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

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          Abstract

          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.

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          Most cited references29

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          Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.

          Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.
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            Acute kidney injury reduces survival in very low birth weight infants.

            Acute kidney injury (AKI) independently predicts mortality in children and adults. Our understanding of the epidemiology of AKI in very LBW (VLBW) infants is limited to retrospective studies. After adjustment for demographics, comorbidities, and interventions, infants with AKI have decreased survival compared with those without AKI. The study was conducted in regional quaternary care NICU of the University of Alabama at Birmingham. VLBW infants were followed prospectively and were classified into a serum creatinine (SCr)-based classification for AKI. Forty-one of 229 (18%) VLBW infants developed AKI. Those with AKI were more likely to have umbilical artery catheters, assisted ventilation, blood pressure medications, and lower 1-and 5-min Apgar scores. Of the infants with AKI, 17 of 41 (42%) died compared with 9 of 188 (5%) of those without AKI (p < 0.001). AKI was associated with mortality with a crude hazard ratio (HR) of 9.3 (95% CI, 4.1-21.0). After adjusting for potential confounders, those with AKI had higher chance of death as the adjusted HR was 2.4 (95% CI 0.95-6.04). AKI is associated with mortality in VLBW infants. Efforts to prevent and ameliorate the impact of AKI may improve the outcomes in this vulnerable population.
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              Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case-control analysis.

              The independent impact of acute kidney injury (AKI) on survival in very low birthweight (VLBW; < or =1,500 g) critically ill infants has not been studied. Cases (non-survivors n = 68) were matched to, at most, two controls (survivors n = 127) by incidence density sampling with replacement, birthweight (+/- 50 g), gestational age (+/- 1 week), and availability of serum creatinine (SCr) levels before the index patient's time of death. Maternal/infant demographic characteristics, co-morbidities, complications and interventions were explored. No difference existed between patients and controls in mean gestational age and birthweight (the matching variables), race, or gender. Compared with the controls, cases had younger mothers, less placental separation, fewer occurrences of hyponatremia, more intra-ventricular hemorrhage, and received chest compressions and cardiac drugs. A 1 mg/dl increase in SCr was associated with almost two-times higher odds of death [odds ratio (OR) = 1.94, 95% confidence interval (95% CI) 1.13-3.32]. OR increased when confounding variables were adjusted (adjusted OR 3.44, 95% CI 1.23-9.61). Similarly, a 100% increase in SCr from trough level was associated with an increased OR = 1.53 (95% CI 1.14-2.04) and became stronger, after adjustment of variables (adjusted OR = 1.90, 95% CI 1.10-3.27). After confounding variables had been controlled for, AKI was independently associated with mortality in VLBW infants. Further prospective multi-center studies are needed to determine whether this association exists.
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                Author and article information

                Contributors
                +45 22 36 46 31 , anna.sellmer@clin.au.dk
                bhb@ph.au.dk
                jesper.bjerre@skejby.rm.dk
                michael.rahbek@clin.au.dk
                vhjortdal@clin.au.dk
                gitte.esberg@gmail.com
                soren.rittig@skejby.rm.dk
                tbh@dadlnet.dk
                Journal
                BMC Pediatr
                BMC Pediatr
                BMC Pediatrics
                BioMed Central (London )
                1471-2431
                10 January 2017
                10 January 2017
                2017
                : 17
                : 7
                Affiliations
                [1 ]Department of Pediatrics, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK 8200 Aarhus, Denmark
                [2 ]Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK 8200 Aarhus, Denmark
                [3 ]Department of Public Health, Section for Epidemiology, Aarhus University, Bartholins Allé 2, DK-8000 Aarhus, Denmark
                [4 ]Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK 8200 Aarhus, Denmark
                [5 ]Department of Cardiothoracic surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK 8200 Aarhus, Denmark
                Author information
                http://orcid.org/0000-0003-2464-5703
                Article
                761
                10.1186/s12887-016-0761-0
                5223413
                28068947
                4d6314d9-bbbf-40fc-8c30-56e34122d9e5
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 September 2016
                : 15 December 2016
                Funding
                Funded by: Aarhus University Faculty of Health and The Institute of Clinical Medicine
                Funded by: FundRef http://dx.doi.org/10.13039/501100003035, Aase og Ejnar Danielsens Fond;
                Funded by: Sophus Jacobsen and Astrid Jacobsen Foundation
                Funded by: Kurt Bønnelycke and Grethe Bønnelycke Foundation
                Funded by: Karl G. Anderssons Foundation
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Pediatrics
                acute kidney injury,neutrophil gelatinase-associated lipocalin,patent ductus arteriosus,very preterm neonates

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