Lower urinary α-Klotho is associated with lower angiotensin-(1-7) and higher blood pressure in young adults born preterm with very low birthweight.

Early-life factors including preterm birth and VLBW increase the risk of hypertension, but the mechanisms remain poorly understood. Reductions in the anti-aging protein α-klotho are associated with hypertension, possibly due to angiotensin (Ang) II activation, but the mechanisms are incompletely understood and clinical evidence is lacking. The association of α-klotho with the alternative Ang-(1-7) pathway, which counteracts Ang II to lower BP, is undescribed. We hypothesized that lower urinary α-klotho is associated with higher BP and lower urinary Ang-(1-7) in preterm-born VLBW young adults. In a cross-sectional analysis of data from a prospective cohort of 141 preterm-born VLBW young adults, we assessed the associations among urinary α-klotho/creatinine, Ang II/creatinine, Ang-(1-7)/creatinine, Ang II/Ang-(1-7), and BP using generalized linear models adjusted for age and hypertensive pregnancy and conducted a sensitivity analysis in 32 term-born young adults. Among those born preterm, lower α-klotho/creatinine was associated with higher systolic BP (adjusted ß (aß): -2.58 mm Hg, 95% CI -4.99 to -0.17), lower Ang-(1-7)/creatinine (ln aß: 0.1, 0.04-0.16), and higher Ang II/Ang-(1-7) (ln aß: -0.14, -0.21 to -0.07). In term-born participants, α-klotho/creatinine was inversely associated with Ang II/creatinine (ln aß: -0.15, -0.27 to -0.03) and Ang II/Ang-(1-7) (ln aß: -0.15, -0.27 to -0.03). In preterm-born young adults with VLBW, lower urinary α-klotho/creatinine was associated with higher SBP, lower urinary Ang-(1-7)/creatinine, and higher urinary Ang II/Ang-(1-7). Reduced renal α-klotho expression could lead to renal Ang-(1-7) suppression as a novel mechanism for the development of hypertension among individuals born preterm with VLBW.

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.

LC-ESI/MS/MS analysis of neonicotinoids in urine of very low birth weight infants at birth.

OBJECTIVES: Neonicotinoid insecticides are widely used systemic pesticides with nicotinic acetylcholine receptor agonist activity that are a concern as environmental pollutants. Neonicotinoids in humans and the environment have been widely reported, but few studies have examined their presence in fetuses and newborns. The objective of this study is to determine exposure to neonicotinoids and metabolites in very low birth weight (VLBW) infants. METHODS: An analytical method for seven neonicotinoids and one neonicotinoid metabolite, N-desmethylacetamiprid (DMAP), in human urine using LC-ESI/MS/MS was developed. This method was used for analysis of 57 urine samples collected within 48 hours after birth from VLBW infants of gestational age 23-34 weeks (male/female = 36/21, small for gestational age (SGA)/appropriate gestational age (AGA) = 6/51) who were admitted to the neonatal intensive care unit of Dokkyo Hospital from January 2009 to December 2010. Sixty-five samples collected on postnatal day 14 (M/F = 37/22, SGA/AGA = 7/52) were also analyzed. RESULTS: DMAP, a metabolite of acetamiprid, was detected in 14 urine samples collected at birth (24.6%, median level 0.048 ppb) and in 7 samples collected on postnatal day 14 (11.9%, median level 0.09 ppb). The urinary DMAP detection rate and level were higher in SGA than in AGA infants (both p<0.05). There were no correlations between the DMAP level and infant physique indexes (length, height, and head circumference SD scores). CONCLUSION: These results provide the first evidence worldwide of neonicotinoid exposure in newborn babies in the early phase after birth. The findings suggest a need to examine potential neurodevelopmental toxicity of neonicotinoids and metabolites in human fetuses.

Urinary tract infection is common in VLBW infants.

OBJECTIVE: Determine the significance of urinary tract infection (UTI) as a cause of late onset sepsis (LOS) in very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU). STUDY DESIGN: Analysis of blood, cerebrospinal fluid and urine culture results in VLBW infants >72-h old, admitted to the Georgetown University Hospital NICU between 2005 and 2015. RESULT: Of 527 VLBW infants, 297 (56.4%) underwent 911 evaluations for LOS; only one-third included urine cultures. UTI was diagnosed in 8.5% of VLBW infants (range 2-15.9%) and in 13.8% of infants weighing < 1000 g at birth. Gram-negative infections predominated. Concomitant blood cultures were negative in 96% of infants. UTI was more common than bloodstream infection by 2015. CONCLUSION: UTI is a significant cause of infection in VLBW infants. Urine culture should be included in all LOS evaluations in order to facilitate accurate diagnosis and appropriate antibiotic therapy.

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.

Preterm Glycosuria - New Data from a Continuous Glucose Monitoring System.

BACKGROUND: Careful control of glucose homeostasis is essential for infants with very low birth weight (VLBW). In clinical practice, blood and urine glucose levels are monitored; however, their correlation has not been fully investigated in VLBW infants. OBJECTIVES: To evaluate the correlation between interstitial fluid glucose concentration (ISFG), glycosuria, and urine output among VLBW infants through continuous glucose monitoring (CGM). METHODS: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birth weight of 1,066 g. CGM (Guardian Real-Time CGM®; Medtronic, Northridge, CA, USA) was used to measure glucose. The urine output was calculated using 4-hour intervals. Reagent strips were used for semiquantitative measurement of glycosuria. RESULTS: The CGM delivered 102,334 glucose measurements. 2,684 urine samples were checked for glycosuria, of which 92.06% remained negative. Corresponding glycemia in samples without glycosuria remained normoglycemic (median 103 mg/dL; 10-90th percentile 80-144 mg/dL). The median glucose concentrations for samples in ascending glycosuria categories 1+, 2+, 3+, and 4+ were 152, 181, 214, and 222 mg/dL, respectively. A moderate correlation between ISFG and urine output was found for categories ≥1+ (rs = 0.56; 95% confidence interval 0.42-0.68; p < 0.001). The urine output was significantly lower when glycosuria was absent (p < 0.05). Polyuria was observed only in glycosuria 4+ (median urine output 9.9; interquartile range 7.4-12.2 mL/kg/h). CONCLUSIONS: The renal glucose threshold in VLBW infants is between 150 and 180 mg/dL. A negative result for glycosuria is a reliable screening test to exclude hyperglycemia. Occurrence of glycosuria ≥1+ is an indication to test blood glucose.

Trace elements, oxidative status and antioxidant capacity as biomarkers in very low birth weight infants.

Reference data on trace elements, oxidative status and antioxidants in very low birth weight infants (VLBW) are limited and need to be updated for use in clinical settings. Serum and urine of 30 VLBW infants (mean weight, 1167g) at mean age of 23.8 (t0) and 37.8 (t1) days were analyzed. Cadmium (Cd), copper (Cu), iron (Fe), mercury (Hg), manganese (Mn), selenium (Se) and zinc (Zn), nitrate/nitrite (NOx), catalase (CAT), CuZnFeMn-superoxide dismutases (CuZnFeMn-SODs), total antioxidant capacity (SAC: sum of thiols, proteins, bilirubin, uric acid, ß-beta-carotene, ascorbic acid, vitamin E) and total oxidative status (SOS: sum of lipo- and hydroperoxides) were determined. A higher urinary excretion of Cu and Zn was observed at t0 than at t1; while an increase in urine Cd was found at t1 respect to t0. A deficiency in serum levels of Cu and Zn was also found. A lower CAT activity, a higher total oxidants level (SOS) and a reduction of total antioxidant barriers (SAC) were observed in some infants. No Fe and Mn deficiency or Hg overload was found; also CuZnFeMn-SODs and NOx levels did not change. The findings showed that losses of trace elements and incomplete mineral body stores were more pronounced in the earlier life stage (at 23.8th day) than later on; moreover, antioxidant defenses were poor and lipo- and hydroperoxides were higher still at 5 weeks of infants' life.

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.

Hidden Toxicity in Neonatal Intensive Care Units: Phthalate Exposure in Very Low Birth Weight Infants.

OBJECTIVE: To determine exposure to endocrine-disrupting phthalates in preterm infants in neonatal intensive care units (NICU). METHODS: Urine samples (n=151) from 36 preterm infants (<32 weeks of gestation and/or <1500 g of birth weight) were collected on the first 3 days of admission to the NICU and biweekly thereafter. Diethylhexyl phthalate contents of indwelling medical devices used in various procedures and the concentrations of phthalate metabolites in the urine samples were analyzed. The relationships between urinary excretion, exposure intensity, postnatal age and birth weight were examined. RESULTS: The mean gestational age and mean birth weight of the study infants were 28.9±1.5 weeks and 1024±262 g, respectively. Diethylhexyl phthalate was detected in umbilical catheters, endotracheal tubes, nasogastric tubes, and nasal cannula. Monoethylhydroxyhexyl phthalate (MEHHP) was the most frequently detected metabolite (81.4%); its concentration increased during the first 4 weeks and then started to decrease but never disappeared. Patients who did not need indwelling catheters (except nasogastric tubes) after 2 weeks were classified as group 1 and those who continued to have indwelling catheters as group 2. Although not of statistical significance, MEHHP levels decreased in group 1 but continued to stay high in group 2 (in the 4th week, group 1: 65.9 ng/mL and group 2: 255.3 ng/mL). Levels of MEHHP in the first urinary samples were significantly higher in infants with a birth weight <1000 g (<1000 g: 63.2±93.8 ng/mL, ≥1000 g: 10.9±22.9 ng/mL, p=0.001). CONCLUSION: Phthalate metabolites were detected even in the first urine samples of very low birth weight newborns. Phthalate levels were higher in the first weeks of intensive invasive procedures and in preterm infants with a birth weight less than 1000 g. MEHHP was the most frequently detected metabolite and could be a suitable biomarker for the detection of phthalate exposure in preterm infants.

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.

Effect of vitamin A supplementation on the urinary retinol excretion in very low birth weight infants.

UNLABELLED: Despite high-dose vitamin A supplementation of very low birth weight infants (VLBW, <1500 g), their vitamin A status does not improve substantially. Unknown is the impact of urinary retinol excretion on the serum retinol concentration in these infants. Therefore, the effect of high-dose vitamin A supplementation on the urinary vitamin A excretion in VLBW infants was investigated. Sixty-three VLBW infants were treated with vitamin A (5000 IU intramuscular, 3 times/week for 4 weeks); 38 untreated infants were classified as control group. On days 3 and 28 of life, retinol, retinol-binding protein 4 (RBP4), glomerular filtration rate, proteinuria, and Tamm-Horsfall protein were quantified in urine. On day 3 of life, substantial retinol and RBP4 losses were found in both groups, which significantly decreased until day 28. Notwithstanding, the retinol excretion was higher (P < 0.01) under vitamin A supplementation as compared to infants of the control group. On day 28 of life, the urinary retinol concentrations were predictive for serum retinol concentrations in the vitamin A treated (P < 0.01), but not in the control group (P = 0.570). CONCLUSION: High urinary retinol excretion may limit the vitamin A supplementation efficacy in VLBW infants. Advanced age and thus postnatal kidney maturation seems to be an important contributor in the prevention of urinary retinol losses.

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.

Oxidative stress early in infancy and neurodevelopmental outcome in very low-birthweight infants.

BACKGROUND: Reactive oxygen species may be involved in serious diseases in premature infants. The objective of this study was to assess the relationship between neurodevelopmental outcome and oxidative stress marker level in the urine of very low-birthweight (VLBW) infants. METHODS: Spot urine samples were collected from 35 VLBW infants. Urinary excretion of 8-hydroxy-2″-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and 8-iso-prostaglandin F2α (8-isoPGF), a marker of lipid peroxidation, was measured at 1, 2, 4, and 6 weeks of age. Neurodevelopmental outcome at 18 months' corrected age was assessed using the Bayley Scales of Infant Development (BSID)-II. RESULTS: Significant correlations were found between urinary 8-OHdG at 2 and 4 weeks and the Mental Development Index of the BSID-II. No significant correlation was found between urinary 8-isoPGF and indices of the BSID-II. CONCLUSIONS: In VLBW infants, urinary 8-OHdG level correlated with mental development rather than psychomotor development at 18 months' corrected age; urinary 8-OHdG might be a predictive marker of neurodevelopmental outcome in VLBW infants.

Fat emulsion given to very low-birthweight infants increases urinary L-FABP.

BACKGROUND: In premature infants, many factors influence the function of renal tubules, such as asphyxia, respiratory disorders, use of high-concentration oxygen, hypotension, and drug treatment. When tubular ischemia and oxidative stress develop due to renal microcirculatory pathology, urinary L-type fatty acid-binding protein (L-FABP) level increases. METHODS: Urinary L-FABP level was measured over time in very low-birthweight infants (VLBWI), and the effect of fat emulsion on L-FABP level was investigated. Thirty-one VLBWI were divided into two groups with regard to treatment with fat emulsion: the lipid group (n = 20) and the control group (n = 11). Urinary L-FABP was measured before (0-3 days of age), during (7-14 days of age), and after fat emulsion treatment (21-28 days of age) in the two groups. RESULTS: Median urinary L-FABP level before treatment was 459 ng/mgCr (range, 22.7-5100 ng/mgCr; mean, 1067 ± 1570 ng/mgCr) and 797 ng/mgCr (range, 69-3900 ng/mgCr; mean, 1066 ± 1188 ng/mgCr) in the lipid and control groups, respectively, showing no significant difference. Median urinary L-FABP level was 624 ng/mgCr (range, 50-2050 ng/mgCr; mean ± SD, 799 ± 655 ng/mgCr) and 273 ng/mgCr (range, 31-987 ng/mgCr; mean ± SD, 359 ± 323 ng/mgCr) at 7-14 days of age, respectively, showing that the level was significantly higher in the lipid group. At 21-28 days of age, the median level was 462 ng/mgCr (range, 49-1867 ng/mgCr; mean ± SD, 557 ± 534 ng/mgCr) and 130 ng/mgCr (range, 20-993 ng/mgCr; mean ± SD, 290 ± 329 ng/mgCr), respectively, showing that L-FABP level tended to be higher in the lipid group. CONCLUSIONS: Fat emulsion treatment induced a significant increase in urinary L-FABP level, suggesting that fat emulsion affected the proximal tubule in VLBWI.

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.

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.

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.

Postnatal kidney function in children born very low birth weight.

INTRODUCTION: There are scarce data on estimating the time of completing kidney maturation in very-low-birth-weight (VLBW) infants. The aim of this study was to determine whether different aspects of kidney function differ between VLBW infants and normal babies at 18 to 30 months postconceptional age. MATERIALS AND METHODS: This study was carried on 23 VLBW infants and 21 normal-birth-weight infants at 18 to 30 months corrected postconceptional age, who were born between June 2007 and June 2008 at Alzahra Hospital and Shahid Beheshti Hospital, in Isfahan, Iran. Very low birth weight was defined as a birth weight between 1000 g and 1500 g, while gestational age is less than 32 weeks. In both groups, children with a history of sepsis, asphyxia, intubation, hypoxic ischemic encephalopathy, and pyelonephritis were excluded. RESULTS: The mean of systolic, diastolic, and mean arterial blood pressure were not significantly different between the two groups. Urine calcium-creatinine ratio, fraction excretion of magnesium, and renal threshold for phosphate were significantly higher in the VLBW children compared with the control group. Glomerular filtration rate was higher in the control group than in the VLBW group. CONCLUSIONS: Our results demonstrated that in VLBW children at the corrected age of 24 ± 6 months, some aspects of tubular and glomerular functions are still impaired. Longer longitudinal cohort studies on VLBW are required to determine the time of completing kidney function maturation in these children.