Current and potential methods to assess kidney structure and morphology in term and preterm neonates.

After birth, the kidney structure in neonates adapt to the functional demands of extrauterine life. Nephrogenesis is complete in the third trimester, but glomeruli, tubuli, and vasculature mature with the rapidly increasing renal blood flow and glomerular filtration. In preterm infants, nephrogenesis remains incomplete and maturation is slower and may be aberrant. This structural and functional deficit has life-long consequences: preterm born individuals are at higher risk for chronic kidney disease and arterial hypertension later in life. This review assembles the literature on existing and potential methods to visualize neonatal kidney structure and morphology and explore their potential to longitudinally document the developmental deviation after preterm birth. X-rays with and without contrast, fluoroscopy and computed tomography (CT) involve relevant ionizing radiation exposure and, apart from CT, do not provide sufficient structural details. Ultrasound has evolved into a safe and noninvasive high-resolution imaging method which is excellent for longitudinal observations. Doppler ultrasound modes can characterize and quantify blood flow to and through the kidneys. Microvascular flow imaging has opened new possibilities of visualizing previously unseen vascular structures. Recent advances in magnetic resonance imaging display renal structure and function in unprecedented detail, but are offset by the logistical challenges of the imaging procedure and limited experience with the new techniques in neonates. Kidney biopsies visualize structure histologically, but are too invasive and remain anecdotal in newborns. All the explored methods have predominantly been examined in term newborns and require further research on longitudinal structural observation in the kidneys of preterm infants.

Enteral zinc supplementation for prevention of morbidity and mortality in preterm neonates.

BACKGROUND: Preterm and low birth weight infants are born with low stores in zinc, which is a vital trace element for growth, cell differentiation and immune function. Preterm infants are at risk of zinc deficiency during the postnatal period of rapid growth. Systematic reviews in the older paediatric population have previously shown that zinc supplementation potentially improves growth and positively influences the course of infectious diseases. In paediatric reviews, the effect of zinc supplementation was most pronounced in those with low nutritional status, which is why the intervention could also benefit preterm infants typically born with low zinc stores and decreased immunity. OBJECTIVES: To determine whether enteral zinc supplementation, compared with placebo or no supplementation, affects important outcomes in preterm infants, including death, neurodevelopment, common morbidities and growth. SEARCH METHODS: Our searches are up-to-date to 20 February 2020. For the first search, we used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 8), MEDLINE via PubMed (1966 to 29 September 2017), Embase (1980 to 29 September 2017), and CINAHL (1982 to 29 September 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. We ran an updated search from 1 January 2017 to 20 February 2020 in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: We included RCTs and quasi-RCTs that compared enteral zinc supplementation versus placebo or no supplementation in preterm infants (gestational age < 37 weeks), and low birth weight babies (birth weight < 2500 grams), at any time during their hospital admission after birth. We included zinc supplementation in any formulation, regimen, or dose administered via the enteral route. We excluded infants who underwent gastrointestinal (GI) surgery during their initial hospital stay, or had a GI malformation or another condition accompanied by abnormal losses of GI juices, which contain high levels of zinc (including, but not limited to, stomas, fistulas, and malabsorptive diarrhoea). DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately screened abstracts, evaluated trial quality and extracted data. We synthesised effect estimates using risk ratios (RR), risk differences (RD), and standardised mean differences (SMD). Our primary outcomes of interest were all-cause mortality and neurodevelopmental disability. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included five trials with a total of 482 preterm infants; there was one ongoing trial. The five included trials were generally small, but of good methodological quality. Enteral zinc supplementation compared to no zinc supplementation Enteral zinc supplementation started in hospitalised preterm infants may decrease all-cause mortality (between start of intervention and end of follow-up period) (RR 0.55, 95% CI 0.31 to 0.97; 3 studies, 345 infants; low-certainty evidence). No data were available on long-term neurodevelopmental outcomes at 18 to 24 months of (post-term) age. Enteral zinc supplementation may have little or no effect on common morbidities such as bronchopulmonary dysplasia (RR 0.66, 95% CI 0.31 to 1.40, 1 study, 193 infants; low-certainty evidence), retinopathy of prematurity (RR 0.14, 95% CI 0.01 to 2.70, 1 study, 193 infants; low-certainty evidence), bacterial sepsis (RR 1.11, 95% CI 0.60 to 2.04, 2 studies, 293 infants; moderate-certainty evidence), or necrotising enterocolitis (RR 0.08, 95% CI 0.00 to 1.33, 1 study, 193 infants; low-certainty evidence). The intervention probably improves weight gain (SMD 0.46, 95% CI 0.28 to 0.64; 5 studies, 481 infants; moderate-certainty evidence); and may slightly improve linear growth (SMD 0.75, 95% CI 0.36 to 1.14, 3 studies, 289 infants; low-certainty evidence), but may have little or no effect on head growth (SMD 0.21, 95% CI -0.02 to 0.44, 3 studies, 289 infants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Enteral supplementation of zinc in preterm infants compared to no supplementation or placebo may moderately decrease mortality and probably improve short-term weight gain and linear growth, but may have little or no effect on common morbidities of prematurity. There are no data to assess the effect of zinc supplementation on long-term neurodevelopment.

Improving diagnostic accuracy in neonates with left heart obstruction in a transport setting.

AIM: Differentiating left heart obstruction (LHO) from other severe illness in the neonatal period is challenging, and important for guiding clinical management. The aim of this study was to identify factors distinguishing LHO from non-LHO in neonates. METHODS: A retrospective, cohort study of neonates referred to the Newborn and Paediatric Emergency Transport Service, New South Wales, with suspected LHO during the epoch 1996-2016. RESULTS: A total of 273 neonates were included; 240 with confirmed LHO. Administration of prostaglandin E1 to infants with a structurally normal heart was not associated with impaired acid-base or oxygenation status. Pre-transport diagnostic accuracy of LHO was 74.4%; sensitivity 84.5%, positive predictive value 86.0%. On multivariable logistic regression, hepatomegaly (odds ratio 2.54; 95% confidence interval 1.05-6.16) was associated with confirmed LHO. CONCLUSIONS: A low threshold for prostaglandin E1 infusion should be maintained in infants with suspected LHO. Hepatomegaly is associated with a diagnosis of LHO and may be more useful than other parameters in predicting the condition.

Comparison of Blood Pressure and Kidney Markers between Adolescent Former Preterm Infants and Term Controls.

BACKGROUND: Preterm infants are at an increased risk of developing hypertension and chronic kidney disease later in life. No recommendations exist for blood pressure (BP) and renal follow up for these patients. AIM: To compare BP and serum and urinary kidney markers between preterm-born adolescents and term-born controls. METHODS: BP measurements in 51 preterm-born (≤32 weeks gestational age) and 82 term-born adolescents at the age of 10-15 years were conducted. Stepwise regression analysis explored the association between BP and participant characteristics. Kidney markers measured in the serum and urine were creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and uromodulin. Kidney markers measured in the serum were cystatin C, beta-2 microglobulin, and beta trace protein. RESULTS: Systolic BP was significantly higher in preterm boys compared with term boys, but not in girls, and low birth weight was associated with higher BP in boys. In the preterm group, maternal hypertension/preeclampsia and adolescent height were associated with higher systolic BP. Serum creatinine and NGAL were significantly higher in the preterm group. CONCLUSIONS: Our study confirms an inverse sex-dependant relationship between birth weight and BP at adolescent age. The higher serum creatinine and NGAL in the preterm group may indicate that premature birth affects kidney function in the long term.

Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents.

Objectives: The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), ß2-microglobulin (B2M), ß-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). Results: ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency. Conclusions: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence.

Novel Chlamydia species isolated from snakes are temperature-sensitive and exhibit decreased susceptibility to azithromycin.

Chlamydia species have recently been recognized as emerging pathogens in snakes. However, isolation of novel snake chlamydiae is critical and their growth characteristics are largely unknown. In this study, two novel chlamydial species are described: Chlamydia serpentis and Chlamydia poikilothermis, isolated after attempts on 23 cloacal and choanal swabs from 18 PCR-positive captive snakes originating from different Swiss snake collections. Isolation success, growth curve and infectivity rates over a 48-hour time period were dependent on temperature (37 °C for C. serpentis, 28 °C for C. poikilothermis). C. serpentis and C. poikilothermis were sensitive to tetracycline and moxifloxacin during evaluation by in vitro antibiotic susceptibility assay but intermediate to resistant (2-4 µg/ml) to azithromycin. Whole genome sequencing of the isolates provided proof of the novel species status, and gives insights into the evolution of these branches of genus Chlamydia.

Preterm birth and ventilation decrease surface density of glomerular capillaries in lambs, regardless of postnatal respiratory support mode.

BACKGROUND: Prematurity is often complicated by respiratory support, including invasive mechanical ventilation (IMV) and noninvasive support (NIS). Compared with IMV, NIS reduces injury to the lung and brain. Prematurity may also disrupt glomerular architecture. Whether NIS differentially affects glomerular architecture is incompletely understood. We hypothesized that IMV would lead to greater disruption of glomerular architecture than NIS. METHODS: This is a secondary analysis of kidneys from moderately preterm lambs delivered at ~131 d gestation (term ~150 d) that had antenatal steroid exposure and surfactant treatment before resuscitation by IMV. At ~3 h of age, half of the lambs were switched to NIS. Support was for 3 d or 21 d. Structural indices of glomerular architecture were quantified. RESULTS: The number of glomerular generations was unaffected by moderate preterm birth and respiratory support, either IMV or NIS. At 3 d and 21 d of IMV or NIS, glomerular capillary surface density was not different. Glomerular capillary surface density was significantly lower in the inner and outer cortex compared with unventilated gestation age-matched or postnatal age-matched reference lambs. CONCLUSION: Moderate preterm birth and invasive or noninvasive respiratory support decreases glomerular capillarization in the lamb kidney. This adverse effect on glomerular development may contribute to increased risk for adult-onset hypertension and renal dysfunction.

Variation in Current Management of Term and Late-preterm Neonates at Risk for Early-onset Sepsis: An International Survey and Review of Guidelines.

BACKGROUND: Uncertainty about the presence of infection results in unnecessary and prolonged empiric antibiotic treatment of newborns at risk for early-onset sepsis (EOS). This study evaluates the impact of this uncertainty on the diversity in management. METHODS: A web-based survey with questions addressing management of infection risk-adjusted scenarios was performed in Europe, North America, and Australia. Published national guidelines (n = 5) were reviewed and compared with the results of the survey. RESULTS: 439 Clinicians (68% were neonatologists) from 16 countries completed the survey. In the low-risk scenario, 29% would start antibiotic therapy and 26% would not, both groups without laboratory investigations; 45% would start if laboratory markers were abnormal. In the high-risk scenario, 99% would start antibiotic therapy. In the low-risk scenario, 89% would discontinue antibiotic therapy before 72 hours. In the high-risk scenario, 35% would discontinue therapy before 72 hours, 56% would continue therapy for 5-7 days, and 9% for more than 7 days. Laboratory investigations were used in 31% of scenarios for the decision to start, and in 72% for the decision to discontinue antibiotic treatment. National guidelines differ considerably regarding the decision to start in low-risk and regarding the decision to continue therapy in higher risk situations. CONCLUSIONS: There is a broad diversity of clinical practice in management of EOS and a lack of agreement between current guidelines. The results of the survey reflect the diversity of national guidelines. Prospective studies regarding management of neonates at risk of EOS with safety endpoints are needed.

Monitoring of urinary calcium and phosphorus excretion in preterm infants: comparison of 2 methods.

OBJECTIVES: Premature babies require supplementation with calcium (Ca) and phosphorus (P) to prevent metabolic bone disease of prematurity. To guide mineral supplementation, 2 methods of monitoring urinary excretion of Ca and P are used: urinary Ca or P concentration and Ca/creatinine (Crea) or P/Crea ratios. We compare these 2 methods in regards to their agreement on the need for mineral supplementation. METHODS: Retrospective chart review of 230 premature babies with birth weight <1500 g, undergoing screening of urinary spot samples from day 21 of life and fortnightly thereafter. Hypothetical cutoff values for urine Ca or P concentration (1 mmol/L) and urine Ca/Crea ratio (0.5 mol/mol) or P/Crea ratio (4 mol/mol) were applied to the sample results. The agreement on whether to supplement the respective minerals based on the results with the 2 methods was compared. Multivariate general linear models sought to identify patient characteristics to predict discordant results. RESULTS: A total of 24.8% of cases did not agree on the indication for Ca supplementation, and 8.8% for P. Total daily Ca intake was the only patient characteristic associated with discordant results. CONCLUSIONS: With the intention to supplement the respective mineral, comparison of urinary mineral concentration with mineral/Crea ratio is moderate for Ca and good for P. The results do not allow identifying superiority of either method on the decision as to which babies require Ca and/or P supplements.

A fatal case of hypernatraemic dehydration in a neonate.

Problems with lactation can result in hypernatraemic dehydration in the neonate, with potentially severe adverse consequences. This is illustrated in this fatal case of a 10 day old neonate who presented with excessive hypernatraemic dehydration due to insufficient breast milk intake, resulting in cerebral sinus vein thrombosis with cerebral haemorrhage and infarction. Differential diagnosis included excessive sodium intake (through inappropriately mixed formula or house remedies or through hyperaldosteronism) and high water deficit (renal or gastrointestinal losses, nephrogenic or central diabetes insipidus), all of which were ruled out by specific investigations or history. No evidence was found for inborn error of metabolism. The dehydration in this baby, however, was accentuated by trans-epidermal water loss due to an ichthyosiform skin condition. This first ever reported Australian fatality from neonatal hypernatraemic dehydration supports the concern of health care professionals over rising incidences of this entity in exclusively breastfed infants, and should encourage endorsement of improved monitoring of weight loss in newborns and breastfeeding support for their mothers.

Point-of-care prothrombin time testing in paediatric intensive care: an observational study of the ease of use of two devices.

BACKGROUND: Two major difficulties arise when taking blood samples in children: the challenge of venous access and the comparatively large amount of blood required. OBJECTIVE: To assess the value of point-of-care prothrombin time testing in paediatric intensive care patients. We evaluated two point-of-care devices, CoaguChek XS Plus and CoaLine, assessing ease of use in clinical practice and correlation with the standard prothrombin time measurement of the haematology laboratory. DESIGN: Single-centre observational study. SETTING: Between October 2007 and March 2008, patients in an interdisciplinary paediatric ICU of a tertiary centre were analysed. PATIENTS OR OTHER PARTICIPANTS: Thirty-eight patients, 22 female and 16 male (58 and 42%), aged between 0 and 13 years, participated in the study. The intention was to evaluate the ease of use of the devices in daily clinical practice, and no exclusion criteria were applied. MAIN OUTCOME MEASURES: The usefulness of the two point-of-care devices in the paediatric setting was evaluated. Measurements of point-of-care and standard laboratory prothrombin time were compared in terms of agreement and correlation. RESULTS: CoaguChek XS Plus had a failure rate of 2%, CoaLine 17% and the laboratory standard 4%. CoaguChek XS Plus received a better ease of use rating than CoaLine by the study personnel. Compared with the laboratory standard, there was considerable variability of the observed measurements with both devices. The measurements of CoaguChek XS Plus and the standard had a correlation coefficient r of being 0.79. CoaLine and the standard had a correlation coefficient r value of 0.72. CONCLUSION: CoaguChek XS Plus showed 'good' agreement, whereas CoaLine showed 'moderate' agreement compared with prothrombin time values using the standard method. The fast availability of results and the reduction of the required blood volume are advantages of point-of-care tests in the paediatric setting.

Norepinephrine-induced hypertension dilates vasospastic basilar artery after subarachnoid haemorrhage in rabbits.

BACKGROUND: Vasopressor-induced hypertension is routinely indicated for prevention and treatment of cerebral vasospasm (CVS) after subarachnoid haemorrhage (SAH). Mechanisms underlying patients' clinical improvement during vasopressor-induced hypertension remain incompletely understood. The aim of this study was to evaluate angiographic effects of normovolaemic Norepinephrine (NE)-induced hypertension therapy on the rabbit basilar artery (BA) after SAH. METHODS: Cerebral vasospasm was induced using the one-haemorrhage rabbit model; sham-operated animals served as controls. Five days later the animals underwent follow-up angiography prior to and during NE-induced hypertension. Changes in diameter of the BA were digitally calculated in mean microm +/- SEM (standard error of mean). FINDINGS: Significant CVS of 14.2% was documented in the BA of the SAH animals on day 5 compared to the baseline angiogram on day 0 (n = 12, p < 0.01), whereas the BA of the control animals remained statistically unchanged (n = 12, p > 0.05). During systemic administration of NE, mean arterial pressure increased from 70.0 +/- 1.9 mmHg to 136.0 +/- 2.1 mmHg in the SAH group (n = 12, p < 0.001) and from 72.0 +/- 3.1 to 137.8 +/- 1.3 in the control group (n = 12, p < 0.001). On day 5 after SAH, a significant dilatation of the BA in response to norepinephrine could be demonstrated in both groups. The diameter of the BA in the SAH group increased from 640.5 +/- 17.5 microm to 722.5 +/- 23.7 microm (n = 12, p < 0.05; ). In the control group the diameter increased from 716.8 +/- 15.5 microm to 779.9 +/- 24.1 microm (n = 12, p < 0.05). CONCLUSION: This study demonstrated that NE-induced hypertension causes angiographic dilatation of the BA in the SAH rabbit model. Based on these observations, it can be hypothesised that clinical improvement during vasopressor-induced hypertension therapy after SAH might be explained with cerebral vasodilatation mechanisms that lead to improvement of cerebral blood flow.

Eukaryotic initiation factor 4E variants alter the morphology, proliferation, and colony-formation properties of MDA-MB-435 cancer cells.

Eukaryotic initiation factor 4E (eIF4E) binds to the 5' m(7)G cap of mRNAs and is a focal point of regulation of initiation of mRNA translation. High levels of expression of eIF4E in many epithelial cancers, including breast, head and neck, colon, and bladder, correlate with increased tissue invasion and metastasis. To further examine the role of eIF4E in the biology of cancer cells, variants of eIF4E with impaired 5' cap binding function were expressed in MDA-MB-435 carcinoma cells. Cell lines overexpressing variants of eIF4E had impaired growth properties and exhibited a different morphology compared to cells expressing similar amounts of exogenous wild-type eIF4E or control cells. Cells expressing variant eIF4E did not form foci in culture and produced smaller colonies in soft agar compared to cells expressing wild-type eIF4E. In addition, analysis of polyribosomes for vascular endothelial growth factor (VEGF) mRNA demonstrated a shift from translationally active to inactive fractions in variant eIF4E cells, while GAPDH mRNA did not. The long G-C rich 5' untranslated region of VEGF mRNA is a feature of other mRNAs encoding growth regulating proteins that are predicted to have their translation enhanced by increases in eIF4E; whereas mRNA with shorter and less structured 5' UTRs, like that of GAPDH, are predicted to be largely unaffected. These data suggest that targeting the 5' cap-binding domain of eIF4E may be a viable option to slow cancer cell growth and alter the malignant phenotype.