Ascites and Renal Dysfunction in Liver DiseasePathogenesis, Diagnosis, and Treatment

PERE GINÈSConsultant in Hepatology, Associate Professor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

VICENTE ARROYOProfessor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

JUAN RODÉSProfessor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

ROBERT SCHRIERProfessor of MedicineDivision of Renal Diseases and Hypertension, University of Colorado School of Medicine4200 East 9th Avenue, Denver, CO 80262, USA

SECOND EDITION

Ascites and Renal Dysfunction in Liver DiseasePathogenesis, Diagnosis, and Treatment

Dedicated to our wives, Nuria, Joana, Paula, and Barbara, in recognition of their contribution to our scientifi c careers.

Ascites and Renal Dysfunction in Liver DiseasePathogenesis, Diagnosis, and Treatment

PERE GINÈSConsultant in Hepatology, Associate Professor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

VICENTE ARROYOProfessor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

JUAN RODÉSProfessor of MedicineLiver Unit, University of Barcelona School of Medicine, Hospital Cliníc Villarroel170 8036 Barcelona, Spain

ROBERT SCHRIERProfessor of MedicineDivision of Renal Diseases and Hypertension, University of Colorado School of Medicine4200 East 9th Avenue, Denver, CO 80262, USA

SECOND EDITION

© 1999, 2005 by Blackwell Publishing LtdBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148–5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

The right of the Authors to be identifi ed as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Pat-ents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, with-out the prior permission of the publisher.

First published 1999Second edition 2005

Library of Congress Cataloging-in-Publication DataAscites and renal dysfunction in liver disease / edited by Pere Ginès ... [et al.].-- 2nd ed. p. ; cm.Includes bibliographical references and index.ISBN-13: 978-1-4051-1804-0 (alk. paper)ISBN-10: 1-4051-1804-0 (alk. paper)

1. Liver--Diseases--Complications. 2. Ascites. 3. Kidneys--Diseases.[DNLM: 1. Liver Diseases--complications. 2. Ascites--etiology. 3. Ascites--therapy. 4. Kidney Diseases--etiology. 5. Liver Diseases--physi-opathology. WI 700 A814 2005] I. Ginès, Pere.

RC846.A83 2005616.3’62--dc22

2004026925

ISBN-13: 978-1-4051-1804-0 ISBN-10: 1-4051-1804-0

A catalogue record for this title is available from the British Library

Set in Palatino 9.5/12pt by Sparks, Oxford – www.sparks.co.ukPrinted and bound by Gopsons Papers, Noida, India

Commissioning Editor: Alison BrownDevelopment Editor: Rebecca HuxleyProduction Controller: Kate Charman

For further information on Blackwell Publishing, visit our website:www.blackwellpublishing.com

The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards.

v

Contents

Contributors, viiPreface to the Second Edition, xiii

Part 1 Regulation of Extracellular Fluid Volume and Renal and Splanchnic Circulation

1 Extracellular Fluid Volume Homeostasis, 3Brian D. Poole, William T. Abraham, and Robert W. Schrier

2 Physiology of the Renal Circulation, 15 Roland C. Blantz and Francis B. Gabbai

3 Physiology of the Gastrointestinal Circulation, 29Thomas Petnehazy, Thorsten Vowinkel, and D. Neil Granger

Part 2 Factors Involved in the Pathogenesis of Renal Dysfunction and Ascites in Cirrhosis

4 The Renin–Angiotensin–Aldosterone System in Cirrhosis, 43Mauro Bernardi and Marco Domenicali

5 The Sympathetic Nervous System in Cirrhosis, 54Francis J. Dudley and Murray D. Esler

6 Atrial Natriuretic Peptide and other Natriuretic Factors in Cirrhosis, 73Giorgio La Villa and Giacomo Laffi

7 Arachidonic Acid Metabolites and the Kidney in Cirrhosis, 84Silvia Ippolito and Kevin P. Moore

8 Nitric Oxide and Systemic and Renal Hemodynamic Disturbances in Cirrhosis, 105Manuel Morales-Ruiz and Wladimiro Jiménez

9 Endothelin and Systemic, Renal, and Hepatic Hemodynamic Disturbances in Cirrhosis, 115Veit Gülberg and Alexander L. Gerbes

10 Carbon Monoxide and the Heme Oxygenase System in Cirrhosis, 125Richard W. Lambrecht, Mercedes Fernández, Ying Shan, and Herbert L. Bonkovsky

Part 3 Systemic and Splanchnic Hemo-dynamic Abnormalities in Cirrhosis

11 The Systemic Circulation in Cirrhosis, 139 Søren Møller and Jens Henriksen

12 The Splanchnic Circulation in Cirrhosis, 156Jaime Bosch and Juan Carlos García-Pagán

13 Physiology of Hepatic Circulation in Cirrhosis, 164Roberto J. Groszmann and Mauricio R. Loureiro-Silva

14 Alterations of Hepatic and Splanchnic Microvascular Exchange in Cirrhosis: Local Factors in the Formation of Ascites, 174Jens H. Henriksen and Søren Møller

15 The Heart in Cirrhosis, 186Hongqun Liu and Samuel S. Lee

Part 4 Ascites and Sodium Retention in Cirrhosis

16 Pathogenesis of Sodium Retention in Cirrhosis: the Arterial Vasodilation Hypothesis of Ascites Formation, 201Patricia Fernández de la Llama, Pere Ginès, and Robert W. Schrier

17 Experimental Models of Cirrhosis and Ascites, 215Joan Clària and Wladimiro Jiménez

vi Contents

18 Medical Treatment of Ascites in Cirrhosis, 227Paolo Angeli and Angelo Gatta

19 Paracentesis for Cirrhotic Ascites, 241Rosa María Morillas, Justiniano Santos, Silvia Montoliu, and Ramon Planas

20 Transjugular Intrahepatic Portosystemic Shunt (TIPS) for the Management of Refractory Ascites in Cirrhosis, 251Guadalupe Garcia-Tsao

21 Prognosis of Patients with Cirrhosis and Ascites, 260Mónica Guevara, Andrés Cárdenas, Juan Uríz, and Pere Ginès

22 Liver Transplantation for Patients with Cirrhosis and Ascites, 271Antoni Rimola, Miguel Navasa, Luis Grande, and Juan-Carlos García-Valdecasas

23 A Practical Approach to Treatment of Patients with Cirrhosis and Ascites, 286Andrés Cárdenas and Pere Ginès

24 Etiology, Diagnosis, and Management of Non-cirrhotic Ascites, 294Egbert Frick and Jürgen Schölmerich

Part 5 Hyponatremia and Water Retention in Cirrhosis

25 Pathogenesis of Hyponatremia: the Role of Arginine Vasopressin, 305San-e Ishikawa and Robert W. Schrier

26 Management of Hyponatremia in Cirrhosis, 315Andrés Cárdenas and Pere Ginès

Part 6 Renal Failure and Hepatorenal Syndrome in Liver Disease

27 Pathogenesis of Renal Vasoconstriction in Cirrhosis, 329Mónica Guevara, Rolando Ortega, Pere Ginès, and Juan Rodés

28 Hepatorenal Syndrome in Cirrhosis: Clinical Features, Diagnosis, and Management, 341Vicente Arroyo, Carlos Terra, Aldo Torre, and Pere Ginès

29 Glomerular Disease in Cirrhosis, 360Brian D. Poole, Robert W. Schrier, and Alkesh Jani

30 Drug-induced Renal Failure in Cirrhosis, 372Francesco Salerno and Salvatore Badalamenti

31 Clinical Disorders of Renal Function in Acute Liver Failure, 383John G. O’Grady

32 Renal Dysfunction in Obstructive Jaundice, 394Antonio Sitges-Serra and Javier Padillo

Part 7 Spontaneous Bacterial Peritonitis in Cirrhosis

33 Experimental Models of Spontaneous Bacterial Peritonitis, 411Agustín Albillos, Antonio de la Hera, and Melchor Alvarez-Mon

34 Pathogenesis and Clinical Features of Spontaneous Bacterial Peritonitis, 422José Such, Carlos Guarner, and Bruce Runyon

35 Treatment and Prophylaxis of Spontaneous Bacterial Peritonitis, 434Alejandro Blasco Pelicano and Miguel Navasa

Index, 441

vii

Contributors

William T. AbrahamProfessor of MedicineChief, Division of Cardiovascular MedicineAssociate Director,

Davis Heart & Lung Research InstituteOhio State UniversityColumbus, Ohio, USA

Agustín AlbillosAssociate Professor of MedicineResearch and Development Unit Associated to the

Spanish National Research Council (CSIC)Department of MedicineUniversity of Alcalá School of MedicineGastroenterology DepartmentHospital Universitario Ramón y CajalMadrid, Spain

Melchor Alvarez-Mon Professor of MedicineResearch and Development Unit Associated to the

Spanish National Research Council (CSIC)Department of MedicineUniversity of Alcalá School of MedicineImmune System and Oncology Diseases DepartmentHospital Universitario Príncipe de AsturiasMadrid, Spain

Paolo AngeliDepartment of Clinical and Experimental MedicineUniversity of PaduaPadua, Italy

Vicente ArroyoProfessor of MedicineDirector, Institute for Digestive DiseasesHospital ClinicUniversity of Barcelona School of MedicineBarcelona, Spain

Salvatore BadalamentiChief, Department of Emergency and NephrologyIstituto Clinico HumanitasMilan, Italy

Mauro BernardiProfessor of Internal MedicineDirector, Department of Internal Medicine,

Cardioangiology, HepatologyAlma Mater Studiorum – University of BolognaItaly

Roland C. BlantzUniversity of California, San DiegoLa Jolla, California, USAVA San Diego Healthcare SystemSan Diego, California, USA

Alejandro Blasco PelícanoResearch Fellow Hospital ClinicBarcelona, Spain

Herbert L. BonkovskyProfessor of Medicine and Molecular,

Microbial and Structural Biology Director, General Clinical Research Center Director, The Liver-Biliary-Pancreatic Center MC-1111, University of Connecticut Health Center Farmington, Connecticut, USA

Jaime BoschProfessor of MedicineSenior Consultant Hepatologist and Chief,

Hepatic Hemodynamic Laboratory Liver Unit, IMDM, Hospital Clinic and IDIBAPSUniversity of BarcelonaBarcelona, Spain

viii Contributors

Andrés CárdenasLiver UnitInstitute of Digestive Diseases, Hospital Clinic and

IDIBAPSBarcelona, Spain

Joan ClàriaAssociate Professor University of Barcelona School of MedicineBarcelona, SpainSenior SpecialistHospital ClinicBarcelona, Spain

Antonio de la Hera Scientifi c Member,

Spanish National Research Council (CSIC)Associate Profesor of ImmunologyResearch and Development Unit Associated to the

Spanish National Research Council (CSIC)Department of MedicineUniversity of Alcalá School of MedicineMadrid, Spain

Marco DomenicaliResearch FellowDepartment of Internal Medicine,

Cardioangiology, Hepatology Alma Mater Studiorum – University of BolognaItaly

Francis J. DudleyGastroenterology DepartmentThe Alfred HospitalMelbourne, Victoria, Australia

Murray D. EslerGastroenterology DepartmentThe Baker Medical Research InstitutePrahran, Victoria, Australia

Mercedes FernandezLiver Unit, IDIBAPSHospital Clinic, University of BarcelonaBarcelona, Spain

Patricia Fernández-LlamaRenal Unit and Hypertension Fundacio Puigvert Cartagena, Barcelona, Spain

Egbert FrickChair of Internal MedicineHospital RodingRoding, Germany

Francis B. GabbaiUniversity of California, San DiegoLa Jolla, California, USAVA San Diego Healthcare SystemSan Diego, California, USA

Juan Carlos García-PagánConsultant HepatologistLiver Unit, IMDM, Hospital Clinic and IDIBAPSUniversity of BarcelonaBarcelona, Spain

Guadalupe Garcia-TsaoProfessor of MedicineYale University School of MedicineDepartment of Internal MedicineNew Haven, Connecticut, USA

Juan-Carlos García-ValdecasasDepartment of SurgeryHospital ClinicBarcelona, Spain

Angelo GattaDepartment of Clinical and Experimental MedicineUniversity of PaduaPadua, Italy

Alexander L. GerbesDepartment of Medicine IIKlinikum of the University – GrosshadernMunich, Germany

Pere GinèsChief, Liver UnitAssociate Professor of MedicineInstitute of Digestive Diseases Hospital ClinicUniversity of Barcelona School of MedicineBarcelona, Spain

Luis GrandeLiver Unit and Department of SurgeryHospital ClinicBarcelona, Spain

ixContributors

D. Neil GrangerDepartment of Molecular and Cellular PhysiologyLouisiana State University Health Sciences CenterShreveport, Louisiana, USA

Roberto J. GroszmannProfessor of MedicineYale University School of MedicineDepartment of Internal MedicineNew Haven, Connecticut, USAChief, Digestive Diseases SectionDirector, Hepatic Hemodynamic LaboratoryVA Connecticut Healthcare SystemWest Haven, Connecticut, USA

Carlos GuarnerChief of Liver UnitAssociate Professor of MedicineHospital de la Santa Creu i Sant PauAutonomous UniversityBarcelona, Spain

Mónica GuevaraAssociate InvestigatorHospital Clinic and IDIBAPSUniversity of BarcelonaBarcelona, Spain

Veit GülbergDepartment of Medicine IIKlinikum of the University – GrosshadernMunich, Germany

Jens H. HenriksenProfessor of Clinical PhysiologyUniversity of CopenhagenCopenhagen, DenmarkHead of DepartmentDepartment of Clinical Physiology

and Nuclear MedicineHvidovre HospitalHvidovre, Denmark

Silvia IppolitoResearch FellowCentre for HepatologyRoyal Free & University College Medical SchoolUniversity College of LondonLondon, UK

San-e IshikawaProfessor of MedicineDepartment of MedicineJichi Medical School, Omiya Medical CenterSaitama, Japan

Alkesh JaniAssistant Professor of MedicineUniversity of Colorado Health Sciences CenterDenver, Colorado, USA

Wladimiro JiménezHormonal LaboratoryHospital Clinic, IDIBAPS, IRSINUniversity of BarcelonaBarcelona, Spain

Giorgio La VillaFull Professor of MedicineUniversity of Florence School of MedicineFlorence, Italy

Giacomo LaffiFull Professor of MedicineUniversity of Florence School of MedicineFlorence, Italy

Richard W. LambrechtAssistant Professor of PharmacologyMC-1111, University of Connecticut Health CenterFarmington, Connecticut, USA

Samuel S. LeeProfessor, Department of MedicineLiver UnitUniversity of CalgaryCalgary, Canada

Hongqun LiuAdjunct Assistant ProfessorDepartment of MedicineLiver UnitUniversity of CalgaryCalgary, Canada

Mauricio R. Loureiro-SilvaAssociate Research ScientistYale University School of MedicineDepartment of Internal MedicineNew Haven, Connecticut, USAVA Connecticut Healthcare SystemHepatic Hemodynamic LaboratoryWest Haven, Connecticut, USA

x Contributors

Søren MøllerChief PhysicianUniversity of CopenhagenCopenhagen, DenmarkDepartment of Clinical Physiology and Nuclear

MedicineHvidovre HospitalHvidovre, Denmark

Silvia MontoliuLiver UnitGastroenterology DepartmentHospital Universitari Germans Trias I PujolBadalona, Spain

Kevin P. MooreProfessor of HepatologyCentre for HepatologyRoyal Free & University College Medical SchoolUniversity College of LondonLondon, UK

Manuel Morales-RuizHormonal LaboratoryHospital Clinic, IDIBAPS, IRSINUniversity of BarcelonaBarcelona, Spain

Rosa María MorillasLiver UnitGastroenterology DepartmentHospital Universitari Germans Trias I PujolBadalona, Spain

Miguel NavasaConsultant of the Liver UnitHospital ClinicBarcelona, SpainAssociate Professor of MedicineUniversity of BarcelonaBarcelona, Spain

John O’GradyInstitute of Liver StudiesKing’s College HospitalLondon, UK

Rolando OrtegaCoordinador Unidad de HepatologíaHospital BocagrandeDepartamento de InvestigacionesFacultad de BacteriologíaUniversidad San BuenaventuraCartagena de Indias, Colombia

Javier PadilloAttending SurgeonDepartment of SurgeryHospital Reina SofíaCórdoba, Spain

Thomas Petnehazy Department of Molecular and Cellular PhysiologyLouisiana State University Health Sciences CenterShreveport, Louisiana, USA

Ramon PlanasLiver UnitGastroenterology DepartmentHospital Universitari Germans Trias I PujolBadalona, Spain

Brian PooleFellowUniversity of Colorado Health Sciences CenterDenver, Colorado, USA

Antoni RimolaLiver UnitHospital Clinic Barcelona, Spain

Juan RodésProfessor of MedicineHospital ClinicUniversity of BarcelonaBarcelona, Spain

Bruce A. Runyon Professor of Medicine Chief, Liver Service Loma Linda University Medical Center Loma Linda, California, USA

Francesco SalernoChief, Department of Internal MedicinePoliclinico San DonatoUniversity of MilanMilan, Italy

Justiniano SantosLiver UnitGastroenterology DepartmentHospital Universitari Germans Trias I PujolBadalona, Spain

xiContributors

Jürgen SchölmerichProfessor of MedicineUniversity of RegensburgChair of Department of Internal Medicine IUniversity HospitalRegensburg, Germany

Robert W. SchrierProfessor of MedicineDepartment of MedicineUniversity of Colorado Health Sciences CenterDenver, Colorado, USA

Ying ShanAssistant Professor of MedicineMC-1111, University of Connecticut Health CenterFarmington, Connecticut, USA

Antonio Sitges-SerraProfessor of SurgeryHead, Department of SurgeryHospital del MarBarcelona, Spain

José SuchLiver UnitHospital General UniversitarioAlicante, Spain

Carlos TerraResearch FellowUniversity of Barcelona Medical School

and Institute of Digestive DiseasesHospital ClinicBarcelona, Spain

Aldo TorreResearch FellowUniversity of Barcelona Medical School

and Institute of Digestive DiseasesHospital ClinicBarcelona, Spain

Juan UrízUnidad Aparato de DigestivoServicio Medicina InternaHospital Virgen del CaminoPamplona, Navarra, Spain

Thorsten Vowinkel Department of Molecular and Cellular PhysiologyLouisiana State University Health Sciences CenterShreveport, Louisiana, USADepartment of General SurgeryUniversity Hospital MünsterMünster, Germany

xiii

Preface to the Second Edition

It has been six years since we published the fi rst edition of Ascites and Renal Dysfunction in Liver Disease. Since then, signifi cant advances have been made in the pathogen-esis of circulatory and renal dysfunction that occur in the setting of chronic liver diseases, particularly cirrhosis. Specifi cally, the role of vasodilatory factors, particularly nitric oxide, has been investigated extensively. Moreover, there is increased recognition of the mechanistic role of impaired heart function on the circulatory dysfunction of liver failure. In this second edition of Ascites and Renal Dysfunction in Liver Disease, these advances in patho-genetics are described in specifi c chapters.

Besides this increased knowledge on pathophysiology, major advances have been made in the clinical manage-ment of renal dysfunction in liver disease. A new thera-peutic method, transjugular intravenous portosystemic shunts, has emerged for patients with ascites refractory to diuretic therapy. A large number of nonrandomized studies (as well as several randomized trials) have been published concerning the effects of this therapeutic ap-proach. For the fi rst time ever, an effective treatment has been described to treat hepatorenal syndrome in patients with cirrhosis, namely administration of vasoconstrictor drugs. Moreover, there are studies showing how hepato-renal syndrome can be effectively prevented in specifi c settings such as spontaneous bacterial peritonitis and alcoholic hepatitis. Finally, specifi c antagonists of the V2 vasopressin receptor are in advanced stages of clini-cal development. These drugs might prove to be useful in the management and prevention of dilutional hypo-natremia, a complication for which there is currently no

effective therapy. All these new topics, as well as other topics on the management of liver disease, are covered in this second edition.

The layout and look of the book have changed from the previous edition. The book has been divided into two sections: the fi rst (Parts 1, 2 and 3) describes the patho-physiology of circulatory and renal abnormalities, whilst the second (Parts 4–7) relates to clinical management of patients. We hope this will make the book easier to read when looking for either pathogenic factors or answers to clinical questions.

Finally, we would like to acknowledge the work of the authors of the chapters, who are internationally recog-nised specialists in their fi elds and have done a tremen-dous job in summarizing the different topics inside the page limits. We thank both Nicki van Berckel and Janet Darling for their administrative assistance, and Black-well Publishing for making the book appealing to the readers.

We hope that this second edition of Ascites and Renal Dysfunction in Liver Disease will be helpful not only to clinical researchers interested in complications of cirrho-sis, but also to those clinicians – whether they be gastro-enterologists, transplant hepatologists, nephrologists, or internists – caring for patients with liver diseases.

P. GinèsV. Arroyo

J. RodésR.W. Schrier

2005

Part 1Regulation of Extracellular Fluid Volume and Renal and Splanchnic Circulation

3

Chapter 1Extracellular Fluid Volume Homeostasis

Brian D. Poole, William T. Abraham, and Robert W. Schrier

of water into the extracellular space. Sodium balance is determined by the equilibrium between sodium intake, extrarenal sodium loss, and renal sodium excretion. Prac-tically, renal sodium excretion is the major determinant of sodium balance, given the ability of the kidney to excrete large amounts of sodium in response to a sodium load. In addition, sodium loading, by increasing serum osmo-lality, stimulates the hypothalamic thirst center leading to increased fl uid intake as well as the osmotic release of arginine vasopressin (AVP). The release of AVP from the posterior pituitary decreases water excretion by increas-ing the permeability of the collecting duct epithelium to water. If the increase in ECF volume is suffi cient to alter the Starling forces governing the transfer of fl uid from the vas-cular to the interstitial compartment then edema results.

One of the major regulators of sodium excretion is the mineralocorticoid hormone aldosterone. Aldosterone is produced in the zona glomerulosa of the adrenal gland and acts to increase sodium reabsorption by increasing the number of epithelial sodium channels in the cortical col-lecting duct. In states of volume depletion, the renin–angi-otensin–aldosterone system (RAAS) is stimulated causing an increase in sodium reabsorption that leads to expansion of the ECF. With expansion, the stimulus for aldosterone secretion is removed and sodium reabsorption is dimin-ished, thereby stabilizing volume status. In states of min-eralocorticoid excess such as primary hyperaldosteronism there is unregulated secretion of aldosterone leading to an increase in sodium reabsorption with resultant volume expansion and hypertension. The effect of aldosterone to cause renal sodium retention can be overridden, how-ever, by the phenomenon of aldosterone escape. In this circumstance the ECF reaches a new, higher steady state, but does not continue to expand despite increased levels of aldosterone. This has been postulated to be mediated by hemodynamic mechanisms whereby an increase in renal artery pressure secondary to expansion of the ECF causes a pressure natriuresis. The increase in renal artery pressure subsequently increases the glomerular fi ltration rate (GFR) and the fractional excretion of sodium (FeNa).Recently it was reported that the chief molecular target of the escape phenomenon is the thiazide-sensitive NaCl

The development of ascites is the most common compli-cation in patients with compensated cirrhosis, occurring in 58% of patients within 10 years of diagnosis. Ascites develops in the context of an increase in the extracellular fl uid volume (ECF) and therefore it is essential to under-stand the regulation of body fl uid volume to appreciate its pathogenesis. Knowledge of the intrarenal and extra-renal factors governing renal sodium excretion is crucial to understanding because the sodium ion is the principal determinant of ECF volume. In normal individuals, if the ECF is expanded by the administration of isotonic saline the kidney will excrete the excess sodium and water in the urine and return the ECF to normal values. However, in pathogenic disease states such as congestive heart failure (CHF) and cirrhosis the kidneys continue to retain sodi-um and water even in the presence of an increased ECF volume. In these edematous disorders the integrity of the kidney as the primary organ controlling ECF volume re-mains intact because transplantation of the kidney from an edematous, cirrhotic patient to a subject with normal liver function totally reverses the renal sodium and water retention (1). Moreover, transplantation of a normal liver into a cirrhotic patient with ascites and edema has been shown to abolish the renal sodium and water retention (2). Thus, the kidney must be responding to extrarenal signals from the afferent limb of a volume regulatory system in these edematous disorders. The study of these edematous states has led to a unifying hypothesis of body fl uid vol-ume regulation (3–8). This chapter will review the afferent and efferent mechanisms that contribute to extracellular fl uid volume homeostasis in health and disease.

Regulation of sodium excretion

Due to active transport processes, the sodium ion is pri-marily located in the ECF and, along with its major ani-ons chloride and bicarbonate, constitutes more than 90%of the extracellular solute. Therefore, because sodium and its anions are the major osmotically active substances in the ECF, they are the major determinants of the ECF vol-ume. With a positive sodium balance, the ECF volume will increase secondary to osmotically driven movement

4 Chapter 1

cotransporter. In a rat model of aldosterone infusion cou-pled with a high sodium diet, it was found that levels of the epithelial sodium channel were unchanged during the escape phenomenon, but the amount of the thiazide-sen-sitive NaCl cotransporter was signifi cantly diminished. Therefore it appears that the so-called pressure natriuresis is mediated at least in part by downregulation of the thi-azide-sensitive NaCl cotransporter.

Homeostasis of the ECF is also mediated by the hor-mones atrial natriuretic peptide (ANP) and, as mentioned previously, AVP. ANP has been shown to be released from the myocardium in response to volume expansion and it has two major actions contributing to maintenance of volume status. It is a direct vasodilator that can lower systemic blood pressure and it also increases the urinary excretion of sodium and water. The natriuresis appears to be mediated by an increase in GFR secondary to afferent arteriole vasodilation coupled with efferent arteriole va-soconstriction. Furthermore, ANP has been shown to di-rectly decrease tubular sodium reabsorption. In another rat model of hyperaldosteronism, it has been shown that the level of ANP increases coinciding with an increase in sodium excretion. Therefore the authors postulate that ANP may also mediate aldosterone escape. It is not known whether ANP has an effect on the thiazide-sensi-tive NaCl cotransporter.

AVP is the chief regulator of renal water excretion and as such can be expected to have a major role in ECF vol-ume regulation. It is known that in edematous disorders like CHF and cirrhosis there are inappropriate levels of AVP relative to plasma osmolality that results in water re-tention and hyponatremia. However, it has been shown that there is also counterregulation of this system. In rats administered AVP plus a water load it was shown that after an initial period of water retention there was subse-quently an increase in urine volume that corresponded to a downregulation of the renal water channel aquaporin 2 despite continued elevated levels of AVP. Therefore, the authors conclude there is a vasopressin-independent downregulation of aquaporin 2 and therefore a limit on water reabsorption in this model.

Unlike in conditions such as primary hyperaldos-teronism where there is an escape from continued sodium reabsorption despite elevated levels of aldosterone, in the edematous disorders there is impaired escape and contin-uous sodium and water reabsorption. It seems that the dif-ference in these disorders is in how the kidney is respond-ing to the afferent limb of the volume regulatory system.

Afferent mechanisms governing extracellular fl uid volume homeostasis

An increase in sodium and water intake is associated with an expansion of the extracellular fl uid volume. This includes expansion of the interstitial fl uid and plasma

components of total body fl uid volume. Under normal circumstances, this expansion of total body fl uid volume results in an increase in renal sodium and water excretion followed by restoration of the normal extracellular fl uid volume. However, in patients with edematous disorders, avid sodium and water retention persists despite expan-sion of total extracellular fl uid and blood volume. Thus, the afferent volume receptors governing extracellular fl uid volume must not primarily sense total extracellular fl uid or blood volume. In such instances, there must be some body fl uid compartment that is still inadequately fi lled even in the presence of expansion of these body fl uid compartments.

Effective blood volume and the concept of arterial underfi lling

John Peters fi rst coined the term effective blood volume in al-lusion to the component of blood or body fl uid volume to which the volume regulatory system responds by altering the renal excretion of sodium and water (9). Peters sug-gested that extrarenal signals that enhance tubular sodium and water reabsorption by the otherwise normal kidney are initiated by this decrease in effective blood volume in the setting of cardiac failure or cirrhosis. In support of this claim is the observation that renal sodium and water re-tention can occur in patients with cardiac or liver failure before any decrease in glomerular fi ltration rate.

Borst and deVries (10) fi rst suggested cardiac output as the primary regulator of renal sodium and water excre-tion, thus constituting effective blood volume. While this notion is attractive, there exist several states of sodium and water retention that are associated with an augment-ed rather than a decreased cardiac output. For example, a signifi cant increase in cardiac output may occur in the presence of avid renal sodium and water retention and expansion of extracellular fl uid volume in association with cirrhosis, high-output cardiac failure, pregnancy, and large arteriovenous fi stulae. Hence, cardiac output must not constitute the sole or primary determinant of effective blood volume.

The unifying hypothesis of body fl uid volume regula-tion suggests that the relative integrity or fullness of the arterial circulation constitutes the primary afferent sig-nal through which the kidneys either increase or decrease their excretion of sodium and water (3–8). This theory explains how an increase in the volume of blood on the venous side of the circulation may cause a rise in total blood volume, whereas a decrease in the relative volume of blood in the arterial circulation may promote contin-ued renal sodium and water retention. A reduction in cardiac output is one way in which a decrease in arterial circulatory integrity may occur. However, as mentioned above, diminished cardiac output cannot be the only af-ferent signal for underfi lling of the arterial circulation.

5Extracellular Fluid Volume Homeostasis

The unifying hypothesis of body fl uid volume regula-tion proposes peripheral arterial vascular resistance and the compliance of the arterial vasculature as the second major determinant of the fullness of the arterial circula-tion (3–8). Thus, peripheral arterial vasodilation may provide another afferent signal for arterial underfi lling, which causes renal sodium and water retention.

In summary, either a decrease in cardiac output or pe-ripheral arterial vasodilation may constitute the afferent signal for arterial underfi lling with resultant renal so-dium and water retention that leads to expansion of the

total blood volume. The afferent receptors or sensors of arterial underfi lling must be responsive to small changes in effective arterial blood volume since the steady-state arterial blood pressure is not a sensitive index of the pres-ence of arterial underfi lling. For example, the rapidity of the compensatory response to arterial underfi lling may obscure a fall in blood pressure until this efferent response becomes inadequate to maintain effective arterial blood volume. The mechanisms involved in this volume regu-latory system are summarized in Figs 1.1 and 1.2, and the sensors of arterial underfi lling are discussed next.

Extracellular fluidvolume

Low output cardiac failure,pericardial tamponade,constrictive pericarditis

Intravascular volume2 to diminishedoncotic pressure

orincreasedcapillary

permeabilityCARDIAC OUTPUT

Activation of ventricularand

arterial receptors

Stimulation ofsympathetic nervous

system

PERIPHERAL AND RENALARTERIAL VASCULAR RESISTANCE

MAINTENANCE OF EFFECTIVEARTERIAL BLOOD VOLUME

RENAL WATERRETENTION

RENAL SODIUMRETENTION

Non-osmoticvasopressinstimulation

Activation of therenin-angiotensin-

aldosterone system

High-outputcardiac failure

Sepsis Cirrhosis Arteriovenousfistula

Pregnancy Arterialvasodilators

PERIPHERALARTERIAL VASODILATION

Activation ofarterial

baroreceptors

Stimulation ofsympathetic

nervous system

Non-osmoticvasopressinstimulation

CARDIACOUTPUT

WATERRETENTION

PERIPHERAL ARTERIALVASCULAR AND RENAL

RESISTANCE

SODIUMRETENTION

MAINTENANCE OF EFFECTIVEARTERIAL BLOOD VOLUME

Activation of therenin-angiotensin-

aldosterone systemFigure 1.2 ·Mechanism by which peripheral arterial vasodilation results in renal sodium and water retention, increased cardiac output, and peripheral and renal vasoconstriction. (Reproduced with permission from Schrier R, Niederberger M. Paradoxes of body fl uid volume regulation in health and disease: a unifying hypothesis. West J Med 1994; 16:393–407.)

Figure 1.1 Mechanism by which decreased cardiac output results in renal sodium and water retention and peripheral and renal vasoconstriction. (Reproduced with permission from Schrier R, Niederberger M. Paradoxes of body fl uid volume regulation in health and disease: a unifying hypothesis. West J Med 1994; 16:393–407.)

6 Chapter 1

Sensors of arterial underfi lling

High-pressure baroreceptors

Afferent receptors for this volume regulatory system must reside in the arterial vascular compartment. In this regard, high-pressure baroreceptors in the left ventricle, carotid sinus, aortic arch, and juxtaglomerular apparatus have been implicated as the primary afferent receptors in-volved in the regulation of renal sodium and water excre-tion and extracellular fl uid volume homeostasis (11–19).The presence of volume-sensitive receptors in the arterial circulation in humans was initially suggested by obser-vations made in patients with traumatic arterio venousfi stulae (20). In such patients, closure of the fi stulae re-sults in a decrease in the rate of emptying of the arterial blood into the venous circulation, as demonstrated by closure-induced increases in diastolic arterial pressure and decreases in cardiac output. This increase in arterial fullness produces an immediate increase in renal sodium excretion without changes in either glomerular fi ltration rate or renal blood fl ow (20).

Various denervation experiments also implicate high-pressure volume receptors, and thus the integrity of the arterial circulation, as primary afferent receptors in modu-lating renal sodium and water excretion. In these studies, pharmacological or surgical interruption of sympathetic afferent neural pathways arising from high-pressure areas inhibited the natriuretic response to volume expansion (21–27). In addition, reduction of pressure or stretch at the carotid sinus has been shown to activate the sympathetic nervous system and to cause renal sodium and water re-tention (28,29). High-pressure baroreceptors also appear to be important factors in regulating the non-osmotic release of vasopressin and thus renal water excretion (30,31).

The juxtaglomerular apparatus is a high-pressure re-ceptor located in the afferent arterioles within the kidney. It responds to decreased stretch or increased renal sympa-thetic activity with enhanced secretion of renin (28). Thus, this renal baroreceptor is an important factor in the control of angiotensin II formation and aldosterone secretion and ultimately in the regulation of renal sodium excretion.

Low-pressure baroreceptors

The low-pressure baroreceptors of the thorax, including the atria, right ventricle, and pulmonary vessels, may also contribute to extracellular fl uid volume homeosta-sis. Loading of these volume-sensitive receptors results in enhanced cardiac release of natriuretic peptides (32) and suppression of non-osmotic vasopressin release from the neurohypophysis (33). Since patients with ad-vanced cardiac failure exhibit avid sodium and water re-tention and activation of neurohormonal vasoconstrictor systems—including enhanced non-osmotic vasopressin

release—despite elevated atrial pressures and increased circulating concentrations of the natriuretic peptides, high-pressure baroreceptors must predominate over these low-pressure ones. This observation also supports the primacy of the arterial circulation as the determinant of extracellular fl uid volume homeostasis.

Cardiac and pulmonary chemoreceptors

In the heart and lungs, both vagal and sympathetic affer-ent nerve endings respond to a variety of exogenous and endogenous chemical substances, including capsaicin, phenyldiguanidine, bradykinin, substance P, and prostag-landins (34–36). Since substances such as bradykinin and prostaglandins may circulate at increased concentrations in subjects with edematous disorders (37), it is possible that altered central nervous system input from chemically sensitive cardiac and/or pulmonary afferents contributes to the sodium and water retention characteristic of these disease states. This possibility may have important impli-cations for the treatment of some sodium-retaining disor-ders. For example, in heart failure, commonly prescribed medications such as angio tensin-converting enzyme in-hibitors may alter circulating bradykinin and prostaglan-din levels, thus potentially infl uencing cardiopulmonary chemoreceptor activity. At the present time, however, the exact role of these cardiac and pulmonary chemoreceptors in body fl uid volume regulation remains unknown.

Hepatic receptors

Conceptually, the liver should be in an ideal position to monitor dietary sodium intake and thus adjust urinary sodium excretion. In support of this notion, infusion of sa-line into the portal circulation has been reported to result in a greater natriuresis when compared with peripheral venous saline administration (38,39). Similarly, the in-crease in urinary sodium excretion has been shown to be greater when the sodium load is given orally than when it is given intravenously (40–42). Moreover, the patho-physiological retention of sodium in patients with severe liver disease is also consistent with an important role for the liver in the control of sodium excretion. However, the experimental evidence in favor of hepatic sodium or vol-ume receptors remains controversial since some investi-gators have been unable to confi rm the above observa-tions of increased sodium excretion in response to portal vein or gastric sodium loading (43–45).

In summary, the afferent mechanisms for sodium and water retention appear to be preferentially localized to the arterial or high-pressure side of the circulation, where arterial fullness may serve as the primary determinant of the renal response. Refl exes emanating from low-pres-sure cardiopulmonary receptors may also be altered so as to infl uence renal sodium and water handling in

7Extracellular Fluid Volume Homeostasis

heart failure. In this regard, increases in atrial pressure also stimulate the release of the natriuretic peptides and inhibit vasopressin release, which may be important at-tenuating factors in renal sodium and water retention. At the present time, the role of cardiac and pulmonary chemoreceptors and possibly hepatic volume receptors and osmoreceptors remains unclear.

Efferent mechanisms involved in extracellular fl uid volume homeostasis

The kidney alters the amount of dietary sodium excreted in response to signals from high-pressure and low-pres-sure volume receptors in the circulation. These receptors may affect renal function by altering renal sympathetic nerve activity and by altering levels of circulating hor-mones with vasoactive (renal hemodynamic) and nonva-soactive (direct sodium- and/or water-retaining) effects on the kidney. In addition to the sympathetic neurotrans-mitter norepinephrine, angiotensin II, aldosterone, ar-ginine vasopressin, and other vasoconstrictor hormones may contribute to renal sodium and water retention. Nitric oxide, vasodilating prostaglandins, bradykinin, and the natriuretic peptides may play important coun-terregulatory roles attenuating both the renal vasocon-striction and antinatriuresis caused by norepinephrine, angiotensin II, and other vasoconstrictor hormones.

Renal hemodynamics

The glomerular fi ltration rate is usually normal early in the course of arterial underfi lling and is reduced only as the disease state becomes more advanced. Renal vascular resistance, however, is often increased early, with a con-comitant decrease in renal blood fl ow (46,47). Thus, the ratio of glomerular fi ltration rate to renal blood fl ow, or the fi ltration fraction, is often increased in such patients. This increased fi ltration fraction is a consequence of pre-dominant constriction of the efferent arterioles within the kidney. These changes in renal hemodynamics alter the hydrostatic and oncotic forces in the peritubular capillar-ies to favor increased proximal tubular reabsorption of sodium and water. These renal hemodynamic changes are primarily mediated by the neurohormonal response to arterial underfi lling.

The neurohormonal response to arterial underfi lling

Arterial underfi lling secondary to a diminished cardiac output or to peripheral arterial vasodilation elicits a se-ries of initially compensatory neuroendocrine responses in order to maintain the integrity of the arterial circula-tion by promoting increased cardiac inotropy, periph-eral vasoconstriction, and expansion of the extracellular

fl uid volume through renal vasoconstriction and renal sodium and water retention (Figs 1.1 and 1.2). The three major neurohormonal vasoconstrictor responses to arte-rial underfi lling are activation of the sympathetic nerv-ous system and the RAAS, and the non-osmotic release of vasopressin.

Baroreceptor activation of the sympathetic nervous system appears to be the primary integrator of the hor-monal vasoconstrictor systems involved in renal sodium and water retention, since the non-osmotic release of vasopressin involves sympathetic stimulation of the su-praoptic and paraventricular nuclei of the hypothalamus (48), and activation of the RAAS involves renal β-adren-ergic stimulation (49). In addition, the renin-angiotensin system may provide positive feedback stimulation of the sympathetic nervous system and non-osmotic vaso-pressin release (50), thus indicating that these vasocon-strictor systems may be co-regulated in various patho-physiological states. The effects of these neurohormonal systems on renal hemodynamics and tubular sodium and water handling are discussed below.

The sympathetic nervous system

The sympathetic nervous system is unquestionably acti-vated in patients with arterial underfi lling. In edematous states such as heart failure and cirrhosis, this sympathetic activity has been documented by both indirect (51–61)and direct (62,63) measures. For example, Leimbach etal. (62) in the case of heart failure and Floras et al. (63) in the case of cirrhosis have demonstrated increased central sympathetic outfl ow to skeletal muscle using direct in-traneuronal recordings of the peroneal nerve. Similarly, employing continuous infusion of tritiated norepineph-rine in patients with mild to moderate heart failure or cir-rhosis, whole-body norepinephrine kinetics studies have shown increased norepinephrine secretion rates and nor-mal norepinephrine clearance rates, compatible with ac-tivation of the sympathetic nervous system (55,61). Final-ly, using similar techniques, renal sympathetic activation has been demonstrated in patients with such edematous disorders as heart failure (51). Signifi cantly, the degree of activation of the sympathetic nervous system strongly correlates with disease severity and poor prognosis in both heart failure and cirrhosis (64,65).

Through renal vasoconstriction, stimulation of the RAAS, and direct effects on the proximal convoluted tu-bule, enhanced renal sympathetic activity may contrib-ute to the avid sodium and water retention associated with arterial underfi lling. Indeed, intrarenal adrenergic blockade has been shown to cause a natriuresis in ex-perimental animals and humans with heart failure or cir-rhosis (21,66,67). In the rat, renal nerve stimulation has been demonstrated to produce an approximately 25% reduction in sodium excretion and urine volume (68).

8 Chapter 1

The diminished renal sodium excretion that accompa-nies renal nerve stimulation may be mediated by at least two mechanisms. Studies performed in rats have dem-onstrated that norepinephrine-induced efferent arteri-olar constriction alters peritubular hemodynamic forces in favor of increased tubular sodium reabsorption (69). As previously mentioned, the increase in fi ltration frac-tion with a normal or only slightly reduced glomerular fi ltration rate that is often seen in edematous patients is due to efferent arteriolar constriction. Constriction of the efferent arterioles in such states has been confi rmed by renal micropuncture studies performed in rats (70) and is at least partially mediated by increased renal sympa-thetic activity and also by angiotensin II. Thus, efferent arteriolar constriction in states of arterial underfi lling shifts the balance of hemodynamic forces in the peritu-bular capillaries in favor of enhanced proximal tubular sodium reabsorption.

In addition, renal nerves have been shown to exert a direct infl uence on sodium reabsorption in the proximal convoluted tubule (66,68). Bello-Reuss et al. (68) demon-strated this direct effect of renal nerve activation to en-hance proximal tubular sodium reabsorption in whole-kidney and individual nephron studies in the rat. In these animals, renal nerve stimulation produced an increase in the tubular fl uid to plasma inulin concentration ratio in the late proximal tubule, an outcome of increased frac-tional sodium and water reabsorption in this segment of the nephron (68). Hence, increased renal nerve activity may promote sodium retention by a mechanism inde-pendent of changes in renal hemodynamics.

The renin–angiotensin–aldosterone system

The RAAS is also activated in response to arterial under-fi lling, as assessed by plasma renin activity and plasma aldosterone concentration (71–73). Moreover, activation of the RAAS is associated with hyponatremia and an unfavorable prognosis in edematous disorders (74,75). Angiotensin II may contribute to sodium and water re-tention through direct and indirect effects on proximal tubular sodium reabsorption and by stimulating the re-lease of aldosterone from the adrenal gland. Angiotensin II causes renal efferent vasoconstriction, resulting in decreased renal blood fl ow and an increased fi ltration fraction. As with renal nerve stimulation, this results in increased peritubular capillary oncotic pressure and re-duced peritubular capillary hydrostatic pressure, which favor the reabsorption of sodium and water in the proxi-mal tubule (70,76). In addition, angiotensin II has been shown to have a direct effect of enhancing sodium reab-sorption in the proximal tubule (77). Finally, angiotensin II enhances aldosterone secretion by the adrenal gland, which promotes tubular sodium reabsorption in the cor-tical and medullary ducts.

A role for aldosterone in the renal sodium retention of human heart failure has been demonstrated (78). The ef-fect of spironolactone on urinary sodium excretion was examined in patients with mild to moderate heart failure, who were withdrawn from all medications prior to study. Sodium was retained in all subjects throughout the period prior to aldosterone antagonism (Fig. 1.3). On an average sodium intake of 97 ± 8 mmol/day, the average sodium excretion before spironolactone was 76 ± 8 mmol/day. During therapy with spironolactone, all heart failure pa-tients demonstrated a signifi cant increase in urinary sodi-um excretion to 131 ± 13 mmol/day. Moreover, the urine sodium concentration to potassium concentration ratio signifi cantly increased during spironolactone administra-tion, consistent with a decrease in aldosterone action in

Net Na+

balancebefore

spironolactone

Net Na+

balanceafter

spironolactone

(mmol)

(mmol)

60

40

20

20

–20

–40

–60

0

0

1 2 3

1 2 3 4

Day

Figure 1.3 Reversal of sodium retention in heart failure patients during aldosterone antagonism. (Top) Net cumulative positive sodium balance, by day, for the period before spironolactone administration. (Bottom) Net cumulative negative sodium balance with spironolactone 400 mg/day. P < 0.01 for increase in sodium excretion with aldosterone antagonism. (Reproduced with permission from Hensen J, Abraham WT, Durr JA et al. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991; 11:441.)

9Extracellular Fluid Volume Homeostasis

the distal nephron. Similarly, there also have been reports of natriuresis occurring in cirrhosis after the administra-tion of spironolactone (79). The near-uniform response to spironolactone in cirrhosis suggests that the high plasma levels of aldosterone frequently seen in these subjects con-tribute to the increased distal sodium reabsorption.

The non-osmotic release of vasopressin

Elevated plasma vasopressin levels have been demon-strated in patients with heart failure and cirrhosis and correlate with the clinical and hemodynamic sever-ity of disease and with the serum sodium concentration (80–89). Through the use of a single intravenous bolus technique, we determined vasopressin clearance to be normal in six patients with mild to moderate heart fail-ure (unpublished observations). Moreover, plasma va-sopressin concentrations are inappropriately elevated in hyponatremic patients with heart failure or cirrhosis, and these levels fail to suppress normally with acute water loading (82,84,85), suggesting that the enhanced release of vasopressin in these settings is due to non-osmotic stimulation. As already suggested, baroreceptor activa-tion of the sympathetic nervous system probably medi-ates this non-osmotic release of vasopressin in states of arterial underfi lling.

Arginine vasopressin, via stimulation of its renal or V 2receptor, enhances water reabsorption in the cortical and medullary collecting ducts. Two lines of evidence impli-cate non-osmotic vasopressin release in the abnormal water retention seen in the edematous disorders. First, in animal models of heart failure, the absence of a pituitary source of vasopressin is associated with normal or near-normal water excretion (17,90). This observation was fi rst made by Anderson and colleagues in the dog dur-ing acute thoracic vena caval constriction (17). In these animals, acute removal of the pituitary source of vaso-pressin by surgical hypophysectomy virtually abolished the defect in water excretion. Abnormal water excretion occurring in the rat with high-output cardiac failure due to aortocaval fi stula also appears to be the result of abnor-mal vasopressin release, since the defect is not demon-strable in rats with central diabetes insipidus (90). The second line of evidence supporting a role for vasopressin in the water retention of heart failure and cirrhosis may be found in studies of selective V2 receptor antagonists. These agents have been shown to reverse the impairment in water excretion in animal models of cardiac failure and cirrhosis and in human heart failure (91–95). Thus, while diminished fl uid delivery to the distal diluting segment may also contribute to the abnormal water excretion seen in states of arterial underfi lling, increased vasopressin appears to exert the predominant effect.

In summary, baroreceptor activation of the three major neurohormonal vasoconstrictor systems is involved in

the avid renal sodium and water retention characteristic of the edematous disorders. Increased adrenergic nerv-ous system activity in response to arterial underfi lling ap-pears to orchestrate this neurohormonal response. Renal nerves, angiotensin II, aldosterone, and vasopressin all may play a role as important effector mechanisms in the abnormal retention of sodium and water.

While the aforementioned neuroendocrine systems conspire to promote sodium and water retention in states of arterial underfi lling, counterregulatory vasodilatory or natriuretic substances may attenuate, to some degree, this neurohormonal vasoconstrictor activation. Chief among these are the natriuretic peptides and vasodilat-ing prostaglandins.

The natriuretic peptides

The natriuretic peptides, including atrial natriuretic pep-tide (ANP) and brain natriuretic peptide (BNP), circulate at increased concentrations in patients with heart fail-ure (96–98) and in some patients with cirrhosis (99,100). These peptide hormones possess natriuretic, vasorelax-ant, and renin-, aldosterone-, and possibly vasopressin- and sympathoinhibiting properties (101–106). In normal humans, ANP and BNP increase glomerular fi ltration rate and urinary sodium excretion with no change or only a slight fall in renal blood fl ow (107,108). The changes in renal hemodynamics are probably mediated by afferent arteriolar vasodilation with constriction of the efferent arterioles, as discerned by micropuncture studies in the rat (109,110). In addition to increasing glomerular fi ltra-tion rate and fi ltered sodium load as a mechanism of their natriuretic effect, ANP and BNP are specifi c inhibitors of sodium reabsorption in the collecting tubule (111–113).

Despite the above observations, the natriuretic ef-fects of these peptide hormones are blunted in states of arterial underfi lling such as heart failure and cirrhosis (107,114–116). Possible mechanisms for natriuretic pep-tide resistance in heart failure and cirrhosis include: (i) downregulation of renal natriuretic peptide receptors; (ii) secretion of biologically inactive, immunoreactive ANP or BNP; (iii) enhanced renal neutral endopeptidase activity that degrades natriuretic peptides, thus limiting the delivery of ANP and BNP to distal nephron recep-tor sites; (iv) hyperaldosteronism causing an increased sodium reabsorption in the distal renal tubule; (v) intra-cellular mechanisms, including increased phosphodi-esterase activity; and (vi) diminished delivery of sodium to the distal renal tubule site of natriuretic peptide ac-tion. According to the unifying hypothesis of body fl uid volume regulation, arterial underfi lling results in renal vasoconstriction, decreased renal perfusion pressure, and activation of the sympathetic and renin–angiotensinsystems. These renal hemodynamic and neurohormonal changes then decrease the glomerular fi ltration rate and

10 Chapter 1

increase proximal tubular sodium reabsorption, thereby resulting in diminished distal tubular sodium delivery that may explain the blunted natriuretic response to ANP and BNP (3–8). This notion is supported by several obser-vations. In sodium-retaining patients with heart failure, a strong positive correlation between levels of plasma ANP and urinary cyclic guanosine monophosphate [the second messenger for the natriuretic effect of ANP in vivo(117)] has been reported, supporting the active biologi-cal responsiveness of renal ANP receptors in heart failure (118). Further, in cirrhosis, maneuvers that increase dis-tal tubular sodium delivery have been shown to reverse ANP resistance (119). Finally, distal tubular sodium de-livery has been reported to be the most potent predictor of renal responsiveness to BNP in heart failure patients (Fig. 1.4) (115).

Renal prostaglandins

In normal subjects and in intact animals, renal prostag-landins do not regulate renal sodium excretion or renal hemodynamics to any signifi cant extent (120,121). In pa-

tients with heart failure or cirrhosis, vasodilating pros-taglandins appear to play an important role in the main-tenance of renal blood fl ow and glomerular fi ltration. For example, inhibition of prostaglandin synthesis in decompensated cirrhotic patients decreases renal blood fl ow, glomerular fi ltration rate, sodium excretion, and solute-free water excretion and impairs the natri uretic response to furosemide or spironolactone (122,123). In-fusion of prostaglandin E1 has been shown to reverse these decreases in renal hemodynamics observed after prostaglandin inhibition (123). Similar observations have been made in patients with chronic heart failure (124). These fi ndings support a counterregulatory role for va-sodilating prostaglandins in the regulation of body fl uid volume in patients with heart failure and cirrhosis.

Summary

The various neurohormonal systems activated in re-sponse to diminished effective arterial blood volume infl uence changes in renal hemodynamics and directly affect tubular sodium and water handling, resulting in an avid sodium- and water-retaining state in an attempt to restore the integrity of the arterial circulation. Activa-tion of neurohormonal vasoconstrictor systems appears to be mediated primarily by high-pressure baroreceptor stimulation of the sympathetic nervous system, leading to activation of the RAAS and the non-osmotic release of vasopressin, in response to arterial underfi lling. Coun-terregulatory vasodilator and natriuretic hormones, such as the natriuretic peptides and vasodilating prostaglan-dins, are also activated in edematous states such as heart failure and cirrhosis. These hormones may serve to atten-uate to some degree the antinatriuretic and antidiuretic effects of vasoconstrictor hormone activation.

References 1· Koppel MH, Coburn JW, Mims MM et al. Transplantation

of cadaveric kidneys from patients with hepatorenal syndrome: evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med 1969; 280:1367 .

2· Iwatsuki S, Popovtzer MM, Corman JL et al. Recovery from hepatorenal syndrome after orthotopic liver transplantation. N Engl J Med 1973; 289:1155.

3· Schrier RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. N Engl J Med 1988; 319:1065.

4· Schrier RW. Body fl uid volume regulation in health and disease: a unifying hypothesis. Ann Intern Med 1990; 113:155.

5· Schrier RW. A unifying hypothesis of body fl uid volume regulation: the Lilly lecture 1992. J Royal Coll Physicians Lond 1992; 26:295.

6· Schrier RW. An odyssey into the milieu interieur: pondering

300r = 0.98p = 0.0001

200

100

–100–10

Change in urinary lithium clearance(ml/min)

0 10 20 30 40

0

Changein

UNa

(mmol/min)

V•

Figure 1.4 Correlation between the natriuretic response to infused brain natriuretic peptide and the change in distal tubular sodium delivery in heart failure patients. UNaV,urinary sodium excretion. (Reproduced with permission from Abraham WT, Lowes BD, Ferguson DA et al. Systemic hemodynamic, neurohormonal, and renal excretory effects of a steady-state infusion of human brain natriuretic peptide in patients with decompensated chronic heart failure. J Card Fail 1998; 4:1.)

11Extracellular Fluid Volume Homeostasis

the enigmas. J Am Soc Nephrol 1992; 2:1549. 7· Schrier RW, Arroyo V, Bernardi M et al. Peripheral arterial

vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8:1151.

8· Abraham WT, Schrier RW. Body fl uid regulation in health and disease. In: Schrier RW, Abboud FM, Baxter JD, Fauci AS, eds. Advances in Internal Medicine, Vol. 39. Chicago: Mosby Year Book, 1994; 23.

9· Peters JP. The role of sodium in the production of edema. N Engl J Med 1948; 239:353.

10· Borst JG, deVries LA. Three types of ‘natural’ diuresis. Lancet 1950; 2:1.

11· Goetz KL, Bond GC, Bloxham DD. Atrial receptors and renal function. Physiol Rev 1975; 55:157.

12 Zucker IH, Earle AM, Gilmore JP. The mechanism of adaptation of left atrial stretch receptors in dogs with chronic congestive heart failure. J Clin Invest 1977; 60:323.

13· Schrier RW, Lieberman RA, Ufferman RC. Mechanism of antidiuretic effect of beta adrenergic stimulation. J Clin Invest 1972; 51:97.

14· Schrier RW, Berl T. Mechanism of effect of alpha-adrenergic stimulation with norepinephrine on renal water excretion. J Clin Invest 1973; 52:502.

15· Berl T, Cadnapaphornchai P, Harbottle JA et al. Mechanism of suppression of vasopressin during alpha-adrenergic stimulation with norepinephrine. J Clin Invest 1974; 53:219.

16· Berl T, Cadnapaphornchai P, Harbottle JA et al. Mechanism of stimulation of vasopressin release during beta adrenergic stimulation with isoproterenol. J Clin Invest 1974; 53:857.

17· Anderson RJ, Cadnapaphornchai P, Harbottle JA etal. Mechanism of effect of thoracic inferior vena cava constriction on renal water excretion. J Clin Invest 1974; 54:1473.

18· Anderson RJ, Pluss RG, Berns AS et al. Mechanism of effect of hypoxia on renal water excretion. J Clin Invest 1978; 62:769.

19· Schrier RW, Berl T. Mechanism of antidiuretic effect of interruption of parasympathetic pathways. J Clin Invest 1972; 51:2613.

20· Epstein FH, Post RS, McDowell M. Effects of an arteriovenous fi stula on renal hemodynamics and electrolyte excretion. J Clin Invest 1953; 32:233.

21· Schrier RW, Humphreys MH. Factors involved in the antinatriuretic effects of acute constriction of the thoracic inferior and abdominal vena cava. Circ Res 1971; 29:479.

22· Schrier RW, Humphreys MH, Ufferman RC. Role of cardiac output and the autonomic nervous system in the antinatriuretic response to acute constriction of the thoracic superior vena cava. Circ Res 1971; 29:490.

23· Gilmore JP. Contribution of baroreceptors to the control of renal function. Circ Res 1964; 14:301.

24· Gilmore JP, Daggett WM. Response of chronic cardiac denervated dog to acute volume expansion. Am J Physiol 1966; 210:509.

25· Knox FG, Davis BB, Berliner RW. Effect of chronic cardiac denervation on renal response to saline infusion. Am J Physiol 1967; 213:174.

26· Pearce JW, Sonnenberg H. Effects of spinal section and renal denervation on the renal response to blood volume expansion. Can J Physiol Pharmacol 1965; 43:211.

27· Schedl HP, Bartter FC. An explanation for and experimental correction of the abnormal water diuresis in cirrhosis. J Clin Invest 1967; 46:1297.

28· Davis JO. The control of renin release. Am J Med 1973; 55:333.

29· Guyton A, Scanlon CJ, Armstrong GG. Effects of pressoreceptor refl ex and Cushing’s refl ex on urinary output. Fed Proc 1952; 11:61.

30· Schrier RW, Berl T, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol 1979; 236:F321.

31· Schrier RW, Berl T, Anderson RJ et al. Nonosmolar control of renal water excretion. In: Andreoli T, Grantham J, Rector F, eds. Disturbances in Body Fluid Osmolality. Bethesda, MD: American Physiological Society, 1977; 149–178.

32· Bichet DG, Schrier RW. Cardiac failure, liver disease and nephrotic syndrome. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney, 4th edn. Boston: Little Brown & Co, 1988; 2703.

33· de Torrente A, Robertson GL, McDonald KM et al.Mechanism of diuretic response to increased left atrial pressure in the anesthetized dog. Kidney Int 1975; 8:355.

34· Baker DG, Coleridge HM, Coleridge JCG et al. Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat. J Physiol 1980; 306: 519.

35· Panzenbeck MJ, Tan W, Hajdu MA et al. PGE2 and arachidonate inhibit the barorefl ex in conscious dogs via cardiac receptors. Am J Physiol 1989; 256:H999.

36· Zucker IH, Panzenbeck MJ, Barker S et al. PGI2 attenuates the barorefl ex control of renal nerve activity by an afferent vagal mechanism. Am J Physiol 1988; 254:R424.

37· Dzau VJ, Packer M, Lilly LS et al. Prostaglandins in severe congestive heart failure: relation to activation of the renin–angiotensin system and hyponatremia. N Engl J Med 1984; 310:347.

38· Daly JJ, Roe JW, Horrocks PA. Comparison of sodium excretion following the infusion of saline into systemic and portal veins in the dog: evidence for hepatic role in the control of sodium excretion. Clin Sci 1967; 33:481.

39· Passo SS, Thornborough JR, Rothballer AB. Hepatic receptors in control of sodium excretion in anesthetized cats. Am J Physiol 1975; 224:373.

40· Carey RM, Smith JR, Ortt EM. Gastrointestinal control of sodium excretion in sodium-depleted conscious rabbits. Am J Physiol 1976; 230:1504.

41· Carey RM. Evidence for a splanchnic sodium input monitor regulating renal sodium excretion in man: lack of dependence upon aldosterone. Circ Res 1978; 43:19.

42· Lennane RJ, Peart WS, Carey RW et al. A comparison of natriuresis after oral and intravenous sodium loading in sodium depleted rabbits: evidence for a gastrointestinal or portal monitor of sodium intake. Clin Sci Mol Med 1975; 49:433.

43· Potkay S, Gilmore JP. Renal response to vena caval and portal venous infusions of sodium chloride in unanesthetized dogs. Clin Sci Mol Med 1970; 39:13.

44· Schneider EG, Davis JO, Robb CA et al. Lack of evidence for a hepatic osmoreceptor in conscious dogs. Am J Physiol 1970; 218:42.

45· Obika LFO, Fitzgerald EM, Gleason SD et al. Lack of evidence for gastrointestinal control of sodium excretion

12 Chapter 1

in unanesthetized rabbits. Am J Physiol 1981; 240:F94. 46· Merrill AJ. Mechanism of salt and water retention in heart

failure. Am J Med 1949; 6:357. 47· Epstein M, Pins DS, Schneider N et al. Determinants of

deranged sodium and water homeostasis in decompensated cirrhosis. J Lab Clin Med 1976; 87:822.

48· Sklar AH, Schrier RW. Central nervous system mediators of vasopressin release. Physiol Rev 1983; 63:1243.

49· Berl T, Henrich WL, Erickson AL et al. Prostaglandins in the beta adrenergic and baroreceptor-mediated secretion of renin. Am J Physiol 1979; 235:F472.

50· Bristow MR, Abraham WT. Anti-adrenergic effects of angiotensin converting enzyme inhibitors. Eur Heart J 1995; 16 (Suppl. K):37.

51· Hasking GJ, Esler MD, Jennings GL et al. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986; 73:615.

52· Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978; 41:233.

53· Levine TB, Francis GS, Goldsmith SR et al. Activity of the sympathetic nervous system and renin–angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49:1659.

54· Davis D, Baily R, Zelis R. Abnormalities in systemic norepinephrine kinetics in human congestive heart failure. Am J Physiol 1988; 254:E760.

55· Abraham WT, Hensen J, Schrier RW. Elevated plasma noradrenaline concentrations in patients with low-output cardiac failure: dependence on increased noradrenaline secretion rates. Clin Sci 1990; 79:429.

56· Henriksen JH, Christensen JJ, Ring-Larsen H. Noradrenaline and adrenaline concentrations in various vascular beds in patients with cirrhosis: relation to hemodynamics. Clin Physiol 1981; 1:293.

57· Bichet DG, van Putten VJ, Schrier RW. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N Engl J Med 1982; 307:1552.

58· Pérez-Ayuso RM, Arroyo V, Camps J et al. Evidence that renal prostaglandins are involved in renal water metabolism in cirrhosis. Kidney Int 1984; 26:72.

59· Arroyo V, Planas R, Gaya J et al. Sympathetic nervous activity, renin–angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion. Eur J Clin Invest 1983; 13:271.

60· Ring-Larsen H, Hesse B, Henriksen JH et al. Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction and renal release. Hepatology 1982; 2:304.

61· Nicholls KM, Shapiro MD, Van Putten VJ et al. Elevated plasma norepinephrine concentration in decompensated cirrhosis: association with increased secretion rates, normal clearance rates, and suppressibility by central blood volume expansion. Circ Res 1985; 56:457.

62· Leimbach WN, Wallin BG, Victor RG et al. Direct evidence from intraneural recordings for increased central sympathetic outfl ow in patients with heart failure. Circulation 1986; 73:913.

63· Floras JS, Legault L, Morali GA et al. Increased sympathetic outfl ow in cirrhosis and ascites: direct evidence from

intraneural recordings. Ann Intern Med 1991; 114:373. 64· Cohn JN, Levine BT, Olivari MT et al. Plasma norepinephrine

as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819.

65· Bichet DG, van Putten VJ, Schrier RW. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N Engl J Med 1982; 307:1552.

66· DiBona GF. Neurogenic regulation of renal tubular sodium reabsorption. Am J Physiol 1977; 233:F73.

67· Gill JR, Mason DT, Bartter GC. Adrenergic nervous system in sodium metabolism: effects of guanethidine and sodium-retaining steroids in normal man. J Clin Invest 1964; 43:177.

68· Bello-Reuss E, Trevino DL, Gottschalk CW. Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest 1976; 57:1104.

69· Meyers BD, Deen WM, Brenner BM. Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafi ltration and proximal tubule fl uid reabsorption in the rat. Circ Res 1975; 37:101.

70· Ichikawa I, Pfeffer JM, Pfeffer MA et al. Role of angiotensin II in the altered renal function in congestive heart failure. Circ Res 1984; 55:669.

71· Francis GS, Benedict C, Johnstone EE et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the studies of left ventricular dysfunction (SOLVD). Circulation 1990; 82:1724.

72· Merrill AJ, Morrison JL, Brannon ES. Concentration of renin in renal venous blood in patients with chronic heart failure. Am J Med 1946; 1:468.

73· Watkins L, Burton JA, Haber E et al. The renin–angiotensin–aldosterone system in congestive heart failure in conscious dogs. J Clin Invest 1976; 57:1606.

74· Dzau VJ, Packer M, Lilly LS et al. Prostaglandins in severe congestive heart failure: relation to activation of the renin–angiotensin system and hyponatremia. N Engl J Med 1984; 310:347.

75· Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modifi cation by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986; 73:257.

76· Ichikawa I, Brenner BM. Importance of efferent arteriolar vascular tone in regulation of proximal tubule fl uid reabsorption and glomerulotubular balance in the rat. J Clin Invest 1980; 65:1192.

77· Liu F-Y, Cogan MG. Angiotensin II: a potent regulator of acidifi cation in the rat early proximal convoluted tubule. J Clin Invest 1987; 80: 272.

78· Hensen J, Abraham WT, Durr JA et al. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991; 11:441.

79· Eggert RC. Spironolactone diuresis in patients with cirrhosis and ascites. Br Med J 1970; 4:401.

80· Szatalowicz VL, Arnold PE, Chaimovitz C et al.Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med 1981; 305:263.

81· Bichet DG, Kortas C, Mettauer B et al. Modulation of plasma and platelet vasopressin by cardiac function in patients with heart failure. Kidney Int 1986; 29:1188.

82· Riegger GAJ, Liebau G, Koschiek K. Antidiuretic hormone

13Extracellular Fluid Volume Homeostasis

in congestive heart failure. Am J Med 1982; 72:49. 83· Pruszczynski W, Vahanian A, Ardailou R et al. Role of

antidiuretic hormone in impaired water excretion of patients with congestive heart failure. J Clin Endocrinol Metab 1984; 58: 599.

84· Goldsmith SR, Francis GS, Cowley AW Jr. Arginine vasopressin and the renal response to water loading in congestive heart failure. Am J Cardiol 1986; 58:295.

85· Bichet D, Szatalowicz VL, Chaimovitz C et al. Role of vasopressin in abnormal water excretion in cirrhotic patients. Ann Intern Med 1982; 96:413.

86· Arroyo V, Rodés J, Guitierrez-Lizarraga MA et al. Prog-nostic value of spontaneous hyponatremia in cirrhosis with ascites. Dig Dis 1976; 21:249.

87· Ralli EP, Leslie SH, Stuek GH et al. Studies of the serum and urine constituents in patients with cirrhosis of the liver during water tolerance tests. Am J Med 1951; 11:157.

88· Reznick RK, Langer B, Taylor BR et al. Hyponatremia and arginine vasopressin secretion in patients with refractory hepatic ascites undergoing peritoneovenous shunting. Gastroenterology 1983; 84:713.

89· Salerno F, DelBo A, Maggi A et al. Vasopressin release and water metabolism in patients with cirrhosis. J Hepatol 1994; 21:822.

90· Handelman W, Lum G, Schrier RW. Impaired water excretion in high output cardiac failure in the rat. Clin Res 1979; 27:173A.

91· Ishikawa S, Saito T, Okada K et al. Effect of vasopressin antagonist on water excretion in inferior vena cava constriction. Kidney Int 1986; 30:49.

92· Yared A, Kon V, Brenner BM et al. Role for vasopressin in rats with congestive heart failure. Kidney Int 1985; 27:337.

93· Claria J, Jiménez W, Arroyo V et al. Blockade of the hydroosmotic effect of vasopressin normalizes water excretion in cirrhotic rats. Gastroenterology 1989; 97:1294.

94· Tsuboi Y, Ishikawa SE, Fujisawa G et al. Therapeutic effi cacy of the nonpeptide AVP antagonist OPC-31260 in cirrhotic rats. Kidney Int 1994; 46:237.

95· Abraham WT, Oren RM, Robertson AD et al. Effects of an oral, nonpeptide, selective V2 receptor AVP antagonist in human heart failure. Nephrology 1997; 3 (Suppl. 1):S15.

96· Burnett JC Jr, Kao PC, Hu C et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 1986; 231:1145.

97· Nakaoka H, Imataka K, Amano M et al. Plasma levels of atrial natriuretic factor in patients with congestive heart failure. N Engl J Med 1985; 313:892.

98· Raine AEG, Erne P, Bürgisser E et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med 1986; 315:533.

99· Ginès P, Jiménez W, Arroyo V et al. Atrial natriuretic factor in cirrhosis with ascites: plasma levels, cardiac release and splanchnic extraction. Hepatology 1998; 8:636.

100· Panos MZ, Anderson JV, Payne N et al. Plasma atrial natriuretic peptide and reninaldosterone in patients with cirrhosis and ascites: basal levels, changes during daily activity and nocturnal diuresis. Hepatology 1992; 16:82.

101· Atlas SA, Kleinert HD, Camargo MJ et al. Purifi cation, sequencing, and synthesis of natriuretic and vasoactive rat atrial peptide. Nature 1984; 309:717.

102· Currie MG, Geller DM, Cole BR et al. Bioactive cardiac substances: potent vasorelaxant activity in mammalian

atria. Science 1983; 221:71.103· Molina CR, Fowler MB, McCrory S et al. Hemodynamic,

renal, and endocrine effects of atrial natriuretic peptide in severe heart failure. J Am Coll Cardiol 1988; 12:175.

104· Atarashi K, Mulrow PJ, Franco-Saenz R et al. Inhibition of aldosterone production by an atrial extract. Science 1984; 224:992.

105· Samson WK. Atrial natriuretic factor inhibits dehydration and hemorrhage-induced vasopressin release. Neuroendo-crinology 1985; 40:277.

106· Floras JS. Sympathoinhibitory effects of atrial natriuretic factor in normal humans. Circulation 1990; 81:1860.

107· Cody RJ, Atlas SA, Laragh JH et al. Atrial natriuretic factor in normal subjects and heart failure patients: plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest 1986; 78:1362.

108· Biollaz J, Nussberger J, Porchet M et al. Four-hour infusion of synthetic atrial natriuretic peptide in normal volunteers. Hypertension 1986; 8:II96.

109· Borenstein HB, Cupples WA, Sonnenberg H et al. The effect of natriuretic atrial extract on renal hemodynamics and urinary excretion in anesthetized rats. J Physiol 1983; 334:133.

110· Dunn BR, Ichikawa I, Pfeffer JM et al. Renal and systemic hemodynamic effects of synthetic atrial natriuretic peptide in the anesthetized rat. Circ Res 1986; 58:237.

111· Kim JK, Summer SN, Dürr J et al. Enzymatic and binding effects of atrial natriuretic factor in glomeruli and nephrons. Kidney Int 1989; 35:799.

112· Koseki C, Hayashi Y, Torikai S et al. Localization of binding sites for alpha-rat atrial natriuretic polypeptide in rat kidney. Am J Physiol 1986; 250:F210.

113· Healy DP, Fanestil DD. Localization of atrial natriuretic peptide binding sites within the rat kidney. Am J Physiol 1986; 250:F573.

114· Hoffman A, Grossman E, Keiser HR. Increased plasma levels and blunted effects of brain natriuretic peptide in rats with congestive heart failure. Am J Hypertens 1991; 4:597–601.

115· Abraham WT, Lowes BD, Ferguson DA et al. Systemic hemodynamic, neurohormonal, and renal excretory effects of a steady-state infusion of human brain natriuretic peptide in patients with decompensated chronic heart failure. J Card Fail 1988; 4:1.

116· Salerno F, Badalamenti S, Incerti P et al. Renal response to atrial natriuretic peptide in patients with advanced liver cirrhosis. Hepatology 1988; 8:21.

117· Huang C-L, Ives HE, Cogan MG. In vivo evidence that cGMP is the second messenger for atrial natriuretic factor. Proc Natl Acad Sci USA 1986; 83:8015.

118· Abraham WT, Hensen J, Kim JD et al. Atrial natriuretic peptide and urinary cyclic guanosine monophosphate in patients with congestive heart failure. J Am Soc Nephrol 1992; 2:697.

119· Abraham WT, Lauwaars ME, Kim JK et al. Reversal of atrial natriuretic peptide resistance by increasing distal tubular sodium delivery in patients with decompensated cirrhosis. Hepatology 1995; 22:737.

120· Swain JA, Heyndrickx GR, Boettcher DH et al. Prostaglandin control of renal circulation in the unanesthetized dog and baboon. Am J Physiol 1975; 229:826.

121· Walker RM, Brown RS, Stoff JS. Role of renal prostaglandins

14 Chapter 1

during antidiuresis and water diuresis in man. Kidney Int 1981; 21:365.

122· Arroyo V, Planas R, Gaya J et al. Sympathetic nervous activity, renin–angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion. Eur J Clin Invest 1983; 13:271.

123· Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin A1 on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979; 77:215.

124· Riegger GA, Kahles HW, Elsner D et al. Effects of acetylsalicylic acid on renal function in patients with chronic heart failure. Am J Med 1991; 90:571.