Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia.

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate-aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post-treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.

Increased Steroid Excretion in Children with Extremely Low Birth Weight at a Median Age of 9.8 years.

BACKGROUND: Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases. AIMS: To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites. METHODS: The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry. RESULTS: In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11ß-hydroxysteroid dehydrogenase activity was not different. CONCLUSION: Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function.

Effects of supplemental oxygen on urinary 8-hydroxy-2'-deoxyguanosine levels in extremely low birth weight infants.

As the effects of supplementary oxygen on urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) are poorly understood, urinary 8-OHdG levels (ng/mg creatinine) were determined longitudinally on the postnatal day (PND) 1, 3, and 30 in 16 neonates with birth weight < 1000 g. No supplementary oxygen was required in 9 neonates during the first 24 h of life. Urinary 8-OHdG level on PND 1 was inversely correlated with birth weight in these 9 neonates (P = 0.0323) and was higher in four with birth weight < 750 g than five with birth weight > 750 g (41.0 ± 6.9 vs. 5.6 ± 2.7, respectively, P = 0.0200). Median urinary 8-OHdG on PND 1 of these 9 neonates was significantly lower than that of 7 neonates with oxygen (9.3 vs. 60.2, respectively), although there were no significant differences in clinical background, such as birth weight, between the two groups. Five of the 9 did not require supplemental oxygen at all during the first 30 days of life. Median urinary 8-OHdG levels were consistently significantly lower in the 5 neonates than in 11 neonates with oxygen transiently or persistently (9.3 vs. 54.6, 19.1 vs. 61.4, and 28.3 vs. 145 on PND 1, 3, and 30, respectively), although there were no differences in clinical background, such as birth weight, between the two groups. Urinary 8-OHdG on PND 30 was significantly positively correlated with supplemental oxygen dose on PND 30 (P < 0.0001), but not with birth weight in the 16 neonates. These results suggest that higher supplemental oxygen tension caused higher urinary 8-OHdG in this population.

Renal vasodilatory action of arginine vasopressin in extremely low birth weight infants.

In extremely low birth weight (ELBW) infants, systemic hypotension is associated with poor neurological outcomes as a result of cerebral hypoperfusion. Treatment with arginine vasopressin (AVP) has been shown to increase blood pressure (BP) and urine output in ELBW infants suffering from refractory hypotension. The purpose of this study was to clarify whether low doses of AVP increased renal blood flow (RBF) in ELBW infants. We retrospectively analyzed data from the medical charts describing nine AVP infusions at 0.3-0.8 mU/kg/min in four ELBW infants. The median gestational age was 23 (22.5-23.5, interquartile range) weeks, and the median birth weight was 466 (414-563) g. Changes in the heart rate, BP, urine output, and RBF velocity patterns in response to the AVP infusions were compared using statistical analyses. The AVP infusion caused significant increases in systolic BP from 44 (41.0-47.0) to 50 (42.5-55.5) mmHg, diastolic BP from 17 (15.0-26.5) to 31 (28.5-33.0) mmHg, mean BP from 26 (24.5-30.5) to 36 (34.5-40.5) mmHg, and urine output from 1.4 (0.2-2.5) to 2.8 (1.0-8.6) mL/kg/hr. We also observed significant decreases in the resistance index from 1.0 (0.96-1.0) to 0.8 (0.71-0.91) and peak systolic flow velocity in the renal artery from 40 (27.2-50.6) to 28 (16.0-28.9) cm/s after AVP infusions. AVP infusions at 0.3-0.8 mU/kg/min in ELBW infants appeared to significantly increase the RBF by inducing renal vascular dilation and increasing the BP. Increasing the RBF most likely induces an increase in the glomerular filtration rate, resulting in the diuretic effect of AVP.

Clinical metabolomics and urinary NGAL for the early prediction of chronic kidney disease in healthy adults born ELBW.

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 genotype-phenotype 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.