Childhood Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C: Importance of Body Composition.

BACKGROUND: Creatinine and cystatin C concentrations are commonly used to estimate glomerular filtration rate (eGFR) in clinical practice and epidemiological studies. To estimate the influence of different body composition measures on eGFR from creatinine and cystatin C blood concentrations, we compared the associations of different anthropometric and body composition measures with eGFR derived from creatinine (eGFRcreat) and cystatin C (eGFRcystC) blood concentrations. METHODS: In a population-based cohort study among 4,305 children aged 6.0 years (95% range 5.7-8.0), we measured weight and height and calculated body mass index (BMI) and body surface area (BSA), and lean and fat mass using dual-energy X-ray absorptiometry. At the same age, we measured creatinine and cystatin C blood concentrations and estimated the GFR. RESULTS: Correlation between eGFR based on creatinine and cystatin C concentrations was r = 0.40 (p value <0.01). Higher BMI was associated with lower eGFRcystC but not with eGFRcreat. Higher BSA was associated with higher eGFRcreat and lower eGFRcystC (p value <0.05). Lean and fat mass percentages were associated with eGFRcreat but not with eGFRcystC. CONCLUSION: Our findings suggest that both eGFRcreat and eGFRcystC are influenced by BMI and BSA. eGFRcreat is more strongly influenced by body composition than eGFRcystC.

Fetal first trimester growth is not associated with kidney outcomes in childhood.

BACKGROUND: Impaired fetal growth is associated with increased risks of kidney diseases in later life. Because human development rates are highest during the first trimester, this trimester may be a particularly critical period for kidney outcomes. We have therefore examined the association of fetal first trimester growth with kidney outcomes in childhood. METHODS: This study was embedded in a prospective population-based cohort study among 1176 pregnant women and their children. We used fetal first trimester crown-length as the growth measure among mothers with a regular menstrual cycle and a known first day of the last menstrual period. At the childhood age of 6 (median 5.7-6.8) years, we measured combined kidney volume, microalbuminuria and estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C concentrations. RESULTS: No consistent associations of fetal first trimester crown-rump length with childhood combined kidney volume, eGFR and microalbuminuria were observed. Compared to children with a fetal first trimester crown-rump length in the highest quintile, those in the lowest quintile had a larger childhood combined kidney volume (difference 5.32 cm3, 95 % confidence interval 1.06 to 9.57), but no differences in kidney function. CONCLUSION: Our results do not support the hypothesis that fetal first trimester growth restriction affects kidney size and function in childhood. Further studies are needed to focus on critical periods in early life for kidney function and disease in later life.

Infant Breastfeeding and Kidney Function in School-Aged Children.

BACKGROUND: Early life factors may influence kidney growth and function throughout the life course. We examined the associations of breastfeeding duration and exclusivity and age at introduction of solid foods with kidney outcomes at school age. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: 5,043 children in the Netherlands. PREDICTORS: Infant feeding was assessed prospectively using questionnaires. OUTCOMES & MEASUREMENTS: In children at a median age of 6.0 years, we measured kidney volume with ultrasound, estimated glomerular filtration rate (eGFR) from serum creatinine level, and microalbuminuria from urinary albumin and creatinine levels. RESULTS: 92% of all children were ever breastfed, of whom 27% were breastfed for more than 6 months and 21% were breastfed exclusively for at least 4 months. Compared with ever-breastfed children, never-breastfed children had smaller combined kidney volumes (-2.69 [95% CI, -4.83 to -0.56] cm(3)) and lower eGFRs (-2.42 [95% CI, -4.56 to -0.28] mL/min/1.73 m(2)) at school age. Among breastfed children, shorter duration of breastfeeding was associated with smaller combined kidney volume and lower microalbuminuria risk (P<0.05). Compared to exclusive breastfeeding for 4 months, nonexclusive breastfeeding in the first 4 months was associated with smaller combined kidney volume and lower eGFR (both P<0.05). Associations with eGFR were explained largely by kidney volume. Age at introduction of solid foods was not associated with any kidney outcome. LIMITATIONS: Observational study, so causality cannot be established. Follow-up measurements were available for 76% of children. CONCLUSIONS: These results suggest that breastfeeding is associated with subclinical changes in kidney outcomes in childhood. Further studies are needed to explore whether early life nutrition also affects the risk of kidney disease in adulthood.

Fetal Smoke Exposure and Kidney Outcomes in School-Aged Children.

BACKGROUND: Fetal smoke exposure may result in developmental adaptations that permanently affect the developing kidney. In this study, the associations of maternal and paternal smoking during pregnancy with childhood kidney size and function were assessed. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: This study was conducted in a group of 5,622 children in Rotterdam, the Netherlands. PREDICTORS: Maternal and paternal smoking were assessed during pregnancy by questionnaires. OUTCOMES & MEASUREMENTS: At a median age of 6.0 (5th-95th percentile, 5.6-7.9) years, we measured childhood kidney volumes, estimated glomerular filtration rate (eGFR), and albumin-creatinine ratio. RESULTS: The confounder model, which included size at birth, shows that compared with children from mothers who did not smoke during pregnancy, those from mothers who continued smoking during pregnancy had smaller combined kidney volumes at the age of 6 years. The strongest effect estimate was observed for mothers who smoked 5 or more cigarettes per day during pregnancy (difference for combined kidney volume, -2.80 [95% CI, -5.15 to -0.45] cm(3)). Similarly, continued maternal smoking during pregnancy also was associated with a lower eGFR in childhood (difference, -2.25 [95% CI, -3.70 to -0.79] mL/min/1.73 m(2)). First-trimester-only smoking was associated with a higher risk of increased albumin-creatinine ratio (OR, 1.45; 95% CI, 1.05-2.01). Among mothers who did not smoke during pregnancy, paternal smoking was associated with smaller childhood combined kidney volume (difference, -1.78 [95% CI, -3.48 to -0.07] cm(3)), but not with childhood kidney function measures. LIMITATIONS: Smoking behavior was measured with questionnaires. Follow-up measurements were available for only 70% of the children. CONCLUSIONS: Continued maternal smoking during pregnancy is associated with smaller combined kidney volume and lower eGFR in school-aged children. Stronger effect estimates for maternal versus paternal smoking suggest that intrauterine adaptive responses may play a role as underlying mechanisms.

Protein intake in infancy and kidney size and function at the age of 6 years: The Generation R Study.

BACKGROUND: High protein intake has been linked to kidney growth and function. Whether protein intake is related to kidney outcomes in healthy children is unclear. METHODS: We examined the associations between protein intake in infancy and kidney outcomes at age 6 years in 2968 children participating in a population-based cohort study. Protein intake at 1 year was assessed using a food-frequency questionnaire and was adjusted for energy intake. At age 6 years we measured the kidney volume and urinary albumin/creatinine ratio (ACR) of all participating children, and we estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C levels. RESULTS: In models adjusted for age, sex, body surface area, and sociodemographic factors, a higher protein intake was associated with a lower ACR and a higher eGFR but was not consistently associated with kidney volume. However, after further adjustment for additional dietary and lifestyle factors, such as sodium intake, diet quality, and television watching, higher protein intake was no longer associated with kidney function. No differences in associations were observed between animal and vegetable protein intake. CONCLUSIONS: Our findings show that protein intake in early childhood is not independently associated with kidney size or function at the age of 6 years. Further study is needed on other early life predictors of kidney size and function in later life.

Fetal and infant growth patterns and kidney function at school age.

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm(3) [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m2 [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.

Childhood kidney outcomes in relation to fetal blood flow and kidney size.

Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5-32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7-6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, -6.36 ml/min per 1.73 m(2); 95% confidence interval, -11.78 to -0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children.

Kidney size and function in a multi-ethnic population-based cohort of school-age children.

BACKGROUND: Subclinical impaired kidney growth and function in childhood may lead to kidney diseases and high blood pressure in adulthood. We assessed the cross-sectional associations of childhood characteristics with kidney size and function in a multi-ethnic cohort. METHODS: This study was embedded in a population-based cohort study of 6,397 children with a median age of 6.0 years.Kidney volume, creatinine and cystatin C blood levels, microalbuminuria and blood pressure were measured, and glomerular filtration rate (GFR) was estimated. RESULTS: Childhood anthropometrics were positively associated with kidney volume, creatinine level and blood pressure (all p < 0.05). We observed ethnic differences in all kidney size and function measures (all p < 0.05). Children with smaller kidneys had higher creatinine and cystatin C blood levels, leading to a lower estimated GFR [difference 5.68 ml/min/1.73 m2 (95% confidence interval 5.14-6.12) per 1 standard deviation increase in kidney volume]. Larger kidney volume was associated with an increased risk of microalbuminuria. CONCLUSIONS: Childhood kidney volume and function are influenced by body mass index and ethnicity. Kidney volume is related with kidney function but not with blood pressure. These results may help to identify individuals at risk for kidney disease in an early stage.

Cardiovascular and metabolic influences of fetal smoke exposure.

Many epidemiological studies showed associations of low birth weight with cardiovascular disease, type 2 diabetes and obesity. The associations seem to be consistent and stronger among subjects with a postnatal catch up growth. It has been suggested that developmental changes in response to adverse fetal exposures might lead to changes in the fetal anatomy and physiology. These adaptations may be beneficial for short term, but may lead to common diseases in adulthood. Maternal smoking during pregnancy is one of the most important adverse fetal exposures in Western countries, and is known to be associated with a 150-200 g lower birth weight. An accumulating body of evidence suggests that maternal smoking during pregnancy might be involved in pathways leading to both low birth weight and common diseases, including cardiovascular disease, type 2 diabetes and obesity, in adulthood. In this review, we discuss epidemiological studies focused on the associations of maternal smoking with fetal growth and development and cardiovascular and metabolic disease in later life. We also discuss potential biological mechanisms, and challenges for future epidemiological studies.

Development of postural control in typically developing children and children with cerebral palsy: possibilities for intervention?

The basic level of postural control is functionally active from early infancy onwards: young infants possess a repertoire of direction-specific postural adjustments. Whether or not direction-specific adjustments are used depends on the child's age and the nature of the postural task. The second level of control emerges after 3 months: children start to develop the capacity to adapt postural activity to environmental constraints. But the adult form of postural adaptation first emerges after adolescence. Children with cerebral palsy (CP) in general have the ability to generate direction-specific adjustments, but they show a delayed development in the capacity to recruit direction-specific adjustments in tasks with a mild postural challenge. Children with CP virtually always have difficulties in the adaptation of direction-specific activity. The limited data available on the effect of intervention on postural development suggest that intervention involving active trial and error experience may accelerate postural development in typically developing infants and may improve postural control in children with or at high risk for a developmental motor disorder.

Associations of Maternal and Paternal Blood Pressure Patterns and Hypertensive Disorders during Pregnancy with Childhood Blood Pressure.

BACKGROUND: Hypertensive disorders in pregnancy may affect the cardiovascular risk of offspring. We examined the associations of maternal blood pressure throughout pregnancy and hypertensive disorders in pregnancy with childhood blood pressure of offspring. Specific focus was on the comparison with paternal blood pressure effects, the identification of critical periods, and the role of birth outcomes and childhood body mass index in the observed associations. METHODS AND RESULTS: This study was embedded in a population-based prospective cohort study among 5310 mothers and fathers and their children. We measured maternal blood pressure in each trimester of pregnancy and paternal blood pressure once. Information about hypertensive disorders in pregnancy was obtained from medical records. We measured childhood blood pressure at the median age of 6.0 years (95% range 5.7-8.0 years). Both maternal and paternal blood pressure were positively associated with childhood blood pressure (all P<0.05), with similar effect estimates. Conditional regression analyses showed that early, mid-, and late-pregnancy maternal blood pressure levels were all independent and positively associated with childhood blood pressure, with the strongest effect estimates for early pregnancy. Compared with children of mothers without hypertensive disorders in pregnancy, children of mothers with hypertensive disorders in pregnancy had higher diastolic blood pressure by a standard deviation score of 0.13 (95% CI 0.05-0.21). The observed associations were not materially affected by birth outcomes and childhood body mass index. CONCLUSIONS: Both maternal and paternal blood pressure affects childhood blood pressure, independent of fetal and childhood growth measures, with the strongest effect of maternal blood pressure in early pregnancy.

Development of proximal arm muscle control during reaching in young infants: from variation to selection.

UNLABELLED: Reaching movements are initiated by activity of the prime mover, i.e. the first activated arm muscle. We aimed to investigate the relationship between prime mover activity and kinematics of reaching in typically developing (TD) infants in supine and sitting position. Fourteen infants were assessed at 4 and 6 months during reaching in supine and supported sitting. Kinematics and EMG-activity of deltoid, pectoralis major, biceps (BB) and triceps brachii were recorded. Kinematic analysis focused on number of movement units (MUs) and transport MU (MU with longest duration). Prime mover use was variable, but at 6 months a dominance of BB emerged in both testing conditions. Kinematics were also variable, but with increasing age the number of MU decreased and the relative proportion of the transport MU increased. BB as prime mover at 6 months was related to a larger transport MU. CONCLUSION: Between 4 and 6 months BB prime mover dominance emerges which is related to relatively efficient reaching characteristics.

Postural adjustments and reaching in 4- and 6-month-old infants: an EMG and kinematical study.

Adequate postural control is a prerequisite for daily activities such as reaching for an object. However, knowledge on the relationship between postural adjustments and the quality of reaching movements during human ontogeny is scarce. Therefore we evaluated the development of the relationship between the kinematic features of reaching movements and the accompanying postural adjustments in young infants. Twelve typically developing (TD) infants were assessed twice, i.e. at 4 and 6 months of age, in supine and supported sitting position. Reaching was elicited by presenting toys in the midline at an arm-length distance while simultaneously surface EMG-activity was recorded from multiple arm-, neck-, trunk- and leg muscles. Concurrently kinematics of reaching were recorded with an ELITE system; kinematic analysis was restricted to the behaviour of so-called movement units, which are sub movements of reaching determined with the help of peaks in the velocity profile of the hand, maximum movement velocity and movement duration. A computer-algorithm determined significant phasic muscle activity. Activity in neck and trunk muscles (postural activity) was related to the onset of the prime mover, which was the arm muscle being activated first. The results indicated that about 50% of reaching movements in lying and sitting infants aged 4 and 6 months were accompanied by direction-specific postural adjustments. At 4 months variation dominated, but at 6 months a preference to recruit muscles in a top-down order (during sitting) and in the configuration of the complete pattern, i.e. the pattern in which all dorsal neck- and trunk muscles are activated in concert, (both conditions) emerged. Interestingly, the postural characteristics such as the presence of direction-specificity, recruitment of the complete pattern and top-down recruitment, were related to how successful the reaching was and the kinematics of reaching. It was concluded that the presence of direction-specific activity is not a prerequisite for the emergence of reaching movements. Nevertheless, already from 4 months onwards a better postural control is associated with a larger success and a better quality of reaching.