Perinatal risk factors of renal outcome in former extremely low birth weight neonates.

Former Extremely Low Birthweight (ELBW) neonates suffer from adverse renal and cardiovascular outcomes later in life. Less is known about additional perinatal risk factors for these adverse outcomes which we have investigated in this study. We compared renal outcome between ELBW children and controls, to find perinatal risk factors for poorer renal outcome and to unveil associations between kidney function and blood pressure. This study included 93 former ELBW children and 87 healthy controls with a mean age of 11 years at assessment. We measured cystatin C-based estimated glomerular filtration rate (eGFR) and blood pressure. Blood pressure and eGFR levels were compared between cases and controls. We subsequently investigated perinatal risk factors for adverse outcome amongst ELBW children. ELBW children have significantly higher blood pressure (mean SBP percentile 75th vs. 47th, p <0.001) and lower mean eGFR (94 vs. 107 ml/min/1.73 m2, p = 0.005) compared to the control group. Elevated blood pressure did not correlate with perinatal characteristics and none of them had microalbuminuria. ELBW children with eGFR <90 ml/min/1.73 m2 were ventilated longer (17 vs. 9 days, p = 0.006), more frequently male (OR = 3.33, p = 0.055) and tended to suffer more from intraventricular hemorrhage (40% vs. 15.8%, p = 0.056). There was no association between blood pressure and kidney dysfunction. CONCLUSIONS: Understanding risk profiles for unfavorable outcomes may help to identify children at increased risk for kidney dysfunction. Poorer eGFR was associated with longer ventilation, male sex, and intra-ventricular hemorrhage but not with blood pressure. This knowledge can lead to safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk. WHAT IS KNOWN: • Extremely Low Birthweight (ELBW) neonates suffer later in life from adverse renal and cardiovascular outcomes. • Perinatal risk factors that further predict the individual risk for adverse outcomes are not well known. WHAT IS NEW: • Poorer eGFR in adolescence was associated with male sex, longer ventilation and intra-ventricular hemorrhage at birth but not with blood pressure. • Former ELBW infants had higher blood pressures compared to controls, but no microalbuminuria. • This knowledge can lead to potential precision medicine, safer neonatal therapeutic regimens for ELBW infants, a more intensive follow-up and earlier treatment initiation for children at highest risk.

Vitamin D Status in Belgian Children: A Regional Study.

Background: Vitamin D deficiency is the most frequent cause of impaired skeletal growth, and can lead to the development of nutritional rickets. The aim of this study was to evaluate the vitamin D status in a large group of children aged 0-18 years. Methods: We collected laboratory data on vitamin D levels from children who underwent blood sampling between 2014 and 2021. Results: We included 14,887 samples. In this group, 17.7% were vitamin D severely deficient (<12 ng/mL), 25.2% were insufficient (12-20 ng/mL), and another large proportion (28.3%) was borderline (20-30 ng/mL). Sufficient levels (>30 ng/mL) were met in 28.8% of children. We observed no association between gender and vitamin D status (p = 0.132). Adolescents aged 13-18 years (n = 3342) had the highest prevalence of severe vitamin D deficiency (24.9%). Vitamin D levels were higher in summer/autumn compared to winter/spring. Conclusions: Vitamin D deficiency/insufficiency has a high prevalence in children, mostly in children above 7 years of age. Many of these children (over 80%) do not meet the 30 ng/mL sufficiency threshold. It is essential that Belgian Health Authorities are aware of this high prevalence, as the current Belgian recommendation suggests ceasing vitamin D supplementation at the age of six. Additional research is required to investigate the consequences of our findings, and what specific approach is needed to achieve normal vitamin D levels in children aged 0 to 18 years.

Self-reported prescribing behaviour of vitamin D prophylaxis in healthy children by Belgian paediatricians.

There is currently no consensus on the guidelines for vitamin D prophylaxis in healthy children. The purpose of this study was to investigate the prescribing behaviour of vitamin D prophylaxis among Belgian paediatricians. Between June and September 2022, a questionnaire was distributed by email to all Belgian paediatricians who are a member of at least one of three scientific or professional organisations, as well as to the heads of every Belgian paediatric or neonatal hospital ward. We analysed 426 completed questionnaires. All regions, age categories and subspecialties were represented. Vitamin D prophylaxis is always or frequently recommended by 98% of paediatricians. Fifty-eight per cent of paediatricians advise vitamin D prophylaxis up to the age of six years and 66% of paediatricians advise a daily dose of 400 IU. In nearly every hospital in Belgium (96%), there is a specific protocol for vitamin D prophylaxis for newborns; but not for the paediatric unit (only 30%). Nearly all Belgian paediatricians prescribe vitamin D prophylaxis to infants. Although not recommended by guidelines, 25(OH)D is frequently measured by paediatricians. Practices regarding duration and dosing of vitamin D prophylaxis show large variability. Most neonatal wards do have a protocol, whereas most paediatric wards do not.

The QTc-Bazett Interval in Former Very Preterm Infants in Adolescence and Young Adulthood is Not Different from Term-Born Controls.

INTRODUCTION: Although relevant for precision pharmacovigilance, there are conflicting data on whether former preterm birth is associated with QTc-Bazett prolongation in later life. METHODS: To explore QTc-Bazett interval differences between former preterm and/or extremely low birth weight (ELBW) cases and term-born controls in adolescence and young adulthood, we analyzed pooled individual data after a structured search on published cohorts. To test the absence of a QTc-Bazett difference, a non-inferiority approach was applied (one-sided, upper limit of the 95% confidence interval [CI] mean QTc-Bazett difference, 5 and 10 ms). We also investigated the impact of characteristics, either perinatal or at assessment, on QTc-Bazett in the full dataset (cases and controls). Data were reported as median and range. RESULTS: The pooled dataset contained 164 former preterm and/or ELBW (cases) and 140 controls born full-term from three studies. The median QTc-Bazett intervals were 409 (335-490) and 410 (318-480) ms in cases and controls. The mean QTc-Bazett difference was 1 ms, with an upper 95% CI of 6 ms (p > 0.05 and p < 0.01 for 5 and 10 ms, respectively). In the full dataset, females had a significantly longer QTc-Bazett than males (415 vs. 401 ms; p < 0.0001). CONCLUSIONS: QTc-Bazett intervals are not significantly different between former preterm and/or ELBW cases and term-born controls, and we rejected a potential prolongation > 10 ms in cases. When prescribing QTc-prolonging drugs, pharmacovigilance practices in this subpopulation should be similar to the general public (NCT05243537).

Blood pressure and cardiovascular risk in relation to birth weight and urinary sodium: an individual-participant meta-analysis of European family-based population studies.

BACKGROUND: Although the relation of salt intake with blood pressure (BP) is linear, it is U-shaped for mortality and cardiovascular disease (CVD). This individual-participant meta-analysis explored whether the relation of hypertension, death or CVD with 24-h urinary sodium excretion (UVNA) or sodium-to-potassium (UNAK) ratio was modified by birth weight. METHODS: Families were randomly enrolled in the Flemish Study on Genes, Environment and Health Outcomes (1985-2004) and the European Project on Genes in Hypertension (1999-2001). Categories of birth weight, UVNA and UNAK (≤2500, >2500-4000, >4000 g; <2.3, 2.3-4.6 and >4.6 g; and <1, 1-2, >2, respectively) were coded using deviation-from-mean coding and analyzed by Kaplan-Meier survival functions and linear and Cox regression. RESULTS: The study population was subdivided into the Outcome ( n  = 1945), Hypertension ( n  = 1460) and Blood Pressure cohorts ( n  = 1039) to analyze the incidence of mortality and cardiovascular endpoints, hypertension and BP changes as function of UVNA changes. The prevalence of low/medium/high birth weight in the Outcome cohort was 5.8/84.5/9.7%. Over 16.7 years (median), rates were 4.9, 8 and 27.1% for mortality, CVD and hypertension, respectively, but were not associated with birth weight. Multivariable-adjusted hazard ratios were not significant for any endpoint in any of the birth weight, UVNA and UNAK strata. Adult body weight tracked with birth weight ( P  < 0.0001). The partial r in the low-birth-weight group associating changes from baseline to follow-up in UVNA and SBP was 0.68 ( P  = 0.023) but not significant in other birth weight groups. CONCLUSION: This study did not substantiate its prior hypothesis but showed tracking of adult with birth weight and suggest that low birth weight increases salt sensitivity.

Perfused boundary region as biomarker for endothelial integrity in former preterms in adolescence.

INTRODUCTION: Extremely low birth weight (ELBW) survivors have microvascular structural differences already described in kidney and retina, suggesting changes in endothelial integrity. A biomarker of endothelial integrity is perfused boundary region (PBR), which measures glycocalycal thickness. The endothelial glycocalyx is a complex, highly versatile structure with essential roles in vascular integrity and function. We explored PBR patterns together with other microvascular markers in healthy controls and former ELBW children. METHODS: In the PREMATCH cohort (87 healthy controls, 93 ELBW survivors), we assessed endothelial integrity by calculating PBR (sidestream dark-field imaging), several microvascular markers (blood pressure, estimated glomerular filtration rate (eGFRcysC)), and retinal imaging in early adolescence. We explored differences between both groups, and searched for perinatal determinants of PBR and correlations between different microvascular markers. RESULTS: We provided reference values for PBR (average 1.90 µm, SD 0.30) in children. PBR was not different from ELBW survivors during early adolescence, despite their higher blood pressure, lower eGFRcysC, and different retinal vessel width and tortuosity. CONCLUSIONS: We generated reference values for PBR in early adolescence. Despite some correlations between microvascular parameters, there seem to be numerous confounders to propose PBR as a marker for endothelial integrity in ELBW survivors. IMPACT: The endothelial glycocalyx is a complex and versatile structure. Changes in blood pressure and retinal and renal vascularization suggest a disturbance of its integrity in extremely low birth weight (ELBW) survivors. Its thickness can be measured by calculating perfused boundary region (PBR) using sidestream dark-field imaging, with a higher PBR indicating a thinner glycocalyx. We generated reference values for PBR in healthy adolescents. These values were not different in former ELBW children. Despite some correlations of PBR with other microvascular biomarkers, these are not strong enough to describe endothelial integrity and its covariates in former ELBW children.

QTc intervals are not prolonged in former ELBW infants at pre-adolescent age.

BACKGROUND: Whether preterm birth is associated with cardiac conduction or repolarization abnormalities in later life is still poorly explored, with conflicting data on QTc prolongation in former extreme low birth weight (ELBW, <1000 g) infants. METHODS: Twelve lead electrocardiograms (ECG) at rest, collected in the PREMATurity as predictor of children's Cardiovascular-renal Health (PREMATCH) study in former ELBW cases and term controls during pre-adolescence (8-14 years) were analyzed on corrected QT time (QTc, Bazett) and QT dispersion (QTd). ECG findings were compared between groups (Mann-Whitney), and associations with clinical and biochemical findings were explored (Spearman). In ELBW cases, associations between QTc and perinatal characteristics (at birth, neonatal stay) were explored (Mann-Whitney, Spearman). RESULTS: QTc and QTd were similar between 93 ELBW cases and 87 controls [409 (range 360-465) versus 409 (337-460); 40 (0-100) versus 39 (0-110)] ms. Age, height, weight, or body mass index were not associated with the QTc interval, while female sex (median difference 11.4 ms) and lower potassium (r = -0.26) were associated with longer QTc interval. We could not observe any significant association between QTc interval and perinatal characteristics. CONCLUSIONS: There were no differences in QTc or QTd between ELBW and term controls in ECGs at rest in pre-adolescents. IMPACT: This study aimed to assess the differences in QTc and QTd intervals between extreme low birth weight infants (ELBW) and term controls in electrocardiographic measurements at rest during pre-adolescence. This analysis confirmed the absence of significant differences in QTc or QTd findings between ELBW cases and term controls, while female sex and lower potassium were associated with a prolonged QTc interval. These data suggest that QTc screening strategies-including for pharmacovigilance-should not differentiate between former ELBW cases and term controls. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02147457.

Dolichocolon Presenting with Bilateral Hydronephrosis in a Neonate.

BACKGROUND: Dolichocolon is an inborn anatomic variant of the colon with redundancies often causing constipation and/or volvulus presenting in childhood, adolescence, or adulthood. To the best of our knowledge, this is the first case of dolichocolon presenting in infancy with constipation and bilateral hydronephrosis. Case Presentation. A nineteen-day-old neonate presented to the emergency department with severe constipation and discomfort. During his admission, he developed pyelonephritis, and subsequent ultrasound of the kidneys and bladder showed bilateral hydroureteronephrosis. A barium enema was performed and it showed a dolichocolon. Enemas and lactulose were initiated with good effect on both the constipation as well as the hydronephrosis. CONCLUSIONS: Dolichocolon in a neonate can cause severe constipation which could also lead to an obstructive nephropathy if untreated. Monitoring of urine flow might be indicated when a neonate presents with severe constipation.

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-ß4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-ß4 abundance was confirmed with ELISA. Knockout of thymosin-ß4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin ß4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.

Retinal and Renal Microvasculature in Relation to Central Hemodynamics in 11-Year-Old Children Born Preterm or At Term.

Background Prematurity disrupts the perinatal maturation of the microvasculature and macrovasculature and confers high risk of vascular dysfunction later in life. No previous studies have investigated the crosstalk between the microvasculature and macrovasculature in childhood. Methods and Results In a case-control study, we enrolled 55 children aged 11 years weighing <1000 g at birth and 71 matched controls (October 2014-November 2015). We derived central blood pressure (BP) wave by applanation tonometry and calculated the forward/backward pulse waves by an automated pressure-based wave separation algorithm. We measured the renal resistive index by pulsed wave Doppler and the central retinal arteriolar equivalent by computer-assisted program software. Compared with controls, patients had higher central systolic BP (101.5 versus 95.2 mm Hg, P<0.001) and backward wave amplitude (15.5 versus 14.2 mm Hg, P=0.029), and smaller central retinal arteriolar equivalent (163.2 versus 175.4 µm, P<0.001). In multivariable analyses, central retinal arteriolar equivalent was smaller with higher values (+1 SD) of central systolic BP (-2.94 µm; 95% CI, -5.18 to -0.70 µm [P=0.011]) and forward (-2.57 µm; CI, -4.81 to -0.32 µm [P=0.026]) and backward (-3.20 µm; CI, -5.47 to -0.94 µm [P=0.006]) wave amplitudes. Greater renal resistive index was associated with higher backward wave amplitude (0.92 mm Hg, P=0.036). Conclusions In childhood, prematurity compared with term birth is associated with higher central systolic BP and forward/backward wave amplitudes. Higher renal resistive index likely moves reflection points closer to the heart, thereby explaining the inverse association of central retinal arteriolar equivalent with central systolic BP and backward wave amplitude. These observations highlight the crosstalk between the microcirculation and macrocirculation in children. Registration URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02147457.

Extremely Low Birth Weight Predisposes to Impaired Renal Health: A Pooled Analysis.

BACKGROUND: A number of studies examined the association between preterm delivery and kidney size and function later in life. However, the number of cases in published cohort studies is low. This study was aimed at performing a multicenter collaboration to pool data to obtain more accurate results to quantify the extent of renal impairment in former extremely low birth weight (ELBW; <1,000 g) children. METHODOLOGY: We performed a subject-level meta-analysis to pool data from Cracow (64 cases/34 controls) and Leuven (93 cases/87 controls). We assessed and analyzed cystatin C, estimated glomerular filtration rate (eGFR), ultrasound kidney length, and blood pressure (BP) in 11-year-old ELBW children compared with controls born at term. The prevalence of hypertension (HT) and prehypertension (preHT) in both groups was also analyzed. RESULTS: The study group comprised 157 former ELBW children (gestational age 23-33 weeks and birth weight 430-1,000 g) and 123 children born at term. Former ELBW children had lower mean eGFR (100.62 ± 16.53 vs. 111.89 ± 15.26 mL/min/1.73 m2; p < 0.001), smaller absolute kidney length (8.56 ± 0.78 vs. 9.008 ± 0.73 cm; <0.001), and higher systolic (111.8 ± 9.8 vs. 107.2 ± 9.07 mm Hg; p = 0.01) and diastolic (68.6 ± 6.8 vs. 66.3 ± 7.7 mm Hg; p = 0.03) BP. Smaller renal size in former ELBW children was positively associated with lower birth weight, shorter gestational age, and severity of perinatal complications (intraventricular hemorrhage, length of stay, mechanical ventilation, and oxygen therapy). CONCLUSION: ELBW is associated with lower eGFR and a high frequency of preHT and HT.

Earlier achievement of full enteral feeding in extremely low birth weight neonates is not associated with growth improvement in the first 2 years of life.

Limiting the number of days until achievement of full enteral feeding in extremely low birth weight neonates (ELBW; < 1000 g) might affect growth in the first years of life. This study compared the Z scores in growth over time of two cohorts of ELBW neonates that were comparable on maternal and neonatal characteristics and characteristics of hospitalization, but differed in enteral feeding strategy during neonatal admission. In the 2010-2014 cohort, full enteral feeding was achieved on average 16 days earlier than in the 2000-2005 cohort. In both cohorts, weight, height, and head circumference were recorded at birth and at the corrected ages of 9 and 24 months. A linear mixed model with repeated measures controlling for neonates small for gestational age showed no significant effect of different strategies in achievement of full enteral feeding on any anthropometric Z scores over time. Although full enteral feeding was achieved earlier in the 2010-2014 cohort, this was not associated with growth patterns during the first two years of life. CONCLUSION: The effect of a change in strategy to achieve full enteral feeding at an earlier stage in ELBW neonates was assessed. Early enteral feeding strategies do not necessarily improve growth during the first two years of life. What is Known: • Feeding strategies during neonatal stay may affect growth in the first years of life. • Strategies to achieve full enteral feeding earlier were implemented, but data on the impact on subsequent growth after discharge are limited. What is New: • Full enteral feeding was achieved earlier, but this was not associated with improved growth during the first 2 years of life after discharge. • Early enteral feeding strategies do not necessarily improve growth during the first 2 years of life.

Correction: Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence.

[This corrects the article DOI: 10.1371/journal.pone.0173349.].

Association between cognition and the retinal microvasculature in 11-year old children born preterm or at term.

BACKGROUND: Retinal microvessels can be visualized non-invasively and mirror the status of the cerebral microvasculature. AIMS: To investigate whether in young children born prematurely or at term cognitive performance is related to retinal microvascular traits. STUDY DESIGN, SUBJECTS: In 93 prematurely born infants (birth weight < 1000 g) and 87 controls born at term, we measured head circumference (HC) and determined intelligence quotient (IQ) by combining matrix reasoning and spatial span (Wechsler Non-Verbal test, Dutch version) and post-processed retinal photographs using Singapore I Vessel Assessment software (version 3.6). OUTCOME MEASURES, RESULTS: Compared with controls, cases had smaller HC (51.7 vs 53.4 cm; p < 0.001), lower IQ (93.9 vs 109.2; p < 0.001), smaller retinal arteriolar (CRAE; 162.7 vs 174.0 µm; p < 0.001) and venular (CRVE; 234.9 vs 242.8 µm; p = 0.003) diameters and CRAE/CRVE ratio (0.69 vs 0.72; p = 0.001). A 1-SD decrease in CRAE was associated with smaller HC (-0.53 cm; p < 0.001) and lower total IQ (-3.74; p < 0.001), matrix reasoning (-1.77; p = 0.004) and spatial span (-2.03; p = 0.002). These associations persisted after adjustment for sex and age and risk factors for cognitive impairment, including blood pressure, body mass index and parental educational attainment. CONCLUSIONS: HC, total IQ, matrix reasoning and spatial span decrease with smaller retinal arteriolar diameter. Our findings suggest that maldevelopment of the cerebral microcirculation, as mirrored by the retinal microvasculature, has lasting effects on the growth of the brain and cognitive performance of prematurely born children.

Reproducibility of Retinal Microvascular Traits Decoded by the Singapore I Vessel Assessment Software Across the Human Age Range.

BACKGROUND: Retinal microvascular traits predict adverse health outcomes. The Singapore I Vessel Assessment (SIVA) software improved automated postprocessing of retinal photographs. In addition to microvessel caliber, it generates measures of arteriolar and venular geometry. Few studies addressed the reproducibility of SIVA measurements across a wide age range. METHODS: In the current study, 2 blinded graders read images obtained by nonmydriatic retinal photography twice in 20 11-year-old children, born prematurely (n = 10) or at term (n = 10) and in 60 adults (age range, 18.9-86.1 years). RESULTS: Former preterm compared with term children had lower microvessel diameter and disorganized vessel geometry with no differences in intraobserver and interobserver variability. Among adults, microvessel caliber decreased with age and blood pressure and arteriolar geometry was inversely correlated with female sex and age. Intraobserver differences estimated by the Bland-Altman method did not reach significance for any measurement. Across measurements, median reproducibility (RM) expressed as percent of the average trait value was 8.8% in children (median intraclass correlation coefficient [ICC], 0.94) and 8.0% (0.97) in adults. Likewise, interobserver differences did not reach significance with RM (ICC) of 10.6% (0.85) in children and 10.4% (0.93) in adults. Reproducibility was best for microvessel caliber (intraobserver/interobserver RM, 4.7%/6.0%; ICC, 0.98/0.96), worst for venular geometry (17.0%/18.8%; 0.93/0.84), and intermediate for arteriolar geometry (10.9%/14.9%; 0.95/0.86). CONCLUSIONS: SIVA produces repeatable measures of the retinal microvasculature in former preterm and term children and in adults, thereby proving its usability from childhood to old age.

Ibuprofen exposure in early neonatal life does not affect renal function in young adolescence.

INTRODUCTION: Ibuprofen exposure results in acute transient renal dysfunction in preterm neonates, but we are unaware of data on long-term renal safety. METHODS: In a previously studied cohort of extreme low birth weight (ELBW, <1000 g) cases, the PREMATurity as predictor of children's Cardiovascular-renal Health study generated data on renal function (renal length, estimated glomerular filtration rate based on cystatin C (eGFRcysC) at the age of 11 years. This data set in 93 ELBW cases may also generate data on long-term drug safety on ibuprofen. In this post hoc analysis, we linked markers of renal function in young adolescence in ELBW cases with their perinatal (prenatal maternal, setting at birth, treatment modalities including drug prescription during neonatal stay, neonatal creatinine values, postdischarge growth) characteristics, including but not limited to ibuprofen exposure during neonatal stay. RESULTS: Ibuprofen exposure was not associated with significant differences in renal length or eGFRcysC. Moreover, we were unable to identify any other risk factor (perinatal characteristics, postnatal creatinine trends, postdischarge growth) on renal outcome in this cohort. CONCLUSIONS: Neonatal exposure to ibuprofen did not affect renal function. Larger studies are needed to explore the confounders of variability in renal function in former ELBW cases. This matters since ELBW relates to risk for hypertension, cardiovascular events and renal disease in later life and identification of risk factors holds the promise of secondary prevention. TRIAL REGISTRATION NUMBER: NCT02147457.

Analysis of renal blood flow and renal volume in normal fetuses and in fetuses with a solitary functioning kidney.

OBJECTIVE: To evaluate renal blood flow and renal volume for the prediction of postnatal renal function in fetuses with solitary functioning kidney (SFK). METHODS: Seventy-four SFK fetuses (unilateral renal agenesis [12], multicystic dysplastic kidney [36], and severe renal dysplasia [26]) were compared with 58 healthy fetuses. Peak systolic velocity (PSV), pulsatility index (PI), and resistance index (RI) of the renal artery (RA) were measured; 2D and 3D (VOCAL) volumes were calculated. Renal length and glomerular filtration rate (GFR) were obtained in SFK children (2 years). RESULTS: Compared with the control group, the PSV RA was significantly lower in nonfunctioning kidneys and significantly higher in SFK. Volume measurements indicated a significantly larger volume of SFK compared with healthy kidneys. All but 4 children had GFR above 70 mL/min/1.73 m2 , and compensatory hypertrophy was present in 69% at 2 years. PSV RA and SFK volume correlated with postnatal renal hypertrophy. No correlation between prenatal and postnatal SFK volume and GFR at 2 years was demonstrated. CONCLUSION: Low PSV RA might have a predictive value for diagnosing a nonfunctioning kidney in fetuses with a SFK. We demonstrated a higher PSV RA and larger renal volume in the SFK compared with healthy kidneys.

A Human Proximal Tubular Epithelial Cell Model to Explore a Knowledge Gap on Neonatal Drug Disposition.

BACKGROUND: Finding the right drug-dosage for neonates is still a challenge. Until now, neonatal doses are extrapolated from adults and children doses. However, there are differences between neonatal and adult kidney physiology that should be considered, especially when it comes to drug metabolism and/or transport. Studying renal drug disposition in neonates is limited by the lack of reliable human cell models. OBJECTIVE: To illustrate the feasibility of developing an in vitro model for neonatal proximal tubule epithelial cells (nPTECs) to study renal drug disposition at this age. METHOD: nPTECs were isolated from urine samples of neonates of different gestational ages and were conditionally immortalized using a temperature sensitive SV40T antigen and human telomerase hTERT. Cell clones were characterized on gene expression level for PTEC markers such as P-glycoprotein (ABCB1), aquaporin1 (AQP1), and organic cation transport protein 2 (SLC22A2), and for kidney progenitor cell and podocyte markers. In addition, protein expression and functional assessment were performed for P-gp and OCT2. RESULTS: We established 101 clonal cell lines of conditionally immortalized nPTECs derived from neonatal urines. Characterization of primary cells lines showed expression of genes from different cell types such as progenitors, PTECs and podocytes, however the developed conditionally immortalized nPTECs only expressed proximal tubule markers. Quantitative PCR analysis confirmed the expression of proximal tubule markers in nPTECs similar to the adult control PTECs. P-gp was expressed in nPTECs derived from the different gestational ages with a similar functionality compared with adult derived PTECs. In contrast, OCT2 functionality was significantly lower in nPTEC cell lines compared with adult PTECs. CONCLUSION: We demonstrate the feasibility of culturing proximal tubule epithelial cells with high efficiency from urine of neonates. These cells expressed PTEC-specific genes and functional drug transporters. The cell model presented is a valuable tool to study proximal tubule physiology and pharmacology in newborns. In addition, we demonstrate the physiological differences between the neonatal and adult kidney, which emphasizes the importance of studying drug disposition in neonatal models instead of extrapolating from adult data.

Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence.

AIM: To investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body composition in childhood. METHODS: ELBW children were examined at birth (n = 140), at 9 and 24 months (n≥96) and at approximately 11 years within the framework of the PREMATCH (PREMATurity as predictor children's of Cardiovascular and renal Health) case-control (n = 93-87) study. Regional growth charts were used to convert anthropometrics into Z-scores. Catch-up growth in the first two years of life was qualified as present if ΔZ-score >0.67 SDS. At 11 years, anthropometrics, neurocognitive performance, body composition, grip strength and puberty scores were assessed. RESULTS: ELBW neonates displayed extra-uterine growth restriction with mean Z-scores for height, weight and head circumference of -0.77, -0.93 and -0.46 at birth, -1.61, -1.67 and -0.72 at 9 months, -1.22, -1.61 and -0.84 at 24 months, and -0.42, -0.49 and -1.09 at 11 years. ELBW children performed consistently worse on neurocognitive testing with an average intelligence quotient equivalent at 11 years of 92.5 (SD 13.1). Catch-up growth was not associated with neurocognitive performance. Compared to controls, ELBW cases had lower grip strength (13.6 vs. 15.9 kg) and percentage lean body weight (75.1 vs. 80.5%), but higher body fat (24.6 vs. 19.2%) and advanced puberty scores at 11 years (all P≤0.025). Catch-up growth for weight and height in the first two years of life in cases was associated with a lower percentage body fat compared to cases without catch-up growth (16.8% catch-up growth for weight vs. 25.7%, P<0.001; 20.9% catch-up for height vs. 25.8%, P = 0.049). CONCLUSIONS: In young adolescence, former ELBW children still have difficulties to reach their target height. Compared to normal birth weight controls, ELBW adolescents show lower neurocognitive performance and grip strength and a higher percentage body fat, a potential risk factor for adverse health outcomes in adulthood. Our key finding is that catch-up growth in ELBW children in the first two years of life is associated with a lower percentage body fat and is therefore likely to be beneficial.