Original Paper Nephron Clin Pract 2013;124:191–201 DOI: 10.1159/000356385
Received: April 18, 2013 Accepted: October 14, 2013 Published online: January 4, 2014
Investigating the Role of Cardiovascular Biomarkers in Children with Pre-Dialysis Chronic Kidney Disease: A Substitute to Echocardiography to Detect Increased Left Ventricular Mass? Joanna C. Clothier a John M. Simpson b Charles Turner c R. Neil Dalton c Pernille Rasmussen a Debbie Rawlins b Caroline J. Booth a Janet L. Peacock d Manish D. Sinha a Departments of a Paediatric Nephrology and b Congenital Heart Disease, Evelina London Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, c WellChild Laboratory and d Division of Health and Social Care Research, King’s College London, London, UK
Key Words Arterial injury · Endothelial dysfunction · Inflammation · Oxidative stress · Chronic kidney disease
Abstract Background: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). Methods: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3–5 of CKD. Results: Of 73 children aged 5–18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular
© 2014 S. Karger AG, Basel 1660–2110/14/1244–0191$39.50/0 E-Mail [email protected] www.karger.com/nec
mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. Conclusions: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD. © 2014 S. Karger AG, Basel
Introduction
Measurement of left ventricular (LV) mass to detect LV hypertrophy (LVH) is the most commonly reported cardiac parameter reported in adults and children with chronic kidney disease (CKD). We and others have recently highlighted the relationship of blood pressure (BP) to LVH in children with CKD [1, 2]. Other investigators have observed that factors such as high body mass index (BMI), male gender and anaemia also have significant impact on LV mass [3]. These and other so called ‘traditional’ cardiovascular (CV) risk factors such as smoking, older age and diabetes were initially identified by the Framingham investigators [4]. It is now well recognised that these traditional risk factors alone underestimate the risk Dr. Manish D. Sinha Department of Paediatric Nephrology, Room 64, SKY LEVEL Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust Westminster Bridge Road, London SE1 7EH (UK) E-Mail manish.sinha @ gstt.nhs.uk
of CV disease in patients with CKD and that there are several ‘CKD-specific’ ‘non-traditional’ risk factors that explain the unacceptably high CV morbidity and mortality in this cohort [5, 6]. Over the recent past CV biomarkers representing different patho-physiological processes including inflammation, endothelial dysfunction, sympathetic over-activity, protein-energy wasting, oxidative stress, vascular calcification and volume overload have been identified within the CKD population and thought likely to be important in both the initiation and progression of CV disease [7]. The evaluation of CV biomarkers in children with CKD is attractive as they are at risk of future adverse CV events, emphasizing the importance of early detection of LVH and dysfunction. In current clinical paediatric practice the diagnosis of LVH is made by echocardiography, by assessing indexed LV mass (LVMI). Previous work from our group has reported the poor sensitivity and specificity of more readily available tests such as an electrocardiogram (ECG) for the detection of LVH in this cohort [8]. CV biomarkers offer the possibility of non-invasively detecting the presence of increased LV mass and would be an attractive alternative to echocardiography which is time consuming and requires skilled operators. In this prospective, single-centre analysis, we hypothesised that higher levels of CV biomarkers would be associated with increased LV mass and LVH, and evaluated this hypothesis in children with predialysis stages 3–5 of CKD.
Materials and Methods Study Population Our unit is the designated government-funded referral centre for paediatric nephrology services for a defined geographical population in the south-east of England. This report is part of an ongoing study investigating CV morbidity in children with pre-dialysis CKD. The study protocol was approved by the institutional ethics committee. Informed consent was obtained from parents and/or patients for participation in the study. All children had predialysis CKD stages 3–5 and attended the CKD clinic at the Evelina Children’s Hospital, London, between March 2006 and October 2009. Renal function was determined by estimating glomerular filtration rate (eGFR) using the Schwartz formula [9] and CKD stage defined according to published definitions [10]. The inclusion criteria were: (1) eGFR ≤70 ml/min/1.73 m2 for at least 3 months; (2) age 5–18 years, and (3) height >120 cm. The exclusion criteria were: (1) failure to obtain good quality ambulatory BP monitoring; (2) peritoneal or haemodialysis; (3) structural cardiac abnormality; (4) ‘uncontrolled hypertension’, defined as clinic BP measurements >95th percentile on three consecutive clinic visits immediately pre-
192
Nephron Clin Pract 2013;124:191–201 DOI: 10.1159/000356385
ceding the day of study. Case notes were reviewed for demographic data and relevant medications. The study population, methods and relevant investigations have been described in detail previously [1]. Investigations on the Day of Study The following were performed in study participants at the same clinic visit: (1) history and physical examination; (2) anthropometry including height, weight and BMI; (3) clinic measurement of systolic BP and diastolic BP with calculation of pulse pressure and mean arterial pressure; (4) ambulatory BP monitoring; (5) echocardiography, and (6) laboratory investigations including haemoglobin, serum creatinine, corrected calcium, phosphorus and intact parathyroid hormone. ‘Time-averaged level’, an average value for laboratory parameters, was calculated for the 18-month period before study entry. CV Biomarkers The following panel of CV biomarkers representing different patho-physiological pathways implicated in the evolution of CV disease in this cohort were analysed [7]: (1) systemic inflammation – high sensitivity C-reactive protein (hs-CRP); (2) arterial injury – homocysteine and uric acid; (3) ventricular stretch/strain – N-terminal pro-B natriuretic peptide (NT-proBNP), and (4) decreased bioavailability of nitric oxide – asymmetric dimethyl arginine (ADMA). All studied biomarkers were measured once and on the same day as the echocardiography assessment. Investigators (C.T. and R.N.D.) involved in the measurement of all biomarkers were not aware of the clinical details of subjects or of their echocardiography findings. BP and Definition of Hypertension Clinic BP was measured using a mercury sphygmomanometer until early 2008 and subsequently using a calibrated aneroid instrument. Ambulatory BP monitoring (ABPM) studies were performed using Spacelabs 90207 and Spacelabs 90217 oscillometric ABP devices (Spacelabs Inc, Redmond, Wash., USA). We have previously reported in detail our ABPM protocol [1]. ABPM was rejected if there were more than 2 h of interrupted recordings at any time during the 24-hour period, or if the duration of ambulatory recording was
Received: April 18, 2013 Accepted: October 14, 2013 Published online: January 4, 2014
Investigating the Role of Cardiovascular Biomarkers in Children with Pre-Dialysis Chronic Kidney Disease: A Substitute to Echocardiography to Detect Increased Left Ventricular Mass? Joanna C. Clothier a John M. Simpson b Charles Turner c R. Neil Dalton c Pernille Rasmussen a Debbie Rawlins b Caroline J. Booth a Janet L. Peacock d Manish D. Sinha a Departments of a Paediatric Nephrology and b Congenital Heart Disease, Evelina London Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, c WellChild Laboratory and d Division of Health and Social Care Research, King’s College London, London, UK
Key Words Arterial injury · Endothelial dysfunction · Inflammation · Oxidative stress · Chronic kidney disease
Abstract Background: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). Methods: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3–5 of CKD. Results: Of 73 children aged 5–18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular
© 2014 S. Karger AG, Basel 1660–2110/14/1244–0191$39.50/0 E-Mail [email protected] www.karger.com/nec
mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. Conclusions: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD. © 2014 S. Karger AG, Basel
Introduction
Measurement of left ventricular (LV) mass to detect LV hypertrophy (LVH) is the most commonly reported cardiac parameter reported in adults and children with chronic kidney disease (CKD). We and others have recently highlighted the relationship of blood pressure (BP) to LVH in children with CKD [1, 2]. Other investigators have observed that factors such as high body mass index (BMI), male gender and anaemia also have significant impact on LV mass [3]. These and other so called ‘traditional’ cardiovascular (CV) risk factors such as smoking, older age and diabetes were initially identified by the Framingham investigators [4]. It is now well recognised that these traditional risk factors alone underestimate the risk Dr. Manish D. Sinha Department of Paediatric Nephrology, Room 64, SKY LEVEL Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust Westminster Bridge Road, London SE1 7EH (UK) E-Mail manish.sinha @ gstt.nhs.uk
of CV disease in patients with CKD and that there are several ‘CKD-specific’ ‘non-traditional’ risk factors that explain the unacceptably high CV morbidity and mortality in this cohort [5, 6]. Over the recent past CV biomarkers representing different patho-physiological processes including inflammation, endothelial dysfunction, sympathetic over-activity, protein-energy wasting, oxidative stress, vascular calcification and volume overload have been identified within the CKD population and thought likely to be important in both the initiation and progression of CV disease [7]. The evaluation of CV biomarkers in children with CKD is attractive as they are at risk of future adverse CV events, emphasizing the importance of early detection of LVH and dysfunction. In current clinical paediatric practice the diagnosis of LVH is made by echocardiography, by assessing indexed LV mass (LVMI). Previous work from our group has reported the poor sensitivity and specificity of more readily available tests such as an electrocardiogram (ECG) for the detection of LVH in this cohort [8]. CV biomarkers offer the possibility of non-invasively detecting the presence of increased LV mass and would be an attractive alternative to echocardiography which is time consuming and requires skilled operators. In this prospective, single-centre analysis, we hypothesised that higher levels of CV biomarkers would be associated with increased LV mass and LVH, and evaluated this hypothesis in children with predialysis stages 3–5 of CKD.
Materials and Methods Study Population Our unit is the designated government-funded referral centre for paediatric nephrology services for a defined geographical population in the south-east of England. This report is part of an ongoing study investigating CV morbidity in children with pre-dialysis CKD. The study protocol was approved by the institutional ethics committee. Informed consent was obtained from parents and/or patients for participation in the study. All children had predialysis CKD stages 3–5 and attended the CKD clinic at the Evelina Children’s Hospital, London, between March 2006 and October 2009. Renal function was determined by estimating glomerular filtration rate (eGFR) using the Schwartz formula [9] and CKD stage defined according to published definitions [10]. The inclusion criteria were: (1) eGFR ≤70 ml/min/1.73 m2 for at least 3 months; (2) age 5–18 years, and (3) height >120 cm. The exclusion criteria were: (1) failure to obtain good quality ambulatory BP monitoring; (2) peritoneal or haemodialysis; (3) structural cardiac abnormality; (4) ‘uncontrolled hypertension’, defined as clinic BP measurements >95th percentile on three consecutive clinic visits immediately pre-
192
Nephron Clin Pract 2013;124:191–201 DOI: 10.1159/000356385
ceding the day of study. Case notes were reviewed for demographic data and relevant medications. The study population, methods and relevant investigations have been described in detail previously [1]. Investigations on the Day of Study The following were performed in study participants at the same clinic visit: (1) history and physical examination; (2) anthropometry including height, weight and BMI; (3) clinic measurement of systolic BP and diastolic BP with calculation of pulse pressure and mean arterial pressure; (4) ambulatory BP monitoring; (5) echocardiography, and (6) laboratory investigations including haemoglobin, serum creatinine, corrected calcium, phosphorus and intact parathyroid hormone. ‘Time-averaged level’, an average value for laboratory parameters, was calculated for the 18-month period before study entry. CV Biomarkers The following panel of CV biomarkers representing different patho-physiological pathways implicated in the evolution of CV disease in this cohort were analysed [7]: (1) systemic inflammation – high sensitivity C-reactive protein (hs-CRP); (2) arterial injury – homocysteine and uric acid; (3) ventricular stretch/strain – N-terminal pro-B natriuretic peptide (NT-proBNP), and (4) decreased bioavailability of nitric oxide – asymmetric dimethyl arginine (ADMA). All studied biomarkers were measured once and on the same day as the echocardiography assessment. Investigators (C.T. and R.N.D.) involved in the measurement of all biomarkers were not aware of the clinical details of subjects or of their echocardiography findings. BP and Definition of Hypertension Clinic BP was measured using a mercury sphygmomanometer until early 2008 and subsequently using a calibrated aneroid instrument. Ambulatory BP monitoring (ABPM) studies were performed using Spacelabs 90207 and Spacelabs 90217 oscillometric ABP devices (Spacelabs Inc, Redmond, Wash., USA). We have previously reported in detail our ABPM protocol [1]. ABPM was rejected if there were more than 2 h of interrupted recordings at any time during the 24-hour period, or if the duration of ambulatory recording was
