Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Relationship of Neutrophil Gelatinase-associated Lipocalin (NGAL) and Procalcitonin Levels with the Presence and Severity of the Preeclampsia (NGAL & PCT in preeclampsia) Burcu Artunc Ulkumen, Yesim Guvenc, Asli Goker, Ceyhun Gozukara doi: 10.3109/14767058.2014.972926 Abstract

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Objective: The aim of the present study was to evaluate changes in maternal serum Neutrophil Gelatinase-associated Lipocalin (NGAL) and procalcitonin (PCT) concentrations in preeclampsia. Material and method: This case-control study consisted of 40 preeclamptic and 40 healthy singleton pregnancies matched for age and body mass index. Serum NGAL and PCT levels were compared between the groups. Diagnostic performance and clinical association of these markers were evaluated. Results: NGAL and PCT concentrations were significantly higher in preeclamptic group (p< 0.0001 and p= 0.001, respectively) and their levels were correlated with the severity of the preeclampsia. There were significant positive correlation between these markers and mean arterial pressure (MAP) and spot urine protein excretion. There was negative correlation between NGAL and apgar scores and fetal birth weight. Pregnancies with higher NGAL (OR: 4.89; 95% CI: 1.81-13.21) and higher PCT (OR:6.67; 95% CI:2.44-18.21) concentrations had higher risk for preeclampsia. Conclusion: NGAL and PCT may be potential biomarkers for preeclampsia. Their levels increase significantly in preeclampsia and they are related to the severity of the disease. These results are in agreement with the generalized endothelial damage and persistant inflammatory status in preeclampsia. NGAL may be also an indicator for adverse neonatal outcomes with decreased placental hypoperfusion.

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Relationship of Neutrophil Gelatinase-associated Lipocalin (NGAL) and Procalcitonin Levels with the Presence and Severity of the Preeclampsia (NGAL & PCT in preeclampsia)

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Burcu Artunc Ulkumen*, Yesim Guvenc**, Asli Goker*, Ceyhun Gozukara*

*Celal Bayar University, School of Medicine, Department of Obstetrics and Gynecology, Manisa, Turkey. ** Celal Bayar University, School of Medicine, Department of Biochemistry, Manisa, Turkey.

Key Words: Preeclampsia, Inflammation, Neutrophil Gelatinase-associated Lipocalin (NGAL), Procalcitonin. Corresponding Author: Burcu Artunc Ulkumen Department/Institution: Obstetrics and Gynecology, Celal Bayar University School of Medicine Obstetrics and Gynecology-Perinatology Department, Manisa, Turkey Address: Celal Bayar University Hafsa Sultan Hospital Uncubozkoy/Manisa City/State/Zip/Country: Manisa, 45210, Turkey Phone: 902362333040 Cell Phone: 905324144162 Fax: 902364652434

e-mail: [email protected] Abstract: Objective: The aim of the present study was to evaluate changes in maternal serum Neutrophil J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 10/17/14 For personal use only.

Gelatinase-associated

Lipocalin

(NGAL)

and

procalcitonin

(PCT)

concentrations

in

preeclampsia. Material and method: This case-control study consisted of 40 preeclamptic and 40 healthy singleton pregnancies matched for age and body mass index. Serum NGAL and PCT levels were compared between the groups. Diagnostic performance and clinical association of these markers were evaluated. Results: NGAL and PCT concentrations were significantly higher in preeclamptic group (p< 0.0001 and p= 0.001, respectively) and their levels were correlated with the severity of the preeclampsia. There were significant positive correlation between these markers and mean arterial pressure (MAP) and spot urine protein excretion. There was negative correlation between NGAL and apgar scores and fetal birth weight. Pregnancies with higher NGAL (OR: 4.89; 95% CI: 1.81-13.21) and higher PCT (OR:6.67; 95% CI:2.44-18.21) concentrations had higher risk for preeclampsia. Conclusion: NGAL and PCT may be potential biomarkers for preeclampsia. Their levels increase significantly in preeclampsia and they are related to the severity of the disease. These results are in agreement with the generalized endothelial damage and persistant inflammatory status in preeclampsia. NGAL may be also an indicator for adverse neonatal outcomes with decreased placental hypoperfusion.

Key words: NGAL, procalcitonin, preeclampsia, pregnancy. Introduction: Preeclampsia is defined as a clinical condition which is characterized by new onset J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 10/17/14 For personal use only.

hypertension and proteinuria after 20 gestational weeks and still continues to be an important factor for maternal morbidity and mortality as well as perinatal morbidity and mortality (1). The incidence varies from 2% to 8% according to the selected population (2). The placenta is the prerequisite for the development of preeclampsia; and hereby, the delivery of the placenta is the only final treatment (3). The proper timing of the delivery is crucial: it should not be too early for the baby and also not too late for the possible complications. In other words, the clinician should weigh the prematurity risks against the possible maternal and neonatal complications. Therefore, recent studies were interested in new possible biomarkers for the early prediction of preeclampsia in order to have better pregnancy outcomes. Neutrophil Gelatinase-associated Lipocalin (NGAL) is a member of lipocalin family whose increase may be alarming for subsequent developing preeclampsia (4). NGAL (also called siderocalin, uterocalin or lipocalin-2) is a 25 kDa sized protein which was firstly detected as a matrix protein in human neutrophiles (5). Then it was discovered that NGAL was secreted also from other tissues such as renal tubular cells, cells belonging to immune system, hepatocytes and adipocytes (4). NGAL levels increase in inflammatory conditions, neoplastic transformation, renal damage or case of dysfunctional epithelial cells (6). The inflammatory status and generalized epithelial damage were thought to be main reason to incease the NGAL levels in preeclampsia (5,6).

Procalcitonin (PCT) is a polypeptide precursor of calcitonin, which takes part in calcium homeostasis. PCT has a half-life between 25-30 hours and is produced by parafollicular cells (C cells) of the thyroid and by the neuroendocrine cells of the lung and the intestine (7). PCT has

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been widely used in clinical practice as it is being known as a new marker in sepsis (7,8). Furthermore, PCT levels has been used recently as indicators for severity assessment and follow up of systemic inflammations mainly induced by microbial infection (9). The fact that the maternal impact of preeclampsia arises from exaggerated maternal systemic inflammatory response inspired us to hypotesize that PCT levels should increase in preeclampsia. To the best of our knowledge, there are only three studies published in order to discover the relation between PCT and preeclampsia (10-12). Preeclampsia is characterised with a systemic persistant inflammation (10). We hypothesized that NGAL and PCT levels would increase in preeclampsia as a part of maternal exaggerated immune response to the ongoing inflammatory status. To the best of our knowledge, our study is the first to evaluate the alterations of both markers in preeclampsia. Materials and methods: This case-control study is consisted of 40 preeclamptic and 40 healthy singleton pregnancies admitted to our clinic between December 2012 and October 2013. Informed consent was signed by all the participants of the study. The institutional ethics committee approved the study. 40 healthy normotensive pregnant women were randomly selected among patients who hospitalised for labor during the latent phase. Women with chronic diseases such as chronic hypertension, chronic renal or hepatic disorder, connective tissue disorders, diabetes mellitus, thrombophilia or pregnancies with multiple fetuses or congenital fetal anomaly were excluded

from the study. Patients with premature rupture of membranes, chorioamnionitis, urinary system infection, pulmonary infection or any sign of another infection were not included in the study. The sample size was calculated with power analysis. With assuming the effect size (d) 0.7

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and α-error 0.05, the power of the study was 80% with the sample size of 40 for each group. The diagnosis of preeclampsia was made on the criteria of American College of Obstetrics and Gynecology (13): the hypertension after 20 gestational week (systolic blood pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg on at least 2 occasions 4-6 hours apart, but no more than 7 days apart) and significant proteinuria (≥300 mg/24 h or ≥1+ on dipstick reading on at least 2 occasions 4-6 hours apart, but no more than 7 days apart). Gestational age (GA) was evaluated with the last menstrual period and confirmed by the early first trimester ultrasonography scans. In the study group, serum samples for NGAL and PCT were obtained when the patients first hospitalized for the evaluation and before any medical treatment such as magnesium sulfate, antenatal corticosteroids were initiated. In control group, maternal venous blood was sampled at the morning (8:00-10:00 AM) after an overnight fasting. The blood sample was centrifuged at 4000 rpm at +4 °C for 15 minutes. The serum samples were discreted into eppendorf tubes and stored at -80°C until the day of analysis. NGAL and PCT analysis was performed for all patients in the study. Quantitative measurement of serum NGAL levels was performed by Human Lipocalin2/NGAL Immunoassay Quantikine ELISA kit ( R&D Systems, Inc., Minneapolis, USA). The mean minimum detectable dose (MDD) was 0.012 ng/mL (0.003-0.040 ng/mL). Three samples of known concentration were tested twenty times on one plate to assess intra-assay precision

(%3.6, %3.1, %4.4). Three samples of known concentration were tested in forty separate assays to assess inter-assay precision (%7.9,%6.1,%5.6). Quantitative measurement of serum PCT levels was performed via immunoanalyzer

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system (Cobas e 411 ,Roche Hitachi,Japan) by using the assays of Elecsys Brahms, Germany. The sensitivity of PCT assay was

Relationship of neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin levels with the presence and severity of the preeclampsia.

The aim of the present study was to evaluate changes in maternal serum neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin (PCT) conce...
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