Effect of increased enteral protein intake on plasma and urinary urea concentrations in preterm infants born at < 32 weeks gestation and < 1500 g birth weight enrolled in a randomized controlled trial - a secondary analysis.

BACKGROUND: Feeding breast milk is associated with reduced morbidity and mortality, as well as improved neurodevelopmental outcome but does not meet the high nutritional requirements of preterm infants. Both plasma and urinary urea concentrations represent amino acid oxidation and low concentrations may indicate insufficient protein supply. This study assesses the effect of different levels of enteral protein on plasma and urinary urea concentrations and determines if the urinary urea-creatinine ratio provides reliable information about the protein status of preterm infants. METHODS: Sixty preterm infants (birthweight < 1500 g; gestational age < 32 weeks) were enrolled in a randomized controlled trial and assigned to either a lower-protein group (median protein intake 3.7 g/kg/d) or a higher-protein group (median protein intake 4,3 g/kg/d). Half the patients in the higher-protein group received standardized supplementation with a supplement adding 1.8 g protein/100 ml milk, the other half received individual supplementation depending on the respective mother's milk macronutrient content. Plasma urea concentration was determined in two scheduled blood samples (BS1; BS2); urinary urea and creatinine concentrations in weekly spot urine samples. RESULTS: The higher-protein group showed higher plasma urea concentrations in both BS1 and BS2 and a higher urinary urea-creatinine-ratio in week 3 and 5-7 compared to the lower-protein group. In addition, a highly positive correlation between plasma urea concentrations and the urinary urea-creatinine-ratio (p < 0.0001) and between actual protein intake and plasma urea concentrations and the urinary urea-creatinine-ratio (both p < 0.0001) was shown. CONCLUSIONS: The urinary urea-creatinine-ratio, just like plasma urea concentrations, may help to estimate actual protein supply, absorption and oxidation in preterm infants and, additionally, can be determined non-invasively. Further investigations are needed to determine reliable cut-off values of urinary urea concentrations to ensure appropriate protein intake. TRIAL REGISTRATION: Clinicaltrials.gov; NCT01773902 registered 15 January 2013, retrospectively registered.

Acute kidney injury in premature newborns-definition, etiology, and outcome.

BACKGROUND: Neonatal acute kidney injury (AKI) is common and is associated with poor outcomes. New criteria for the diagnosis of AKI were introduced based on the increase in serum creatinine (SCr) levels and/or reduction of urine output (UOP). Yet, there is no generally accepted opinion so far, which criteria (whether SCr, UOP, or their combination) are the most appropriate to diagnose neonatal AKI. METHODS: The retrospective study included 195 prematurely born neonates who fulfilled all inclusion criteria (with at least two SCr measurements). In all the neonates included in the study, AKI was diagnosed using three different definitions: (1) SCr criteria (an increase in SCr values of ≥0.3 mg/dl), (2) UOP criteria (UOP < 1.5 ml/kg/h), and (3) SCr + UOP criteria. RESULTS: Out of all of the patients the study included, 85 (44%) were diagnosed with AKI. The neonates who had AKI had a significantly lower gestational age, birth weight, and Apgar score, longer duration of mechanical ventilation, and a higher mortality rate. SCr + UOP criteria showed higher sensitivity for prediction of death compared to SCr or UOP alone (p = 0.0008, 95% CI 0.040-0.154, and p = 0.0038, 95% CI 0.024-0.125, respectively). If only SCr or only UOP criterion are used, they fail to identify AKI in 61 and 67%, respectively. AKI was an independent risk factor for death (OR 7.4875; CI 3.1887-17.5816). CONCLUSIONS: Similar to other studies, our data showed that neonates with AKI have worse outcome. Neonatal AKI defined based on SCr + UOP criteria is a better predictor of death than neonatal AKI defined based only on the SCr or UOP criteria. Also, by using SCr + UOP criteria for diagnosing neonatal AKI, more patients with AKI are recruited than when only one of those criteria is used.

Increased urinary neutrophil gelatinase-associated lipocalin in very-low-birth-weight infants with oliguria and normal serum creatinine.

BACKGROUND: In infants, oliguria is defined as a urine output of <1.5 mL/kg/h. The aim of our study was to assess the impact of oliguria on urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) levels in very-low-birth-weight infants (VLBWIs) with a normal serum creatinine (Cr) level. METHODS: Fifty-seven VLBWIs were enrolled in the study. Urinary NGAL, serum CysC and Cr levels and urinary NGAL/Cr ratios were measured. Infants with Apgar scores of >5 at 5 min and/or a serum Cr level of >1.5 mg/dL or those treated for patent ductus arteriosus were excluded. In case of antibiotic treatment, blood and urine samples were collected at ≥48 h after discontinuation of antibiotic treatment. RESULTS: There was a significant difference in gestational age between infants with oliguric episodes during hospitalization and those without, but not in birth weight, perinatal or postnatal factors. Gestational age was negatively correlated with urinary NGAL and serum CysC levels and urinary NGAL/Cr ratio (p < 0.05), whereas postnatal age was negatively correlated with serum Cr level and urinary NGAL/Cr ratio (p < 0.05). Of the 117 urine and blood samples collected, 25 (21.4%) were obtained from neonates with oliguric episodes. After adjusting for gestational age and postnatal age, comparison of samples collected in infants with and without oliguric episodes revealed significant differences in the mean level of urinary NGAL and in the urinary NGAL/Cr ratio, but not in mean serum CysC or serum Cr levels. The urinary NGAL level [area under the curve (AUC) 0.886, 95% confidence interval (CI) 0.814-0.937] and urinary NGAL/Cr ratio (AUC 0.853, 95% CI 0.775-0.911) showed significantly greater discrimination for oliguria than serum CysC (AUC 0.610, 95% CI: 0.515-0.699) or serum Cr (AUC 0.747, 95%CI 0.659-0.823) levels. CONCLUSIONS: Urinary NGAL level and urinary NGAL/Cr ratio were more sensitive markers for the presence of oliguria in VLBWIs with normal serum Cr levels than serum CysC level.

Acute Kidney Injury Urine Biomarkers in Very Low-Birth-Weight Infants.

BACKGROUND AND OBJECTIVES: Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a prospective cohort study on 113 VLBW infants (weight ≤1200 g or <31 weeks' gestation) admitted to a regional neonatal intensive care unit at the University of Alabama at Birmingham between February 2012 and June 2013. SCr was measured on postnatal days 1, 2, 3, and 4 and was combined with clinically measured SCr to determine AKI according to Kidney Disease Improving Global Outcomes AKI definition (increase in SCr ≥0.3 mg/dl or ≥50% increase from previous lowest value). Urine was collected on the first 4 days (average number of urine collections, 3; range, 1-4). The maximum urine biomarkers and urine biomarker/creatinine levels were calculated for 12 urine biomarkers, and the minimum urine biomarker and biomarker/creatinine levels were assessed for two urine biomarkers. We compared these values between infants with and those without AKI. Ideal cutoffs, area under the receiver-operating characteristic curve , and area under the curve adjusted for gestational age were calculated. RESULTS: Cumulative incidence of AKI during the first 2 postnatal weeks was 28 of 113 (25%). Infants with AKI had higher maximum levels of urine cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin, and α glutathione S-transferase (2.0, 1.8, 1.7, 1.7, and 3.7 times higher, respectively) than infants without AKI. In addition, infants with AKI had lower minimum levels of epithelial growth factor and uromodulin than those without AKI (1.4 and 1.6 times lower, respectively). Most but not all participants had their maximum (or minimum) biomarker values preceding AKI. These associations remained after adjustment for gestational age. CONCLUSIONS: Urine biomarkers measured in the first 4 days of life are associated with AKI during the first postnatal weeks. Further evaluations are necessary to determine whether these biomarkers can predict important clinical outcomes. In addition, intervention studies that use biomarkers to stratify enrollment groups are needed before bedside evaluations can be incorporated into care.

Increased levels of phthalates in very low birth weight infants with septicemia and bronchopulmonary dysplasia.

Very low birth weight infants (VLBW; birth weight<1500g) are exposed to potentially harmful phthalates from medical devices during their hospital stay. We measured urinary phthalate concentrations among hospitalized VLBW infants participating in a nutritional study. Possible associations between different phthalates and birth weight (BW), septicemia and bronchopulmonary dysplasia (BPD) were evaluated. Forty-six VLBW infants were enrolled in this randomized controlled nutritional study. The intervention group (n=24) received increased quantities of energy, protein, fat, essential fatty acids and vitamin A, as compared to the control group (n=22). The concentrations of 12 urinary phthalate metabolites were measured, using high-performance liquid chromatography coupled to tandem mass spectrometry, at 3 time points during the first 5weeks of life. During this study, the levels of di (2-ethylhexyl) phthalate (DEHP) metabolites decreased, whereas an increasing trend was seen regarding metabolites of di-iso-nonyl phthalate (DiNP). Significantly higher levels of phthalate metabolites were seen in infants with lower BW and those diagnosed with late onset septicemia or BPD. A significant positive correlation between the duration of respiratory support and DEHP metabolites was observed (p≤0.01) at 2.9weeks of age. Birth weight was negatively associated with urinary phthalate metabolite concentrations. Infants with lower BW and those diagnosed with septicemia or BPD experienced prolonged exposure from medical equipment containing phthalates, with subsequent higher levels of phthalate metabolites detected. Clinical Trial Registration no.: NCT01103219.

Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates.

BACKGROUND: Urine proteins may help in understanding physiology and diagnosing disease in premature infants. Determining how urine proteins vary by degree of prematurity, sex, and postnatal day is warranted. METHODS: We performed a prospective cohort study to assess the independent correlation of 14 urine biomarkers (measured on postnatal days 1-4) with gestational age (GA), sex, and postnatal age in 81 premature infants (mean, 1017 g) without acute kidney injury using a random-effects mixed model. RESULTS: Neutrophil gelatinase-associated lipocalin (NGAL) and vascular endothelial growth factor (VEGF) showed significant associations for sex, GA, and postnatal age. Cystatin C, osteopontin (OPN), and trefoil factor 3 (TFF3) were associated with postnatal age and GA, but not sex. Epithelial growth factor (EGF) and uromodulin were associated with GA only. Clusterin was associated with postnatal age and sex. Albumin was associated with sex only. Beta-2-microglbulin (B2M), osteoactivin, kidney injury molecule -1 (KIM-1), and alpha glutathione S-transferase (αGST) were associated with postnatal age only. CONCLUSIONS: Postnatal age affects B2M, cystatin C, NGAL, OPN, clusterin, Kim-1, osteoactivin, TFF3, VEGF, αGST. GA affects cystatin C, EGF, NGAL, OPN, UMOD, TFF3, and VEGF. Sex affects albumin, NGAL, and clusterin. Interpretation of urine biomarkers will need to account for these associations.

Increased urinary angiotensinogen is an effective marker of chronic renal impairment in very low birth weight children.

BACKGROUND: Recent advancements in perinatal and neonatal care have increased the survival of preterm infants with lower birth weight and very low birth weight (VLBW; < 1,500 g) infants. Such infants are exposed to a higher risk of renal insufficiency in later life due to congenitally fewer nephrons; however, urinalysis in order to detect renal insufficiency in those infants at school age has not yet been established. The aim of the study was to assess chronic renal impairment in VLBW infants during their childhood after discharge from the neonatal intensive care unit (NICU) until adolescence using urinary angiotensinogen (uAGT). METHODS: We compared serum levels of angiotensinogen (sAGT), creatinine, ß2-microglobulin (sß2MG) and cystatin C (sCysC), and urinary levels of uAGT, creatinine (uCre),ß2-microglobulin (uß2MG) and albumin between two infant groups-the VLBW group (50 children who were admitted to our NICU as infants), and a control group of 25 children who were born as full-term infants with birth weight ≥2,500 g. The median age of the VLBW group and control group infants was 60 months (range 7-135) and 57 months (range 5-144), respectively, at the time of evaluation. RESULTS: In the VLBW group, sCysC levels were high (p < 0.05) and estimated glomerular filtration rate (eGFR) was low (p < 0.05). There were no significant differences in the ratios of uß2MG to creatinine and urinary albumin to creatinine between the two groups. Although there were no differences in concentration of sAGT between the two groups (p = 0.062), the ratio of uAGT to creatinine was significantly higher in the VLBW group (p < 0.01). The examination of 19 VLBW infants (19/50) with eGFR ≤90 ml/min/1.73 m(2) showed a positive correlation between uAGT/creatinine and urinary albumin/creatinine (r = 0.531, p < 0.05). Furthermore, the analysis of correlation between the ratio of uAGT to creatinine and eGFR showed a reverse correlation in 19 VLBW infants (19/50) with eGFR ≤90 ml/min/1.73 m(2), 18 of whom had stage II chronic kidney disease and one who had stage III disease (r = -0.512, p ≤ 0.05). CONCLUSIONS: uAGT is an effective marker for predicting the progression of chronic renal impairment in preterm VLBW infants after their growth. uAGT measurement is easier to conduct, less invasive and more sensitive than conventional uß2MG or urinary albumin measurement.

Urine gonadotropin and estradiol levels in female very-low-birth-weight infants.

BACKGROUND: The postnatal activation of the hypothalamic-pituitary-gonadal axis is more exaggerated in preterm than in full-term born infants and may be important for future reproductive function. AIM: The objective of this study was to investigate the postnatal activation of the hypothalamic-pituitary-gonadal axis in female very-low-birth-weight infants. STUDY DESIGN: We performed serial measurements of gonadotropin and estradiol levels in urine samples of female very-low-birth-weight infants collected at 1 and 4weeks postnatal age, at 32weeks postmenstrual age, at expected date of delivery and at the corrected age of three and six months. SUBJECTS: Twenty-two very-low-birth-weight infants (gestational age 25.4-30.1weeks), participating in the Neonatal Insulin Replacement Therapy in Europe trial, were included in this study. OUTCOME MEASURES: Gonadotropin and estradiol levels were measured in serial urine samples. RESULTS: Longitudinal analysis shows that after birth FSH and LH levels increase until 32weeks postmenstrual age (4weeks postnatal age) and then decrease until 3months corrected age (26weeks postnatal age). Estradiol levels decrease from 28weeks postmenstrual age (1week postnatal age) until 6months corrected age (39weeks postnatal age). CONCLUSIONS: Serial urine sampling for measurement of gonadotropin and estradiol levels provides an accurate description of the postnatal activation of the hypothalamic-pituitary-gonadal axis in very-low-birth-weight girls. Levels of FSH and LH peak at a mean postmenstrual age of 32weeks (postnatal age of 4weeks) whereas estradiol levels are highest shortly after birth.

Urinary NT-proBNP, NGAL, and H-FABP may predict hemodynamic relevance of patent ductus arteriosus in very low birth weight infants.

BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) is the most common functional cardiovascular disease in preterm infants. The necessity to treat hsPDA can neither be derived solely from clinical nor from echocardiographic criteria. OBJECTIVE: The aim of this study was to establish non-invasive parameters which can differentiate hsPDA from non-hsPDA. METHODS: Urinary protein levels of NT-proBNP, NGAL, and H-FABP were measured and correlated with the necessity of therapy for PDA. In 37 neonates (<1,500 g), urinary protein concentrations were tested on days 0, 2, and 7 by ELISA methodology. Of 37 infants, 12 required therapeutic interventions according to current treatment standards. RESULTS: Infants receiving an intervention for PDA showed significantly higher levels of pro-BNP, NGAL, and H-FABP at all time points except for NT-proBNP on day 0. Infants requiring a second or third course of ibuprofen had significantly higher levels of H-FABP and NGAL. In all samples, the concentration of the three proteins correlated positively with each other. CONCLUSIONS: The present study shows that measurement of urinary proteins is a powerful and non-invasive method to quantify the effect of PDA on systemic perfusion in preterm infants. Furthermore, NGAL and H-FABP may be used to indicate the necessity of pharmacological or surgical treatment of PDA.

Correlation of urinary inflammatory and oxidative stress markers in very low birth weight infants with subsequent development of bronchopulmonary dysplasia.

Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) ('classic' BPD) and with minimal early lung disease ('atypical' BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1(st), 3(rd) and 7(th) day of life and measured the levels of leukotriene E(4) (LTE(4)) and 8-hydroxydeoxyguanosine (8-OHdG). The 8-OHdG values on the 3(rd) day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7(th) day were the independent risk factor for developing moderate/severe BPD. In 'classic' BPD, the 8-OHdG values on the 3(rd) day were higher than those of 'atypical' BPD. In 'atypical' BPD, the LTE(4) values on the 7(th) day were higher than the values in 'classic' BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in 'atypical' BPD.

Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants.

Acute kidney injury (AKI) is common in premature infants and is associated with poor outcomes. Novel biomarkers can detect AKI promptly. Because premature infants are born with underdeveloped kidneys, baseline biomarker values may differ. We describe baseline values of urinary neutrophil gelatinase-associated lipocalin (NGAL), IL-18, kidney injury molecule-1 (KIM-1), osteopontin (OPN), beta-2 microglobulin (B2mG), and Cystatin-C (Cys-C). Next, we test the hypothesis that these biomarkers are inversely related to GA. Candidate markers were compared according to GA categories in 123 infants. Mixed linear regression models were performed to determine the independent association between demographics/interventions and baseline biomarker values. We found that urine NGAL, KIM-1, Cys-C, and B2mG decreased with increasing GA. With correction for urine creatinine (cr), these markers and OPN/cr decreased with increasing GA. IL-18 (with or without correction for urine creatinine) did not differ across GA categories. Controlling for other potential clinical and demographic confounders with regression analysis shows that NGAL/cr, OPN/cr, and B2mG/cr are independently associated with GA. We conclude that urine values of candidate AKI biomarkers are higher in the most premature infants. These findings should be considered when designing and analyzing biomarker studies in newborn with AKI.

Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants.

Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing ≤1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 ± 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 ± 0.2 to 0.53 ± 0.13 mg/dL; eGFR, from 15.3 ± 4.1 to 28.6 ± 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 ± 0.27 to 0.98 ± 0.43 mg/dL; eGFR from 23 ± 14.7 to 16.4 ± 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants.

Urinary neutrophil gelatinase-associated lipocalin is a promising biomarker for late onset culture-positive sepsis in very low birth weight infants.

Need for the early identification of sepsis in very low birth weight (VLBW) infants has led to the search for reliable biomarkers. This study aims to determine whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) rises in culture-positive sepsis and, if so, is elevated at the time sepsis is suspected. This is a prospective study of 91 VLBW infants whose urine was collected daily for uNGAL analysis. In 65 episodes of suspected sepsis, four groups were identified: a) culture-positive sepsis; b) single culture positive for Staphylococcus epidermidis; c) and d) negative culture with antibiotic treatment for >or=7 d and <7 d, respectively. Daily means of uNGAL of each group were estimated for comparison. Mean uNGAL in group A (179 ng/mL) was significantly elevated on the day blood culture was drawn (day 0) compared with the mean of healthy VLBW infants (6.5 ng/mL), and to the means in groups B, C, and D (p<0.05). In group A, mean uNGAL was significantly elevated on day 0 and daily for 5 days when compared with that of the day before culture (p<0.05 to <0.005). uNGAL shows promise as an early marker for culture-positive sepsis in VLBW infants.

Reference values of urinary neutrophil gelatinase-associated lipocalin in very low birth weight infants.

In very low birth weight (VLBW) infants, acute renal impairment (ARI) is common, but there is no consensus about criteria for its diagnosis. Neutrophil gelatinase-associated lipocalin (NGAL) is an early and sensitive indicator of renal impairment in experimental animals, children, and adults. Urinary NGAL (UNGAL) is detectable in VLBW infants; however, there is no reference range in this population. The objective of this study is to define the reference range for UNGAL in VLBW infants with no risk factors for acute renal impairment. UNGAL concentration was determined in urine samples collected from day of life (DOL) 4 through DOL 30 in 50 newborns with uncomplicated clinical courses, selected from a total of 145 prospectively enrolled appropriate for gestational age inborn VLBW premature infants. The birth weight and gestational age ranges were 790-1490 g and 26-33 wk, respectively. The median, 95th and 99th percentiles, and range of pooled UNGAL values were 5 ng/mL, 50 ng/mL, 120 ng/mL, and 2-150 ng/mL, respectively. Greater variability and higher quantile levels of UNGAL were observed in females versus males. In conclusion, a reference range for UNGAL in VLBW infants, similar to that in children and adults, has been established.

Reference range of urinary neutrophil gelatinase-associated lipocalin in very low-birth-weight infants: preliminary data.

We sought to determine the reference range for urinary neutrophil gelatinase-associated lipocalin (UNGAL) in very low-birth-weight (VLBW) infants with uncomplicated clinical courses. Samples of urine from 53 VLBW infants between 3 and 28 days of life were prospectively collected weekly for measurement of UNGAL. A subset of 22 infants with uncomplicated medical courses without risk factors for renal impairment was selected for study. Mean +/- standard deviation and range for birth weight and gestational age of study infants were 1156 +/- 191, 790 to 1440 g and 29 +/- 2, 27 to 33 weeks, respectively. The 95th and 99th percentiles for UNGAL concentration from this group of infants were 25 ng/mL and 75 ng/mL, respectively. Bootstrapped mean 95th and 99th percentile values and their standard errors and 95 percent confidence intervals in ng/mL were 33.1 +/- 13.0 (7.7, 58.6) and 67.5 +/- 15.1 (37.9, 97.1), respectively. These values fall within the adult reference range. UNGAL values were stable across the ranges of gestational and postnatal age of the study infants. A preliminary reference range for UNGAL in VLBW infants has been established. Further investigation with more frequent urine collections in a larger population of VLBW infants that includes those with birth weights < 750 g and gestational ages < 27 weeks is necessary to confirm this reference range.

[Metabolic bone disease in premature infants and genetic polymorphisms]. / Koraszülöttek csontanyagcsere-betegsége és genetikai polimorfizmusok.

UNLABELLED: Metabolic bone disease is an important complication among infants very-low-birth-weight (< 1500 g). In adults, osteoporosis has been shown to be associated with polymorphisms of vitamin D receptor, estrogen receptor, and collagen Ialpha1 receptor genes. AIM: The primary goal of the study was to investigate the possible association between metabolic bone disease and the allelic polymorphisms of these three genes. METHOD: 104 infants very-low-birth-weight were enrolled to the study. Bone formation (serum alkaline phosphatase, osteocalcin) and bone resorption (urinary excretion of calcium and pyridinium crosslink) markers were determined and x-rays of the chest and wrist (together with the distal portions of associated long bones) were obtained. RESULTS: Thirty infants (28,8%) were diagnosed with metabolic bone disease based on high activity of bone formation, bone resorption markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA) n ] allelic variant of estrogen receptor gene and bone disease was observed. Infants with metabolic bone disease more often carried low number of repeats [(TA) n < 19] [odds ratio (OR): 5.82, 95% confidence interval (CI): 2.26-14.98]. Significantly higher number of repeats [(TA)n > 18] was found more frequently in the control group (OR: 0.20, 95% CI: 0.05-0.82). Furthermore significant interaction between vitamin D receptor and collagen Ialpha1 receptor genotypes ( p = 0.023) was observed. In a forward stepwise logistic regression model, bone disorder of preterms correlated with male gender ( p = 0.001), duration of hospitalization ( p = 0.007), homozygous allelic variants of high number of (TA) n repeats ( p = 0.025) and interaction between vitamin D receptor (Tt) and estrogen receptor (homozygous allelic variants of low number of repeats) genotype ( p = 0.037). CONCLUSION: The results suggest that the development of metabolic bone disease in infants very-low-birth-weight may be associated with genetic polymorphisms.

The role of serum and urinary urea in the evaluation of enteral protein intake in adequate and small-for-gestational-age very low birth weight infants

INTRODUÇÃO E OBJETIVOS: Os recém-nascidos de muito baixo-peso (RNMBP) têm necessidades nutricionais especiais. Existe uma tendência atual de se individualizar a oferta protéica para essas crianças. O objetivo do trabalho é determinar a utilidade da uréia sérica e urinária como indicadores da oferta protéica em RNMBP adequados (AIG) e pequenos para a idade gestacional (PIG). TIPO DE ESTUDO E LOCAL: Estudo prospectivo realizado no Berçário Anexo à Maternidade Instituto da Criança "Prof. Pedro de Alcântara" do Hospital das Clínicas, Departamento de Pediatria da Faculdade de Medicina, Universidade de São Paulo, Brasil. MÉTODOS: Setenta e dois RNMBP (oferta protéica média = 3,7 g/kg/dia) foram incluídos, em um estudo de coorte prospectivo, em dois grupos: AIG (n = 34) e PIG (n = 38). Amostras de sangue, coletas de urina de seis horas (Ur6h) e em amostras isoladas (AIUr) foram obtidas para determinação de uréia e creatinina após a 3ª semana de vida e duas semanas após. Análise estatística: teste t de Student, correlação de Pearson e regressão linear (p < 0,05). RESULTADOS: Não houve diferença entre os grupos quanto aos níveis de uréia sérica, uréia Ur6h e uréia AIUr, bem como entre as duas avaliações dentro de cada grupo. A uréia sérica correlacionou-se à uréia Ur6h nos RNAIG e nos PIG, bem como à uréia AIUr nos RNPIG. A uréia Ur6h correlacionou-se à uréia AIUr nos RNAIG e nos RNPIG. Não houve correlação entre a oferta protéica e a uréia sérica ou urinária. CONCLUSÕES: A uréia sérica e a urinária não refletiram a oferta protéica quando foram utilizadas ofertas médias de 3,7 g/kg/dia. Uréia AIUr pode ser tão confiável quanto uréia da urina coletada por períodos mais longos.

Urinary leukotriene E(4) excretion during the first month of life and subsequent bronchopulmonary dysplasia in premature infants.

BACKGROUND: Inflammation plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD), but the exact nature of this inflammatory process is incompletely understood. Older infants with established BPD have higher levels of urinary leukotriene E(4) (LTE(4)) compared to healthy infants of the same age. This suggests that cysteinyl leukotrienes may play a role in the abnormalities seen in BPD. OBJECTIVES: To measure urinary LTE(4) levels during the first month of life in premature infants, and to determine whether there are significant differences in premature infants who develop BPD, as compared to those who do not develop BPD. DESIGN: Prospective, blinded, controlled study. SETTING: Neonatal ICUs of a tertiary-care university hospital. METHODS: Thirty-seven premature infants (< 33 weeks of gestational age) were enrolled prospectively at birth. Urinary LTE(4) levels were measured blinded, using a standard radioimmunoassay technique at 2 days, 7 days, and 28 days of life. At 1 month of age, infants were classified as with or without BPD, based on need for supplemental oxygen, and characteristic chest radiographs. Clinical features and urinary LTE(4) were compared between the two groups. RESULTS: Mean +/- SD gestational age was 29 +/- 2.6 weeks. None of the infants had a family history of asthma. Thirteen of 37 infants were classified as having BPD at 28 days after birth. Mean gestational age in infants who developed BPD was 27 +/- 2.4 weeks, compared to 30 +/- 2 weeks in infants who did not develop BPD (p < 0.05). In infants with BPD, mean urinary LTE(4) levels of urinary creatinine were 1,762 +/- 2,003 pg/mg, 1,236 +/- 992 pg/mg, and 5,541 +/- 5,146 pg/mg at days 2, 7, and 28, respectively, compared to 1,304 +/- 1,195 pg/mg, 1,158 +/- 1,133 pg/mg, and 2,800 +/- 2,080 pg/mg in infants without BPD. LTE(4) levels at 2 days, 7 days, and 28 days did not correlate with the subsequent development of BPD. LTE(4) levels at day 28 were significantly higher than LTE(4) levels at day 2 and day 7 in both groups, even after correcting for gestational age or birth weight (p < 0.05). There was significant inverse correlation between LTE(4) levels at day 2 with gestational age and birth weight (p < 0.05). All 13 infants with BPD received steroid pulses, compared to 3 of 26 infants without BPD. Gestational age and use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with the subsequent development of BPD. CONCLUSION: Urinary LTE(4) levels measured on the second day of life in very-low-birth-weight infants inversely correlate with gestational age and birth weight. Urinary LTE(4) levels may reflect lung injury and/or inflammation in premature infants, not necessarily related to BPD as it is presently defined.