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      Intrauterine Growth Restriction following Ligation of the Uterine Arteries Leads to More Severe Glomerulosclerosis after Mesangioproliferative Glomerulonephritis in the Offspring

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          Abstract

          Background: Low birth weight is a risk factor for the development of a more severe course of secondary renal diseases. We tested the hypothesis that experimental mesangioproliferative glomerulonephritis (GN) shows an aggravated course in rats inflicted with experimental uteroplacental insufficiency during gestation. Methods: Intrauterine growth restriction (IUGR) was induced by ligation of both uterine arteries on day 19 in pregnant Wistar rat dams. GN was induced in male offspring at the age of 9 weeks by intravenous injection of an anti-Thy-1.1 antibody. At day 14 of GN, kidneys were taken and analyzed for glomerular morphometry, markers of inflammation, glomerulosclerosis and tubulointerstitial fibrosis. Results: Despite a similar extent of mesangiolysis, former IUGR animals presented with a higher level of glomerulosclerosis and increased deposition of glomerular collagens I and IV compared to nephritic control animals. Arterial blood pressure, renal function, and proteinuria after 14 days of GN were not influenced by former IUGR. Conclusion: Ligation of the uterine arteries in the rat leads to more pronounced sclerotic changes in the glomerulus in the offspring suffering from acute GN. This finding supports the hypothesis that former IUGR increases the susceptibility for a more severe course of secondary renal diseases.

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          Most cited references32

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          Nephron number in patients with primary hypertension.

          A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension. To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents. Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli. The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension. Copyright 2003 Massachusetts Medical Society
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            Glomerular number and size in autopsy kidneys: the relationship to birth weight.

            In the Southeast United States, African Americans have an estimated incidence of hypertension and end-stage renal disease (ESRD) that is five times greater than Caucasians. Higher rates of low birth weight (LBW) among African Americans is suggested to predispose African Americans to the higher risk, possibly by reducing the number of glomeruli that develop in the kidney. This study investigates the relationships between age, race, gender, total glomerular number (Nglom), mean glomerular volume (Vglom), body surface area (BSA), and birth weight. Stereologic estimates of Nglom and Vglom were obtained using the physical disector/fractionator combination for autopsy kidneys from 37 African Americans and 19 Caucasians. Nglom was normally distributed and ranged from 227,327 to 1,825,380, an 8.0-fold difference. A direct linear relationship was observed between Nglom and birth weight (r = 0.423, P = 0.0012) with a regression coefficient that predicted an increase of 257,426 glomeruli per kilogram increase in birth weight (alpha = 0.050:0.908). Among adults there was a 4.9-fold range in Vglom, and in adults, Vglom was strongly and inversely correlated with Nglom (r =-0.640, P = 0.000002). Adult Vglom showed no significant correlation with BSA for males (r = -0.0150, P = 0.936), although it did for females (r = 0.606, P = 0.022). No racial differences in average Nglom or Vglom were observed. Birth weight is a strong determinant of Nglom and thereby of glomerular size in the postnatal kidney. The findings support the hypothesis that LBW by impairing nephron development is a risk factor for hypertension and ESRD in adulthood.
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              Progression of glomerular diseases: is the podocyte the culprit?

              The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2010
                October 2010
                16 August 2010
                : 32
                : 4
                : 287-295
                Affiliations
                Departments of aPediatrics and Adolescent Medicine and bRenal Pathology, University of Erlangen-Nuremberg, Erlangen, and cDepartment of Nephrology, Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University Berlin, Berlin, and dDepartment of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany
                Author notes
                *Christian Plank, MD, Kinder- und Jugendklinik, Universitätsklinikum Erlangen, Loschgestrasse 15, DE–91054 Erlangen (Germany), Tel. +49 9131 853 3118, Fax +49 9131 853 3113, E-Mail christian.plank@uk-erlangen.de
                Article
                319045 Am J Nephrol 2010;32:287–295
                10.1159/000319045
                20714134
                f96e519a-1c7e-47b1-96e2-7142fd782bbd
                © 2010 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
                : 29 March 2010
                : 10 July 2010
                Page count
                Figures: 3, Tables: 4, References: 40, Pages: 9
                Categories
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Collagens,Intrauterine growth restriction,Uterine artery ligation,Thy-1.1 nephritis,Small for gestational age,Glomerulosclerosis

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