15 mL/min per 1.73 m2 (n=6); and missing data (n=6). Baseline characteristics are presented in Table 1 for participants with abnormal cTnT (≥0.01 ng/mL) and normal cTnT (<0.01 ng/mL) levels. Overall, cTnT levels were abnormal or detectable in 66 (2.2%), with measurements ranging from 0.01 to 0.63 ng/mL. Participants with abnormal cTnT levels were older and more likely to be male and have comorbidities including hypertension, diabetes, myocardial infarction, and stroke compared with those with normal cTnT levels. However, no significant racial difference was observed. The eGFR was lower, whereas the cardiovascular biomarker, hsCRP level, was higher in those with abnormal cTnT levels.
      Table 1Comparison of Baseline Characteristics Between Participants With Abnormal cTnT and Normal cTnT Levels
      BMI = body mass index; cTnT = cardiac troponin T; eGFR = estimated glomerular filtration rate; HMG Co-A = 3-hydroxy-3-methyl-glutaryl-CoA; hsCRP = high-sensitivity C-reactive protein; RAAS = renin-angiotensin-aldosterone system.
      ,
      Values are presented as median (25th, 75th percentile) or as No. (percentage).
      CharacteristicAbnormal cTnT Levels (n=66)Normal cTnT Levels (n=2984)P value
      P value from the (1) 2-sample rank sum test or (2) χ2 test, as appropriate.
      Demographic and cardiovascular risk factors
       Age (y)67 (59, 72)57 (49, 64)<.001 (1)
       Race: African American41 (62.1)1614 (54.1).2 (2)
       Sex: Male41 (62.1)1067 (35.8)<.001 (2)
       Education.14
      Precollege46 (69.7)1615 (55.3)
      University13 (19.7)846 (28.4)
      Graduate4 (6.1)242 (8.1)
      Trade3 (4.6)245 (8.2)
       BMI (kg/m2)29 (27, 35)30 (26, 34).65 (1)
       Hypertension62 (93.9)2112 (70.8)<.001 (2)
       Diabetes34 (51.5)493 (16.5)<.001 (2)
       Myocardial infarction19 (28.8)131 (4.4)<.001 (2)
       Stroke12 (18.2)97 (3.3)<.001 (2)
      Medications
       Hypertension medication58 (87.9)1832 (61.4)<.001 (2)
       RAAS blockade agent31 (47.0)673 (22.6)<.001 (2)
       Lipid-lowering medication13 (19.7)328 (11.0).03 (2)
       HMG Co-A reductase inhibitor13 (19.7)286 (9.6).006 (2)
      Examination measurements
       Systolic blood pressure (mm Hg)143 (126, 166)132 (120, 146)<.001 (1)
       Systolic blood pressure>150 mm Hg26 (39.4)607 (20.3)<.01 (2)
       Diastolic blood pressure (mm Hg)76 (67, 87)78 (71, 85).64 (1)
       Pulse (beats/min)70 (62, 80)68 (62, 76).34 (1)
      Laboratory measurements
       Serum creatinine level (mg/dL)1.4 (1.2, 1.9)1.1 (1.0, 1.3)<.001 (1)
       eGFR (mL/min per 1.73 m2)52 (41, 63)66 (57, 74)<.001 (1)
       eGFR<.001 (2)
      ≥6021 (31.8)2037 (68.3)
      45-5922 (33.3)815 (27.3)
      30-4413 (19.7)122 (4.1)
      15-2910 (15.2)10 (0.3)
       Glucose level (mg/dL)103 (93, 157)93 (86, 105)<.001 (1)
       Total cholesterol level (mg/dL)195 (159, 229)204 (178, 231).07 (1)
       Low-density lipoprotein level (mg/dL)115 (85, 145)124 (98, 150).09 (1)
       High-density lipoprotein level (mg/dL)49 (37, 60)52 (42, 63).04 (1)
       Triglyceride level (mg/dL)171 (121-217)140 (105-196).02 (1)
       Log triglyceride level7.4 (6.9, 7.8)7.1 (6.7, 7.6).01 (1)
       hsCRP level (mg/L)3.9 (1.9, 10.6)3.2 (1.4, 7.0)<.001 (1)
       hsCRP level>3 mg/L40 (60.6)1534 (51.4).14 (2)
       Log hsCRP level1.9 (0.9, 3.3)1.7 (0.5, 2.8).03 (1)
      a BMI = body mass index; cTnT = cardiac troponin T; eGFR = estimated glomerular filtration rate; HMG Co-A = 3-hydroxy-3-methyl-glutaryl-CoA; hsCRP = high-sensitivity C-reactive protein; RAAS = renin-angiotensin-aldosterone system.
      b Values are presented as median (25th, 75th percentile) or as No. (percentage).
      c P value from the (1) 2-sample rank sum test or (2) χ2 test, as appropriate.

       Outcome: All-Cause Death

      During a median follow-up period of 11.5 years (25th, 75th percentile, 10.6, 12.4 years), 308 participants died (incidence density, 0.90 per 100 person-years). An abnormal cTnT level was significantly associated with the risk of all-cause death (log-rank, P<.001) (Figure 1 and Table 2). At 10 years, the estimated cumulative incidence of death was 47% (95% CI, 33.4%-57.7%) among those with abnormal cTNT levels compared with 7.3% (95% CI, 6.3%-8.2%) among those with normal cTNT. The leading cause of death was cardiac in those with and without abnormal cTnT levels at baseline (52.8% vs 35.3%, respectively) (Figure 2). There was an increased risk of all-cause death with an abnormal cTnT level that remained significant even after multivariable adjustment (HR, 3.46; 95% CI, 2.3-5.1) (Table 2). The final model for mortality without cTnT had a C statistic of 0.779 (95% CI, 0.75-0.8), which increased to 0.784 (95% CI, 0.76-0.81) with cTnT. A forest plot showing the effect of cTnT within subgroups made no suggestion that the effect of cTnT differed between other subgroups (Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org). Although the risk of death with an abnormal cTnT level was higher with an eGFR of 60 mL/min per 1.73 m2 or higher than with an eGFR of less than 60 mL/min per 1.73 m2 (HR, 10.47 vs 6.35), the interaction was not statistically significant (P=.2) even when eGFR was modeled as continuous (P=.7).
      Figure thumbnail gr1
      Figure 1Risk of all-cause death by abnormal vs normal cardiac troponin T (cTnT) levels.
      Table 2Risk of All-Cause Death With Abnormal cTnT Levels
      cTnT = cardiac troponin T; eGFR = estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein.
      ModelHazard ratio95% CIP valueC statistic
      1. Unadjusted8.435.95-11.94<.0010.552
      2. Adjusted for demographic factors (age, sex, and race)4.493.13-6.43<.0010.768
      3. Adjusted for demographic factors and traditional risk factors
      Hypertension, diabetes, myocardial infarction, low-density lipoprotein cholesterol level, and smoking.
      3.752.57-5.47<.0010.783
      4. Adjusted for demographic factors, traditional risk factors,
      Hypertension, diabetes, myocardial infarction, low-density lipoprotein cholesterol level, and smoking.
      and eGFR
      3.522.40-5.18<.0010.783
      5. Adjusted for demographic factors, traditional risk factors,
      Hypertension, diabetes, myocardial infarction, low-density lipoprotein cholesterol level, and smoking.
      eGFR, and Log hsCRP level
      3.462.35-5.09<.0010.784
      a cTnT = cardiac troponin T; eGFR = estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein.
      b Hypertension, diabetes, myocardial infarction, low-density lipoprotein cholesterol level, and smoking.
      Figure thumbnail gr2
      Figure 2Primary cause of death by baseline cardiac troponin T (cTnT) status.

       Outcome: ESRD

      During a median follow-up period of 9.8 years (25th, 75th percentile, 8.9, 10.8 years), 52 participants developed ESRD (incidence density, 0.18 per 100 person-years). An abnormal cTnT level was significantly associated with the risk of ESRD (log-rank, P<.001) (Figure 3 and Table 3). At 10 years, the estimated cumulative incidence of ESRD was 27.4% (95% CI, 12.4%-39.8%) among those with abnormal cTNT levels compared with 1.3% (95% CI, 0.9%-1.8%) among those with normal cTNT. The primary cause of ESRD was attributed to diabetes in 59.6%, and other causes were due to glomerulonephritis, multiple myeloma, unspecified, or unknown. There was an increased risk of ESRD with an abnormal cTnT level that remained significant even after adjusting for demographic characteristics, hypertension, diabetes, and eGFR (HR, 2.81; 95% CI, 1.34-5.90). This adjusted risk remained significant, with death modeled as a competing risk in the fully adjusted model (HR, 2.37; 95% CI, 1.02-5.53). The final model for ESRD without cTnT had a C statistic of 0.901 (95% CI, 0.85-0.95), which increased to 0.909 (95% CI, 0.86-0.96) with cTnT. A forest plot showing the effect of cTnT within subgroups suggested that the effect of cTnT differed between those with and without diabetes (Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org). The likelihood ratio test provided evidence of an interaction between cTnT status and diabetes (P=.008). Inspection of the interaction between cTnT status and diabetes (Figure 4) revealed that individuals with normal cTnT levels and no diabetes were at a low risk of ESRD.
      Figure thumbnail gr3
      Figure 3Risk of end-stage renal disease by abnormal vs normal cardiac troponin T (cTnT) levels.
      Table 3Risk of End-Stage Renal Disease With Abnormal cTnT Levels
      ModelHazard ratio95% CIP valueC statistic
      1. Unadjusted23.9112.92-44.24<.0010.635
      2. Adjusted for demographic factors (age, sex, and race)20.8410.58-41.05<.0010.757
      3. Adjusted for demographic factors, hypertension, and diabetes11.956.05-23.60<.0010.853
      4. Adjusted for demographic factors, hypertension, diabetes, and eGFR2.811.34-5.90.010.909
      cTnT = cardiac troponin T; eGFR = estimated glomerular filtration rate.
      Figure thumbnail gr4
      Figure 4Risk of end-stage renal disease by diabetes and cardiac troponin T (cTnT) status.

      Discussion

      In this study of community-dwelling individuals with hypertension, an abnormal cTnT level (≥0.01 ng/mL) independently predicted death and ESRD events. Our GENOA study participants with abnormal cTnT levels were generally older with comorbid conditions and reduced kidney function. However, abnormal cTnT levels provided prognostic information independent of traditional risk factors for cardiovascular disease or ESRD. Findings in our predominantly hypertensive population are similar to those of other reports in which a mildly increased or detectable cTnT level in patients with heart failure or kidney disease or even healthy older individuals portends worsened prognosis.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update: a report from the american heart association.
      • Bansal N.
      • Katz R.
      • Dalrymple L.
      • et al.
      NT-proBNP and troponin T and risk of rapid kidney function decline and incident CKD in elderly adults.
      However, our study is the first to demonstrate the ability of cTnT to predict ESRD beyond traditional risk markers and kidney function.
      Despite the known relationship between hypertension, kidney function, and cTnT, cTnT has not previously been studied as a risk marker for ESRD. Recently, Bansal et al
      • Bansal N.
      • Katz R.
      • Dalrymple L.
      • et al.
      NT-proBNP and troponin T and risk of rapid kidney function decline and incident CKD in elderly adults.
      found that cTnT levels, measured with high-sensitivity assays not yet clinically available in the United States, and N-terminal pro-B-type natriuretic peptide levels were associated with a rapid decline in kidney function and incident chronic kidney disease in elderly patients without heart failure. Our investigations to date are plausible, given the well-described biological interaction between cardiac and kidney function.
      • Bongartz L.G.
      • Cramer M.J.
      • Doevendans P.A.
      • Joles J.A.
      • Braam B.
      The severe cardiorenal syndrome: ‘Guyton revisited’.
      • Ronco C.
      • Haapio M.
      • House A.A.
      • Anavekar N.
      • Bellomo R.
      Cardiorenal syndrome.
      • Ronco C.
      • Di Lullo L.
      Cardiorenal syndrome.
      • McCullough P.A.
      • Li S.
      • Jurkovitz C.T.
      • et al.
      KEEP Investigators
      Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality.
      • McIntyre C.W.
      • Harrison L.E.
      • Eldehni M.T.
      • et al.
      Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease.
      • Breidthardt T.
      • Burton J.O.
      • Odudu A.
      • Eldehni M.T.
      • Jefferies H.J.
      • McIntyre C.W.
      Troponin T for the detection of dialysis-induced myocardial stunning in hemodialysis patients.
      Dysfunction of the heart often leads to dysfunction of the kidney, and vice versa. In patients with chronic kidney disease, the high cardiovascular morbidity and all-cause death rates observed are believed to be multifactorial in etiology from accelerated atherosclerotic vascular disease, congestive heart failure, left ventricular hypertrophy, and toxicity from the circulating uremic milieu.
      • McCullough P.A.
      • Li S.
      • Jurkovitz C.T.
      • et al.
      KEEP Investigators
      Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality.
      • Foley R.N.
      • Murray A.M.
      • Li S.
      • et al.
      Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999.
      Hence, cTnT serves as a marker of this cardiorenal interplay, allowing for the selection of a group with higher risk of ESRD.
      Race also plays an important role in the risk of all-cause death, with African Americans having life expectancy 3 to 8 years less than that of white counterparts.
      • Kochanek K.D.
      • Arias E.
      • Anderson R.N.
      How did cause of death contribute to racial differences in life expectancy in the United States in 2010?.
      • Xu J.
      • Kochanek K.D.
      • Murphy S.L.
      • Arias E.
      Mortality in the United States, 2012.
      • Keppel K.G.
      • Pearcy J.N.
      • Wagener D.K.
      Trends in racial and ethnic-specific rates for the health status indicators: United States, 1990-98.
      One advantage of our cohort was the balanced racial sampling, which allowed testing for racial differences in the cTnT relationships. Most previous investigations of cTnT had few African American participants. Wallace et al
      • Wallace T.W.
      • Abdullah S.M.
      • Drazner M.H.
      • et al.
      Prevalence and determinants of troponin T elevation in the general population.
      assessed the prevalence and determinants of cTnT level elevations with conventional cTnT assays in 3557 participants of the Dallas Heart Study, a multiethnic study of subclinical cardiovascular disease, which oversampled African Americans (∼52%). They found that African American race was associated with detectable cTnT levels in univariable analysis, but in multivariable analysis, only diabetes, left ventricular hypertrophy, chronic kidney disease, and congestive heart failure were associated with detectable cTnT levels. Similarly, we did not find race to be a determinant of abnormal cTnT levels in our GENOA study cohort. Taken together, these studies suggest that cTnT, as a composite marker of myocardial or endothelial damage caused by comorbid conditions, identifies a high-risk group regardless of race, albeit this is generally more common in African Americans.
      The prevalence (2.2%) of an abnormal cTnT level may appear low in this study. However, in healthy populations studied previously,
      • Wallace T.W.
      • Abdullah S.M.
      • Drazner M.H.
      • et al.
      Prevalence and determinants of troponin T elevation in the general population.
      • Daniels L.B.
      • Laughlin G.A.
      • Clopton P.
      • Maisel A.S.
      • Barrett-Connor E.
      Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study.
      the prevalence of a detectable or abnormal cTnT level is rare, ranging from 0.7% to 4%. The prevalence of a cTnT level increases with age and with multimorbidity, hence illustrating why we intentionally examined a higher-risk, community-based cohort. Despite the small number of participants with abnormal cTnT levels, cTnT proved to be an independent predictor of all-cause death and ESRD in our study population. Recently, a more sensitive assay for cTnT not yet clinically available in the United States has been associated with death and cardiovascular morbidity in community-based samples.
      • deFilippi C.R.
      • de Lemos J.A.
      • Christenson R.H.
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      • Saunders J.T.
      • Nambi V.
      • de Lemos J.A.
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      • de Lemos J.A.
      • Drazner M.H.
      • Omland T.
      • et al.
      Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
      In a study of 4221 community-dwelling adults aged 65 years and older from the Cardiovascular Health Study (51% hypertensives and 16% African Americans), very low levels of cTnT measured with a highly sensitive assay were associated with cardiovascular death and incident heart failure independent of other biomarkers, including C-reactive protein and N-terminal pro-B-type natriuretic peptide. Other investigations
      • deFilippi C.R.
      • de Lemos J.A.
      • Christenson R.H.
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      • de Lemos J.A.
      • Drazner M.H.
      • Omland T.
      • et al.
      Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
      revealed that variations in levels of this marker over time were associated with concordant changes in the risk of heart failure and cardiovascular death. The additive information from high-sensitivity assays for cTnT has allowed for the identification of individuals at high risk of death who have both elevated high-sensitivity cTnT levels and left ventricular hypertrophy.
      • Chin C.W.
      • Shah A.S.
      • McAllister D.A.
      • et al.
      High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis.
      • Neeland I.J.
      • Drazner M.H.
      • Berry J.D.
      • et al.
      Biomarkers of chronic cardiac injury and hemodynamic stress identify a malignant phenotype of left ventricular hypertrophy in the general population.
      Given these observations, it is possible that slight elevations in high-sensitivity cTnT levels previously undetected by our conventional cTnT assay may predict a significant proportion of deaths in the remaining participants of our study who died having had undetectable levels at baseline.
      Our study had some limitations. First, the aim of the baseline examination in the GENOA study was not to identify genetic predictors of target organ damage. Hence, we lacked baseline measurements of urine protein excretion rates in addition to electrocardiogram and echocardiogram studies, which may have provided insight into the presence of left ventricular hypertrophy, a condition previously associated with abnormal cTnT levels. The limitation due to the lack of urine samples is important, particularly given the findings of the Prevention of Renal and Vascular Endstage Disease study that albuminuria added significantly to the identification of individuals at risk of cardiovascular morbidity and all-cause death,
      • Smink P.A.
      • Lambers Heerspink H.J.
      • Gansevoort R.T.
      • et al.
      Albuminuria, estimated GFR, traditional risk factors, and incident cardiovascular disease: the PREVEND (Prevention of Renal and Vascular Endstage Disease) study.
      development of progressive albuminuria,
      • Scheven L.
      • Halbesma N.
      • de Jong P.E.
      • de Zeeuw D.
      • Bakker S.J.
      • Gansevoort R.T.
      Predictors of progression in albuminuria in the general population: results from the PREVEND cohort.
      and its association with high-sensitivity cTnT assays.
      • Hellemons M.E.
      • Lambers Heerspink H.J.
      • Gansevoort R.T.
      • de Zeeuw D.
      • Bakker S.J.
      High-sensitivity troponin T predicts worsening of albuminuria in hypertension; results of a nested case-control study with confirmation in diabetes.
      Second, we were unable to determine the impact of changes in medical therapy, cardiac interventions, and subsequent cardiac or renal events leading to adverse outcomes over time. Third, our cohort consists of individuals belonging to hypertensive families and therefore may limit applicability to the general population. Fourth, multiple factors influence cTnT levels, and a single measurement may not appropriately represent an individual's true baseline.

      Conclusion

      We report that cTnT levels provide prognostic information with respect to all-cause death and ESRD independent of traditional risk factors and baseline kidney function in community-dwelling individuals at potentially higher risk by virtue of ascertainment through hypertension. As patient populations grow older with increasing multimorbidity, identifying those at the highest risk of death or ESRD could improve patient management strategies. Unfortunately, abnormal cTnT levels, measured with the standard assay, are relatively uncommon and thus do not improve risk prediction enough to support routine use. Further study is needed to determine whether there is a particular patient group in which cTnT screening would meaningfully improve discrimination between the low- and high-risk patients for these sequelae.

      Acknowledgments

      We acknowledge the contribution of Jodie van de Rostyne for laboratory support; Daniel Crusan, BS, Cindy Crowson, MS, and Eric Bergstralh, MS, for statistical support; and Fernando Cosio, Mira Keddis, and Ziad el-Zoghby for critical review of manuscript and study design.

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at: http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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