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      Pre-Eclampsia: Clinical Manifestations and Molecular Mechanisms

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          Abstract

          Preeclampsia affects 3–5% of pregnancies and can have a significant impact on health for both mother and fetus. Risk factors include maternal co-morbidities such as obesity and chronic hypertension, paternal factors, and genetic factors. New hypertension and proteinuria during the second half of pregnancy are key diagnostic criteria, but the clinical features and associated prognostic implications are somewhat heterogeneous and may reflect different mechanisms of disease. Renal dysfunction and proteinuria correspond to the pathologic finding of glomerular endotheliosis, and generally resolve after cure of preeclampsia through fetal and placenta delivery. The molecular mechanisms behind this disease are being discovered and refined. The initial etiologic agents are currently unknown. Pathologic studies show abnormal development of an ischemic placenta with a high-resistance vasculature, which cannot deliver an adequate blood supply to the fetoplacental unit. Endothelial dysfunction plays a central role in the pathogenesis of the maternal syndrome. Dysfunctional endothelial cells produce altered quantities of vasoactive mediators, which lead to a tip in the balance towards vasoconstriction. An imbalance in circulating angiogenic factors is emerging as a prominent mechanism that mediates the endothelial dysfunction and the clinical signs and symptoms of preeclampsia. Soluble fms-like tyrosine kinase 1 (sFlt1), an endogenous anti-angiogenic factor that is a potent vascular endothelial growth factor (VEGF) antagonist, is highly elevated in preeclampsia. VEGF is not only important in angiogenesis, but also in maintaining endothelial health including the formation of endothelial fenestrae (a hallmark of the glomerular vascular endothelium). sFlt1 overexpression in animals induces glomerular endotheliosis with the loss of endothelial fenestrae that resembles the renal histological lesions of preeclampsia. More severe forms of preeclampsia, including the HELLP syndrome, may be explained by a concomitant elevation in both sFlt1 and soluble endoglin, another anti-angiogenic factor. Unraveling of the molecular mechanisms behind preeclampsia may help to expand our armamentarium to treat patients in a more directed fashion, as current management consists of supportive care and expedited delivery. Finally, long-term outcomes of women with preeclampsia include a significantly increased risk for hypertension and cardiovascular disease, including mortality, which may warrant more aggressive screening and treatment in this population.

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          Circulating angiogenic factors and the risk of preeclampsia.

          The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society
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            A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.

            Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P 0.20 for all comparisons). Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. Copyright 2003 Massachusetts Medical Society
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              Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.

              Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women. We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia ( or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone. Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia. Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                978-3-8055-8311-4
                978-3-318-01479-2
                1660-2110
                2007
                June 2007
                06 June 2007
                : 106
                : 2
                : c72-c81
                Affiliations
                Departments of aMedicine and bObstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass., USA
                Article
                101801 Nephron Clin Pract 2007;106:c72–c81
                10.1159/000101801
                17570933
                e0364edf-992f-49ce-bc89-f8cd0605e700
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 1, References: 83, Pages: 1
                Categories
                Paper

                Cardiovascular Medicine,Nephrology
                Hypertension,Proteinuria,Angiogenesis,Vascular endothelial growth factor,Endotheliosis

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