The aim of this study was to better define, by immunohistochemistry, the molecular markers of ren... more The aim of this study was to better define, by immunohistochemistry, the molecular markers of renal stem/progenitor cells localized in the different niches of ten human preterm kidneys with gestational age ranging from 11 up to 25 weeks. Our data evidence the existence of multiple stem/progenitor pools in different zones of the human developing kidney that are characterized by different phenotypes: capsular stem cells were EMA (MUC1)+, MDM2+, Vimentin+ and Wnt1+; progenitors of the sub-capsular nephrogenic zone were MDM2+ and Wnt1+; cap mesenchymal cells were EMA (MUC1)+, CD15+, vimentin+, Wt1+, CD10+, Bcl2+, Wnt1+ and PAX2+; interstitial progenitor cells were Vimentin+, Wt1+ and α1Anti-tripsin+. Our data evidence the existence of multiple stem/progenitor cell pools in the fetal and neonatal human kidney. Progenitors of these different pools are characterized by a peculiar phenotype, indicating a different differentiation stage of these renal progenitors. A better knowledge of the m...
Journal of Maternal-Fetal and Neonatal Medicine, 2011
To date, we have little knowledge on the overall metabolic status of neonates with intrauterine g... more To date, we have little knowledge on the overall metabolic status of neonates with intrauterine growth retardation (IUGR). In the last few years, the analysis of metabolomics has assumed an important clinical role in identifying "disorders" in the metabolic profile of patients. The aim of this work has been to analyze the urine metabolic profiles of neonates with IUGR and compare them with controls to define the metabolic patterns associated with this pathology. To our knowledge, this is the first study of metabolomics performed on neonates with IUGR. Recruited for the study were 26 neonates with IUGR diagnosed in the neonatal period and with weight at birth below the 10th percentile and 30 neonates of proper gestational weight at birth (controls). In the first 24 hours (prior to feeding) (T1) and about 4 days after birth (T2), a urine sample was taken non-invasively from each neonate. The samples were then frozen at −80°C up to the time of the analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). The data contained in the NMR spectra obtained from the single samples were statistically analyzed using the Principal Components Analysis and the Partial Least Squares-Discriminate Analysis. By means of a multivariate analysis of the NMR spectra obtained, it was possible to highlight the differences between the two groups (IUGRs and controls) owing to the presence of different metabolic patterns. The discriminants in the urine metabolic profiles derived essentially from significant differences in certain metabolites such as: myo-inositol, sarcosine, creatine and creatinine. The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences.
This paper describes the manifestaton in a child of a new syndrome characterized by unusual, seve... more This paper describes the manifestaton in a child of a new syndrome characterized by unusual, severe, persistent hyponatremia associated with hyposmolarity, euvolemia, inappropriately concentrated urine and elevated natriuresis. This is the fourth case of this syndrome reported to date, and the first to be reported in a neonate. The clinical features resemble those typically observed in patients with inappropriate antidiuretic hormone secretion, although high arginine vasopressin (AVP) levels are lacking. The findings led the authors to hypothesise a nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The previously described R137C gain-of-function mutation was detected by means of mutation analysis of the V2R gene. Our results indicate that NSIAD is already present during the neonatal period and that molecular analysis of the V2R receptor should therefore be carried out, in all newborns with prolonged euvolemic hyponatremia with hypo-osmolarity, high urinary sodium and normal/low or undetectable AVP levels.
Journal of Pediatric and Neonatal Individualized Medicine, Oct 21, 2014
Necrotizing enterocolitis (NEC) is an acute inflammatory disease of the neonatal intestine that s... more Necrotizing enterocolitis (NEC) is an acute inflammatory disease of the neonatal intestine that strikes in 1 of 1,000 live births. Its etiology is unknown. This review describes in detail the new NECs especially those which affect preterm infants: contagion or lymphocytosis associated, transfusion associated and cow's milk allergy associated. A wide repertory of images are presented, together with algorithms for differential diagnosis.
Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care... more Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care unit (NICU). Recently, soluble CD14 subtype (sDC14-ST) also named presepsin, was proposed as an effective biomarker for diagnosing, monitoring, and assessing the risk of neonatal sepsis and septic shock. The aim of this study was to investigate the diagnostic accuracy of sCD14-ST presepsin in diagnosing neonatal bacterial sepsis and in discriminating non-bacterial systemic inflammatory response syndrome (SIRS) from bacterial sepsis. This study involved 65 critically ill full-term and preterm newborns admitted to the neonatal intensive care unit (NICU), divided into three groups: 25 newborns with bacterial neonatal sepsis (group A); 15 newborns with a diagnosis of non-bacterial SIRS and with no localizing source of bacterial infection (group B); and 25 babies with no clinical or bacteriological signs of systemic or local infection receiving routine NICU care, most of them treated with phototherapy for neonatal jaundice (group C). A total of 102 whole blood samples were collected, 40 in group A, 30 in group B and 32 in group C. In 10 babies included in group A, sCD14-ST presepsin was also measured in an additional second blood sample collected 3days after the start of antibiotic treatment. sCD14-ST presepsin was measured by a commercially available chemiluminescent enzyme immunoassay (CLEIA) optimized on an automated immunoassay analyzer. Statistical analysis was performed by means of MedCalc® statistical package; receiver operating characteristic (ROC) analysis was computed, and the area under the ROC curve (AUC) was used to evaluate the ability of sCD14-ST to discriminate neonatal bacterial sepsis from non-bacterial SIRS. Blood sCD14-ST presepsin levels were found significantly higher in bacterial sepsis when compared with controls (p<0.0001); similarly, they were higher in non-bacterial SIRS when compared with controls (p<0.0001). However, no statistically significant difference was found between bacterial sepsis and non-bacterial SIRS (p=0.730). In our population, CRP and sCD14-ST did not correlate with each other. ROC analysis revealed that sCD14-ST presepsin has an area under the curve (AUC) of 0.995 (95% C.I.: 0.941-1.00) greater than that of CRP (0.827; 95% C.I.: 0.72-0.906). Similarly, in the group of babies with non-infectious SIRS, sCD14-ST AUC was greater than CRP AUC (0.979; 95% C.I.: 0.906-0.999 versus 0.771; 95% C.I.: 0.647-0.868). In controls, preliminary reference intervals for sCD14-ST ranged 223.4-599.7ng/L, being significantly different from those previously published elsewhere. In conclusion, sCD14-ST presepsin could be introduced in clinical practice as a diagnostic tool for improving the management of neonatal sepsis and non-bacterial SIRS.
The development of the mammalian kidney is a complex and in part unknown process which requires i... more The development of the mammalian kidney is a complex and in part unknown process which requires interactions between pluripotential/stem cells, undifferentiated mesenchymal cells, epithelial and mesenchymal components, eventually leading to the coordinate development of multiple different specialized epithelial, endothelial and stromal cell types within the kidney architectural complexity. We will describe the embryology and molecular nephrogenetic mechanisms, a fascinating traffic of cells and tissues which takes place in five stages: (1) ureteric bud (UB) development; (2) cap mesenchyme formation; (3) mesenchymal-epithelial transition (MET); (4) glomerulogenesis and tubulogenesis; (5) interstitial cell development. In particular, we will analyze the multiple cell types involved in these dramatic events as characters moving between different worlds, from the mesenchymal to the epithelial world and back, and will start to define the multiple factors that propel these cells during their travels throughout the developing kidney. Moreover, according with the hypothesis of renal perinatal programing, we will present the results reached in the fields of immunohistochemistry and molecular biology, by means of which we can explain how a loss or excess of molecular factors governing nephrogenesis may cause the onset of pathologies of different gravity, in some cases leading to a chronic kidney disease at different times from birth.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
The survival rate for extremely low birth weight (ELBW) infants born preterm is on an increasing ... more The survival rate for extremely low birth weight (ELBW) infants born preterm is on an increasing upward trend, despite the possibility of neuro-cerebral consequences in later life. To date, scarce information is available on the effect of extreme prematurity on cardiovascular system. To verify the presence of standard echocardiographic and ECG alterations in ex-ELBW young healthy adults. A color Doppler echocardiogram and an ECG were performed on 24 ex-ELBW (4 males and 20 females; mean: 23.2 ± 3.3 years), compared with 24 healthy subjects born at term (C). ECG parameters examined: PR, QT, QT(c), and QT dispersion (QT(d)). Gestational age, birth weight, and duration of stay in neonatal intensive care unit were obtained from clinical records. Transthoracic echocardiography did not reveal differences between ex-ELBW and C, while a significant difference was displayed by ex-ELBW with regard to PR (141.5 ± 13.4 ms vs. 164.2 ± 24.0 ms, p < 0.0003), QT(c) (417.0 ± 23.6 ms vs. 369.9 ± 19.5 ms, p =0.00001), and QT(d) (30.4 ± 14.1 ms vs. 24.6 ± 8.2 ms, p < 0.00001). In two patients (8.3%), QT(c) exceeded the upper limit of normal range. A statistically significant inverse correlation was observed between QT(c) and gestational age (r = -0.67, p < 0.0003). QT(c) and QT(d) in ex-ELBW were found to be at the upper limit of normal range and correlated with gestational age and birth weight; in two cases, QT(c) exceeded the upper limit. This study, irrespective of the pathophysiological mechanism involved, underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval. QT(c) and QT(d) in young adults previously born preterm with an ELBW (401-1000 g) were generally found to be at the upper limit of normal range and correlated with gestational age and birth weight. This finding underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
Background: Clinical metabolomics is a recent "omic" technology which is defined as a global holi... more Background: Clinical metabolomics is a recent "omic" technology which is defined as a global holistic overview of the personal metabolic status (fingerprinting). This technique allows to prove metabolic differences in different groups of people with the opportunity to explore interactions such as genotypephenotype and genotype-environment type, whether normal or pathological. Aim: To study chronic kidney injury 1) using urine metabolomic profiles of young adults born extremely low-birth weight (ELBW) and 2) correlating a biomarker of kidney injury, urinary neutrophil gelatinase-associated lipocalin (NGAL), in order to confirm the metabolomic injury profile. Method: Urine samples were collected from a group of 18 people (mean: 24-year-old, std: 4.27) who were born with ELBW and a group of 13 who were born at term appropriate for gestational age (AGA) as control (mean 25-year-old, std: 5.15). Urine samples were analyzed by 1 H-nuclear magnetic resonance spectroscopy, and then submitted to unsupervised and supervised multivariate analysis. Urine NGAL (uNGAL) was measured using ARCHITECT (ABBOTT diagnostic NGAL kit). Results: With a multivariate approach and using a supervised analysis method, PLS-DA, (partial least squares discriminant analysis) we could correlate ELBW metabolic profiles with uNGAL concentration. Conversely, uNGAL could not be correlated to AGA. Conclusions: This study demonstrates the relevance of the metabolomic technique as a predictive tool of the metabolic status of exELBW. This was confirmed by the use of uNGAL as a biomarker which may predict a subclinical pathological process in the kidney such as chronic kidney disease.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
To date, we have little knowledge on the overall metabolic status of neonates with intrauterine g... more To date, we have little knowledge on the overall metabolic status of neonates with intrauterine growth retardation (IUGR). In the last few years, the analysis of metabolomics has assumed an important clinical role in identifying "disorders" in the metabolic profile of patients. The aim of this work has been to analyze the urine metabolic profiles of neonates with IUGR and compare them with controls to define the metabolic patterns associated with this pathology. To our knowledge, this is the first study of metabolomics performed on neonates with IUGR. Recruited for the study were 26 neonates with IUGR diagnosed in the neonatal period and with weight at birth below the 10th percentile and 30 neonates of proper gestational weight at birth (controls). In the first 24 hours (prior to feeding) (T1) and about 4 days after birth (T2), a urine sample was taken non-invasively from each neonate. The samples were then frozen at −80°C up to the time of the analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). The data contained in the NMR spectra obtained from the single samples were statistically analyzed using the Principal Components Analysis and the Partial Least Squares-Discriminate Analysis. By means of a multivariate analysis of the NMR spectra obtained, it was possible to highlight the differences between the two groups (IUGRs and controls) owing to the presence of different metabolic patterns. The discriminants in the urine metabolic profiles derived essentially from significant differences in certain metabolites such as: myo-inositol, sarcosine, creatine and creatinine. The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences.
Journal of Maternal-Fetal and Neonatal Medicine, 2009
Objective. We retrospectively investigated a cohort of very low birthweight infants (VLBWI) by co... more Objective. We retrospectively investigated a cohort of very low birthweight infants (VLBWI) by comparing two methods for assessment of albuminuria: nephelometry (standard) and high performance liquid chromatography (HPLC), measuring urinary immunoreactive and non-immunoreactive albumin to evaluate if the latter is more sensitive in identifying childhood onset of albuminuria and hypertension in VLBWI individuals. Methods. Spot urine samples of a total of 109 subjects (5.3 + 2.2 years old) who were VLBWI were investigated by HPLC and nephelometry. Twenty-eight subjects were small for gestational age (SGA) and 81 were appropriate for gestational age (AGA). Blood Pressure (BP) was also recorded. Results. Twelve children (11%) with albuminuria 20 mg/g Cr by nephelometry versus 48 (44.5%) by HPLC ( p 5 0.001) were identified. The mean + SD of values in the range of normoalbuminuria was 2.9 + 5.81 by nephelometry versus 22.6 + 14 for HPLC ( p 5 0.001). The values were not statistically different in the two birthweight categories (51000, 1000-1499 g), in AGA versus SGA and in high BP (490th percentile) versus normal BP children. Conclusions. Microalbuminuria by HPLC was more marked in VLBWI than in adults and the difference between values using the two methods was significative.
Journal of Maternal-Fetal and Neonatal Medicine, 2013
The cardiovascular vulnerability of young adults who were born preterm was first acknowledged ove... more The cardiovascular vulnerability of young adults who were born preterm was first acknowledged over a decade ago. (1) To examine the echocardiographic characteristics of a group of young adults born preterm with an extremely low birthweight (<1000 g; ex-ELBW) in comparison with healthy controls born at term (C); (2) to identify a correlation between the potential echocardiographic abnormalities detected in ex-ELBW and their anthropometric parameters, age, presence of respiratory distress, patency of ductus arteriosus, length of stay in Neonatal Intensive Care Unit. Thirty-seven ex-ELBW (11 males, 26 females; mean age: 22.2 ± 1.8 years) were compared with 37 C (11 males, 26 females). Both groups underwent standard mono- and bi-dimensional transthoracic echocardiogram with color Doppler. No statistically significant differences were detected between the two groups regarding mono-dimensional echocardiography or Doppler measurements (p = ns). Conversely, a statistically significant difference was observed between the prevalence of interatrial septal aneurysm (ASA) in ex-ELBW compared to C (p = 0.0016). A significant association was likewise observed between ASA and the presence of both respiratory distress at birth (p < 0.05) and patency of the ductus arteriosus (p < 0.05). A significant prevalence of ASA was detected in ex-ELBW subjects compared to C, underlining a probable correlation with respiratory distress and patent ductus arteriosus. In view of the association between ASA and stroke in young adults devoid of other cerebrovascular risk factors, this unexpected observation suggests that all ex-preterm subjects should undergo transthoracic or transesophageal echocardiographic examination with the aim of detecting this potentially emboligenic cardiac abnormality.
Journal of Maternal-Fetal and Neonatal Medicine, 2012
Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14... more Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14 (sCD14), consisting of 64 amino acid residues. Systemic inflammation and sepsis are characterized by an early, significant increase in sCD14-ST presepsin blood concentration and thus, this small polypeptide has been proposed as a novel, reliable biomarker for the management of sepsis. We enrolled twenty-six consecutive non-septic preterm newborns with gestational age (GA) between 26 and 36 weeks) admitted to NICU after the first day of life for various severe diseases. sCD14-ST presepsin was measure on whole blood samples by a rapid commercial available chemiluminescent enzyme immunoassay (CLEIA) based on a non-competitive CLEIA. The mean sCD14-ST presepsin blood level in 26 preterm newborns was 643.1 ng/L, with a standard deviation (SD) of 303.8 ng/L; the median value was 578 ng/L. Our results clearly suggest no correlation between GA and sCD14-ST presepsin blood level between 26 and 36 weeks and thus it is reasonable to adopt a unique reference range for preterm newborns.
Journal of Maternal-Fetal and Neonatal Medicine, 2013
Background: Prematurity at birth is a known risk factor for the development of an early chronic r... more Background: Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. Aims: (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (51000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. Methods: Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 AE 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. Results: Urinary NGAL levels were higher in ex-ELBW subjects compared to C (p50.05), as well as hematic ADMA concentrations (p50.05). A statistically significant correlation was found between urinary NGAL and ADMA (r ¼ À0.60, p50.04). Conclusions: Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.
Journal of Maternal-Fetal and Neonatal Medicine, 2010
The kidney of low birthweight preterm infants is characterized by a reduced number of mature neph... more The kidney of low birthweight preterm infants is characterized by a reduced number of mature nephrons at birth. The aim of the present study was to determine whether, in preterms, active glomerulogenesis occurs in the postnatal period and whether it may compensate the reduced number of nephrons developed during the intrauterine life. Kidney samples were obtained at autopsy from 8 human fetuses, 12 premature infants, and 3 term newborns. Glomerulogenesis, as measured by radial glomerular count (RGC), was markedly decreased in all preterm infants as compared with term newborns. A marked interindividual variability was detected in the level of glomerulogenesis, which, in the vast majority of cases, did neither correlate with the gestational age at birth nor with birthweight. Active glomerulogenesis, as demonstrated by the presence of S-shaped bodies in the subcapsular region, was present in all preterm infants in the perinatal period, but it ceased in a preterm surviving for 3 months. Our data show that active glomerulogenesis continues even after birth for a short period, although it is not able to compensate a marked oligonephronia at birth. As a consequence, the incomplete nephrogenesis typical of all extremely low birthweight preterm infants possibly results in a persistent oligonephronia which should likelihood represent a major risk factors of progressive renal disease in adulthood.
Journal of Maternal-Fetal and Neonatal Medicine, 2009
Procalcitonin (PCT) has been proposed as an interesting marker in the diagnosis, prognosis, and r... more Procalcitonin (PCT) has been proposed as an interesting marker in the diagnosis, prognosis, and response to treatment of patient with neonatal sepsis. Fifty-nine neonates (34 males and 25 females) with a mean gestational age of *31 weeks and a mean weight of about 1750 g admitted in the Neonatal Intensive Care Unit of Cagliari (Italy) were evaluated in controls and in infected neonates, before and after 48 h of life. From our experience it emerges that PCT is a marker of early and late neonatal sepsis which is reliable in preterm neonates. A cut-off of 0.5 ng/ml starting from the third day of life appears to be capable of ensuring good test sensitivity and specificity.
The aim of this study was to better define, by immunohistochemistry, the molecular markers of ren... more The aim of this study was to better define, by immunohistochemistry, the molecular markers of renal stem/progenitor cells localized in the different niches of ten human preterm kidneys with gestational age ranging from 11 up to 25 weeks. Our data evidence the existence of multiple stem/progenitor pools in different zones of the human developing kidney that are characterized by different phenotypes: capsular stem cells were EMA (MUC1)+, MDM2+, Vimentin+ and Wnt1+; progenitors of the sub-capsular nephrogenic zone were MDM2+ and Wnt1+; cap mesenchymal cells were EMA (MUC1)+, CD15+, vimentin+, Wt1+, CD10+, Bcl2+, Wnt1+ and PAX2+; interstitial progenitor cells were Vimentin+, Wt1+ and α1Anti-tripsin+. Our data evidence the existence of multiple stem/progenitor cell pools in the fetal and neonatal human kidney. Progenitors of these different pools are characterized by a peculiar phenotype, indicating a different differentiation stage of these renal progenitors. A better knowledge of the m...
Journal of Maternal-Fetal and Neonatal Medicine, 2011
To date, we have little knowledge on the overall metabolic status of neonates with intrauterine g... more To date, we have little knowledge on the overall metabolic status of neonates with intrauterine growth retardation (IUGR). In the last few years, the analysis of metabolomics has assumed an important clinical role in identifying "disorders" in the metabolic profile of patients. The aim of this work has been to analyze the urine metabolic profiles of neonates with IUGR and compare them with controls to define the metabolic patterns associated with this pathology. To our knowledge, this is the first study of metabolomics performed on neonates with IUGR. Recruited for the study were 26 neonates with IUGR diagnosed in the neonatal period and with weight at birth below the 10th percentile and 30 neonates of proper gestational weight at birth (controls). In the first 24 hours (prior to feeding) (T1) and about 4 days after birth (T2), a urine sample was taken non-invasively from each neonate. The samples were then frozen at −80°C up to the time of the analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). The data contained in the NMR spectra obtained from the single samples were statistically analyzed using the Principal Components Analysis and the Partial Least Squares-Discriminate Analysis. By means of a multivariate analysis of the NMR spectra obtained, it was possible to highlight the differences between the two groups (IUGRs and controls) owing to the presence of different metabolic patterns. The discriminants in the urine metabolic profiles derived essentially from significant differences in certain metabolites such as: myo-inositol, sarcosine, creatine and creatinine. The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences.
This paper describes the manifestaton in a child of a new syndrome characterized by unusual, seve... more This paper describes the manifestaton in a child of a new syndrome characterized by unusual, severe, persistent hyponatremia associated with hyposmolarity, euvolemia, inappropriately concentrated urine and elevated natriuresis. This is the fourth case of this syndrome reported to date, and the first to be reported in a neonate. The clinical features resemble those typically observed in patients with inappropriate antidiuretic hormone secretion, although high arginine vasopressin (AVP) levels are lacking. The findings led the authors to hypothesise a nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The previously described R137C gain-of-function mutation was detected by means of mutation analysis of the V2R gene. Our results indicate that NSIAD is already present during the neonatal period and that molecular analysis of the V2R receptor should therefore be carried out, in all newborns with prolonged euvolemic hyponatremia with hypo-osmolarity, high urinary sodium and normal/low or undetectable AVP levels.
Journal of Pediatric and Neonatal Individualized Medicine, Oct 21, 2014
Necrotizing enterocolitis (NEC) is an acute inflammatory disease of the neonatal intestine that s... more Necrotizing enterocolitis (NEC) is an acute inflammatory disease of the neonatal intestine that strikes in 1 of 1,000 live births. Its etiology is unknown. This review describes in detail the new NECs especially those which affect preterm infants: contagion or lymphocytosis associated, transfusion associated and cow's milk allergy associated. A wide repertory of images are presented, together with algorithms for differential diagnosis.
Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care... more Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care unit (NICU). Recently, soluble CD14 subtype (sDC14-ST) also named presepsin, was proposed as an effective biomarker for diagnosing, monitoring, and assessing the risk of neonatal sepsis and septic shock. The aim of this study was to investigate the diagnostic accuracy of sCD14-ST presepsin in diagnosing neonatal bacterial sepsis and in discriminating non-bacterial systemic inflammatory response syndrome (SIRS) from bacterial sepsis. This study involved 65 critically ill full-term and preterm newborns admitted to the neonatal intensive care unit (NICU), divided into three groups: 25 newborns with bacterial neonatal sepsis (group A); 15 newborns with a diagnosis of non-bacterial SIRS and with no localizing source of bacterial infection (group B); and 25 babies with no clinical or bacteriological signs of systemic or local infection receiving routine NICU care, most of them treated with phototherapy for neonatal jaundice (group C). A total of 102 whole blood samples were collected, 40 in group A, 30 in group B and 32 in group C. In 10 babies included in group A, sCD14-ST presepsin was also measured in an additional second blood sample collected 3days after the start of antibiotic treatment. sCD14-ST presepsin was measured by a commercially available chemiluminescent enzyme immunoassay (CLEIA) optimized on an automated immunoassay analyzer. Statistical analysis was performed by means of MedCalc® statistical package; receiver operating characteristic (ROC) analysis was computed, and the area under the ROC curve (AUC) was used to evaluate the ability of sCD14-ST to discriminate neonatal bacterial sepsis from non-bacterial SIRS. Blood sCD14-ST presepsin levels were found significantly higher in bacterial sepsis when compared with controls (p<0.0001); similarly, they were higher in non-bacterial SIRS when compared with controls (p<0.0001). However, no statistically significant difference was found between bacterial sepsis and non-bacterial SIRS (p=0.730). In our population, CRP and sCD14-ST did not correlate with each other. ROC analysis revealed that sCD14-ST presepsin has an area under the curve (AUC) of 0.995 (95% C.I.: 0.941-1.00) greater than that of CRP (0.827; 95% C.I.: 0.72-0.906). Similarly, in the group of babies with non-infectious SIRS, sCD14-ST AUC was greater than CRP AUC (0.979; 95% C.I.: 0.906-0.999 versus 0.771; 95% C.I.: 0.647-0.868). In controls, preliminary reference intervals for sCD14-ST ranged 223.4-599.7ng/L, being significantly different from those previously published elsewhere. In conclusion, sCD14-ST presepsin could be introduced in clinical practice as a diagnostic tool for improving the management of neonatal sepsis and non-bacterial SIRS.
The development of the mammalian kidney is a complex and in part unknown process which requires i... more The development of the mammalian kidney is a complex and in part unknown process which requires interactions between pluripotential/stem cells, undifferentiated mesenchymal cells, epithelial and mesenchymal components, eventually leading to the coordinate development of multiple different specialized epithelial, endothelial and stromal cell types within the kidney architectural complexity. We will describe the embryology and molecular nephrogenetic mechanisms, a fascinating traffic of cells and tissues which takes place in five stages: (1) ureteric bud (UB) development; (2) cap mesenchyme formation; (3) mesenchymal-epithelial transition (MET); (4) glomerulogenesis and tubulogenesis; (5) interstitial cell development. In particular, we will analyze the multiple cell types involved in these dramatic events as characters moving between different worlds, from the mesenchymal to the epithelial world and back, and will start to define the multiple factors that propel these cells during their travels throughout the developing kidney. Moreover, according with the hypothesis of renal perinatal programing, we will present the results reached in the fields of immunohistochemistry and molecular biology, by means of which we can explain how a loss or excess of molecular factors governing nephrogenesis may cause the onset of pathologies of different gravity, in some cases leading to a chronic kidney disease at different times from birth.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
The survival rate for extremely low birth weight (ELBW) infants born preterm is on an increasing ... more The survival rate for extremely low birth weight (ELBW) infants born preterm is on an increasing upward trend, despite the possibility of neuro-cerebral consequences in later life. To date, scarce information is available on the effect of extreme prematurity on cardiovascular system. To verify the presence of standard echocardiographic and ECG alterations in ex-ELBW young healthy adults. A color Doppler echocardiogram and an ECG were performed on 24 ex-ELBW (4 males and 20 females; mean: 23.2 ± 3.3 years), compared with 24 healthy subjects born at term (C). ECG parameters examined: PR, QT, QT(c), and QT dispersion (QT(d)). Gestational age, birth weight, and duration of stay in neonatal intensive care unit were obtained from clinical records. Transthoracic echocardiography did not reveal differences between ex-ELBW and C, while a significant difference was displayed by ex-ELBW with regard to PR (141.5 ± 13.4 ms vs. 164.2 ± 24.0 ms, p < 0.0003), QT(c) (417.0 ± 23.6 ms vs. 369.9 ± 19.5 ms, p =0.00001), and QT(d) (30.4 ± 14.1 ms vs. 24.6 ± 8.2 ms, p < 0.00001). In two patients (8.3%), QT(c) exceeded the upper limit of normal range. A statistically significant inverse correlation was observed between QT(c) and gestational age (r = -0.67, p < 0.0003). QT(c) and QT(d) in ex-ELBW were found to be at the upper limit of normal range and correlated with gestational age and birth weight; in two cases, QT(c) exceeded the upper limit. This study, irrespective of the pathophysiological mechanism involved, underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval. QT(c) and QT(d) in young adults previously born preterm with an ELBW (401-1000 g) were generally found to be at the upper limit of normal range and correlated with gestational age and birth weight. This finding underlines a potential risk for ex-ELBW of developing ventricular arrhythmias when using drugs capable of prolonging QT interval.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
Background: Clinical metabolomics is a recent "omic" technology which is defined as a global holi... more Background: Clinical metabolomics is a recent "omic" technology which is defined as a global holistic overview of the personal metabolic status (fingerprinting). This technique allows to prove metabolic differences in different groups of people with the opportunity to explore interactions such as genotypephenotype and genotype-environment type, whether normal or pathological. Aim: To study chronic kidney injury 1) using urine metabolomic profiles of young adults born extremely low-birth weight (ELBW) and 2) correlating a biomarker of kidney injury, urinary neutrophil gelatinase-associated lipocalin (NGAL), in order to confirm the metabolomic injury profile. Method: Urine samples were collected from a group of 18 people (mean: 24-year-old, std: 4.27) who were born with ELBW and a group of 13 who were born at term appropriate for gestational age (AGA) as control (mean 25-year-old, std: 5.15). Urine samples were analyzed by 1 H-nuclear magnetic resonance spectroscopy, and then submitted to unsupervised and supervised multivariate analysis. Urine NGAL (uNGAL) was measured using ARCHITECT (ABBOTT diagnostic NGAL kit). Results: With a multivariate approach and using a supervised analysis method, PLS-DA, (partial least squares discriminant analysis) we could correlate ELBW metabolic profiles with uNGAL concentration. Conversely, uNGAL could not be correlated to AGA. Conclusions: This study demonstrates the relevance of the metabolomic technique as a predictive tool of the metabolic status of exELBW. This was confirmed by the use of uNGAL as a biomarker which may predict a subclinical pathological process in the kidney such as chronic kidney disease.
Journal of Maternal-Fetal and Neonatal Medicine, 2011
To date, we have little knowledge on the overall metabolic status of neonates with intrauterine g... more To date, we have little knowledge on the overall metabolic status of neonates with intrauterine growth retardation (IUGR). In the last few years, the analysis of metabolomics has assumed an important clinical role in identifying "disorders" in the metabolic profile of patients. The aim of this work has been to analyze the urine metabolic profiles of neonates with IUGR and compare them with controls to define the metabolic patterns associated with this pathology. To our knowledge, this is the first study of metabolomics performed on neonates with IUGR. Recruited for the study were 26 neonates with IUGR diagnosed in the neonatal period and with weight at birth below the 10th percentile and 30 neonates of proper gestational weight at birth (controls). In the first 24 hours (prior to feeding) (T1) and about 4 days after birth (T2), a urine sample was taken non-invasively from each neonate. The samples were then frozen at −80°C up to the time of the analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). The data contained in the NMR spectra obtained from the single samples were statistically analyzed using the Principal Components Analysis and the Partial Least Squares-Discriminate Analysis. By means of a multivariate analysis of the NMR spectra obtained, it was possible to highlight the differences between the two groups (IUGRs and controls) owing to the presence of different metabolic patterns. The discriminants in the urine metabolic profiles derived essentially from significant differences in certain metabolites such as: myo-inositol, sarcosine, creatine and creatinine. The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences.
Journal of Maternal-Fetal and Neonatal Medicine, 2009
Objective. We retrospectively investigated a cohort of very low birthweight infants (VLBWI) by co... more Objective. We retrospectively investigated a cohort of very low birthweight infants (VLBWI) by comparing two methods for assessment of albuminuria: nephelometry (standard) and high performance liquid chromatography (HPLC), measuring urinary immunoreactive and non-immunoreactive albumin to evaluate if the latter is more sensitive in identifying childhood onset of albuminuria and hypertension in VLBWI individuals. Methods. Spot urine samples of a total of 109 subjects (5.3 + 2.2 years old) who were VLBWI were investigated by HPLC and nephelometry. Twenty-eight subjects were small for gestational age (SGA) and 81 were appropriate for gestational age (AGA). Blood Pressure (BP) was also recorded. Results. Twelve children (11%) with albuminuria 20 mg/g Cr by nephelometry versus 48 (44.5%) by HPLC ( p 5 0.001) were identified. The mean + SD of values in the range of normoalbuminuria was 2.9 + 5.81 by nephelometry versus 22.6 + 14 for HPLC ( p 5 0.001). The values were not statistically different in the two birthweight categories (51000, 1000-1499 g), in AGA versus SGA and in high BP (490th percentile) versus normal BP children. Conclusions. Microalbuminuria by HPLC was more marked in VLBWI than in adults and the difference between values using the two methods was significative.
Journal of Maternal-Fetal and Neonatal Medicine, 2013
The cardiovascular vulnerability of young adults who were born preterm was first acknowledged ove... more The cardiovascular vulnerability of young adults who were born preterm was first acknowledged over a decade ago. (1) To examine the echocardiographic characteristics of a group of young adults born preterm with an extremely low birthweight (<1000 g; ex-ELBW) in comparison with healthy controls born at term (C); (2) to identify a correlation between the potential echocardiographic abnormalities detected in ex-ELBW and their anthropometric parameters, age, presence of respiratory distress, patency of ductus arteriosus, length of stay in Neonatal Intensive Care Unit. Thirty-seven ex-ELBW (11 males, 26 females; mean age: 22.2 ± 1.8 years) were compared with 37 C (11 males, 26 females). Both groups underwent standard mono- and bi-dimensional transthoracic echocardiogram with color Doppler. No statistically significant differences were detected between the two groups regarding mono-dimensional echocardiography or Doppler measurements (p = ns). Conversely, a statistically significant difference was observed between the prevalence of interatrial septal aneurysm (ASA) in ex-ELBW compared to C (p = 0.0016). A significant association was likewise observed between ASA and the presence of both respiratory distress at birth (p < 0.05) and patency of the ductus arteriosus (p < 0.05). A significant prevalence of ASA was detected in ex-ELBW subjects compared to C, underlining a probable correlation with respiratory distress and patent ductus arteriosus. In view of the association between ASA and stroke in young adults devoid of other cerebrovascular risk factors, this unexpected observation suggests that all ex-preterm subjects should undergo transthoracic or transesophageal echocardiographic examination with the aim of detecting this potentially emboligenic cardiac abnormality.
Journal of Maternal-Fetal and Neonatal Medicine, 2012
Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14... more Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14 (sCD14), consisting of 64 amino acid residues. Systemic inflammation and sepsis are characterized by an early, significant increase in sCD14-ST presepsin blood concentration and thus, this small polypeptide has been proposed as a novel, reliable biomarker for the management of sepsis. We enrolled twenty-six consecutive non-septic preterm newborns with gestational age (GA) between 26 and 36 weeks) admitted to NICU after the first day of life for various severe diseases. sCD14-ST presepsin was measure on whole blood samples by a rapid commercial available chemiluminescent enzyme immunoassay (CLEIA) based on a non-competitive CLEIA. The mean sCD14-ST presepsin blood level in 26 preterm newborns was 643.1 ng/L, with a standard deviation (SD) of 303.8 ng/L; the median value was 578 ng/L. Our results clearly suggest no correlation between GA and sCD14-ST presepsin blood level between 26 and 36 weeks and thus it is reasonable to adopt a unique reference range for preterm newborns.
Journal of Maternal-Fetal and Neonatal Medicine, 2013
Background: Prematurity at birth is a known risk factor for the development of an early chronic r... more Background: Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. Aims: (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (51000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. Methods: Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 AE 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. Results: Urinary NGAL levels were higher in ex-ELBW subjects compared to C (p50.05), as well as hematic ADMA concentrations (p50.05). A statistically significant correlation was found between urinary NGAL and ADMA (r ¼ À0.60, p50.04). Conclusions: Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.
Journal of Maternal-Fetal and Neonatal Medicine, 2010
The kidney of low birthweight preterm infants is characterized by a reduced number of mature neph... more The kidney of low birthweight preterm infants is characterized by a reduced number of mature nephrons at birth. The aim of the present study was to determine whether, in preterms, active glomerulogenesis occurs in the postnatal period and whether it may compensate the reduced number of nephrons developed during the intrauterine life. Kidney samples were obtained at autopsy from 8 human fetuses, 12 premature infants, and 3 term newborns. Glomerulogenesis, as measured by radial glomerular count (RGC), was markedly decreased in all preterm infants as compared with term newborns. A marked interindividual variability was detected in the level of glomerulogenesis, which, in the vast majority of cases, did neither correlate with the gestational age at birth nor with birthweight. Active glomerulogenesis, as demonstrated by the presence of S-shaped bodies in the subcapsular region, was present in all preterm infants in the perinatal period, but it ceased in a preterm surviving for 3 months. Our data show that active glomerulogenesis continues even after birth for a short period, although it is not able to compensate a marked oligonephronia at birth. As a consequence, the incomplete nephrogenesis typical of all extremely low birthweight preterm infants possibly results in a persistent oligonephronia which should likelihood represent a major risk factors of progressive renal disease in adulthood.
Journal of Maternal-Fetal and Neonatal Medicine, 2009
Procalcitonin (PCT) has been proposed as an interesting marker in the diagnosis, prognosis, and r... more Procalcitonin (PCT) has been proposed as an interesting marker in the diagnosis, prognosis, and response to treatment of patient with neonatal sepsis. Fifty-nine neonates (34 males and 25 females) with a mean gestational age of *31 weeks and a mean weight of about 1750 g admitted in the Neonatal Intensive Care Unit of Cagliari (Italy) were evaluated in controls and in infected neonates, before and after 48 h of life. From our experience it emerges that PCT is a marker of early and late neonatal sepsis which is reliable in preterm neonates. A cut-off of 0.5 ng/ml starting from the third day of life appears to be capable of ensuring good test sensitivity and specificity.
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Papers by Melania Puddu