Urinary NT-proBNP as a potential noninvasive biomarker for screening of pulmonary hypertension in preterm infants: a pilot study.

OBJECTIVE: This pilot study aimed to determine the feasibility of urinary NT-proBNP (NT-proBNP) as a potential noninvasive screening marker for pulmonary hypertension (PH). STUDY DESIGN: A prospective cross-sectional study was conducted. Preterm infants (PI) (birthweight <1500 gm and <30 weeks gestational age (GA)) were enrolled. Serial urinary NT-proBNP measurements and echocardiograms (ECHO) were performed at 28, 32, and 36 weeks. RESULTS: Thirty-six patients were included in the final analysis (BPD-PH group = 6, BPD group = 20, control = 10). Urinary NT-proBNP levels were higher in the BPD-PH group compared with BPD and control groups at all study intervals. A urine NT-proBNP cutoff level of 2345 pg/ml at 28 weeks of GA had a sensitivity and specificity of 83.3% and 84.2%, respectively, for detection of BPD-PH (AUC 0.816, p = 0.022). CONCLUSION: Urinary NT-proBNP measurement is feasible in preterm infants and appears to be a good noninvasive screening tool for PH.

Urine gastrin-releasing peptide in the first week correlates with bronchopulmonary dysplasia and post-prematurity respiratory disease.

RATIONALE: Bronchopulmonary dysplasia (BPD) is associated with post-prematurity respiratory disease (PRD) in survivors of extreme preterm birth. Identifying early biomarkers that correlate with later development of BPD and PRD may provide insights for intervention. In a preterm baboon model, elevated gastrin-releasing peptide (GRP) is associated with BPD, and GRP inhibition mitigates BPD occurrence. OBJECTIVE: We performed a prospective cohort study to investigate whether urine GRP levels obtained in the first postnatal week were associated with BPD, PRD, and other urinary biomarkers of oxidative stress. METHODS: Extremely low gestational age infants (23-28 completed weeks) were enrolled in a US multicenter observational study, The Prematurity and Respiratory Outcomes Program (http://clinicaltrials.gov/ct2/show/NCT01435187). We used multivariable logistic regression to examine the association between urine GRP in the first postnatal week and multiple respiratory outcomes: BPD, defined as supplemental oxygen use at 36 + 0 weeks postmenstrual age, and post-PRD, defined by positive quarterly surveys for increased medical utilization over the first year (PRD score). RESULTS: A total of 109 of 257 (42%) infants had BPD, and 120 of 217 (55%) had PRD. On adjusted analysis, GRP level more than 80 was associated with BPD (adjusted odds ratio [aOR], 1.83; 95% confidence interval [CI], 1.03-3.25) and positive PRD score (aOR, 2.46; 95% CI, 1.35-4.48). Urine GRP levels correlated with duration of NICU ventilatory and oxygen support and with biomarkers of oxidative stress: allantoin and 8-hydroxydeoxyguanosine. CONCLUSIONS: Urine GRP in the first postnatal week was associated with concurrent urine biomarkers of oxidative stress and with later diagnoses of BPD and PRD.

Polycythemia, capillary rarefaction, and focal glomerulosclerosis in two adolescents born extremely low birth weight and premature.

BACKGROUND: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs. CASE-DIAGNOSIS/TREATMENT: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction. CONCLUSIONS: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Urinary Neutrophil Gelatinase-associated Lipocalin in the evaluation of Patent Ductus Arteriosus and AKI in Very Preterm Neonates: a cohort study.

BACKGROUND: A patent ductus arteriosus (PDA) is frequently found in very preterm neonates and is associated with increased risk of morbidity and mortality. A shunt across a PDA can result in an unfavorable distribution of the cardiac output and may in turn result in poor renal perfusion. Urinary Neutrophil Gelatinase-associated Lipocalin (U-NGAL) is a marker of renal ischemia and may add to the evaluation of PDA. Our primary aim was to investigate if U-NGAL is associated with PDA in very preterm neonates. Secondary, to investigate whether U-NGAL and PDA are associated with AKI and renal dysfunction evaluated by fractional excretion of sodium (FENa) and urine albumin in a cohort of very preterm neonates. METHODS: A cohort of 146 neonates born at a gestational age less than 32 weeks were consecutively examined with echocardiography for PDA and serum sodium, and urine albumin and sodium were measured on postnatal day 3 and U-NGAL and serum creatinine day 3 and 6. AKI was defined according to modified neonatal Acute Kidney Injury Network (AKIN) criteria. The association between U-NGAL and PDA was investigated. And secondly we investigated if PDA and U-NGAL was associated with AKI and renal dysfunction. RESULTS: U-NGAL was not associated with a PDA day 3 when adjusted for gestational age and gender. A PDA day 3 was not associated with AKI when adjusted for gestational age and gender; however, it was associated with urine albumin. U-NGAL was not associated with AKI, but was found to be associated with urine albumin and FENa. CONCLUSIONS: Based on our study U-NGAL is not considered useful as a diagnostic marker to identify very preterm neonates with a PDA causing hemodynamic changes resulting in early renal morbidity. The interpretation of NGAL in preterm neonates remains to be fully elucidated.

Analysis of urine biomarkers for early determination of acute kidney injury in non-septic and non-asphyxiated critically ill preterm neonates.

OBJECTIVE: We designed the present study to test the hypothesis that urinary biomarkers might predict acute kidney injury (AKI) development in non-septic and non-asphyxiated critically ill preterm infants. We evaluated urine (u) sistatin-C (uCys-C), kidney injury molecule-1 (uKIM-1) and neutrophil gelatinase associate lipocaline (uNGAL) as markers of AKI. METHODS: Sixty-four preterm infants with gestational age between 28 and 32 weeks were included in this study. Biomarkers were measured on day of life (DOL) 1, 3, and 7. RESULTS: uNGAL levels in the AKI group were significantly higher than in no-AKI group on DOL 1, 3 and 7 (p = 0.016, p = 0.007 and p = 0.0014, respectively). CONCLUSIONS: uNGAL is sensitive, early, and noninvasive AKI biomarkers, increasing significantly in non-septic and non-asphyxiated critically ill preterm neonates.

The relationship of red blood cell transfusion to intestinal mucosal injury in premature infants.

OBJECTIVE: To determine the incidence of intestinal mucosal injury before and after transfusions in premature infants. STUDY DESIGN: Urine was collected throughout the hospital stay of 62 premature infants and specimens obtained within 24h before and after transfusion were assayed for intestinal fatty acid binding protein (iFABP). A urinary iFABP:creatinine ratio (iFABPu:Cru) of 2.0pg/nmol was considered elevated. RESULT: Forty-nine infants were transfused. iFABPu:Cru was elevated following 71 (75.6%) of 94 transfusions for which urine was available. In 51 (71.8%) of these, iFABPu:Cru was also elevated prior to the transfusion. Among four cases of transfusion-associated NEC, iFABPu was elevated following every sentinel transfusion and prior to three of them. CONCLUSION: Subclinical intestinal mucosal injury is frequent following blood transfusions in premature infants and, when present, usually precedes transfusion. This suggests that transfusion may not be a primary mediator of intestinal injury so much as anemia and its associated conditions. LEVEL OF EVIDENCE: Prognosis study/level 3.

Glucosuria as an early marker of late-onset sepsis in preterms: a prospective cohort study.

BACKGROUND: Early and accurate diagnosis of late-onset sepsis (LONS) in preterm infants is difficult since presenting signs are subtle and non-specific. Because neonatal sepsis may be accompanied by glucose intolerance and glucosuria, we hypothesized that glucosuria may be associated with LONS in preterms, in an early stage. We aim to evaluate the association of glucosuria and late-onset neonatal sepsis (LONS) in preterm infants, in an attempt to improve early and accurate diagnosis of LONS. METHODS: We performed a prospective observational cohort study in 316 preterms (<34 weeks). We daily measured glucosuria and followed patients for occurrence of LONS, defined as clinical and blood culture-proven sepsis occurring after 72 h. Attending physicians were blinded to glucosuria results. We assessed the diagnostic value of glucosuria for clinical and blood culture-proven LONS using logistic regression analysis. RESULTS: Glucosuria was found in 65.8% of 316 preterm patients, and sepsis was suspected 157 times in 123 patients. LONS was found in 47.1% of 157 suspected episodes. The presence of glucosuria was associated with LONS (OR 2.59, 95% CI 1.24-5.43, p = 0.012) with sensitivity 69.0% and specificity 53.8% (Likelihoodratio 1.49). After adjustment for gestational age, birth weight, and postnatal age, this association weakened and was no longer significant (adjusted OR 2.16; 95% CI 0.99-1.85, p = 0.055). An increase in glucosuria 48-24 h before onset of symptoms was not associated with LONS. CONCLUSION: In preterms glucosuria is associated with LONS within 24 h, however this association is too weak to be of diagnostic value.

[OPTIMIZATION OF EARLY DIAGNOSIS OF ACUTE KIDNEY INJURY IN NEWBORNS IN CRITICAL CONDITION].

UNLABELLED: Current diagnosis of acute kidney injury (AKI) is one of the most pressing problems in the newborn in critical condition. OBJECTIVE: To determine the diagnostic value of indicators of renal blood flow as a marker of acute kidney injury in critically ill newborns. MATERIALS AND METHODS: The study included 40 infants in critical condition. A clinical assessment of severity of the condition during admission was carried out with Neonatal Multiple Organ Dysfunction Score (NEOMOD) and Neonatal Therapeutic Intervention Scoring System (NTISS). All patients underwent evaluation of clinical and instrumental parameters, including ultrasound of the renal vessels, renal vascular resistance index and speed performance. CONCLUSIONS: 1) biochemical markers used in routine clinical practice were not sufficiently informative for the diagnosis of AKI. 2) For a more accurate assessment of the risk of AKI using serum creatinine, GFR calculation and evaluation on a scale RIFLE it is should be focused on performance standards, appropriate for gestational age and birth weight. 3) Evaluation of blood flow at a particular index in the resistance of the main renal arteries had the greatest predictive value and had a relatively high sensitivity and specificity for the diagnosis of AKI.

Intestinal fatty-acid binding protein and metronidazole response in premature infants.

OBJECTIVES: In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection. STUDY DESIGN: We conducted an intravenous metronidazole pharmacokinetic study, collecting ≤3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates. RESULTS: Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I-FABP concentration (p = 0.006). CONCLUSION: While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants.

Early detection of impending necrotizing enterocolitis with urinary intestinal fatty acid-binding protein.

BACKGROUND: Necrotizing enterocolitis (NEC) is diagnosed after the development of feeding intolerance and characteristic physical and imaging findings. Earlier detection of a subclinical prodrome might allow for the institution of measures that could prevent or attenuate the severity of the disease. OBJECTIVES: We sought to determine whether urinary intestinal fatty acid-binding protein (iFABPu) might be elevated prior to the first clinical manifestations of NEC. METHODS: Urine was collected daily from 62 infants of a gestational age of 24-28 weeks. Based on clinical, imaging and operative findings, subjects were determined to have Bell stage 2 or 3 NEC. In all the subjects with NEC and in 21 age-matched controls, iFABPu was determined using an ELISA, and was expressed in terms of its ratio to urinary creatinine (Cr), i.e. iFABPu/Cru. Receiver operating characteristic (ROC) curves were constructed to define the predictive value of iFABPu/Cru for impending NEC in the days prior to the first clinical manifestations. RESULTS: Five subjects developed NEC (stage 2: n = 3 and stage 3: n = 2). The day before the first clinical manifestation of NEC, a ROC curve showed that an iFABPu/Cru >10.2 pg/nmol predicted impending NEC with a sensitivity of 100% and a specificity of 95.6%. iFABPu/Cru did not predict NEC 2 days prior to the first sign of disease. CONCLUSIONS: An elevated iFABPu was a sensitive and specific predictor of impending NEC 1 day prior to the first clinical manifestations. iFABPu screening might identify infants at a high risk and allow for the institution of measures that could ameliorate or prevent NEC.

Intestinal fatty acid-binding protein in neonates with imminent necrotizing enterocolitis.

BACKGROUND: Intestinal fatty acid-binding protein (I-FABP) is a promising marker for necrotizing enterocolitis (NEC). It can be measured in plasma (I-FABPp) and urine (I-FABPu). Data on the best way to measure I-FABP (in plasma or urine) and the necessity of simultaneous measurement of the urinary creatinine concentration to correct for physiological variations in urine concentration are not available. This holds also true for the reciprocal relation between I-FABPp, I-FABPu and other more conventional laboratory parameters. OBJECTIVES: To evaluate the above-mentioned correlations of I-FABP measurements in neonates with suspected NEC. METHODS: All neonates with suspected NEC were prospectively included. I-FABPp and I-FABPu were analyzed at regular intervals during the first 24 h after onset of symptoms. Correlation and agreement were assessed between these and other parameters (i.e., IL-6, WBC, platelet count, CRP, pH and lactate). RESULTS: Included were 24 boys, 13 girls [median (range) GA 28 weeks (24-36), median birth weight 1,190 g (570-2,400)]. I-FABPu correlated strongly with I-FABPp (r 0.80, p < 0.001) with an adequate agreement. A very strong correlation between I-FABPu and I-FABPu/urine creatinine ratio (r 0.98, p < 0.001) existed. Correlations between I-FABPp/u and conventional parameters were moderate to strong until 8 h after onset of symptoms. CONCLUSION: In neonates with suspected NEC, I-FABPu correlates strongly with I-FABPp, offering an opportunity to choose the most appropriate way of measuring I-FABP. Calculating urinary IFABP/creatinine ratio seems redundant. Moderately strong correlations between I-FABPu and IL-6, WBC and lactate were found.

Urinary neutrophil gelatinase-associated lipocalin as an early biomarker for prediction of acute kidney injury in preterm infants.

BACKGROUND: Our aims are to determine whether the urinary neutrophil gelatinase-associated lipocalin (uNGAL) can predict acute kidney injury (AKI) development in nonseptic and nonasphyxiated but critically ill preterm infants. METHODS: Fifty preterm infants, gestational age (GA) between 28 and 34 weeks, were included in this case control study. Blood and urine samples were taken for blood urea nitrogen, serum creatinine, and uNGAL on postnatal (PN) days 1 and 7. uNGAL levels were measured by enzyme-linked immunoassay. Clinical and laboratory characteristics of the AKI group were compared with the non-AKI group. RESULTS: AKI was diagnosed in six infants during the first week. The median uNGAL levels were significantly higher in the preterm infants with AKI than those of the controls on PN days 1 and 7 (p = 0.006 and p = 0.023, respectively). Backward stepwise logistic regression analysis identified that 5-minute Apgar score and uNGAL levels were significantly associated with the development of AKI, even after controlling for GA, birth weight, gender, and 1-minute Apgar score in nonseptic and nonasphyxiated but critically ill preterm infants. CONCLUSIONS: uNGAL can be useful as a predictive marker of AKI in nonseptic and nonasphyxiated but critically ill preterm infants.

Metabolomics in the developing infant.

PURPOSE OF REVIEW: The aim of this review is to update readers on the most recent publications concerning clinical metabolomics in developing infants. RECENT FINDINGS: Only a limited number of neonatal and pediatric metabolomic studies have been published, in comparison to the adult. However, this number of pediatric and neonatal papers is constantly increasing. The latest papers are related to intrauterine growth restricted and small for gestational age neonates, prematurity, mode of delivery, hypoxic ischemic encephalopathy, persistent ductus arteriosus, respiratory syndrome and surfactant therapy, cytomegalovirus infection, nephrouropathy, inborn errors of metabolism, pharmametabolomics, and nutrimetabolomics (including study of maternal milk and formula). Also numerous papers have been presented in experimental neonatology. In particular, the fluids most frequently used were as follows: urine, cord blood plasma, but also milk and stools. Each condition or disease presents a specific discriminating set of metabolites, which can be considered like a 'bar code'. SUMMARY: In the near future, improved tools for metabolomic analysis (like simplified 'dipsticks' for urine) and its integration with other 'omics' will make this technology available in the clinical setting, leading to better or easier clinical decision making. Urinary metabolomics will probably be one of the most used tools in pediatrics and the metabolome will be 'our world'.

Elevated Activin A urine levels are predictors of intraventricular haemorrhage in preterm newborns.

AIM: Intraventricular haemorrhage (IVH) is the most common variety of cerebral haemorrhage and cause of neurological disabilities in preterm newborns. We evaluated the usefulness of urine Activin A concentrations for the early detection of perinatal IVH. METHODS: We conducted a case-control study on 100 preterm newborns (20 with IVH and 80 without IVH) in whom urine Activin A was measured at five predetermined time-points in the first 72 h after birth. IVH diagnosis and the extension of the lesion were performed by ultrasound scanning within the first 72 h and at 1 week after birth, respectively. RESULTS: Urine Activin A in infants who developed IVH was significantly higher than in controls at all monitoring time-points (p < 0.01 for all), increasing progressively from first urination to 24 h when it reached the highest peak (p < 0.001). At a cut-off 0.08 ng/L, at the first void, Activin A sensitivity and specificity were 68.7% (CI: 41.3-89%) and 84.5% (CI: 75-91.5%). CONCLUSION: Activin A measurements in urine soon after birth can constitute a promising tool for identifying preterm infants at risk of IVH.

Low urine vascular endothelial growth factor levels are associated with mechanical ventilation, bronchopulmonary dysplasia and retinopathy of prematurity.

BACKGROUND: Organ-specific vascular endothelial growth factor (VEGF) expression is decreased during the pathogenesis of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) several weeks before either disease can be diagnosed. Early measurement of organ-specific tissue VEGF levels might allow identification of infants at high risk for these diseases, but is not clinically feasible. Urine VEGF is easily measured and useful in early diagnosis of several diseases. OBJECTIVES: Our aims were to assess the correlation of urine VEGF levels measured in the first postnatal month with subsequent BPD or ROP diagnosis and to determine whether various infant characteristics influence urine VEGF levels. METHODS: 106 subjects born at <29 weeks' gestation and surviving to 36 weeks' postmenstrual age were selected from an existing database and biorepository. Urine VEGF and total protein were measured in 2-3 samples per subject. RESULTS: Urine VEGF/protein levels increased by 72% per week (p < 0.0001) during the first postnatal month. In multivariable analysis controlling for postnatal age, lower VEGF/protein was associated with higher levels of mechanical respiratory support (p = 0.006), male gender (p = 0.001) and early sepsis (p = 0.003) but not with fraction of inspired oxygen. Lower urine VEGF/protein and mechanical ventilation were each associated with BPD and ROP. In analyses adjusted for respiratory support, lower urine VEGF/protein and ROP remained associated but urine VEGF/protein and BPD did not. CONCLUSIONS: Low urine VEGF/protein levels in the first postnatal month are associated with mechanical ventilation, BPD, and ROP.

Urinary neutrophil gelatinase-associated lipocalin in septic preterm babies: a preliminary study.

OBJECTIVE: This study was conducted to evaluate the predictive value of urinary neutrophil gelatinase-associated lipocalin (uNGAL) for acute kidney injury (AKI) among septic preterm infants. METHODS: Twenty-six very low-birth-weight (VLBW) babies were separated into three groups: group I, healthy preterms; group II, preterms with sepsis but without AKI; group III, preterms with sepsis and AKI. Demographic, clinical, and laboratory data of the babies were recorded. uNGAL and creatinine values were obtained on days 1, 3, and 7 of life. RESULTS: uNGAL levels differed statistically among three groups for all 3 days. Levels in group I (days 1, 3, and 7) were significant lower than levels in both groups II and III [median (interquartile range): 4.5 (10.8) µ/L, 8.7 (18.5) µ/L, and 4.3 (1.1) µ/L, respectively]. In group III, uNGAL levels on days 1 and 3 were significantly higher than levels in group II (p = 0.001, 0.016, respectively). CONCLUSION: First-day uNGAL levels were higher in VLBW preterm infants who later developed sepsis; whether the baby had AKI or not; but uNGAL levels were higher in septic babies with AKI compared with the infants without AKI. uNGAL is a promising early biomarker of AKI in VLBW infants with sepsis.

Transient postnatal secretion of androgen hormones is associated with acne and sebaceous gland hypertrophy in early infancy.

CONTEXT: Sebaceous gland hypertrophy (SGH) and acne-like skin eruptions are frequent during the first months of life, yet the etiology and prevalence of these conditions in infants are not clear. OBJECTIVE: The objective of the study was to evaluate the association of postnatal androgens with SGH and acne in infants. DESIGN: This was a longitudinal, monthly follow-up from 1 wk (D7) to 6 months of age (M1-M6). PATIENTS: Patients included 54 full-term (FT; 26 boys) and 48 preterm (PT; gestational age at birth 27.7-36.6 wk, 22 boys) infants. MAIN OUTCOME MEASURES: The occurrence of SGH (present/absent) and acne (5-10, 10-50, and >50 papules) was registered and compared with urinary levels of dehydroepiandrosterone and its sulphate and testosterone measured by liquid chromatography-tandem mass spectrometry. RESULTS: SGH was observed in 89% of FT and 96% of PT infants (P = 0.28). Acne (more than five papules) was observed in 91% of FT infants and in 75% of PT infants (P = 0.06). Both SGH and acne were associated with developmental rather than calendar age: SGH was limited to postmenstrual age less than 46 wk and acne was not observed less than 37 wk of postmenstrual age. Urinary androgen levels showed severalfold differences in magnitude between sexes and between the FT and PT groups. After grouping according to sex and maturity, the occurrence of SGH and the severity of acne were associated with higher urinary dehydroepiandrosterone sulphate and testosterone levels in each group. CONCLUSIONS: SGH and acne are common during the first months of life and associated with endogenous, physiologically elevated levels of androgens originating from the adrenals and gonads. These data suggest a novel role for postnatal androgen secretion in infancy.