Part One Cardiac Biomarkers in Pediatric CKD—a Prospective Follow‑up Study
Jun 16, 2023
Abstract
1. Background
The N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive cardiac-specific troponin T (hs-cTnT) are associated with abnormal cardiac structure and function and an increased risk of cardiovascular death in chronic kidney disease (CKD) patients. There is limited knowledge about these cardiac markers in pediatric CKD patients.
2. Methods
Longitudinal levels of NT-proBNP and hs-cTnT were analyzed in 48 pediatric patients, 22 with CKD (GFR range 8.8–68 mL/min/1.73 m2 ) and 26 transplanted patients (CKD-T; GFR range 30–99 mL/min/1.73 m2 ). Follow-up was scheduled after 1 and 3 years. Longitudinal patterns and associations to kidney function, cardiovascular risk markers, and echocardiographic parameters were assessed.
3. Results
High NT-proBNP was present in 27% of CKD and 11% of CKD-T patients. Similarly, 32% of CKD and 8% of CKD-T patients had elevated hs-cTnT levels. In longitudinal multivariate analyses, high log NT-proBNP was associated with low GFR (β= −0.01, p=0.01) and elevated left ventricular mass index (LVMI; β=0.02, p=0.05). The strong association to LVMI remained when using GFR-adjusted NT-proBNP in a similar analysis. Patients with left ventricular hypertrophy (LVH) also had higher NT-proBNP (235 [146–301] ng/L) than patients without LVH (86 [11–477] ng/L), p=0.02. High hs-cTnT over time was also associated with low GFR (β= −0.007, p=0.01) and a low cc-TDI e´/a´, indicating a worse LV diastolic function (β= −0.09, p=0.05). This association did not persist for GFR-adjusted hs-cTnT.
4. Conclusions
NT-proBNP and hs-cTnT are elevated in pediatric CKD and CKD-T patients. GFR-adjusted NT-proBNP was associated with longitudinal levels of elevated LVMI suggesting this might be a marker for early subclinical myocardial damage.
Keywords
Chronic kidney disease · Kidney transplantation · Troponin · NT-proBNP · Left ventricular hypertrophy · Left ventricular dysfunction.
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Introduction
Cardiovascular disease (CVD) represents one of the most important causes of death in chronic kidney disease (CKD) patients [1]. Several pathological mechanisms common in CKD increase the risk of developing CVD. Cardiac biomarkers are commonly used to assess various cardiovascular events, where cardiac-specific troponins (cTn) are characterized as markers of myocardial injury [2] and N-terminal pro-B-type natriuretic peptide (NT-proBNP) a marker of increased volume and cardiac load [3].
Troponins T and I (cTnT and cTnI) are widely used in adult cardiology to diagnose patients with acute myocardial infarction (AMI) [4], while NT-proBNP is used to assess patients with left ventricular hypertrophy (LVH), left ventricular dysfunction, and heart failure [3]. It is today established that both cTns and NTproBNP are valid indicators of all-cause death and cardiovascular events in CKD patients and other populations [5, 6].
Importantly, patients with advanced CKD reveal elevated levels of these cardiac biomarkers, despite no obvious signs of AMI or heart failure. Two possible mechanisms are discussed, either continuous subclinical myocardial damage related to CKD comorbidities and/or reduced renal clearance per se [7, 8]. NT-proBNP is dominantly filtered directly by the kidneys, and the levels increase as GFR decreases [8] making it tricky to interpret in CKD patients. As most of the variation in cTnT also is explained by GFR [7], it is proposed that the levels of these cardiac biomarkers should be adjusted for GFR in CKD patients. The diagnostic value of cTnI is similar to cTnT, but compared with cTnT, cTnI has the advantage of being less influenced by kidney function [9].
Unfortunately, the risk of CVD and cardiac-related death is increased already in pediatric CKD [1]. While the risk decreases after kidney transplantation, it is still higher among pediatric kidney transplant recipients compared to healthy peers [10]. Indeed, the prevalence of preclinical cardiac changes like LVH and left ventricular (LV) diastolic dysfunction is high in these patients [11–13]. Large cross-sectional and prospective studies on adult CKD patients have shown that NT-proBNP and cTnT are associated with changes in left ventricular structure and function [14, 15]. Still, only a few studies are exploring the importance of cardiac biomarkers in pediatric CKD patients [16–19]. Analyzing cardiac biomarkers prospectively in children with CKD may improve diagnostic accuracy and facilitate the prediction of CVD, thus improving clinical outcomes.
The present study set out to analyze associations between longitudinal levels of high-sensitive (hs)-cTnT, hs-cTnI, and NT-proBNP and structural and functional cardiac abnormalities assessed by echocardiography in a cohort of pediatric CKD patients and kidney transplant recipients. Previously published algorithms to correct levels of NT-proBNP and hscTnT for kidney function based on adult studies were also assessed in this pediatric cohort, and in a sub-analysis, two different methods used to assess hs-cTnI were also compared.
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Subjects and methods
1. Study population and design
The study was designed as an observational prospective cohort study of children with CKD, either non-dialysis CKD stage 2–5 patients (CKD) or kidney transplant recipients (CKD-T). All patients were treated at the outpatient Pediatric Nephrology Clinic at Astrid Lindgren Children’s Hospital, Karolinska University Hospital Huddinge in Sweden, with recruitment taking place between 2007 and 2008. The final study population consisted of 22 CKD and 26 CKD-T patients. The patients were seen at baseline, after 1 year, and after 3 years. Seven CKD patients were transplanted during the follow-up period.
2. Clinical characteristics
Medical records were reviewed for the etiology of kidney disease, duration of CKD, time after kidney transplantation, and records of medication. Clinical data were collected including values for height, weight, body mass index (BMI), and office blood pressure.
Standard deviation scores (z-scores) for systolic and diastolic blood pressure as well as height, weight, and BMI were obtained [20, 21]. Hypertension was defined as systolic and/or diastolic blood pressure equal to or greater than the 95th percentile for age, sex, and height [20] and/ or current treatment with antihypertensive medication. Obesity was defined as BMI equal to or greater than the 95th percentile for age and sex [21].
3. Biochemical data
Blood was drawn in a standardized manner during a clinical visit in the morning and following an overnight fast. Serum analyses of hemoglobin, creatinine, cystatin C, calcium, phosphate, intact (i)-PTH, albumin, and high-sensitive (hs)-CRP were performed in all study participants. Early morning spot urine was also collected to assess albuminuria, with a cut-off set at urinary albumin≥20 mg/L. GFR was assessed by using iohexol or inulin/PAH clearances in most assessments (92.4%). In the remaining patients (7.6%), GFR was estimated from cystatin C, or in a few patients where cystatin C values were not analyzed, GFR was assessed using creatinine levels [22].
The prevalence of anemia (hemoglobin < 5th percentile for age) [23], hypercalcemia, and hyperphosphatemia (albumin-adjusted calcium as well as phosphate level>97.5th percentile for age) [24] were assessed. Secondary hyperparathyroidism was defined as i-PTH>97.5th percentile corresponding to a level above 65 ng/L according to local laboratory standards.
Serum hs-cTnT and NT-proBNP were analyzed using electrochemiluminescence (ECL) immunoassays on the Cobas e 411 (Roche Diagnostics, Mannheim, Germany). Serum hs-cTnI was also analyzed and compared using two methods: STAT High Sensitive Troponin I immunoassay on the Architect Plus analyzer (Abbott Diagnostics, USA) and Access hs-cTnI on the DxI 800 system (Beckman Coulter, USA). Elevated levels were defined as>97.5th percentile for age and sex for hs-cTnT and NT-proBNP [25, 26] and>95th percentile for age for hs-cTnI (Architect) [27]. As there were no published reference values for children for Access hscTnI (DxI), we used adult reference values published by the manufacturer where the upper limit was defined as>99th percentile for sex (11.6 ng/L for females and 19.8 ng/L for males) [28]. We used the female reference as the upper limit for both sexes as the reference for Architect analysis only adjusted for age.
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4. Adjusting cardiac biomarkers for GFR
Due to the strong association to GFR for both NT-proBNP and hs-cTnT, we also assessed GFR-adjusted levels based on adult data [29, 30]. The following equations were used: GFR adjusted NT-proBNP=NT-proBNP/e1,892 – 0.025 × GFR and GFR adjusted hs-cTnT=(GFR/90)×hs-cTnT. Depending on GFR, concentrations of the assessed GFR-adjusted hs-cTnT may be lower than the detection limit of the assay, 3 ng/L.
5. Echocardiographic examination
Echocardiographic data were available for 19 CKD and 18 CKD-T patients (77%) at baseline, 18 CKD and 27 CKD-T patients (94%) in year 1, and 14 CKD and 31 CKD-T patients (94%) in year 3. The echocardiographic examinations were carried out using a standard system (Vivid 7, GE VingMed Ultrasound, version 108.0.1, Horten, Norway). A two-dimensional guided M-mode measurement, conventional pulse wave Doppler (PWD), and color-coded tissue Doppler imaging (cc-TDI) were performed according to the American Society of Echocardiography (ASE) guidelines [31, 32]. Left ventricular mass index (LVMI) was assessed (left ventricular mass/height2.7) [31, 33] as well as the presence of LVH [34]. Left ventricular diastolic function was evaluated with cc-TDI analyzing the peak myocardial velocities (cm/ sec) during early (e´) and late (a´) diastole. The mean velocities of the septal and lateral margins of the mitral annulus were assessed for the e´/a´ ratio, according to recommendations [32]. The diastolic function was also assessed by PWD measuring mitral inflow velocity in early (E) diastole, and the PWD E/cc-TDI e´ ratio was calculated [35]. We used both raw data and calculated z-scores for cc-TDI é and PWD E analyses with cut-offs to define left ventricular diastolic dysfunction set at<5th percentile [36]. An ejection fraction (EF)<50% was used to define left ventricular systolic dysfunction. The detailed methods, longitudinal changes, and intra-observer variability of these echocardiographic analyses have recently been published [13].
6. Statistical analysis
Statistical analyses were performed using Stata (StataCorp, TX, USA, version 16.0). Results are expressed as mean ± standard deviation and median [range]. Univariate analyses at baseline were performed using a t-test or Wilcoxon rank-sum test for comparisons between groups.
For univariate and multivariate longitudinal analyzes, linear mixed models with a restricted maximum likelihood (real) approach were used, which includes a random subject effect taking into account that a subject is measured several times. Non-normally distributed outcome variables were log-transformed before analyses.
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The primary outcomes in the linear mixed models were logged NT-proBNP, log GFR-adjusted NT-proBNP, log hs-cTnT, log GFR-adjusted hs-cTnT, and log hscTnI. The models included both baseline and follow-up measurements for the independent variables. In a subanalysis, two different methods (Architect and DxI) for analyzing hs-cTnI were also assessed. Secondary outcomes were markers of cardiovascular morbidity; LVMI, LVH, cc-TDI e´ z-score, and PWD E z-score, as well as cc-TDI e´/a´ and PWD E/cc-TDI e´. Variables with p-values < 0.10 in univariate models were tested in the multivariable models to fit the best model. Due to potential confounding, the patient group (CKD or CKD-T), age at baseline (years), and GFR (ml/min/1.73 m2 ) were forced into the model. A p-value<0.05 was considered statistically significant.
Subjects initiating kidney replacement therapy (dialysis or kidney transplant) during the study were analyzed separately following transplantation, resulting in potential bias due to nonrandom missing values as subjects with the most advanced disease were “lost to follow-up.” These patients were assessed to estimate the immediate effect of transplantation using a Mann–Whitney U test.
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Ylva Tranæus Lindblad1,2,3 Georgios Vavilis4,5 Milan Chromek1,2 Abdul Rashid Quershi6 Christian Löwbeer7,8 Peter Bárány2,6
1 Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
2 Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden
3 Huddinge BUMM, Paradistorget 4, 5tr, S-141 47 Huddinge, Sweden
4 Department of Medicine, Karolinska Institutet, Stockholm, Sweden
5 Division of Coronary and Valvular Heart Disease, Karolinska University Hospital, Stockholm, Sweden
6 Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
7 Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
8 Department of Clinical Chemistry at SYNLAB Medilab, Täby, Sweden
