© Borgis - Postępy Nauk Medycznych 9/2014, s. 604-610
*Magdalena Okarska-Napierała1, Piotr Skrzypczyk1, Helena Ziółkowska1, Radosław Pietrzak2, Katarzyna Jankowska1, Bożena Werner2, Maria Roszkowska-Blaim1
Czynniki ryzyka uszkodzenia serca i tętnic u dzieci z przewlekłą chorobą nerek
Determinants of heart and arterial system damage in children with chronic kidney disease
1Department of Pediatrics and Nephrology, Medical University of Warsaw
Head of Department: prof. Maria Roszkowska-Blaim, MD, PhD
2Department of Pediatric Cardiology and General Pediatrics, Medical University of Warsaw
Head of Department: prof. Bożena Werner, MD, PhD
Streszczenie
Wstęp. Dzieci z przewlekłą chorobą nerek (PChN) cechują się najwyższym ryzykiem sercowo-naczyniowym wśród pacjentów pediatrycznych.
Cel pracy. Celem pracy była ocena serca i tętnic u dzieci z PChN w powiązaniu z wybranymi parametrami klinicznymi i biochemicznymi oraz określenie przydatności oznaczania NT-proBNP jako markera uszkodzenia układu sercowo-naczyniowego w tej grupie chorych.
Materiał i metody. U 17 dzieci w śr. wieku 13,5 ± 4,3 lat z PChN st. 2-5 oceniono: badanie echokardiograficzne, kompleks błona środkowa-wewnętrzna t. szyjnych wspólnych (cIMT), kształt i prędkość fali tętna (PWV), NT-proBNP, ciśnienie tętnicze, leki i wybrane parametry biochemiczne.
Wyniki. W badanej grupie śr. indeks masy lewej komory (LVMI) wynosił 29,3 ± 6,2 g/m2,7, cIMT 0,46 ± 0,05 mm, PWV 4,65 ± 0,94 m/s, wskaźnik wzmocnienia skorygowany do akcji serca 75/min (AIx75HR) 5,85 ± 16,32%, aortalne ciśnienie skurczowe (AoSP) 102,0 ± 12,8 mmHg, rozkurczowe (AoDP) 73,9 ± 13,0 mmHg. Wartość LVMI korelowała z NT-proBNP (r = 0,55, p = 0,029), PTH (r = 0,69, p = 0,003), fosfatazą alkaliczną (r = 0,65, p = 0,009); PWV z cIMT (r = 0,66, p = 0,004) i grubością tylnej ściany lewej komory (r = 0,56; p = 0,025); wskaźnik PWV/wzrost z GFR (r = -0,52, p = 0,032) i wskaźnikiem wypełnienia t. wieńcowych (r = -0,52, p = 0,034); AIx75HR z NT-proBNP i fosfatazą alkaliczną (r = 0,58, p = 0,015; r = 0,57, p = 0,02); AoSP i AoDP z NT-proBNP (r = 0,63, p = 0,006; r = 0,50, p = 0,04) i PTH (r = 0,62, p = 0,007; r = 0,57, p = 0,02). Wykazano tendencję do korelacji dobowej dawki węglanu wapnia z PWV (r = 0,45, r = 0,08) i cIMT (0,49; p = 0,055).
Wnioski. 1. U dzieci z PChN NT-proBNP jest użytecznym markerem przerostu lewej komory serca, sztywności tętnic i ciśnienia centralnego. 2. U pediatrycznych pacjentów z PChN zaburzenia gospodarki wapniowo-fosforanowej wydają się być kluczową determinantą masy lewej komory i sztywności tętnic. 3. Dawka węglanu wapnia może wpływać na sztywność tętnic i grubość kompleksu IMT u dzieci z PChN, ale ta zależność wymaga dalszych badań na większych grupach pacjentów.
Summary
Introduction. Children with chronic kidney disease (CKD) are among pediatric patients with highest cardiovascular risk.
Aim. The aim of the study was to evaluate heart and arterial system in children with CKD in relation to selected clinical and biochemical parameters and to assess usefulness of NT-proBNP as a marker of cardiovascular damage in this group of patients.
Material and methods. In 17 children (13.5 ± 4.3 years), with CKD stage 2-5, we assessed: echocardiography, carotid intima-media thickness (cIMT), pulse wave velocity (PWV) and analysis, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), blood pressure, medications, and selected biochemical parameters.
Results. Left ventricular mass index (LVMI) was 29.3 ± 6.2 g/m2,7, cIMT 0.46 ± 0.05 mm, PWV 4.65 ± 0.94 m/s, augmentation index at heart rate 75/min (AI x 75HR) 5.85 ± 16.32%, aortic systolic blood pressure (AoSP) 102.0 ± 12.8 mmHg, and aortic diastolic blood pressure (AoDP) 73.9 ± 13.0 mmHg. LVMI correlated with NT-proBNP (r = 0.55, p = 0.029), PTH (r = 0.69, p = 0.003), alkaline phosphatase (ALP) (r = 0.65, p = 0.009); PWV with cIMT (r = 0.66, p = 0.004), left ventricular posterior wall thickness (r = 0.56; p = 0.025); PWV/height ratio with GFR (r = -0.52, p = 0.032), subendocardial viability ratio (r = -0.52, p = 0.034); AI x 75HR with NT-proBNP and ALP (r = 0,58, p = 0.015; r = 0.57, p = 0.02); AoSP and AoDP with NT-proBNP (r = 0.63, p = 0.006; r = 0.50, p = 0.04) and PTH (r = 0.62, p = 0.007; r = 0.57, p = 0.02). We found tendency toward correlations of calcium carbonate dose with PWV (r = 0.45, r = 0.08) and cIMT (0.49, p = 0.055).
Conclusions. 1. In children with CKD, NT-proBNP is a useful marker of left ventricular hypertrophy, arterial stiffness and central blood pressure. 2. In pediatric patients with CKD calcium-phosphate disturbances seem to be key determinants of left ventricle mass and arterial stiffness. 3. Calcium carbonate dose may influence arterial stiffness and IMT in children with CKD, but this relation requires further investigations in larger groups of patients.
Introduction
Cardiovascular disease (CVD) is a leading cause of increased mortality in children and young adults with chronic kidney disease (CKD). The risk of cardiovascular death in patients aged 25-34 years, with CKD stage 5, is the same as in general population at the age of 75 (1). Patients with CKD present with both: typical cardiovascular risk factors (e.g. hyperlipidemia, hypertension, insulin resistance), which occur more frequently in course of CKD (2), and non-typical, uremia-related cardiovascular risk factors (e.g. anemia, hypervolemia, chronic inflammation, calcium-phosphate metabolism disturbances) which are particularly important in CVD development in young adults (3-5). Cardiovascular complications of CKD include structural and functional damage to the heart and abnormalities within the blood vessels (6).
Within the heart, CKD leads to left ventricular hypertrophy (LVH) and diastolic dysfunction. LVH in children can be assessed on echocardiography by calculating left ventricular mass index (LVMI). LVH is a frequent finding in children with CKD (7-9). Diastolic dysfunction can also be determined on echocardiography, as a decrease in early/atrial ventricular filling velocity ratio (E/A ratio) and tissue Doppler imaging (TDI) abnormalities. Disturbed diastolic function, correlating with decreasing GFR, has been reported in children with CKD (10, 11).
In response to cardiac structural damage, myocardium cells excrete B-type natriuretic peptide (BNP) and its inactive metabolite – N-terminal prohormone BNP (NT-proBNP). The latter is a useful biochamical marker of cardiac strain in both adults and children (12, 13).
Within the blood vessels, both atherosclerosis and arterial calcifications develop in course of CKD. Augmentation index, aortic pulse wave velocity and carotid intima media thickness are well established surrogate markers of vascular damage and cardiovascular risk in adults with CKD, but they still need standardization and validation in pediatric population (14, 15).
AIM
The aim of this study was to evaluate the heart and arterial system in children with CKD in relation to selected clinical and biochemical parameters and to assess usefulness of NT-proBNP as a marker of cardiovascular damage in this group of patients.
Material and methods
We studied 17 children (11 boys and 6 girls) aged from 5.4 to 17.1 years (mean 13.5 ± 4.3 years) treated in the Department of Pediatrics and Nephrology of Medical University of Warsaw for chronic kidney disease. Causes of CKD in the analyzed children were as follows: congenital anomalies of kidney and urinary tract (CAKUT) in 9 (52.9%), glomerulonephritis in 4 (23.5%), other causes in 3 (17.6%): cortical necrosis after post-ischemic acute kidney injury in 2, lupus nephritis in 1; in 1 (5.9%) child cause of CKD was unknown. Children with congenital heart defects were excluded from the study.
In all studied children cardiovascular status was evaluated by assessment of peripheral blood pressure, 2d echocardiography, assessment of arterial stiffness by applanation tonometry and carotid intima media thickness by 2d ultrasonography, and assessment of serum NT-proBNP level.
Peripheral blood pressure [mmHg] was measured oscillometrically in each patient on the right arm using the Welch Allyn ASM 300 Patient Monitor device (Welch Allyn, USA).
Detailed conventional 2-dimensional echocardiographic examinations (Philips iE33 xMATRIX Echocardiography System, Philips Healthcare, Netherlands) were performed in all patients by the same experienced paediatric cardiologist following the same protocol. Left ventricular end systolic (LVES) and end diastolic diameters (LVED), interventricular septum and posterior wall thicknesses in systole and in diastole (IVES, IVED, PWES, PVED, respectively) were measured. LVM was calculated using the Devereux formula (16), and LVM index (LVMI; mass divided by height raised to a power of 2.7 g/m2,7) was used to evaluate LVH (17). LVH was defined as LVMI greater than the 95th percentile for normal children and adolescents (18). All parameters were measured during three consecutive cardiac cycles, and their mean value was calculated.
Arterial pulse waveform and aortal pulse wave velocity were evaluated using the Sphygmocor device (AtCor Medical, Australia). Peripheral pressure waveforms were recorded from the radial artery at the right wrist, using applanation tonometry. After 20 sequential waveforms had been acquired, a validated generalized transfer function was used to generate the corresponding central aortic pressure waveform. We evaluated the following parameters: aortic systolic pressure (AoSP) [mmHg], aortic diastolic pressure (AoDP) (mmHg], aortic pulse pressure (AoPP) [mmHg], augmentation pressure (AP) [mm Hg], augmentation index (AIx(AP/PP), (AIx(P2/P1)) [%], augmentation index (AIx(AP/PP)) corrected for heart rate of 75 beats per minute (AIx75HR) [%], and an index of myocardial oxygen supply and demand, subendocardial viability ratio (SEVR or Buckberg index) [%]. AP was calculated as the difference between the second (P2) and first (P1) systolic peak of the central pressure waveform. AIx was defined as the AP divided by pulse pressure and expressed as a percentage. Because AIx is influenced by heart rate, an index normalized for heart rate of 75 bpm (AIx-75HR) was used. SEVR was defined as the ratio of diastolic and systolic area under the curve (19-21). Only high-quality recordings, defined as an in-device quality index > 80%, were included in the analysis. PWV was calculated as the difference in the carotid-to-femoral path length divided by the difference in the R wave from the ECG to the foot of the pressure wave taken from the superimposed ECG and pressure tracings. The distance traveled by the flow wave was measured with an external tape measure over the body surface, as the distance from the right carotid sampling site to the manubrium subtracted from the distance from the manubrium to the right femoral sampling site. All pulse wave analyses and velocity measurements were performed in the sitting position in a quiet, temperature-controlled room (20 ± 5°C) after a period of rest (for at least 5 minutes).
Carotid intima media thickness (cIMT) was measured in the patient group by the same ultrasonographer following the same protocol using Aloka Prosound Alpha6 (Hitachi Aloka Medical Ltd., Japan) ultrasound system and a 13-MHz linear transducer. Intima-media thickness was defined as the mean distance from the leading edge of the lumen-intima interface to the leading edge of the media adventitia interface of the far wall, approximately 1 cm proximal to the carotid bulb. Six determinations of IMT (three on the left, and three on the right side) were obtained and averaged (15).
NT-proBNP concentration [pg/mL] was determined using Enzyme-Linked Fluorecent Assay (ELFA) technique. Normal value for NT-proBNP was < 125.0 pg/mL (VIDAS, BioMerieux, Lyon, France). In all children following biochemical parameters were assessed: hemoglobin [g/dL], serum creatinine [mg/dL], urea [mg/dL], uric acid [mg/dL], glucose [mg/dL], albumin [g/dL], calcium [mEq/l], phosphate [mEq/l], calcium-phosphate product [mEq2/l2], parathormone [pg/mL], alkaline phosphatase [U/L], 25(OH) vitamin D [ng/mL], total, HDL (high-density lipoprotein), LDL (low-density lipoprotein) cholesterol [mg/dL], triglycerides [mg/dL], acid-base balance parameters: pH, HCO3- [mEq/L], BE (base excess) [mEq/L]. Intact parathormone was assessed using IMMULITE 2000 assay (Siemens Healthcare Diagnostics, Deerfield, IL, USA), 25(OH)D using ARCHIECT assay (Abbott Laboratories, Abbott Park, IL, USA); other biochemical parameters were assessed with standard laboratory methods on VITROS 250 analyzer (Ortho Clinical Diagnostics, Rochester, NY, USA). Glomerular filtration rate was calculated using revised Schwartz formula (22). Target levels of calcium, phosphate and PTH were taken after National Kidney Foundation K/DOQI guidelines for children published in 2005 (23), target 25(OH)D levels after Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe (24).
In our clinical analysis, we also included data on the presence of hypertension and medications used (antihypertensives, sodium bicarbonate, calcium carbonate, iron, erithropoiesis stimulating agents).
Statistical analyses were performed using the Statistica 9.0 PL software (StatSoft, College Station, TX, USA). Normal variable distribution was tested using the Shapiro-Wilk test. Normally distributed variables are presented as mean values ± standard deviation, and non-normally distributed variables as medians and ranges. Differences in normally distributed variables were tested using the Student t test, and differences in non-normally distributed variables were tested using the Mann-Whitney U test. Correlations between variables were evaluated using Pearson and Spearman correlations, where applicable. P < 0.05 was considered statistically significant.
Results
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