Pediatr Nephrol DOI 10.1007/s00467-016-3350-4
ORIGINAL ARTICLE
Dyslipidemia, carotid intima-media thickness and endothelial dysfunction in children with chronic kidney disease Priyanka Khandelwal 1 & Vijaya Murugan 1 & Smriti Hari 2 & Ramakrishnan Lakshmy 3 & Aditi Sinha 1 & Pankaj Hari 1 & Arvind Bagga 1
Received: 1 September 2015 / Revised: 5 February 2016 / Accepted: 8 February 2016 # IPNA 2016
Abstract Background Chronic kidney disease (CKD) predisposes to accelerated atherosclerosis that is measured by carotid artery intima-media thickness (cIMT) and brachial artery flowmediated dilation (FMD). Information on the association of these parameters with dyslipidemia in pre-dialysis pediatric CKD is limited. Methods Eighty patients aged 9.9 ± 3.2 years, with estimated glomerular filtration rate of 38.8 ± 10.8 ml/1.73 m2/min, and 42 pediatric controls underwent cross-sectional analysis of lipid profile, cIMT, and brachial artery FMD. Significant differences in these parameters between patients and controls were analyzed using Student’s t test. Predictors of cIMT and dyslipidemia were assessed using linear and logistic regression respectively. Results Patients had elevated blood levels of triglyceride and of total and LDL cholesterol than controls (P ≤ 0.001); 73.8 % were dyslipidemic. Mean cIMT was higher (0.421 ± 0.054 mm vs 0.388 ± 0.036 mm, P = 0.001) and brachial artery FMD was reduced (10.6 ± 4.9 % vs 18.9 ± 4.1 %, P < 0.0001) in patients compared with controls. On multivariate analysis, hypertension (OR 3.68, P = 0.044) and male gender (OR 10.21, P = 0.004) were associated with
* Pankaj Hari [email protected]
1
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2
Department of Radiology, All India Institute of Medical Sciences, New Delhi, India
3
Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
dyslipidemia; cIMT was significantly associated with LDL cholesterol (β = 28.36, P = 0.033). Conclusion Dyslipidemia was prevalent and cIMT significantly elevated in pre-dialysis pediatric CKD, indicating increased cardiovascular risk. Elevated LDL cholesterol predicted increased cIMT, strengthening the association between dyslipidemia and atherosclerosis in early CKD. Keywords Atherosclerosis . Low-density lipoprotein cholesterol . Chronic renal insufficiency . Triglyceride . Hypertension
Introduction Cardiovascular disease is the most common cause of mortality in children with chronic kidney disease (CKD) [1]. These children are stratified into the highest tier of cardiovascular risk in the American Heart Association pediatric consensus guidelines for cardiovascular health because of their predisposition to accelerated atherosclerosis [2]. Atherosclerosis originates early in childhood and is associated with hypertension, dyslipidemia, obesity, and abnormal glucose metabolism [2, 3]. Uremic risk factors such as fluid overload, anemia, abnormal calcium–phosphorus metabolism, malnutrition, and inflammation additionally contribute to cardiovascular morbidity in patients with CKD [4]. Dyslipidemia is a modifiable risk factor that contributes to the progression of CKD [5] and, therefore, is a focus of clinical research. Subclinical atherosclerosis has been demonstrated in the early stages of CKD, both in adults [6] and in children [7, 8]. Structural and functional abnormality on vascular imaging, assessed respectively by ultrasound measurement of increased carotid intima-media thickness (cIMT) and reduced flow-mediated dilation (FMD) of the brachial artery, implicate subclinical atherosclerosis and
Pediatr Nephrol
predict cardiovascular risk in adults with CKD [9, 10]. While cIMT is increased in children with hypertension, obesity, diabetes, and metabolic syndrome [11], data on its association with atherosclerosis in pediatric CKD are limited [12, 13]. South Asians have the highest rates of premature cardiovascular disease in the world [14] and children have high rates of malnutrition, anemia, and mineral bone disease that predispose them to even greater cardiovascular morbidity [15]. Although the high prevalence of dyslipidemia [16, 17] and subclinical vascular damage demonstrated by increased cIMT has been reported in children with early CKD in a multicenter study from North America [18], similar information from countries of South Asian origin is limited. The present study describes the prevalence of dyslipidemia in Indian children with pre-dialysis CKD and its association with premature atherosclerotic vascular disease, as measured by cIMT and brachial artery FMD.
Materials and methods This cross-sectional analytical study was conducted at the All India Institute of Medical Sciences, New Delhi, India. Following approval by the Institute Ethics Committee (approval number AA12/ 27. 02. 2009) and informed written consent, patients between 5 and 18 years of age diagnosed with CKD for more than 2 years with estimated glomerular filtration rate (eGFR, by modified Schwartz equation [19, 20]) between 15 and 59 ml/min/1.73 m2 were enrolled. Patients were classified as CKD stage G3a, G3b or G4 with eGFR of 45–59, 30–44, and 15–29 ml/min/1.73 m2 respectively, according to the revised recommendations by Kidney Disease: Improving Global Outcomes (KDIGO) for the staging of CKD by cause, GFR, and albuminuria [21]. Children receiving lipid-lowering drugs and those with a family history of premature (≤55 years in men or ≤65 years in women [22]) cardiovascular disease were excluded. Controls were children between 5 and 18 years of age, who presented for vaccination, minor surgeries or evaluation of non-inflammatory illnesses; subjects with recent febrile illness (1 to ≤2, whereas obesity was defined as BMI-SDS >2 [23]. Blood pressure was measured twice at enrollment and average systolic and diastolic pressures were used to derive age–sex– height-specific blood pressure percentiles [24]; antihypertensive medications were recorded. Hypertension was present if either systolic or diastolic blood pressure exceeded the 95th centile, or the patients were receiving antihypertensive medications; those prescribed antihypertensive medications solely for the control of proteinuria were not classified as hypertensive. Blood levels of urea, creatinine, calcium, phosphate, alkaline phosphatase, and hemoglobin were evaluated and defined as abnormal based on KDIGO guidelines [21]. Serum total cholesterol, low-density lipoprotein (LDL), very lowdensity lipoprotein (VLDL), high-density lipoprotein (HDL), and triglycerides were estimated following a 12-h overnight fasting period. Total cholesterol and triglyceride levels were measured using the enzymatic endpoint method [25]. HDL was estimated after the precipitation of LDL and VLDL using phosphotungstic acid and magnesium [26]. LDL cholesterol (mg/dl) was calculated as follows [27]: LDL cholesterol ¼ Total cholesterol–triglyceride=5–HDL Dyslipidemia was defined as total cholesterol, LDL cholesterol or triglyceride >95th centile, and/or HDL cholesterol 145 mg/dl [2]. cIMT and brachial artery FMD were determined by one radiologist using high-resolution ultrasound with a multifrequency linear probe (5–12 MHz) and standardized image settings [29]. Bilateral distal common carotid arteries, 1 cm proximal to the bifurcation, were imaged during end diastole, with the patient in a supine position and the neck slightly extended. cIMT was defined as the distance between the leading edges of the lumen–intima interface and the media–adventitia interface of the far wall of the carotid artery; the mean of six recordings (three on each side) was calculated. Assessment of brachial artery FMD was done after 10-min rest in a temperature controlled room, in a fasting state, according to standard guidelines [30]. A blood pressure cuff was applied to the widest part of the forearm below the antecubital fossa, inflated to 50 mm Hg above systolic BP and deflated after 4 min. Images were obtained at baseline, following inflation, immediately after deflation and 45 s after deflation; maximum dilatation was recorded. The change in the diameter of the brachial artery from the baseline expressed as a percentage of the baseline diameter represented the FMD. Data are presented as mean ± SD, median (interquartile range) or proportions, wherever appropriate, and analyzed
Pediatr Nephrol
using SPSS (IBM statistics, version 17). Parameters of patients and controls were compared using Student’s t test or Wilcoxon rank-sum tests. Analysis of covariance (ANCOVA) was used to determine significant differences in lipid profile, mean cIMT, and brachial artery FMD between cases and controls after adjusting for confounders. Linear regression was used for quantifying the association of cIMT with demographic and biochemical variables, and expressed as a coefficient of regression (β, 95 % confidence interval, CI). Blood pressure and lipid profile were dichotomized into categorical variables (elevated and normal) for regression analysis; LDL cholesterol, total cholesterol, non-HDL cholesterol and triglycerides were used in separate models owing to high collinearity. Factors predicting dyslipidemia were determined by binomial logistic regression analysis and expressed as odds ratios (OR; 95 % CI). Factors with P < 0.25 on univariate analysis were used for multivariate linear and logistic regression analysis; P < 0.05 was considered significant. Table 1 Clinical, biochemical, and radiological parameters in patients with chronic kidney disease
Results Eighty patients (83.8 % boys), aged 9.9 ± 3.2 years with an eGFR of 38.8 ± 10.8 ml/1.73 m2/min, were studied. Children had CKD stage 3 (G3a 32.5 %; G3b 45 %) or stage 4 (G4, 22.5 %) and had received therapy for 4.6 ± 2.6 years. The antecedent etiology was either a nonglomerular pathological condition in 70.0 % (19 with posterior urethral valves, 16 with vesicoureteric reflux, 7 with renal dysplasia, 6 with a neurogenic bladder, 4 with a ureteric stone or nephrocalcinosis, 2 with polycystic kidney disease, and 2 with acute tubular necrosis) or a glomerular disease in 16.3 % (9 with chronic glomerulonephritis, 4 with hemolytic uremic syndrome); in 11 patients (13.7 %) the etiology was not determined. Baseline characteristics of patients compared with 42 healthy controls are shown in Table 1. Children with CKD were shorter and had higher systolic (P ≤0.0001) and diastolic blood pressures (P = 0.009). Weight-for-age and height-forage were below −2 SDS in 36.3 % and 76.3 % patients
Characteristics
Patients (n = 80)
Controls (n = 42)
P value
Age (years) Sex (male, %) Height (cm)
9.9 ± 3.2 67 (83.8) 115.5 ± 16.0
9.7 ± 3.0 22 (52.4) 129.5 ± 18.04
0.64 0.0002
ORIGINAL ARTICLE
Dyslipidemia, carotid intima-media thickness and endothelial dysfunction in children with chronic kidney disease Priyanka Khandelwal 1 & Vijaya Murugan 1 & Smriti Hari 2 & Ramakrishnan Lakshmy 3 & Aditi Sinha 1 & Pankaj Hari 1 & Arvind Bagga 1
Received: 1 September 2015 / Revised: 5 February 2016 / Accepted: 8 February 2016 # IPNA 2016
Abstract Background Chronic kidney disease (CKD) predisposes to accelerated atherosclerosis that is measured by carotid artery intima-media thickness (cIMT) and brachial artery flowmediated dilation (FMD). Information on the association of these parameters with dyslipidemia in pre-dialysis pediatric CKD is limited. Methods Eighty patients aged 9.9 ± 3.2 years, with estimated glomerular filtration rate of 38.8 ± 10.8 ml/1.73 m2/min, and 42 pediatric controls underwent cross-sectional analysis of lipid profile, cIMT, and brachial artery FMD. Significant differences in these parameters between patients and controls were analyzed using Student’s t test. Predictors of cIMT and dyslipidemia were assessed using linear and logistic regression respectively. Results Patients had elevated blood levels of triglyceride and of total and LDL cholesterol than controls (P ≤ 0.001); 73.8 % were dyslipidemic. Mean cIMT was higher (0.421 ± 0.054 mm vs 0.388 ± 0.036 mm, P = 0.001) and brachial artery FMD was reduced (10.6 ± 4.9 % vs 18.9 ± 4.1 %, P < 0.0001) in patients compared with controls. On multivariate analysis, hypertension (OR 3.68, P = 0.044) and male gender (OR 10.21, P = 0.004) were associated with
* Pankaj Hari [email protected]
1
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2
Department of Radiology, All India Institute of Medical Sciences, New Delhi, India
3
Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
dyslipidemia; cIMT was significantly associated with LDL cholesterol (β = 28.36, P = 0.033). Conclusion Dyslipidemia was prevalent and cIMT significantly elevated in pre-dialysis pediatric CKD, indicating increased cardiovascular risk. Elevated LDL cholesterol predicted increased cIMT, strengthening the association between dyslipidemia and atherosclerosis in early CKD. Keywords Atherosclerosis . Low-density lipoprotein cholesterol . Chronic renal insufficiency . Triglyceride . Hypertension
Introduction Cardiovascular disease is the most common cause of mortality in children with chronic kidney disease (CKD) [1]. These children are stratified into the highest tier of cardiovascular risk in the American Heart Association pediatric consensus guidelines for cardiovascular health because of their predisposition to accelerated atherosclerosis [2]. Atherosclerosis originates early in childhood and is associated with hypertension, dyslipidemia, obesity, and abnormal glucose metabolism [2, 3]. Uremic risk factors such as fluid overload, anemia, abnormal calcium–phosphorus metabolism, malnutrition, and inflammation additionally contribute to cardiovascular morbidity in patients with CKD [4]. Dyslipidemia is a modifiable risk factor that contributes to the progression of CKD [5] and, therefore, is a focus of clinical research. Subclinical atherosclerosis has been demonstrated in the early stages of CKD, both in adults [6] and in children [7, 8]. Structural and functional abnormality on vascular imaging, assessed respectively by ultrasound measurement of increased carotid intima-media thickness (cIMT) and reduced flow-mediated dilation (FMD) of the brachial artery, implicate subclinical atherosclerosis and
Pediatr Nephrol
predict cardiovascular risk in adults with CKD [9, 10]. While cIMT is increased in children with hypertension, obesity, diabetes, and metabolic syndrome [11], data on its association with atherosclerosis in pediatric CKD are limited [12, 13]. South Asians have the highest rates of premature cardiovascular disease in the world [14] and children have high rates of malnutrition, anemia, and mineral bone disease that predispose them to even greater cardiovascular morbidity [15]. Although the high prevalence of dyslipidemia [16, 17] and subclinical vascular damage demonstrated by increased cIMT has been reported in children with early CKD in a multicenter study from North America [18], similar information from countries of South Asian origin is limited. The present study describes the prevalence of dyslipidemia in Indian children with pre-dialysis CKD and its association with premature atherosclerotic vascular disease, as measured by cIMT and brachial artery FMD.
Materials and methods This cross-sectional analytical study was conducted at the All India Institute of Medical Sciences, New Delhi, India. Following approval by the Institute Ethics Committee (approval number AA12/ 27. 02. 2009) and informed written consent, patients between 5 and 18 years of age diagnosed with CKD for more than 2 years with estimated glomerular filtration rate (eGFR, by modified Schwartz equation [19, 20]) between 15 and 59 ml/min/1.73 m2 were enrolled. Patients were classified as CKD stage G3a, G3b or G4 with eGFR of 45–59, 30–44, and 15–29 ml/min/1.73 m2 respectively, according to the revised recommendations by Kidney Disease: Improving Global Outcomes (KDIGO) for the staging of CKD by cause, GFR, and albuminuria [21]. Children receiving lipid-lowering drugs and those with a family history of premature (≤55 years in men or ≤65 years in women [22]) cardiovascular disease were excluded. Controls were children between 5 and 18 years of age, who presented for vaccination, minor surgeries or evaluation of non-inflammatory illnesses; subjects with recent febrile illness (1 to ≤2, whereas obesity was defined as BMI-SDS >2 [23]. Blood pressure was measured twice at enrollment and average systolic and diastolic pressures were used to derive age–sex– height-specific blood pressure percentiles [24]; antihypertensive medications were recorded. Hypertension was present if either systolic or diastolic blood pressure exceeded the 95th centile, or the patients were receiving antihypertensive medications; those prescribed antihypertensive medications solely for the control of proteinuria were not classified as hypertensive. Blood levels of urea, creatinine, calcium, phosphate, alkaline phosphatase, and hemoglobin were evaluated and defined as abnormal based on KDIGO guidelines [21]. Serum total cholesterol, low-density lipoprotein (LDL), very lowdensity lipoprotein (VLDL), high-density lipoprotein (HDL), and triglycerides were estimated following a 12-h overnight fasting period. Total cholesterol and triglyceride levels were measured using the enzymatic endpoint method [25]. HDL was estimated after the precipitation of LDL and VLDL using phosphotungstic acid and magnesium [26]. LDL cholesterol (mg/dl) was calculated as follows [27]: LDL cholesterol ¼ Total cholesterol–triglyceride=5–HDL Dyslipidemia was defined as total cholesterol, LDL cholesterol or triglyceride >95th centile, and/or HDL cholesterol 145 mg/dl [2]. cIMT and brachial artery FMD were determined by one radiologist using high-resolution ultrasound with a multifrequency linear probe (5–12 MHz) and standardized image settings [29]. Bilateral distal common carotid arteries, 1 cm proximal to the bifurcation, were imaged during end diastole, with the patient in a supine position and the neck slightly extended. cIMT was defined as the distance between the leading edges of the lumen–intima interface and the media–adventitia interface of the far wall of the carotid artery; the mean of six recordings (three on each side) was calculated. Assessment of brachial artery FMD was done after 10-min rest in a temperature controlled room, in a fasting state, according to standard guidelines [30]. A blood pressure cuff was applied to the widest part of the forearm below the antecubital fossa, inflated to 50 mm Hg above systolic BP and deflated after 4 min. Images were obtained at baseline, following inflation, immediately after deflation and 45 s after deflation; maximum dilatation was recorded. The change in the diameter of the brachial artery from the baseline expressed as a percentage of the baseline diameter represented the FMD. Data are presented as mean ± SD, median (interquartile range) or proportions, wherever appropriate, and analyzed
Pediatr Nephrol
using SPSS (IBM statistics, version 17). Parameters of patients and controls were compared using Student’s t test or Wilcoxon rank-sum tests. Analysis of covariance (ANCOVA) was used to determine significant differences in lipid profile, mean cIMT, and brachial artery FMD between cases and controls after adjusting for confounders. Linear regression was used for quantifying the association of cIMT with demographic and biochemical variables, and expressed as a coefficient of regression (β, 95 % confidence interval, CI). Blood pressure and lipid profile were dichotomized into categorical variables (elevated and normal) for regression analysis; LDL cholesterol, total cholesterol, non-HDL cholesterol and triglycerides were used in separate models owing to high collinearity. Factors predicting dyslipidemia were determined by binomial logistic regression analysis and expressed as odds ratios (OR; 95 % CI). Factors with P < 0.25 on univariate analysis were used for multivariate linear and logistic regression analysis; P < 0.05 was considered significant. Table 1 Clinical, biochemical, and radiological parameters in patients with chronic kidney disease
Results Eighty patients (83.8 % boys), aged 9.9 ± 3.2 years with an eGFR of 38.8 ± 10.8 ml/1.73 m2/min, were studied. Children had CKD stage 3 (G3a 32.5 %; G3b 45 %) or stage 4 (G4, 22.5 %) and had received therapy for 4.6 ± 2.6 years. The antecedent etiology was either a nonglomerular pathological condition in 70.0 % (19 with posterior urethral valves, 16 with vesicoureteric reflux, 7 with renal dysplasia, 6 with a neurogenic bladder, 4 with a ureteric stone or nephrocalcinosis, 2 with polycystic kidney disease, and 2 with acute tubular necrosis) or a glomerular disease in 16.3 % (9 with chronic glomerulonephritis, 4 with hemolytic uremic syndrome); in 11 patients (13.7 %) the etiology was not determined. Baseline characteristics of patients compared with 42 healthy controls are shown in Table 1. Children with CKD were shorter and had higher systolic (P ≤0.0001) and diastolic blood pressures (P = 0.009). Weight-for-age and height-forage were below −2 SDS in 36.3 % and 76.3 % patients
Characteristics
Patients (n = 80)
Controls (n = 42)
P value
Age (years) Sex (male, %) Height (cm)
9.9 ± 3.2 67 (83.8) 115.5 ± 16.0
9.7 ± 3.0 22 (52.4) 129.5 ± 18.04
0.64 0.0002
