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Canadian Journal of Cardiology

Glomerular Filtration Rate-Specific Cutoffs Can Refine the Prognostic Value of Circulating Cardiac Biomarkers in Advanced Chronic Kidney Disease

      Abstract

      Background

      Using standard cutoffs derived from healthy adults, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are frequently elevated in patients with reduced glomerular filtration rate (GFR), with unclear implications. We sought to compare GFR-specific cutoffs of each biomarker with standard cutoffs for discrimination of cardiovascular risk in asymptomatic patients with chronic kidney disease.

      Methods

      We investigated a prospective cohort of 1956 participants with median GFR of 27 mL/min/1.73 m2. Cox proportional hazards models were used to examine the association between each biomarker and first adjudicated cardiovascular event (unstable angina, myocardial infarction, heart failure, stroke, cardiovascular death). We used an outcome-based approach to identify optimal risk-based cutoffs for each biomarker within GFR strata (< 20, 20-29, 30-44 mL/min/1.73 m2). We evaluated the added prognostic value of each biomarker to a multivariable base model, comparing GFR-specific with standard cutoffs.

      Results

      Hs-cTnT and NT-proBNP were elevated in 76% and 82% of participants, respectively. A total of 401 events were recorded during 6772 person-years at risk. Both biomarkers were independent predictors of cardiovascular events. Optimal cutoffs for each biomarker were higher than standard thresholds, being highest at GFR values < 20 mL/min/1.73 m2. Addition of hs-cTnT to the base model using GFR-specific cutoffs significantly improved reclassification for events (52%) and nonevents (21%). Similar findings were observed for NT-proBNP. In contrast, use of standard cutoffs failed to reclassify patients who had no event as lower risk.

      Conclusions

      Among asymptomatic patients with advanced chronic kidney disease, optimal cutoffs for hs-cTnT and NT-proBNP differed according to GFR level and outperformed standard cutoffs for discrimination of cardiovascular risk.

      Résumé

      Contexte

      À l’aune des valeurs seuils standard établies chez les adultes en bonne santé, on constate que les taux de troponines cardiaques hypersensibles et de propeptide natriurétique de type B N-Terminal (NT-proBNP) sont fréquemment élevés chez les patients présentant un débit de filtration glomérulaire (DFG) réduit. Les implications de cette observation restent à élucider. Nous avons cherché à comparer les valeurs seuils de chaque biomarqueur selon le DFG aux valeurs seuils standards afin de déterminer le risque cardiovasculaire chez des patients asymptomatiques atteints d’insuffisance rénale chronique.

      Méthodologie

      Nous avons mené une étude de cohorte prospective regroupant 1956 sujets présentant un DFG médian de 27 ml/min/1,73 m2. Des modèles à risques proportionnels de Cox ont servi à examiner l’association entre chaque biomarqueur et le premier événement cardiovasculaire confirmé (angine instable, infarctus du myocarde, insuffisance cardiaque, accident vasculaire cérébral, décès d’origine cardiovasculaire). Nous avons adopté une approche axée sur la survenue des événements afin de déterminer les valeurs seuils optimales fondées sur le risque au regard de chaque biomarqueur selon la stratification du DFG (< 20, 20-29, 30-44 ml/min/1,73 m2). Nous avons évalué la valeur pronostique ajoutée de chaque biomarqueur dans un modèle de base à variables multiples, comparant les valeurs seuils selon le DFG aux valeurs seuils standards.

      Résultats

      Les taux de troponines cardiaques hypersensibles et de NT-proBNP étaient élevés chez 76 % et 82 % des participants, respectivement. Au total, 401 événements ont été consignés au cours de 6772 années-personnes à risque. Les deux biomarqueurs ont constitué des prédicteurs indépendants des événements cardiovasculaires. Les valeurs seuils optimales de chaque biomarqueur étaient plus élevées que les valeurs seuils standards, culminant en présence d’un DFG < 20 ml/min/1,73 m2. L’ajout de la troponine cardiaque hypersensible au modèle de base compte tenu des valeurs seuils selon le DFG a amélioré sensiblement la reclassification des cas où il y avait présence d’événements (52 %) ou absence d’événements (21 %). Des résultats similaires ont été observés pour la NT-proBNP. En revanche, l’utilisation des valeurs seuils standards n’a pas entraîné la reclassification des patients n’ayant pas eu d’événement dans une catégorie de risque inférieure.

      Conclusions

      Chez les patients asymptomatiques atteints d’insuffisance rénale chronique avancée, les valeurs seuils optimales de troponines cardiaques hypersensibles et de NT-proBNP différaient selon le DFG et se sont avérées plus concluantes que les valeurs seuils standards pour déterminer le risque cardiovasculaire.
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      References

        • Gansevoort R.T.
        • Correa-Rotter R.
        • Hemmelgarn B.R.
        • et al.
        Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
        Lancet. 2013; 382: 339-352
        • 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.
        JAMA. 2010; 304: 2503-2512
        • Linssen G.C.
        • Bakker S.J.
        • Voors A.A.
        • et al.
        N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population.
        Eur Heart J. 2010; 31: 120-127
        • Colbert G.
        • Jain N.
        • de Lemos J.A.
        • Hedayati S.S.
        Utility of traditional circulating and imaging-based cardiac biomarkers in patients with predialysis CKD.
        Clin J Am Soc Nephrol. 2015; 10: 515-529
        • Bansal N.
        • Hyre Anderson A.
        • Yang W.
        • et al.
        High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study.
        J Am Soc Nephrol. 2015; 26: 946-956
        • Scheven L.
        • de Jong P.E.
        • Hillege H.L.
        • et al.
        High-sensitive troponin T and N-terminal pro-B type natriuretic peptide are associated with cardiovascular events despite the cross-sectional association with albuminuria and glomerular filtration rate.
        Eur Heart J. 2012; 33: 2272-2281
        • Gregg L.P.
        • Adams-Huet B.
        • Li X.
        • et al.
        Effect modification of chronic kidney disease on the association of circulating and imaging cardiac biomarkers with outcomes.
        J Am Heart Assoc. 2017; 6e005235
        • Dubin R.F.
        • 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; 14: 229
        • Levin A.
        • Rigatto C.
        • Brendan B.
        • et al.
        Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).
        BMC Nephrol. 2013; 14: 121
        • Jia X.
        • Sun W.
        • Hoogeveen R.C.
        • et al.
        High-sensitivity troponin I and incident coronary events, stroke, heart failure hospitalization, and mortality in the ARIC study.
        Circulation. 2019; 139: 2642-2653
        • Matsushita K.
        • Sang Y.
        • Ballew S.H.
        • et al.
        Cardiac and kidney markers for cardiovascular prediction in individuals with chronic kidney disease: the Atherosclerosis Risk in Communities study.
        Arterioscler Thromb Vasc Biol. 2014; 34: 1770-1777
        • Di Castelnuovo A.
        • Veronesi G.
        • Costanzo S.
        • et al.
        NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the risk of stroke.
        Stroke. 2019; 50: 610-617
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • et al.
        2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2016; 37: 2129-2200
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Tangri N.
        • Kitsios G.D.
        • Inker L.A.
        • et al.
        Risk prediction models for patients with chronic kidney disease: a systematic review.
        Ann Intern Med. 2013; 158: 596-603
        • Major R.W.
        • Cheng M.R.I.
        • Grant R.A.
        • et al.
        Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis.
        PLoS One. 2018; 13e0192895
        • Matsushita K.
        • Coresh J.
        • Sang Y.
        • et al.
        Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.
        Lancet Diabetes Endocrinol. 2015; 3: 514-525
        • Chandra P.
        • Sands R.L.
        • Gillespie B.W.
        • et al.
        Predictors of heart rate variability and its prognostic significance in chronic kidney disease.
        Nephrol Dial Transplant. 2012; 27: 700-709
        • Spoto B.
        • Mattace-Raso F.
        • Sijbrands E.
        • et al.
        Association of IL-6 and a functional polymorphism in the IL-6 gene with cardiovascular events in patients with CKD.
        Clin J Am Soc Nephrol. 2015; 10: 232-240
        • Kim R.B.
        • Morse B.L.
        • Djurdjev O.
        • et al.
        Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.
        Kidney Int. 2016; 89: 1144-1152
        • Contal C.
        • O’Quigley J.
        An application of changepoint methods in studying the effect of age on survival in breast cancer.
        Computational Statistics and Data Analysis. 1999; 30: 253-270
        • Williams B.A.
        • Mandrekar J.N.
        • Mandrekar S.J.
        • Cha S.S.
        • Furth A.F.
        Technical Report Series #79: Finding Optimal Cutpoints for Continuous Covariates with Binary and Time-to-Event Outcomes.
        Department of Health Science Research, Mayo Clinic, Rochester, MN2006
        • Chambless L.E.
        • Cummiskey C.P.
        • Cui G.
        Several methods to assess improvement in risk prediction models: extension to survival analysis.
        Stat Med. 2011; 30: 22-38
        • Chambless L.E.
        • Diao G.
        Estimation of time-dependent area under the ROC curve for long-term risk prediction.
        Stat Med. 2006; 25: 3474-3486
        • Pencina M.J.
        • D’Agostino Sr., R.B.
        • D’Agostino Jr., R.B.
        • Vasan R.S.
        Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
        Stat Med. 2008; 27: 157-172
        • Januzzi J.L.
        • van Kimmenade R.
        • Lainchbury J.
        • et al.
        NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.
        Eur Heart J. 2006; 27: 330-337
        • Tonelli M.
        • Muntner P.
        • Lloyd A.
        • et al.
        Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study.
        Lancet. 2012; 380: 807-814
        • Twerenbold R.
        • Wildi K.
        • Jaeger C.
        • et al.
        Optimal cutoff levels of more sensitive cardiac troponin assays for the early diagnosis of myocardial infarction in patients with renal dysfunction.
        Circulation. 2015; 131: 2041-2050
        • Miller-Hodges E.
        • Anand A.
        • Shah A.S.V.
        • et al.
        High-sensitivity cardiac troponin and the risk stratification of patients with renal impairment presenting with suspected acute coronary syndrome.
        Circulation. 2018; 137: 425-435
        • Tsutamoto T.
        • Kawahara C.
        • Yamaji M.
        • et al.
        Relationship between renal function and serum cardiac troponin T in patients with chronic heart failure.
        Eur J Heart Fail. 2009; 11: 653-658
        • Mishra R.K.
        • Li Y.
        • DeFilippi C.
        • et al.
        Association of cardiac troponin T with left ventricular structure and function in CKD.
        Am J Kidney Dis. 2013; 61: 701-709
        • deFilippi C.
        • Seliger S.L.
        • Kelley W.
        • et al.
        Interpreting cardiac troponin results from high-sensitivity assays in chronic kidney disease without acute coronary syndrome.
        Clin Chem. 2012; 58: 1342-1351

      Linked Article

      • Is It Time to Recalibrate Cardiac Prediction Tools to Accommodate Chronic Kidney Disease?
        Canadian Journal of CardiologyVol. 35Issue 9
        • Preview
          Cardiovascular disease disproportionately affects patients with chronic kidney disease (CKD) compared with the remainder of the population. In fact, CKD has historically been considered a cardiovascular disease “risk equivalent” along with other well known risk factors such as diabetes mellitus and peripheral vascular disease.1 Moreover, there is a clear “dose-response” relationship with more advanced stages of CKD associated with progressively higher rates of cardiovascular disease.2
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