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

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

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

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

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

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

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

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

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

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

Metabolomics in the developing infant.

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

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

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

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.

Kidney injury molecule-1 as a promising biomarker for acute kidney injury in premature babies.

OBJECTIVE: To evaluate the role of urinary kidney injury molecule-1 (uKIM-1) in early determination of renal injury in premature infants with respiratory distress syndrome (RDS). STUDY DESIGN: Forty-eight premature babies hospitalized in the neonatal intensive care unit were included in the study and divided into three groups: group I, healthy premature infants; group II, preterm infants with RDS without acute kidney injury (AKI); group III, preterm infants with RDS and AKI. uKIM-1 and creatinine along with serum creatinine levels were measured with enzyme-linked immunosorbent assay on days 1, 3, and 7 of life. RESULTS: On day 1, uKIM-1 levels in babies with RDS and AKI were higher than the other two groups. In this group, a significant increase in uKIM-1 levels were detected on day 3 (p = 0.015). The sensitivity and specificity of uKIM-1 were calculated as 73.3% and 76.9%, respectively, along with the increase of 0.5 ng per milligram of creatinine of uKIM-1 in day 3, when compared with values on day 1. Elevated uKIM-1 on day 7 was found to increase the risk of death by 7.3 times. CONCLUSION: Serial uKIM-1 measurements can be used as a noninvasive indicator of kidney injury and uKIM-1 can be an ideal biomarker in premature infants.

The validity of biochemical markers in metabolic bone disease in preterm infants: a systematic review.

UNLABELLED: To establish the validity of biochemical markers of metabolic bone disease (MBD) in preterm infants. CONCLUSION: There is insufficient evidence that any of the frequently used serum measurements are valid biochemical markers of MBD in preterm infants. Increased urinary calcium concentration may be a valid biochemical marker, but more research is necessary to confirm this.

[Prevention of bone mineral deficiency in premature infants: review of the literature with focus on monitoring of urinary calcium and phosphate]. / Knochenmineralmangel bei Frühgeborenen: Prävention mittels Urinmonitoring von Kalzium und Phosphat.

BACKGROUND: Bone mineral deficiency of prematurity (BMDoP) is caused by the lack of simultaneous availability of calcium (Ca) and anorganic phosphate (P) during rapid skeletal growth. METHODS: Review of the literature on the prevention of BMDoP, with specific attention to the limitations of the monitoring of urinary calcium and phosphate concentrations. RESULTS: Intrauterine bone mineral accretion (BMA) can be achieved in preterm infants if urinary concentrations of Ca and P continuously show that the supplementation with these ions slightly exceeds the actual need. An individually adjusted supplementation with Ca and P appears rational because both growth velocity and enteral Ca absorption are highly variable and determine the need for enteral Ca and P administration. If, however, urinary concentrations of Ca and P are used to determine whether Ca and P supplementation is adequate, mechanisms affecting the urinary excretion of these ions other than nutrition have to be taken into account. Specifically, methylxanthines and diuretics increase the renal Ca losses, and the renal P threshold may be lowered in premature infants. A positive effect of physical activity on BMA has been shown in several studies. CONCLUSIONS: An individualized Ca and P supplementation in preterm infants aiming for supplementation in a slight excess of the actual need and guided by urinary Ca and P concentrations appears able to prevent BMDoP. Monitoring of urinary Ca and P concentrations needs to take into account non-nutritional factors affecting these concentrations. BMA may further be improved by physical activity.

Calcium and phosphor intake in preterm infants: sensitivity and specifity of 6-hour urine samples to detect deficiency.

Aim of the present study was to test whether six-hour (6 h) urine specimens predict the 24-hour (24 h) mineral homeostasis in individual infants born preterm. Urinary Calcium (Ca) and Phosphate (P) concentrations were studied in 60 stable infants; gestational age 34 (25-42) weeks. In 58 infants four 6 h urine specimens and in 2 infants all spot urine specimens obtained within 24 h were analyzed. In 39 infants born preterm coefficients of variation were 0.42 (SD 0.26) and 0.41 (SD 0.26) for Ca and P measurements in the four 6 h urine specimens obtained within 24 h, respectively, The mineral homeostasis of the infants was defined as Ca or P surplus homeostasis if the 24 h urinary concentrations were ≥1 mmol/l. The sensitivity, specificity, and PPV of a 6 h urinary specimen to predict Ca deficiency homeostasis (24 h urinary Ca <1 mmol/l) were 0.93 (0.77-0.98; 95%CI), 0.72 (0.43-0.90) and 0.90 (0.74-0.96). The sensitivity, specificity and PPV for urinary P were 0.8 (0.38-0.96), 0.97 (0.85-0.995), and 0.8 (0.38-0.96). In conclusion, in infants born preterm on regular 3 or 4 h feedings, 6 h urine sampling is sufficiently precise for prediction of Ca and P mineral deficiency homeostasis (PPV 0.92 and 0.83). However, measurements at regular intervals (twice weekly) are recommended not to miss any infant in mineral deficiency homeostasis.

Isoprostane levels in urine of preterm newborns treated with ibuprofen for patent ductus arteriosus closure.

Patent ductus arteriosus (PDA) is the most common cardiovascular abnormality of the preterm infant usually treated with ibuprofen (IBU). PDA is strictly related to oxidative stress (OS) in neonates. This study tests the hypothesis that OS occurs in neonates with PDA and that IBU treatment reduces OS. Forty-three preterm babies with gestational age (GA) <33 weeks were studied prospectively. Three urine samples were collected: at time 0 (before starting treatment), time 1 (after pharmacological PDA closure), and time 2 (7 days after the end of treatment) in all patients. OS was studied by measuring urinary isoprostane (IPs) levels. The results showed significant changes in urinary IP levels from time 0 to time 2 (Kruskal-Wallis, p=0.047). Time trend showed a significant decrease in IPs from time 0 to time 1 after IBU therapy (p=0.0067). This decrease was followed by an increase in IPs levels 7 days after treatment. IBU therapy for PDA closure reduced the risk of OS related to free-radical (FR) generation. This antioxidant effect of IBU may be beneficial in preterm babies with PDA who are at high risk for OS.

Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus.

AIM: Water channel AQP2 is the target for vasopressin (AVP) and a major determinant of urinary concentrating capacity. In mature kidneys, prostaglandins counteract the effect of AVP on AQP2 expression at functional sites. We investigated whether disturbances in water homeostasis in infants with patent ductus arteriosus (PDA) treated with prostaglandin inhibitors can be attributed to activation of AQP2. METHODS: In 53 infants with symptomatic PDA (gestational age 24-33 weeks), 30 receiving ibuprofen and 23 indomethacin starting at 2-15 days of life, clinical and biochemical data were collected before treatment and after each dose of the drugs. Urinary AQP2 was determined by dot immunoblotting. RESULTS: Urinary AQP2 level and osmolality were decreased in both groups. Urinary osmolality was overall low and correlated inversely with fluid uptake. In ibuprofen group, there was no correlation of AQP2 level with urinary osmolality. CONCLUSION: There was no AQP2 upregulation in the infants. The low urinary osmolality and dissociation between urinary osmolality and urinary AQP2 level indicate that the fluid retention sometimes observed in PDA infants treated with prostaglandin inhibitors is not caused by increased levels of functional AQP2. Thus, knowledge about the renal physiology of the adult cannot always be transferred to the infant kidney.

Developmental pattern of urinary bile acid profile in preterm infants.

BACKGROUND: Bile acid metabolism in preterm infants is yet to be fully characterized. We compared the developmental pattern of urinary bile acid profiles in ten infants born at gestational ages from 25 to 33 weeks with previous data from full-term infants from birth to about 7 months of age. METHODS: Gas chromatography-mass spectrometry was performed on serial samples. RESULTS: Total urinary bile acid concentrations gradually increased until 1 to 2 months of age. After this peak of excretion (30 to 60 micromol/mmol creatinine), total urinary bile acid concentrations gradually decreased to less than 20 micromol/mmol creatinine. The percentage of usual bile acids (mainly cholic acid) relative to total urinary total bile acids gradually deceased from approximately 30% at birth to less than 15% at 7 months of age. On the other hand, 1beta-hydroxylated bile acids (mainly 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acid) relative to total urinary bile acids were increased gradually from 60% at birth to reach 70% to 80% at 1 month of age. The percentage of 1beta-hydroxylated bile acids relative to total urinary bile acids then remained stable at a high percentage (70% to 90%) until the age of 7 months. CONCLUSION: Physiological cholestasis in preterm infants persists longer than in full-term infants. Moreover, as large amounts of cholic and 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acids were detected in urine from preterm infants during this study, the 25-hydroxylation pathway may be particularly important for bile acid synthesis in early preterm infants.

[Airway resistance and urinary LTE4 in children with bronchopulmonary dysplasia. Preliminary report]. / Resistencia de las vías aéreas y LTE4 urinario en niños con displasia broncopulmonar. Informe preliminar.

OBJECTIVE: To assess airway resistance values and urinary leukotriene E4 (LTE4) concentrations before and after salbutamol inhalation in children with bronchopulmonary dysplasia (BPD). MATERIAL AND METHODS: Children with BPD were cross-sectionally studied to measure airway resistance by the interrupter technique (Rint), before and after inhaling 200 ig salbutamol, and to quantify urinary leukotriene E4 (LTE4) by immunoassay. RESULTS: Thirty one children with BPD (15 females) aged between 3 months and 9 years were studied. Our results showed that LTE4 did not correlate with Rint values (r = 0.12, p = 0.52) even after adjusting by gender, atopy history, steroid use, and gastroesophageal reflux. Likewise, LTE4 did not correlate with the degree of the airway response to salbutamol (r = -0.13, p = 0.50). A strong inverse association between age and Rint (r = -0.58, p < 0.001) was observed. CONCLUSION: We concluded that urinary LTE, did not correlate with airway resistance or with the response to a bronchodilator drug in children with BPD, suggesting that leukotrienes are not involved in airway obstruction in this disease.

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

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

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.

Urinary loss of erythropoietin after intravenous versus subcutaneous epoetin-beta in preterm infants.

Hematopoietic and non-hematopoietic effects of recombinant erythropoietin (Epo) given to preterm infants are controversially discussed. Because renal loss of Epo was significantly higher after intravenous versus subcutaneous Epoetin-beta administration, we suggest a reconsideration of whether subcutaneous recombinant Epo is more efficient and safer because of lower peaks of circulating Epo.