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मुख्य Urinary Tract Stone Disease
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Urinary Tract Stone Disease P. Nagaraja Rao • Glenn M. Preminger John P. Kavanagh Editors Urinary Tract Stone Disease Editors P. Nagaraja Rao, Ch.M., F.R.C.S (Ed) Formerly Director Total Stone Management Centre University Hospital of South Manchester Manchester, UK Currently Visiting Professor of Urology NTR University of Health Sciences Vijayawada, India Glenn M. Preminger Division of Urologic Surgery Duke University Medical Center Durham, NC, USA John P. Kavanagh Department of Urology University Hospital of South Manchester Manchester, UK ISBN 978-1-84800-361-3 e-ISBN 978-1-84800-362-0 DOI 10.1007/978-1-84800-362-0 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2010937973 © Springer-Verlag London Limited 2011 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface The surgical management of urinary sto; ne disease has advanced quite dramatically since the introduction of shock wave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), ureteroscopy (URS), and more recently retrograde intrarenal surgery (RIRS) with small, flexible fiber-optic ureteroscopes. As a result, "cutting for stones" has become a rare procedure. These minimally invasive techniques are now used in the pediatric population as well with great safety and success. In the practice of medicine, it is far more important to prevent a disease than try to treat it once the symptoms have manifested. In this respect, our understanding on how stones form has also advanced significantly, particularly in the last decade. It is also being recognized that while it is possible to remove the stones with minimal morbidity, it is far better and more economical if stones can be prevented. Given such advances, there is the need for a "text book" that brings together all aspects of urinary stone disease, and we have been fortunate to be able to recruit experts and opinion leaders from 15 countries across the globe to contribute. The book consists of 60 chapters divided into nine sections. The first three sections are devoted to basic sciences on subjects ranging from epidemiology of urinary calculi to shock wave physics. The fourth section deals with diagnostic, laboratory, and research methods in the diagnosis and investigation of stones. Stone disease in children is dealt with in Chap. 5 followed by three sections on surgical management of stones. Finally there is an entire section on medical management of stones. Most of the chapters are highly illustrated with diagrams, photographs, and X-rays. We believe that this is the most comprehensive reference book on urinary stones currently available. In a work of this nature, there is bound to be some overlap between some of the chapters. However, this only enhances the information provided rather than being repetitive. We hope that this book would be of value and interest to urological surgeons, physicians with an interest in urolithiasis, scientists with a research interest as well as other health care professionals dealing with stones. P. Nagaraja Rao Glenn M. Preminger John P. Kavanagh v Contents Part I Basic Sciences 1 Epidemiology............................................................................................................ Gary C. Curham 3 2 Genetics and Molecular Biology of Renal Stones.................................................. Giovanni Gambaro, Laura Soldati, and Giuseppe Vezzoli 9 3 Physicochemical Aspects of Uro-crystallization and Stone Formation............... John P. Kavanagh 17 4 The Possible Roles of Inhibitors, Promoters, and Macromolecules in the Formation of Calcium Kidney Stones......................................................... Rosemary Lyons Ryall 31 Renal Cellular Dysfunction/Damage and the Formation of Kidney Stones....................................................................................................... Saeed R. Khan 61 5 6 Interaction of Stone Components with Cells and Tissues.................................... Jack G. Kleinman 87 7 Randall's Plaques..................................................................................................... Michel Daudon, Olivier Traxer, James C. Williams Jr, and Dominique C. Bazin 103 8 Dietary Factors......................................................................................................... Roswitha Siener 113 9 Obesity, Metabolic Syndrome, and Stones............................................................ Bernhard Hess 125 10 Stone Disease in Animals......................................................................................... Doreen M. Houston, Andrew Moore, Denise A. Elliott, and Vincent C. Biourge 131 11 Pathogenesis of Stones: Summary of Current Concepts...................................... Allen Rodgers 151 vii Contents viii Part II Basic Sciences 12 Calcium Metabolism and Hypercalciuria.............................................................. George E. Haleblian and Glenn M. Preminger 159 13 Vitamin D Metabolism and Stones......................................................................... Joseph E. Zerwekh 169 14 Urinary Citrate and Citrate Metabolism............................................................... Bernhard Hess 181 15 Uric Acid Metabolism and Uric Acid Stones......................................................... Khashayar Sakhaee 185 16 Oxalate Metabolism and the Primary Hyperoxalurias......................................................................................................... Christopher J. Danpure 195 17 Cystinuria and Cystine Stones................................................................................ Patrick Krombach, Gunnar Wendt-Nordahl, and Thomas Knoll 207 18 Urinary Infection and Struvite Stones................................................................... Sean P. Stroup and Brian K. Auge 217 19 Drug-Induced Renal Stones.................................................................................... Michel Daudon and Paul Jungers 225 20 Endemic Bladder Stones......................................................................................... Narmada P. Gupta and Anup Kumar 239 21 Economic Implications of Medical and Surgical Management........................... Walter Ludwig Strohmaier 245 Part III Basic Sciences 22 What Are Shock Waves?......................................................................................... Achim M. Loske 253 23 Extracorporeal Shock Wave Lithotriptors............................................................ Kai Uwe Köhrmann and Jens Rassweiler 263 24 Biological Effects Produced by High-Energy Shock Waves................................. Yifei Xing, Eric C. Pua, W. Neal Simmons, F. Hadley Cocks, Michael Ferrandino, Glenn M. Preminger, and Pei Zhong 279 25 Intracorporeal Nonlaser Lithotripsy...................................................................... Jorge Gutierrez-Aceves, Oscar Negrete-Pulido, and Marnes Molina-Torres 293 Contents ix 26 Laser Lithotripsy Physics........................................................................................ Andrew J. Marks, Jinze Qiu, Thomas E. Milner, Kin Foong Chan, and Joel M.H. Teichman 27 Alternative Laser Energy Sources: Clinical Implications................................................................................................ Andreas J. Gross and Thorsten Bach Part IV 301 311 Diagnostic and Laboratory Methods 28 Imaging for Stones................................................................................................... Alison J. Bradley and P. Nagaraja Rao 319 29 Urinary Stone Analysis............................................................................................ Gernot Schubert 341 30 Risk Indices.............................................................................................................. Norbert Laube and Lisa Kleinen 355 31 Blood and Urinary Tests in Stone Formers........................................................... Michelle Jo Semins and Brian R. Matlaga 369 32 Crystallization and Other Studies.......................................................................... Dirk J. Kok 375 33 Experimental Models for Investigation of Stone Disease........................................................................................................ Kemal Sarica 34 Clinical Trials in Stone Disease............................................................................... Loris Borghi, Umberto Maggiore, Antonio Nouvenne, and Tiziana Meschi Part V 383 391 Pediatric Stone Disease 35 Epidemiology of Pediatric Urolithiasis.................................................................. José Manuel Reis-Santos and Alberto Trinchieri 409 36 Metabolic Stone Disease in Children...................................................................... Kemal Sarica and Mustafa Berber 421 37 The Role of Minimally Invasive Techniques.......................................................... Ben Thomas and David Tolley 431 Part VI Surgical Management I 38 Indications for Surgical Removal, Including Asymptomatic Stones................... J. Graham Young and Francis X. Keeley 441 Contents x Part VII Extracorporeal Shock Wave Lithotripsy 39 Renal Stones............................................................................................................. Tamer El-Husseiny, Athanasios Papatsoris, Junaid Masood, and Noor N.P. Buchholz 455 40 Extracorporeal Shock Wave Lithotripsy for Ureteral Stones.............................. Jay D. Raman and Margaret S. Pearle 469 Part VIII Surgical Management II: Endoscopy 41 Percutaneous Nephrolithotomy.............................................................................. Mahesh Desai and Stephanie J. Symons 481 42 Ureteroscopy for Ureteric Stones............................................................................ Amy E. Krambeck and James E. Lingeman 497 43 Indications for and Technique of Retrograde Intrarenal Surgery for Renal Stones....................................................................................................... Gregory S. Rosenblatt and Gerhard J. Fuchs 509 44 Urolithiasis in Pregnancy........................................................................................ Chandra Shekhar Biyani, Mary Garthwaite, and Adrian D. Joyce 525 45 Surgical Management of Urolithiasis in Transplanted Kidneys.......................... Yehoshua Gdor and J. Stuart Wolf, Jr. 537 46 Stents and Stenting.................................................................................................. Reem Al-Bareeq and John D. Denstedt 543 47 Flexible Ureterorenoscopy: Tips and Tricks......................................................... Olivier Traxer 553 48 Training Implications for Stone Management...................................................... Aldrin Joseph R. Gamboa and Elspeth M. McDougall 577 Part IX Surgical Management III: Open Surgery 49 Open Surgery to Remove Stones: When and How?............................................. Gunnar Wendt-Nordahl, Thomas Knoll, and Peter Alken 591 50 Autotransplantation and Ureteric Replacement: In Whom and How?.............. Jack M. Zuckerman and Dean G. Assimos 601 51 Liver and Renal Transplantation in Primary Hyperoxaluria............................. Katharine V. Jamieson and Katharine A. Jamieson 617 52 Chemolytic Treatment of Patients with Urinary Tract Stones............................ Hans-Göran Tiselius 627 Contents xi Part X Medical Management 53 Establishment and Management of a Stone Clinic............................................... William G. Robertson 641 54 Medical Expulsive Therapy.................................................................................... Kim Davenport and Francis X. Keeley 651 55 Metabolic Investigations: When and in Whom..................................................... David S. Goldfarb 659 56 Medical Management of Idiopathic Calcium Stone Disease................................ Samuel P. Sterrett and Stephen Y. Nakada 667 57 Medical Management: Uric Acid and Cystine Stones.......................................... Khashayar Sakhaee 673 58 Medical Management of Struvite Stones............................................................... Tarık Esen and Tayfun Oktar 681 59 Dietary Assessment and Advice.............................................................................. Roswitha Siener and Albrecht Hesse 687 60 Stone Management in the Presence of Morbid Obesity....................................... Aaron Potretzke and Manoj Monga 695 Index.................................................................................................................................. 707 Contributors Reem Al-Bareeq, M.D., F.R.C.S.I., C.A.B.U. Department of Urology, The University of Western Ontario, London, ON, Canada Peter Alken, M.D. Department of Urology, University Clinic Mannheim, Heidelberg Medical School, Mannheim, Germany Dean G. Assimos, M.D. Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Brian K. Auge, M.D., F.A.C.S. Department of Urology, Naval Medical Center San Diego, San Diego, CA, USA Thorsten Bach, M.D. Department of Urology, Asklepios Hospital Barmbek, Hamburg, Germany Dominique C. Bazin, Ph.D. Laboratoire de Physique des Solides, Bat 510, Université Paris XI, Orsay, France Mustafa Berber, M.D. Department of Pediatrics, Yeditepe University Hospital, Istanbul, Turkey Vincent C. Biourge, D.V.M., Ph.D., Diplomate A.C.V.N. & E.C.V.C.N. Health and Nutrition Scientific Director, Royal Canin, Centre de Recherche, BP4, 650 Avenue de la Petite Camargue, Aimargues, 30470, France Chandra Shekhar Biyani, M.B.B.S., M.S. (Gen Surg), D.Urol., F.R.C.S. (Urol), F.E.B.U. Department of Urology, Pinderfields General Hospital, Wakefield, West Yorkshire, UK Loris Borghi, M.D. Department of Clinical Sciences, University of Parma, Parma, Italy Alison J. Bradley, M.B., Ch.B., M.R.C.P., F.R.C.R. Department of Radiology, University Hospital of South Manchester, Manchester, Lancashire, UK Noor N.P. Buchholz, M.B.B.S., M.D., F.S.S.U., F.K.N.M.G. Department of Urology, Barts and The London NHS Trust, London, UK Kin Foong Chan, Ph.D. Reliant Technologies, Inc., Mountain View, CA, USA F. Hadley Cocks, B.S., M.S., Ph.D. Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA xiii xiv Gary C. Curham, M.D., Sc.D. Department of Medicine and Epidemiology, Brigham and Women's Hospital, Harvard Medical School/Harvard School of Public Health, Boston, MA, USA Christopher J. Danpure, B.Sc., Ph.D. Department of Cell and Developmental Biology, University College London, London, UK Michel Daudon, Ph.D. Department of Biochemistry, Stone Laboratory, Necker Hospital, Paris, France Kim Davenport, M.D., F.R.C.S. (Urol) North Bristol NHS Trust, Bristol Urological Institute, Bristol, Avon, UK John D. Denstedt, M.D. Division of Urology, The University of Western Ontario, London, ON, Canada Mahesh Desai, M.S., F.R.C.S. (Eng.), F.R.C.S. (Edinburgh) Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India Tamer El-Husseiny, M.B.B.Ch., M.Sc. (Urol), M.R.C.S. (Ed) Department of Urology, Barts and the London NHS Trust, London, UK Denise A. Elliott, B.V.S.C. (Hons), Ph.D., Dipl. A.C.V.I.M., Dipl. A.C.V.N. Department of Research and Development, Royal Canin, Aimarges, France Tarık Esen, M.D. Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey Michael Ferrandino, M.D. Division of Urology and Department of Surgery, Duke University Medical Center, Zootrent Drive, DUMC 2803, Durham, North Carolina, 27713, USA Gerhard J. Fuchs, M.D., F.A.C.S. Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Giovanni Gambaro, M.D., Ph.D. Dipartimento di Medicina Interna e di Scienze Mediche Specialistiche, Università Cattolica del Sacro Cuore, Rome, Italy Aldrin Joseph R. Gamboa, M.D. Department of Urology, University of California, Irvine, UCI Medical Center, Paranaque City, Philippines Mary Garthwaite, M.B.B.S., Ph.D., F.R.C.S. (Urol) Department of Urology, St James' University Hospital, Leeds, West Yorkshire, UK Yehoshua Gdor, M.D. Department of Urology, University of Michigan Health System, Ann Arbor, MI, USA David S. Goldfarb, M.D. Nephrology Section, New York Harbor VA Medical Center, New York, NY, USA Andreas J. Gross, M.D. Department of Urology, Asklepios Hospital Barmbek, Hamburg, Germany Narmada P. Gupta, M.S., M.Ch., D.Sc. Department of Urology, All India Institute of Medical Sciences, New Delhi, India Jorge Gutierrez-Aceves, M.D. Department of Urology, Hospital Civil Nuevo, Universidad de Guadalajara, Guadalajara, México Contributors Contributors xv George E. Haleblian, M.D. Division of Urology, The Warren School of Brown University, Rhode Island Hospital, Providence, RI, USA Bernhard Hess, M.D. Department of Internal Medicine & Nephrology/Hypertension, Klinik Im Park, Zurich, Switzerland Albrecht Hesse, M.D. Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Bonn, Germany Doreen M. Houston, D.V.M., D.V.Sc., Diplomate A.C.V.I.M. (Internal Medicine) Division of Scientific Communication and Clinical Trials, Medi-Cal Royal Canin Veterinary Diets, Guelph, ON, Canada Katharine A. Jamieson, M.A., B.M.B.Ch. Department of Paediatrics, North London Deanery, London, UK Katharine V. Jamieson, M.A., M.D., F.R.C.S. Department of Transplantation Surgery, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK Adrian D. Joyce, M.S., F.R.C.S., (Urol) Pyrah Department of Urology, St. James' University Hospital, Leeds, West Yorkshire, UK Paul Jungers, M.D. Department of Nephrology, Necker Hospital, Paris, France John P. Kavanagh, Ph.D. Department of Urology, University Hospital of South Manchester, Manchester, UK Francis X. Keeley, M.D., F.R.C.S. (Urol) Department of Urology, Southmead Hospital, Bristol, UK Saeed R. Khan, M.Sc., Ph.D. Departments of Pathology and Urology, University of Florida, College of Medicine, Gainesville, FL, USA Lisa Kleinen, Dipl. Phys. Kaiserslautern University of Technology, Institute of Thin Film Technology, Rheinbreitbach, Germany Jack G. Kleinman, M.D. Department of Nephrology, Veterans Affairs Medical Center and the Medical College of Wisconsin, Milwaukee, WI, USA Thomas Knoll, M.D., Ph.D., M.Sc. Department of Urology, Sindelfingen-Böblingen Medical Center, Sindelfingen, Germany Kai Uwe Köhrmann, M.D. Department of Urology, Theresienkrankenhaus, Mannheim, Germany Dirk J. Kok, Ph.D. Department of Pediatric Urology, Erasmus Medical Center, Rotterdam, The Netherlands Amy E. Krambeck, M.D. Department of Urology, Mayo Clinic Rochester, Rochester, MN, USA Patrick Krombach, M.D. Urologische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany xvi Anup Kumar, M.Ch. (Urol) Department of Urology, All India Institute of Medical Sciences, New Delhi, India Norbert Laube, Ph.D. Medizinisches Zentrum Bonn Friedensplatz, Academic Teaching Center of the University of Bonn, Bonn, Germany James E. Lingeman, M.D. Department of Research, Methodist Hospital Institute for Kidney Stone Disease, Indianapolis, IN, USA Achim M. Loske, Ph.D. Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autónoma de México, Querétaro, México Umberto Maggiore, M.D. Department UO Nefrologia, Azienda Ospedaliero – Universitaria di Parma, Parma, Italy Andrew J. Marks Division of Urology, Department of Urologic Sciences, St. Paul's Hospital, Providence Healthcare, University of British Columbia, Vancouver, BC, Canada Junaid Masood, M.B.B.S., F.R.C.S. (Eng), M.Sc. (Urol), F.R.S.C. (Urol) Department of Urology, Barts and the London NHS Trust, London, UK Brian R. Matlaga, M.D., M.P.H. James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD, USA Elspeth M. McDougall, M.D., F.R.C.S.C., M.H.P.E. Department of Urology, UCI Medical Center, Orange, CA, USA Tiziana Meschi, M.D. Department of Clinical Sciences, University of Parma, Parma, Italy Thomas E. Milner, Ph.D. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA Marnes Molina-Torres, M.D. Instituto de Endourología, Centro Medico Puerta de Hierro and Nuevo Hospital Civil, Zapopan, Jalisco, México Manoj Monga, M.D., F.A.C.S. Department of Urologic Surgery, University of Minnesota, Minneapolis, MN, USA Andrew Moore, B.Sc., M.Sc. Canadian Veterinary Urolith Centre, University of Guelph, Laboratory Services, Guelph, ON, Canada Stephen Y. Nakada, M.D. Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Oscar Negrete-Pulido, M.D. Instituto de Endourología, Centro Medico Puerta de Hierro and Nuevo Hospital Civil, Zapopan, Jalisco, México Antonio Nouvenne, M.D. Department of Clinical Sciences, University of Parma, Parma, Italy Contributors Contributors xvii Tayfun Oktar Istanbul Faculty of Medicine Department of Urology, Division of Pediatric Urology, Istanbul University, Istanbul, Turkey Athanasios Papatsoris, M.D., M.Sc., Ph.D., F.E.B.U. Department of Urology, Barts and The London NHS Trust, London, UK Margaret S. Pearle, M.D., Ph.D. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA Aaron Potretzke, M.D. Department of Urology, University of Minnesota Medical Center, Minneapolis, MN, USA Glenn M. Preminger, M.D. Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA Eric C. Pua Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA Jinze Qiu, M.A. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA Jay D. Raman, M.D. Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA P. Nagaraja Rao, Ch.M., F.R.C.S. (Ed) Formerly Director, Total Stone Management Centre, University Hospital of South Manchester, Manchester, UK; Currently Visiting Professor of Urology, NTR University of Health Sciences, Vijayawada, India Jens Rassweiler Department of Urology, SLK Kliniken Heilbronn GMBH, Heilbronn, Germany José Manuel Reis-Santos, M.D. Faculdade De Engenharia, Universidade Católica Portuguesa, Rio de Mouro, Portugal William G. Robertson, Ph.D., D.Sc. Department of Physiology (Centre for Nephrology), Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Allen Rodgers, M.Sc., Ph.D. Department of Chemistry, University of Cape Town, Cape Town Western Cape, South Africa Gregory S. Rosenblatt, M.D. Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Rosemary Lyons Ryall, B.Sc. (Hons), Ph.D., D.Sc. Department of Surgery, Flinders Medical Centre and Flinders University, 5042, Adelaide, SA, Australia Khashayar Sakhaee, M.D. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA xviii Kemal Sarica, M.D. Department of Urology, University of Yeditepe, Medical School, Istanbul, Turkey Gernot Schubert Dipl. Kristallograph Institute of Laboratory Diagnostics, Vivantes Klinikum im Friedrichshain, Berlin, Germany Michelle Jo Semins, M.D. The Brady Urological Institute, The Johns Hopkins Medical Institution, Baltimore, MD, USA Roswitha Siener, Ph.D. Department of Urology, University of Bonn, Bonn, Germany W. Neal Simmons Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA Laura Soldati, Ph.D. Department of Medicine, Surgery, and Dentistry, Università degli Studi di Milano, Milano, Italy Samuel P. Sterrett, DO Department of Urology, University of Wisconsin, Madison, WI, USA Walter Ludwig Strohmaier, M.D., Ph.D., F.E.B.U. Department of Urology and Paediatric, RegioMed, Klinikum Coburg, Coburg, Bayern, Germany Sean P. Stroup, M.D. Department of Urology, Naval Medical Center San Diego, San Diego, CA, USA Stephanie J. Symons, F.R.C.S. (Urol) Department of Urology, Pinderfields General Hospital, Wakefield, West Yorkshire, UK Joel M.H. Teichman, M.D., F.R.C.S. Department of Urologic Sciences, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada Ben Thomas, M.D., F.R.C.S. (Urol) Department of Urology, Western General Hospital, Scottish Lithotripter Centre, Edinburgh, UK Hans-Göran Tiselius, M.D., Ph.D. Department of Urology, Karolinska University Hospital Huddinge, Stockholm, Sweden David Tolley, M.B., F.R.C.S., F.R.C.S. (Ed) Department of Urology, Western General Hospital, Scottish Lithotripter Centre, Edinburgh, UK Olivier Traxer, M.D. Department of Urology, Hôpital Tenon, Paris, France Alberto Trinchieri, M.D. Department of Urology, Lecco, Italy Giuseppe Vezzoli Istituto Scientifico San Raffaele, Università Vita Salute, Milan, Italy Contributors Contributors xix Gunnar Wendt-Nordahl, M.D. Department of Urology, Sindelfingen-Böblingen Medical Center, Sindelfingen, Germany James C. Williams, Jr. Ph.D. Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA J. Stuart Wolf, Jr. M.D. Department of Urology, The University of Michigan, Ann Arbor, MI, USA Yifei Xing Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA J. Graham Young, M.A., B.M., B.Ch., Ph.D., F.R.C.S., (Urol) Department of Minimally, Invasive Surgery, and Stone Disease, University Hospital of South Manchester, Manchester, UK Joseph E. Zerwekh, Ph.D. University of Texas Southwestern Medical Center, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, TX, USA Pei Zhong, Ph.D. Department of Mechanical Engineering and Materials Science, Duke University, Durham NC, USA Jack M. Zuckerman, B.S. Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem NC, USA Part Basic Sciences I 1 Epidemiology Gary C. Curham Abstract Substantial progress has been made in our understanding of the epidemiology of nephrolithiasis. Epidemiologic studies have quantified the burden of this common and painful condition, and they have expanded our understanding of risk factors for stone disease. A variety of dietary, non-dietary, and urinary risk factors contribute to the risk of stone formation, and the importance of these varies by age, sex, and body mass index (BMI). Scientifically, results from these studies have forced a reappraisal of our view of risk factors for stone disease. Importantly, the results from epidemiologic studies can be considered in the clinical setting when devising treatment plans for reducing the likelihood of stone formation. Nephrolithiasis is a common and complex disorder. Epidemiologic studies have quantified the burden of disease and have identified a variety of risk factors, which may help improve our understanding of the pathophysiology as well as lead to new approaches to reduce the risk of stone formation. 1.2 Prevalence The prevalence of nephrolithiasis – defined as a history of stone disease – varies by age, sex, race, and geography. The prevalence increases with age, and the lifetime risk of stone formation in the USA exceeds 12% in men and 6% in women.1,2 The prevalence appeared to be increasing in the last quarter of the twentieth century for men and women, whether black or white2 (see Figs. 1.1 and 1.2). A history of stone disease in the USA is most common among older white males (~12%) and lowest in younger black females (~1%); frequencies for Asians and Hispanics fall in between.2,3 Increased detection of asymptomatic stones resulting from G.C. Curham (*) Department of Medicine and Epidemiology, Brigham and Women's Hospital, Harvard Medical School/Harvard School of Public Health, Boston, MA, USA e-mail: email@example.com the increasing use and sensitivity of radiologic studies may explain, in part, the rise in prevalence. Few population-based studies of the prevalence of nephrolithiasis have been conducted outside of the USA. Prevalence of stone disease has increased in Japan4 and Germany.5 A study of more than one million individuals found geographic variability with a north–south and west–east gradient; the highest prevalence of self-reported nephrolithiasis was in the Southeastern USA.6 A decrease in the male-to-female ratio was suggested by a recent study of hospital discharges.7 Data from the Nationwide Inpatient Survey between 1997 and 2002 found 16 14 % with history of kidney stones 1.1 Introduction 12 10 8 6 4 2 0 male male male 20–39 40–59 60–74 1976–80 female female female 20–39 40–59 60–74 1988–94 Fig. 1.1 Prevalence of stone disease by sex and age (Adapted and reprinted from Ref.2 Copyright 2003, with permission from Nature Publishing Group) P.N. Rao et al. (eds.), Urinary Tract Stone Disease, DOI 10.1007/978-1-84800-362-0_1, © Springer-Verlag London Limited 2011 3 4 G.C. Curham 1.5 Risk Factors 16 % with history of kidney stones 14 12 Information on the importance of a variety of risk factors for stone formation has increased substantially over the past several decades. Risk factors are generally divided into nondietary, dietary, and urinary. 10 8 6 4 2 0 white white white 20–39 40–59 60–74 black black black 20–39 40–59 60–74 1.5.1 Non-dietary 1976–80 1988–94 Fig. 1.2 Prevalence of stone disease by race and age (Adapted and reprinted from Ref.2 Copyright 2003, with permission from Nature Publishing Group) a male to female ratio 1.3:1; substantially lower than the commonly reported ratio of 2–3:1. Population-based studies of this interesting observation are needed. 18.104.22.168 Family History Studies of twins and populations have demonstrated that the common forms of stone disease are heritable.17 The risk of stone formation is twofold higher in individuals with a family history of stone disease.18 The increased risk is likely due to both genetic predisposition and similar environmental exposures (e.g., diet). Genetic causes of rare forms of nephrolithiasis (e.g., cystinuria, Dent disease) have been identified, but information is still limited on genes that contribute to risk of the common forms of stone disease. 1.3 Incidence The incidence of nephrolithiasis – defined as the first stone event – varies by age, sex, and race. As with prevalence, white males have the highest incidence rates. In men, the incidence begins to rise after age 20, peaks between 40 and 60 years at ~3/1,000/year and then declines.1,8,9 In women, the incidence is higher in their late twenties at 2.5/1,000/year and then decreases to 1/1,000/year by age 50, remaining at this rate for the next several decades.1,9–11 A recent study from Rochester, Minnesota, raised the possibility that incidence rates may be decreasing. Using the same methodology as a study performed 30 years earlier, the recent study reported incidence rates since 1990 may be falling in men and have leveled off in women.12 Because there were only 157 cases in men and 91 in women, additional larger studies are needed to explore this important issue. 1.4 Recurrence Rates Few studies provide reliable information on recurrence rates. Case series suggested 30–40% percent of untreated individuals will form another stone within 5 years after the initial episode.1 Obviously, the risk of recurrence is influenced by a variety of factors including stone type and urinary composition. Fortunately, randomized trials demonstrated that interventions can reduce the likelihood of recurrence by 50% or more.13–16 These interventions emphasize that prevention of stone recurrence is possible. 22.214.171.124 Race/Ethnicity In a cross-sectional Canadian study, individuals of Arabic, west Indian, west Asian, and Latin American descent were more likely to be stone formers than those of European descent.19 Overall, in the general population, African-Americans have a lower frequency of stones; however, among individuals with end-stage renal disease, African-Americans had a higher than expected prevalence of stone disease.20 188.8.131.52 Systemic Disorders There is substantial evidence that nephrolithiasis is a systemic disorder. Well-known conditions associated with calciumcontaining stones include primary hyperparathyroidism, renal tubular acidosis, and Crohn's disease. Several other common conditions, including obesity, gout, and diabetes mellitus (DM), have recently been convincingly linked to nephrolithiasis. Increasing body size, assessed by weight, body mass index (BMI), or waistline, increases the risk of stone formation independent of other risk factors including diet21; for unexplained reasons, the impact is greater in women than in men. For example, the risk of stone formation for individuals with a BMI ³ 30 kg/m2 compared to those with a BMI 21–23 was 30% higher among men but nearly twofold higher among women. Urinary composition by body size; for example, higher BMI, is associated with higher urine oxalate and lower urine pH, changes that would increase risk for calcium oxalate or uric acid stones.22 1 Epidemiology In a cross-sectional study, individuals with gout were 50% more likely to have a history of stones.23 When examined prospectively, individuals with a history of gout had a twofold higher risk of incident nephrolithiasis, independent of diet, weight, and medications.24 Possible mechanisms for this relation include insulin resistance and acidification defects. Diabetes mellitus (DM) has also been associated with an increased risk of stone formation, independent of diet and body size.25 Cross-sectionally, individuals with a history of diabetes were more than 30% more likely also to have a history of nephrolithiasis. Prospectively, a history of DM increased the risk of stone formation by 30–50% in women but not in men.26,27 In support of these findings, a recent study based on National Health and Nutrition Examination Survey (NHANES) III data found that the risk of being a stone former increased with an increasing number of metabolic syndrome traits.28 220.127.116.11 Environmental Factors Occupations or settings with higher insensible fluid losses, such as a hot environment, increase the risk of stone formation.29 The risk will also be higher when individuals have restricted access to water or bathroom facilities, leading to lower fluid intake and lower urine volume. 1.5.2 Dietary Factors Dietary intake influences urine composition, thereby modifying the risk of nephrolithiasis. Implicated nutrients include calcium, animal protein,30 oxalate,31 sodium,32 sucrose,33 fructose,34 magnesium,35 and potassium.36 Care must be taken when interpreting studies of diet and stone risk. Retrospective studies may be biased because individuals who develop stones may subsequently change their diet. Results from studies that use change in urine composition as a surrogate for actual stone formation should be viewed with caution because the composition of the urine does not completely predict risk and not all the components that modify risk are included in the calculation of supersaturation (e.g., urine phytate). Thus, prospective studies that assess a variety of nutrients are best suited for examining the associations between dietary factors and risk of actual stone formation. 188.8.131.52 Calcium The associations between dietary factors and the risk of incident stone disease have been examined prospectively in three large cohorts: Health Professionals Follow-up Study (HPFS) involving more than 45,000 male health professionals aged 5 40–75 years at baseline; Nurses' Health Study I (NHS I) involving more than 80,000 female nurses aged 34–59 at baseline; and NHS II involving more than 80,000 female nurses aged 27–44 at baseline.8,10,11 Prior to these studies, higher calcium intake had been strongly suspected of raising the risk of stone disease. However, these studies demonstrated that individuals with a higher intake of dietary calcium actually had a lower risk of incident nephrolithiasis independent of other risk factors.8,10,11 Although this may seem counter-intuitive, lower calcium intake increases dietary oxalate absorption and urinary oxalate excretion.37 Another possible explanation is that there is some other protective factor present in milk (dairy products are the major source of dietary calcium in the USA). Even among individuals with a family history of nephrolithiasis, lower dietary calcium intake was associated with an increased risk of stone formation.18 Borghi and colleagues performed a randomized controlled study diet that confirmed these observational findings. Men with elevated urine calcium and a history of calcium oxalate stones were randomized to one of two diets: a low calcium diet (400 mg/day) or a diet containing 1,200 mg of calcium along with low sodium and low animal protein intake.13 Men in the higher calcium intake group had a 50% lower risk of recurrence. The evidence is now overwhelming that calcium restriction is not beneficial and may in fact be harmful, both for stone formation and bone loss. In contrast to dietary calcium, supplemental calcium does not appear to reduce risk in men or younger women8,11 and may in fact increase the risk of stone formation in older women. In an observational study10 and randomized trial,38 calcium supplement users were ~20% more likely to form a stone than women who did not take supplements, after adjusting for dietary factors. However, the results from the randomized trial should be interpreted cautiously as the participants were instructed to take their supplements with meals, and the supplements contained both calcium and vitamin D. The timing of the supplemental calcium intake may account for the differences in risk. In the cohort studies, calcium supplements were typically not taken with meals, which would diminish binding of dietary oxalate in the intestine. 220.127.116.11 Oxalate Urine oxalate is clearly an important risk factor for calcium oxalate stone formation; however, the role of dietary oxalate in the pathogenesis of calcium oxalate nephrolithiasis is less clear.39 The proportion of dietary oxalate that is absorbed is estimated to range from 10% to 50%.39 The factors influencing the absorption are incompletely characterized but likely include other dietary factors (e.g., calcium), genetic factors, and possibly intestinal flora. In addition, the bioavailability of oxalate in food is unknown. Urinary oxalate is also derived 6 from the endogenous metabolism of glycine, glycolate, hydroxyproline, and vitamin C. A recent study found individuals with a history of calcium oxalate nephrolithiasis were less likely to be colonized with Oxalobacter formigenes, an intestinal bacterium that degrades oxalate.40 Prospective studies of dietary oxalate and stone risk were performed after modern approaches to measure the oxalate content of food provided information on the oxalate content of many foods.41,42 Surprisingly the impact of dietary oxalate was minimal in men and older women and not associated with stone formation in younger women.43 18.104.22.168 Other Nutrients A variety of other nutrients have been implicated in stone formation. Of note, the magnitudes of the associations often vary by age, sex, or body mass index. For example, higher animal protein intake may increase urinary calcium and decrease urinary citrate,44 thereby increasing the risk of stone formation. However, when studied prospectively, animal protein was associated with an increased risk in men but not in women.8,10,11 Further, the increased risk in men was only found among men with BMI < 25 kg/m2.45 Higher dietary potassium intake decreased risk in men and older women8,10,45 possibly by reducing urine calcium excretion36 or increasing urine citrate. Higher intake of sodium32 or sucrose33 increases urinary calcium excretion independent of calcium intake. In prospective studies, sucrose was associated with an increased risk in women and fructose increased risk in men and women.10,11,34 Phytate, found in whole grains and beans, was observed to reduce risk of stone formation in younger women,11 possibly by directly inhibiting calcium oxalate crystal formation. Although magnesium may reduce dietary oxalate absorption, randomized trials of magnesium supplements did not find a protective effect on stone recurrence, though the dropout rates were high. In prospective observational studies, higher dietary magnesium was associated with a lower risk of stone formation in men45 but not women.10,11 Vitamin C (ascorbic acid) can be metabolized to oxalate. Consumption of 1,000 mg of supplemental vitamin C twice daily increased urinary oxalate excretion by 22%.46 In a prospective observational study, men who consumed 1,000 mg or more per day of vitamin C had a 40% higher risk of stone formation compared to men who consumed less than 90 mg/ day (the recommended dietary allowance).45 While restricting dietary vitamin C is not recommended (because foods high in vitamin C contain inhibitory factors such as potassium), calcium oxalate stone formers should avoid vitamin C supplements. Although high-dose vitamin B6 (pyridoxine) may reduce oxalate production in selected patients with type 1 primary G.C. Curham hyperoxaluria, it is unclear if there would be benefit from the use of vitamin B6 supplements to prevent common stone disease. In observational studies, higher intake of vitamin B6 was associated with a reduced risk of kidney stone formation in women47 but not in men.48 126.96.36.199 Fluid Intake and Beverages The main determinant of urine volume is fluid intake. Urine volume, and therefore fluid intake, is an important determinant of stone risk. When the urine output is less than 1 L/day, risk of stone formation is markedly higher. Higher fluid intake has been demonstrated to reduce the likelihood of stone formation in observational studies8,10,11 and a randomized controlled trial.49 Patients with stone disease often ask which beverages they should drink and which they should avoid. Coffee, tea, beer, and wine were associated with a reduced risk of stone formation in prospective studies.50,51 Although citrus juices theoretically could reduce the risk of stone formation by increasing urine citrate,52 the prospective studies did not find an independent association with orange juice and grapefruit juice was associated with a significantly higher risk.50,51 Grapefruit juice is known to affect several intestinal enzymes, but the mechanism for the observed increased risk of stone formation is unknown. Consumption of sugared soda was not associated with a higher risk of stone formation.50,51 Milk intake reduces the risk of calcium kidney stone formation. 1.6 Urinary Factors The 24-h urine collection is the cornerstone of the metabolic evaluation and the urine chemistries provide important prognostic information and guide preventive recommendations. Like many laboratory tests, urine results have traditionally been categorized into "normal" and "abnormal." However, recent data has revealed this grouping is unsatisfactory. Urine values are continuous so the dichotomization into "normal" and "abnormal" is arbitrary and potentially misleading. In addition, stone formation is a disorder of concentration, not just the absolute amount excreted. Although terms of abnormal excretion, such as "hypercalciuria" or "hypocitraturia" are often used clinically and in the scientific literature, the limitations of these terms should be acknowledged. Hypercalciuria is commonly defined as urine calcium excretion ³ 300 mg/day (7.5 mmol/day) in men and ³ 250 mg/day (6.25 mmol/day) in women53 on a 1,000-mg/ day calcium diet (but a variety of definitions are in use). Using these traditional definitions, approximately 20–40% of patients 1 Epidemiology with calcium stone disease will have hypercalciuria. Although possibly reasonable from a calcium balance perspective, there is insufficient justification for different thresholds for males and females. In fact, the sex-based definitions are particularly concerning because nephrolithiasis is a disorder of concentration and 24-h urine volumes are slightly higher in women than in men.54 Hyperoxaluria is typically defined as urinary oxalate excretion >45 mg/day (0.5 mmol/day), though here too a variety of thresholds are in use. Elevated urinary oxalate excretion is three to four times more common among men (~40%) than in women (~10%).54 Mean urinary oxalate levels are only slightly higher in cases than in controls, but in multivariate models oxalate is clearly an important independent risk factor for stone formation.54 Of note, the risk begins to rise well below the 45 mg/day level. The relation between uric acid excretion and calcium stone disease is unsettled. Some early cross-sectional studies reported that hyperuricosuria (typically defined as greater than 800 mg/day (4.76 mmol/day) in men or 750 mg/day (4.46 mmol/day) in women) is more frequent in patients who form calcium stones than controls.55 However, a recent study of more than 2,200 stone formers and 1,100 non-stone formers reported that a higher urine uric acid was associated with a lower likelihood of being a stone former in men, and there was no increase in risk for women.54 A double-blind trial of allopurinol successfully decreased recurrence rates of calcium stones in patients with hyperuricosuria suggesting that uric acid is important,16 but it is possible that the beneficial effect of allopurinol was through a mechanism unrelated to lowering of urine uric acid. Hypocitraturia, often defined as 24-h excretion£ 320 mg/ day (1.67 mmol/day), increases risk of stone formation56 and is found in 5–11% of first-time stone formers.54 There is suggestive evidence that increasing urinary citrate into the highnormal range provides additional protection.54 Low urine volume, for which a variety of definitions have been used, is a common and modifiable risk factor. When defined as 24-h urine volume less than 1 L/day, 12–25% of first-time stone formers will have this abnormality.54 Observational studies and a randomized trial have demonstrated the risk of stone formation decreases with increasing total urine volume.49,54 1.7 Conclusions Epidemiologic studies have expanded our understanding of the magnitude and risk factors for stone disease. A variety of dietary, non-dietary, and urinary risk factors contribute to the risk of stone formation and the importance of these varies by 7 age, sex, and BMI. Scientifically, results from these studies have forced a reappraisal of our view of risk factors for stone disease. Importantly, the results from epidemiologic studies can be considered in the clinical setting when devising treatment plans for reducing the likelihood of stone formation. Acknowledgment This work was supported by grant DK070756 from the National Institutes of Health. References 1. Johnson CM, Wilson DM, O'Fallon WM, Malek RS, Kurland LT. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int. 1979;16(5):624-631. 2. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int. 2003;63(5):1817-1823. 3. Soucie JM, Thun MJ, Coates RJ, McClellan W, Austin H. Demographic and geographic variability of kidney stones in the United States. Kidney Int. 1994;46(3):893-899. 4. Yoshida O, Okada Y. Epidemiology of urolithiasis in Japan: a chronological and geographical study. Urologia Internationalis. 1990;45:104-111. 5. Hesse A, Brändle E, Wilbert D, Köhrmann KU, Alken P. Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000. Eur Urol. 2003;44(6):709-713. 6. Soucie J, Coates RJ, McClellan W, Austin H, Thun M. Relation between geographic variability in kidney stones prevalence and risk factors for stones. Am J Epidemiol. 1996;143:487-495. 7. Scales CD Jr, Curtis LH, Norris RD, et al. Changing gender prevalence of stone disease. J Urol. 2007;177(3):979-982. 8. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833-838. 9. Hiatt RA, Dales LG, Friedman GD, Hunkeler EM. Frequency of urolithiasis in a prepaid medical care program. Am J Epidemiol. 1982;115:255-265. 10. Curhan G, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-504. 11. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses' Health Study II. Arch Intern Med. 2004;164(8):885-891. 12. Lieske JC, de la Vega LS Peña, Slezak JM. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 2006;69(4): 760-764. 13. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84. 14. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol. 1988;139(4):679-684. 15. Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol. 1997;158(6): 2069-2073. 16. Ettinger B, Tang A, Citron JT, Livermore B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med. 1986;315(22):1386-1389. 8 17. Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int. 2005;67(3): 1053-1061. 18. Curhan G, Willett WC, Rimm EB, Stampfer MJ. Family history and risk of kidney stones. J Am Soc Nephrol. 1997;8:1568-1573. 19. Mente A, Honey RJ, McLaughlin JR, Bull SB, Logan AG. Ethnic differences in relative risk of idiopathic calcium nephrolithiasis in North America. J Urol. 2007;178(5):1992-1997. discussion 1997. 20. Stankus N, Hammes M, Gillen D, Worcester E. African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III. Urol Res. 2007;35(2):83-87. 21. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. Jama. 2005;293(4):455-462. 22. Taylor EN, Curhan GC. Body size and 24-hour urine composition. Am J Kidney Dis. 2006;48(6):905-915. 23. Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Kidney Dis. 2002;40(1):37-42. 24. Kramer HJ, Choi HK, Atkinson K, Stampfer M, Curhan GC. The association between gout and nephrolithiasis in men: The Health Professionals' Follow-Up Study. Kidney Int. 2003;64(3): 1022-1026. 25. Taylor EN, Stampfer MJ, Curhan GC. Diabetes mellitus and the risk of nephrolithiasis. Kidney Int. 2005;68(3):1230-1235. 26. Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol. 2006;17(7):2026-2033. 27. Lieske JC, de la Vega LS, Gettman MT, et al. Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. Am J Kidney Dis. 2006;48(6):897-904. 28. West B, Luke A, Durazo-Arvizu RA, Cao G, Shoham D, Kramer H. Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988-1994. Am J Kidney Dis. 2008;51(5):741-747. 29. Atan L, Andreoni C, Ortiz V, et al. High kidney stone risk in men working in steel industry at hot temperatures. Urology. 2005;65(5): 858-861. 30. Robertson WG, Peacock M, Hodgkinson A. Dietary changes and the incidence of urinary calculi in the U.K. between 1958 and 1976. J Chron Dis. 1979;32:469-476. 31. Larsson L, Tiselius HG. Hyperoxaluria. Miner Electrolyte Metab. 1987;13(4):242-250. 32. Muldowney FP, Freaney R, Moloney MF. Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int. 1982;22(3): 292-296. 33. Lemann J Jr, Piering WF, Lennon EJ. Possible role of carbohydrateinduced calciuria in calcium oxalate kidney-stone formation. N Engl J Med. 1969;280(5):232-237. 34. Taylor EN, Curhan GC. Fructose consumption and the risk of kidney stones. Kidney Int. 2008;73(2):207-212. 35. Johansson G, Backman U, Danielson BG, Fellström B, Ljunghall S, Wikström B. Biochemical and clinical effects of the prophylactic treatment of renal calcium stones with magnesium hydroxide. J Urol. 1980;124:770-774. 36. Lemann J Jr, Pleuss JA, Gray RW, Hoffmann RG. Potassium administration reduces and potassium deprivation increases urinary calcium G.C. Curham excretion in healthy adults [corrected]. Kidney Int. 1991;39(5): 973-983. 37. Bataille P, Charransol G, Gregoire I, et al. Effect of calcium restriction on renal excretion of oxalate and the probability of stones in the various pathophysiological groups with calcium stones. J Urol. 1983;130(2):218-223. 38. Jackson RD, LaCroix AZ, Gass M, et al. Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683. 39. Holmes RP, Assimos DG. The impact of dietary oxalate on kidney stone formation. Urol Res. 2004;32(5):311-316. 40. Kaufman DW, Kelly JP, Curhan GC, et al. Oxalobacter formigenes May Reduce the Risk of Calcium Oxalate Kidney Stones. J Am Soc Nephrol. 2008;19(6):1197-1203. 41. Holmes R, Kennedy M. Estimation of the oxalate content of foods and daily oxalate intake. Kidney Int. 2000;57:1662-1667. 42. Siener R, Hönow R, Voss S, Seidler A, Hesse A. Oxalate content of cereals and cereal products. J Agric Food Chem. 2006;54(8): 3008-3011. 43. Taylor EN, Curhan GC. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol. 2007;18(7):2198-2204. 44. Breslau N, Brinkley L, Hill KD, Pak CY. Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism. J Clin Endocrinol Metab. 1988;66:140-146. 45. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. 2004;15(12):3225-3232. 46. Traxer O, Huet B, Poindexter J, Pak CY, Pearle MS. Effect of ascorbic acid consumption on urinary stone risk factors. J Urol. 2003;170(2 Pt 1):397-401. 47. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845. 48. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155(6):1847-1851. 49. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155: 839-843. 50. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Stampfer MJ. Prospective study of beverage use and the risk of kidney stones. Am J Epidemiol. 1996;143(3):240-247. 51. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Beverage use and risk for kidney stones in women. Ann Intern Med. 1998;128(7): 534-540. 52. Wabner C, Pak C. Effect of orange juice consumption on urinary stone risk factors. J Urol. 1993;149:1405-1409. 53. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46(195):10-18. 54. Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008;73(4):489-496. 55. Coe FL. Hyperuricosuric calcium oxalate nephrolithiasis. Kidney Int. 1978;13(5):418-426. 56. Pak CY. Citrate and renal calculi: an update. Miner Electrolyte Metab. 1994;20(6):371-377. 2 Genetics and Molecular Biology of Renal Stones Giovanni Gambaro, Laura Soldati, and Giuseppe Vezzoli Abstract Genetic studies of calcium kidney stones have hitherto assessed single candidate genes by testing for linkage disequilibria or associations between a locus and stone disease. They have identified the potential involvement of the calcium-sensing receptor (CaSR), vitamin D receptor, (VDR), and bicarbonate-sensitive adenylyl cyclase genes. In addition to research in humans, studies on different strains of knock-out mice have enabled us to include the phosphate reabsorption carrier NPT2 gene, the caveolin-1 gene, the protein NHERF-1 gene modulating calcium and urate reabsorption, osteopontin, and Tamm–Horsfall protein among the possible determinants. Interactions between genes, and between environmental factors and genes, are generally considered fundamental to calcium stone formation, however. To date, therefore, genetic studies have failed to significantly advance our understanding of the causes of calcium kidney stones, though they have enabled us to assess the dimension of the problem and establish criteria for facing it. Further progress in our knowledge of what causes calcium stones may derive from using the tools afforded to researchers by modern biotechnology and bioinformatics. 2.1 Introduction Metabolic studies on patients have established that calcium kidney stones can be associated with various defects of mono- and bivalent electrolyte excretion. The most well known of these conditions is primary hypercalciuria, detected in 50% of patients with stones.1 Others, such as hypo-citraturia, renal hypophosphatemia, hyperuricuria, and an elevated sodium and chloride excretion accompany stone-forming disease less frequently. It is consequently impossible to predict the onset of a calcium stone on the strength of these conditions alone, which leads us to assume that a number of factors interact and/or combine together to predispose an individual to calcium kidney stones. In the last decade, nephrological research has focused on establishing the genetic causes of calcium nephrolithiasis. Our understanding of this topic has not improved substantially, however, and it has consequently not been possible to develop effective prevention and treatment criteria. Among G. Gambaro (*) Dipartimento di Medicina Interna e di Scienze Mediche Specialistiche, Università Cattolica del Sacro Cuore, Rome, Italy e-mail: email@example.com the predisposing factors, we tend to consider those of genetic and environmental origin, though the distinction between the two is hazy because kidney stones are probably the outcome of an interaction between genes and environment.1–4 Nephrolithiasis is consequently among the complex diseases with a multifactorial pathogenesis, like hypertension, diabetes, ischemic cardiopathy, and osteoporosis. Studying its causes is bound to be difficult, although advances in our biological/molecular knowledge and new biotechnologies have provided us with powerful analytical tools. These methods have certainly enabled progress to be made in genetic research, but our awareness of the complexity of the pathogenic picture, and of the commitment that will be needed to fully understand it, has likewise grown. 2.2 Genetic Linkage Studies The genetic study of calcium kidney stones developed starting from the latter half of the 1990s. Early studies were conducted using linkage methods that assess the cosegregation of the nephrolithiasis with a chromosomal locus in members of stone-forming families. These methods are strong and P.N. Rao et al. (eds.), Urinary Tract Stone Disease, DOI 10.1007/978-1-84800-362-0_2, © Springer-Verlag London Limited 2011 9 10 accurate in pointing to the genes involved in a given disease, especially in monogenic diseases, which is why they were applied to nephrolithiasis.5 Some studies also evaluated the phenotypes implicated in the disease, such as hypercalciuria. Some linkage studies considered the loci of candidate genes believed to have a pathogenic role in the light of the prevailing pathophysiological hypotheses. This strategy was applied to a sample of more than 300 pairs of French–Canadian brothers suffering from kidney stones, whose chromosomal loci coding for renal 1a (alpha)-hydroxylase of 25(OH) vitamin D, the vitamin D receptor (VDR), or the calcium-sensing receptor (CaSR) were tested. Each region was assayed using specific polymorphic markers. The locus of the 1a (alpha)-hydroxylase of 25-dihydroxy-vitamin D (chromosomal locus 12q13.1q13.3) was the first to be studied in this sample, but the results could confirm no role for it.6 The locus of the VDR on chromosome 12q12–14 was analyzed using six different markers, four of which emerged in linkage disequilibrium with nephrolithiasis and only one with hypercalciuria, but with only a low significance.7 Finally, no linkage was found between the locus of the CaSR (3q13.3–21) and the onset of nephrolithiasis in the series of French–Canadian brothers.8 Linkage studies have produced more significant results when members of stone formers' families were studied, by generation. One study reconsidered the locus of the VDR in Indian families and substantially confirmed the results obtained in the French–Canadian brothers.9 Another confirmed the absence of CaSR gene mutations in seven European families.10 Only one family-based study used chromosomal markers covering the whole genome (a genome-wide scan): this method enabled them to proceed without any preliminary pathogenic hypothesis or definition of a candidate gene. After exploring the whole genome with polymorphic markers, the results of the study suggested the loci where the genes implicated in nephrolithiasis could be found. In other words, a genomewide scan enables a pathogenic hypothesis to be developed on the strength of the results obtained. Taking this approach, a linkage was identified between chromosome 1q23.3-q24 and hypercalciuria in three families suffering from absorptive hypercalciuria and kidney stones.11 The interpretation of this finding was entrusted to a subsequent case-control study, which found an association between hypercalciuria and six polymorphisms of the soluble (bicarbonate-sensitive) adenylate cyclase (sAC) gene. The same polymorphisms were also associated with a low bone mineral mass.12 The functional role of the sAC gene has yet to be clarified, though we know that it is expressed in the kidney, intestine, and bone cells, and that its function is activated by bicarbonate and modulated by bivalent cations.13 The linkage between the sAC gene and hypercalciuria was not confirmed, however, in a European study of nine families.14 Despite the greater reliability of linkage studies, studies conducted using other strategies, such as analyzing the G. Gambaro et al. association between genotype and calcium nephrolithiasis, have been far more numerous. The reasons for this tendency lie in the numerous practical and theoretical problems involved. First, there is the difficulty of finding family groups covering at least three generations and numerically large enough to enable linkage studies. Another problem lies in the inability of linkage studies to identify genes with a scarce phenotypic effect.3,5 This problem applies particularly to nephrolithiasis because stones may be caused not by a mutation in one or a few genes with a strongly predominant effect, but by compound changes induced by numerous genes, each incapable alone of giving rise to the disease.15 This being the case, the causal substrate might be so variable and heterogeneous as to make it extremely difficult to conduct genetic studies and identify individual genes. In addition to these specific problems, there is also the more general difficulty of classifying an individual as a stoneformer; in fact, a kidney stone can develop at any age, and may even go unrecognized. It may also be that an individual possessing the predisposing genetic heritage forms no stones because other genes or nutrients with an antilithogenic effect prevail over the lithogenic factors.16 A clear example of this phenomenon in the kidney stone setting is the low-sodium diet prescribed for hypercalciuric individuals. The lithogenic risk in these people is increased by their higher calcium excretion levels, but restricting their dietary intake of sodium and chloride reduces their stone-forming potential related to their hypercalciuria, which is known to have a genetic component.17 It may also be that several genetic causes come into play in patients with recurrent kidney stones, but not in those who produce only one stone in a lifetime.18 2.3 Genetic Association Studies The studies associating a genotype with calcium kidney stones are the most common alternative to genetic linkage studies. They assess whether an allele or a genotype is more or less common in patients with kidney stones than in those without them. The search for this association can involve analyzing of the whole genome or only a candidate gene. In the nephrolithiasis setting, only candidate genes have been tested to date,2 but analyses with genome-wide markers represent the way forward.19 In association studies, patients and controls are genotyped for single-base polymorphisms arranged along the sequence of candidate genes. These polymorphisms have a mean frequency of one for every 1,200 bases and contribute to the variability of the phenotype. They can be placed in coding regions and cause an amino acid change, or in untranscribed regions and leave the amino acid sequence in the protein unchanged. Their potential influence on the phenotype often remains unknown and this is a crucial drawback of such analyses.20 2 Genetics and Molecular Biology of Renal Stones 11 The first gene to be analyzed using this method was the VDR gene, considering the polymorphisms of the untranscribed 3¢ region or of the transcription start codon. These polymorphisms emerged as being associated with calcium kidney stones in various studies, and some also observed that patients carrying allele variants to 3¢-terminal region polymorphisms developed stones earlier in life and had a more aggressive form of the disease and lower urinary citrate excretion levels.21–23 Although some works have not confirmed these associations,24 overall the results obtained give the impression that VDR gene polymorphisms can play a part in the onset of calcium nephrolithiasis. It remains to be seen whether the VDR gene polymorphisms identified have an important functional effect on the disease or whether the association is simply due to their cosegregation (i.e., they are in linkage disequilibrium) with other functionally relevant polymorphisms. Their functional link to nephrolithiasis is generally justified by the fact that the VDRvitamin D complex activates intestinal calcium absorption (Fig. 2.1). It seems, however, that the VDR-vitamin D complex Ca− lumen TRPV6 Ca2+ VDRE ⊕ is also capable of reducing urinary citrate excretion. In fact, it can derepress the expression of phosphoenolpyruvate carboxyl kinase that can limit its renal excretion by stimulating the citrate reabsorption carrier on the luminal membrane of the proximal tubule cells.25 Particular results were obtained by analyzing the CaSR gene, studying its polymorphisms of exon 7 (3¢-terminal) and the polymorphisms of the first intron and of the untranscribed 5¢ region near the promoter. The Arg990Gly polymorphism of exon 7 is associated with hypercalciuria in patients with and without kidney stones. Results in vitro on HEK293 embryonal renal cells transfected with the CaSR gene indicate that the Arg990Gly polymorphism can give rise to a functional gain for the CaSR gene.26,27 This hypothesis is confirmed by the fact that patients with primary and secondary hyperparathyroidism carrying the allele variant have lower mean circulating levels of PTH than carriers of the arginine allele.28 It is consequently feasible that the glycine allele at codon 990 is less effective in inhibiting calcium reabsorption in the cells of the thick ascending limb of the Henle's loop, predisposing carriers to higher calcium excretion levels (Fig. 2.2). This poses the question of why these same individuals are not hypocalcemic too, like the carriers of CaSR gene activating mutations: maybe the Arg990Gly polymorphism has a different influence on the signaling systems used by parathyroid and renal cells, so it could inhibit tubular calcium reabsorption and PTH production in CaBP VDR Ca2+ vitD Ca2+ Ca2+ VDR +8mV IP3 vitD Ca2+ ATP ADP Ca2+ Na+ G protein PLA2 VDR - K+ 2Cl+ Na+ PMCA Ca2+ Ca2+ AA CASR K+ vitD - 3Na+ Ca2+ ATP Ca2+ Fig. 2.1 Intestinal absorption of calcium is considered particularly important in stone formation. Transcellular absorption is mediated by a transport system involving the transfer of calcium from the lumen into the enterocyte through the calcium channel TRPV6, while on the basolateral membrane the calcium pump (PMCA) and sodium–calcium exchange carry the calcium ion into the interstitium. PMCA is only involved in absorption in the jejunum and duodenum, where absorption is active. In the cytoplasm, calbindin 9k (CBP) binds the calcium ions absorbed and guides them toward the carriers of the basolateral membrane. The vitamin D receptor (VDR) complex controls the gene expression of all these carriers and CBP, and it regulates TRPV6 activity via a non-genomic effect. The VDR complex binds to a specific gene sequence called VDRE (vitamin D response element), which derepresses the genes of the vitamin-D-dependent proteins. Alongside these mechanisms, there is also a paracellular calcium absorption 0 mV Ca2+ Ca ⊕ interstitium Ca2+ PLC Ca2+ ⊕ PTH lumen ADP Ca2+ PMCA interstitium Fig. 2.2 The figure schematically shows a cell of the thick ascending limb, illustrating the effects of the calcium-sensing receptor (CaSR) gene, which inhibits Na–K–Cl cotransport and sodium reabsorption via phospholipase A2 (PLA2) activation and the production of arachidonic acid (AA) and eicosatetraenoic acid. This inhibitory effect reduces the electric potential between the interstitium and the lumen, which in itself obstructs the passive paracellular reabsorption of calcium and other cations. In addition, the activation of calcium reabsorption has a direct effect on the calcium pump (PMCA), which inhibits the active reabsorption of calcium 12 parathyroid cells to a different degree. The importance of this polymorphism in calciuria has also been confirmed in patients with primary hyperparathyroidism, because patients who carry the 990Gly allele variant have higher urinary calcium excretion levels and form stones more frequently.28 Polymorphisms of the CaSR gene promoter region located in the first intron or the untranscribed 5¢ region were recently associated with nephrolithiasis in the Italian population.29 They do not entail an amino acid change and they can presumably take effect by modifying the gene's transcription and the expression of the CaSR in the tubule cells of the renal papilla, given the nearness of the gene promoter. With high calcium concentrations in the renal papilla, a different cell expression of the CaSR is likely to be crucial to the precipitation of calcium salts and the formation of oxalate stones.30 Polymorphisms of the genes coding for osteopontin, urokinase, interleukin receptor-1, intestinal transient receptor potential cation channel (TRPV6), E-cadherin and epidermal growth factor have also been associated with kidney stones.14,31–36 The physiopathological role of these genes in nephrolithiasis is still not clear and there are still no works to confirm the preliminary results. On the other hand, a functional result has been obtained for the gene TRPV6, coding for the calcium channel expressed in the intestinal mucosa, according to which the activating mutations would be associated with nephrolithiasis32 via an increase in intestinal calcium absorption (Fig. 2.2). Association studies are certainly easier to perform than linkage analyses, but they are not without their problems. The previously mentioned difficulties in classifying an individual as affected apply in this case too; and they suffer from a poor repeatability of the results in different populations due to differences in genetic substrate or environmental factors that can lead to unrecognized stratifications, which make the various populations unsuitable for comparison.37 This can also apply in the opposite sense; that is, creating the conditions for false-positive results due to unwitting favorable stratifications. These studies can nonetheless also reveal genes with a limited effect on the phenotype, as is probably the case of the relationship between hypercalciuria and the CaSR gene Arg990Gly polymorphism. The allele variant 990Gly was found associated with hypercalciuria and explained 4% of the phenotypic variability of calciuria in one study population24; vice versa, the locus of the CaSR gene was not in linkage with hypercalciuria or nephrolithiasis in the pairs of French–Canadian brothers.8 This scarce influence of the Arg990Gly polymorphism on the variability of calciuria is probably responsible for the negative outcome of the linkage studies. The association and linkage studies conducted to date chose the genes and polymorphisms to investigate in advance. While the choice of genes was generally based on physiopathological knowledge, the choice of polymorphisms was only rarely guided by functional knowledge.20 This important G. Gambaro et al. weakness can now be avoided thanks to the introduction of genome-wide scanning methods, which can now be undertaken at a still considerable but sustainable cost, but this demands technologies and bioinformatic software products capable of testing and processing massive numbers of samples and amounts of data. Finally, irrespective of the study strategy adopted, it is fundamental for genetic findings to be confirmed by functional studies on cell and animal models. These potential developments and the previously mentioned experiences have led to association studies being progressively reconsidered in recent years. 2.4 Animal Models of Genetic Disease Knockout mice are animals genetically programmed not to express a given gene. The development of kidney stones in the phenotype of a knockout strain indicates that the silenced gene is important in preventing the onset of nephrolithiasis. Five strains of knockout mice are known to develop kidney stones. The mice without the slc26a13 gene lack the carrier that secretes oxalate in the intestinal lumen. As a consequence, these animals accumulate oxalate in the organism and its renal excretion is increased, leading to urinary precipitation and stone formation.38 Caveolin-1 knockout mice are incapable of producing caveol in the renal cells; that is, the plasma membrane invaginations where proteins important to cell functions (such as the calcium pump, CaSR, and VDR) collect. These mice fail to absorb calcium from the tubular lumen and consequently become hypercalciuric, developing calcium–phosphate deposits in the tubule.39 The third knockout mouse strain lacks a protein, Na+/H+ exchanger regulatory factor (NHERF-1), that modulates sodium, calcium, and uric acid reabsorption. Calcium and urate excretion increases with the consequent formation of papillary calcium deposits.40 In the double knockout mouse strain, for osteopontin and the Tamm–Horsfall protein, papillary interstitial deposits are found in 39% of the animals, presumably because of their urine's inability to inhibit calcium salt precipitation. The two proteins seem to have a synergetic antilithogenic effect, since knocking out only one or the other induces papillary deposits in only 10–15% of the animals.41 Finally, knockout mice for the renal sodium/phosphate cotransporter (NPTa) are an interesting model with a phenotype characterized by hypophosphatemia secondary to renal phosphate loss, high renal vitamin D synthesis, hypercalciuria, and renal stone formation.42 This picture is similar to the one that develops in patients with autosomal dominant hereditary hypophosphotemic rickets with hypercalciuria (HHRH). Knockout mice for NPT2a have consequently been considered as a model of the renal impairment in patients with HHRH. No NPT2a gene mutation has been 2 Genetics and Molecular Biology of Renal Stones 13 found, however, in patients with HHRH, while mutations have been identified in the proximal phosphate NPT2c carrier.43 This means that there is a different organization of proximal phosphate reabsorption in humans and mice: while the former probably uses NPT2c as the main carrier for phosphate reabsorption in the proximal tubule cell (Fig. 2.3), the latter uses NPT2a. The two carriers differ functionally because NPT2a sustains the electrogenic cotransport of three sodium ions and one phosphate, while NPT2c produces an electroneutral cotransport that reabsorbs two sodium ions and one phosphate. NPT2a or NPT2c deficiency seems to differently affect bone, since the phenotype in mice does not include the rickets observed in humans. It may be that the two phosphate carriers are differently expressed in the bone cells: in particular, NPT2a occurs in the osteoclasts and the NPT2a knockout mice seem to have fewer, less active osteoclasts.44 Experience gained with the previously mentioned animal strains shows that knockout mice are a source of useful information and relatively easy to obtain. They may pave the way to new research hypotheses, but they do not represent a cornerstone for research because in any case transferring findings from mice to humans demands knowledge of the role played by the proteins under study in human physiology. Osteopontin and Tamm–Horsfall protein are known for their antilithogenic activity in humans, while the role of the slc26a13 oxalate carrier and NHERF-1 have yet to be ascertained. The studies on NPT2 go to show that transferring data obtained in the mouse to human beings is not always possible. PTH FGF23 Phosphate intake ⊕ HPO4− Na− NPT2 HPO4− NPT2 vesicle NPT2 lisosome interstitium 2.5 Future Areas of Study It is easy to see from the previous considerations that the genes involved in nephrolithiasis and how the disease is transmitted have yet to be explained. In choosing candidate genes to investigate, researchers have focused on genes specifically related to calcium metabolism, among which the VDR, CaSR, and sAC genes seem to contribute to the formation of calcium stones, though the extent of the contribution is not yet clear. These genes may be involved in the onset of primary hypercalciuria and osteoporosis, so the association of these disorders with nephrolithiasis emphasizes the importance of hypercalciuria as a pathogenic factor and explains the high frequency of osteoporosis among stone formers, irrespective of calciuria levels. It is nonetheless highly likely that, in addition to calcium metabolism, other aspects of renal electrolyte metabolism remaining to be explored are also important in the pathogenesis behind stone formation. An example comes from studies indicating the potentially stone-forming role of the sAC gene. Genome-wide scans are consequently awaited with much interest; specifically for the opportunity they will give us to formulate new hypotheses and research perspectives that overcome the limits of our current understanding. In the main, the studies listed here considered a single gene, while the interactions between different genes, and between genes and the environment are generally considered fundamental to the development of kidney stones. Stone-forming genes can interact with the environment in a more or less complex manner, giving rise to multiple forms of interaction. As at the current state of research, the most interesting interactions are of epigenetic type, in which environmental influences can modify the phenotype in a stable manner, transmissible to subsequent generations, without changing the genotype.45 They do so by modifying gene expression through various mechanisms. In humans, the most common of these consists in the methylation of the gene promoter regions, which can mean that gene transcription is repressed or rearranged, respectively, in the event of hyper- or hypo-methylation.46 In fetal and perinatal life, different environmental conditions are thought to be able to produce epigenetic changes, thereby influencing the newborn's susceptibility to chronic diseases. Studies on interactions between genes and the environment are destined to expand progressively in the nephrolithiasis setting, also thanks to epigenetic analyses, but such research is yet to be conducted at either epidemiological level or in animal models. lumen Fig. 2.3 The NPT2 transporter/carrier in humans serves the purpose of reabsorbing phosphate in the proximal tubule. To be specific, the NPT2c isoform is responsible for 85% of phosphate reabsorption, while 15% is mediated by NPT1. Phosphate, FGF23, and PTH intake inhibits NPT2 expression on the luminal membrane because their presence causes NPT2 to be internalized and lysed in the lysosomes. This is the mechanism by which they reduce phosphate reabsorption 2.6 Conclusions In conclusion, we might say that 10 years of genetic studies on nephrolithiasis have been unable to substantially improve our understanding of what causes calcium kidney stones. 14 But this conclusion would be ungenerous to all those who have committed themselves to this difficult, insidious area of research, and anyway the same could be said, more in general, of all complex diseases. In fact, the genetic investigation tools available up until not long ago produced exciting results for the monogenic, Mendelian-transmission diseases, but disappointing results for more complex diseases. New human genome scanning methods, less expensive high throughput gene investigation tools, and bio-informatic software capable of managing the body of data collected from large population samples (in terms of numerosity) have all become available in recent years, however. The studies conducted so far have served as preliminary investigations and, despite their limits, they can be used to provide the basis on which to found future research efforts. The results obtained relate mainly to changes in calcium metabolism in nephrolithiasis, but they have also produced criteria and tested the dimension of the problem. In the light of these studies, modern biotechnological and bioinformatic tools, provided they are put to good use, should be able to help us make further advances in our knowledge of the genetic causes behind calcium kidney stones. In this effort, however, it is important to acknowledge that a fundamental step concerns sample collection, to make it as phenotypically homogeneous as possible. To obtain significant results with our modern tools, we still need to rely on the ancient art of clinical patient assessment and our ability to obtain precise and standardized information on their characteristics. References 1. Hodkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stones of renal origin. Brit J Surg. 1958;46:10-18. 2. Manolio TA, Bailey-Wilson JE, Collins FS. Genes, environment and the value of prospective cohort studies. Nature Rev Genet. 2006;7:812-820. 3. Colhourn HM, McKeigue PM, Smith JD. Problems of reporting genetics associations with complex outcomes. Lancet. 2003;361: 865-872. 4. Loredo-Osti JC, Roslin NM, Tessier J, et al. Segregation of urine calcium excretion in families ascertained for nephrolithiasis: evidence for a major gene. Kidney Int. 2005;68:966-971. 5. Lander ES, Schork NJ. Gentic dissection of complex traits. Science. 1994;265:2037-2048. 6. Scott P, Ouimet D, Proulx Y, et al. The 1 alpha hydroxylase locus is not linked to calcium stone formation or calciuric phenotype in French-Canadian families. J Am Soc Nephrol. 1998;9:425-432. 7. Scott P, Ouimet D, Valiquette L, et al. Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation. J Am Soc Nephrol. 1999;10:10071013. 8. Petrucci M, Scott P, Ouimet D, et al. Evaluation of the calciumsensing receptor gene in idiopathic hypercalciuria and calcium nephrolithiasis. Kidney Int. 2000;58:38-42. G. Gambaro et al. 9. Khullar M, Relan V, Singh SK. VDR gene and urinary calcium excretion in nephrolithiasis. Kidney Int. 2006;69:943. 10. Lerolle N, Coulet F, Lantz B, et al. No evidence for point mutations of the calcium-sensing receptor in familial idiopathic hypercalciuria. Nephrol Dial Transplant. 2001;16:2317-2322. 11. Reed BY, Heller HJ, Gitomer WL, et al. Mapping a gene defect in absorptive hypercalciuria to chromososme 1q23.3-q24. J Clin Endocrinol Metab. 1999;84:3907-3913. 12. Reed BY, Gitomer WL, Heller HJ, et al. Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spine bone density. J Clin Endocrinol Metab. 2002;87:1476-1485. 13. Geng W, Wang Z, Zhang J, et al. Cloning and characterization of the human soluble adenylyl cyclase. Am J Physiol Cell Physiol. 2005;288:C1305-C1316. 14. Muller D, Hoenderop JGJ, Vennekens R, et al. Epithelial Ca channel (ECAC1) in autosomal dominant idiopathic hypercalciuria. Nephrol Dial Transplant. 2002;17:1614-1620. 15. Goodman HO, Holmes RP, Assimov DG. Genetic factors in calcium oxalate stone disease. J Urol. 1995;153:301-307. 16. Wright A, Charlesworth B, Rudan I, et al. A polygenic basis for late-onset disease. Trends Genet. 2003;19:97-106. 17. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346:77-84. 18. Gambaro G, Vezzoli G, Casari G, et al. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis. 2004;44:963-986. 19. Wang WYS, Barratt BJ, Clayton DG, et al. Todd JA. Genome-wide assocition studies: theoretical and practical concerns. Nature Rev Genet. 2005;6:109-118. 20. Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complelx genetic traits: practical considerations. Nature Rev Genet. 2002;3:1-7. 21. Soylemezoglu O, Ozkaya O, Gonen S, et al. Vitamin D receptor gene polymorphism in hypercalciuric children. Pediatr Nephrol. 2004;19:724-727. 22. Rendina D, Mossetti G, Viceconti R, et al. Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology. 2004;64:833-838. 23. Relan V, Khullar M, Singh SK, et al. Association of vitamin D receptor genotypes with calcium excretion in nephrolithiatic subjects in northern India. Urol Res. 2004;32:236-240. 24. Vezzoli G, Soldati L, Proverbio MC, et al. Polymorphism of vitamin D receptor gene start codon in patients with calcium kidney stones. J Nephrol. 2002;15:158-164. 25. Sugiyama T, Wang JC, Scott DK, Granner DK. Transcriptionactivation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-trascription factor I (COUP-TFI). J Biol Chem. 2000;275: 3446-3454. 26. Vezzoli G, Tanini A, Ferrucci L, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol. 2002;13:2517-2523. 27. Vezzoli G, Terranegra A, Arcidiacono T, et al. R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int. 2007;71: 1155-1162. 28. Corbetta S, Eller-Vainicher C, Filopanti M, et al. The A990G polymorphism of calcium sensing receptor gene (CaSR) is associated with nephrolithiasis in patients with primary hyperparathyroidism (PHPT). Eur J Endocr. 2006;155:687-692. 29. Terranegra A, Arcidiacono T, Biasion R, et al. Calcium-sensing receptor (CaSR), a candidate gene for calcium kidney stone disease. Nephrol Dial Transplant. 2006;21(suppl 4):292. 30. Bushinsky DA. Nephrolithiasis: site of the initial solid phase. J Clin Invest. 2003;111:602-605. 2 Genetics and Molecular Biology of Renal Stones 31. Gao B, Yasui T, Itoh Y. Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int. 2007;72:592-598. 32. Suzuki Y, Pasch A, Bonny O, et al. Gain of function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet. 2008;17(11):1613-8. 33. Chen WC, Wu HC, Chen HY, et al. Interleukin-1beta gene and receptor antagonist gene polymorphisms in patients with calcium oxalate stones. Urol Res. 2001;29:321-324. 34. Tsai FJ, Lin CC, Lu HF, et al. Urokinase gene 3'-UTR T/C polymorphism is associated with urolithiasis. Urology. 2002;59: 458-461. 35. Tsai FJ, Wu HC, Chen HY, et al. Association of E-cadherin gene 3-UTR C/T polymorphism with calcium oxalate stone disease. Urol Int. 2003;70:278-281. 36. Chen WC, Chen HY, Wu HC, et al. Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease. Urol Res. 2003;31:218-222. 37. Freedman ML, Reich D, Penney KL, et al. Assessing the impact of population stratification on genetic association studies. Nat Genet. 2004;36:388-993. 38. Jiang Z, Asplin JR, Evan AP, et al. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet. 2006; 38:474-478. 15 39. Cao G, Yang G, Timme TL, et al. Disruption of the caveolin-1 gene impairs renal calcium reabsorption and leads to hypercalciuria and urolithiasis. Am J Pathol. 2003;162:1241-1248. 40. Weinman EJ, Mohanlal V, Stoycheff N, et al. Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Am JPhysiol Renal Physiol. 2006;290:F838-843. 41. Mo L, Liaw L, Evan AP, et al. Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsf all protein, or both. Am J Physiol Renal Physiol. 2007;293:F1935-1943. 42. Chau H, El-Maadawy S, McKee M, et al. Renal calcification in mice homozygous for the disrupted type Iia Na/Pi cotransporter gene Npt2. J Bone Miner Res. 2003;18:64-657. 43. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006;78:193-201. 44. Gupta A, Tenenhouse HS, Hoag HM, et al. Identification of the type II Na+–Pi cotransporter (Npt2) in the osteoclast and the skeletal phenotype of Npt2−/− mice. Bone. 2001;29:467-476. 45. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nature Rev Genet. 2007;8:253-262. 46. Robertson KD. DNA metilation and human disease. Nature Rev Genet. 2005;6:597-610. 3 Physicochemical Aspects of Uro-crystallization and Stone Formation John P. Kavanagh Abstract Urinary stones are predominantly crystalline and the precipitation of uro-crystals must obey the physical-chemical principles applicable to crystallization in a broader sense. Key amongst these is the requirement for supersaturation to be generated, providing the necessary thermodynamic driving force for crystallization. The three main processes of nucleation, growth, and aggregation are all dependent on the degree of supersaturation. Nucleation of uro-crystals will be heterogeneous (occurring at a surface) and can only be sustained at a supersaturation above the equilibrium condition. Once nucleation has occurred, growth and aggregation can proceed until a saturated equilibrium is achieved, although in the continuous flow of the urinary system the supersaturation may be maintained by replenishment with fresh solute. A new crystallization process has recently been recognized involving the ordered clustering of nanocrystals, which brings together elements of nucleation, growth, and aggregation. The relevance of this to uro-crystallization is not yet clear. Of established significance is the presence of crystallization inhibitors and promoters in urine. These might act through changes in supersaturation or directly at the interface between crystals and solution or crystals and their nucleating substrate. Symbols and Abbreviations a activity Da activity driving force (supersaturation) A pre-exponential factor (in Arrhenius reaction rate equation) c concentration Dc concentration driving force (supersaturation) CaOx calcium oxalate (crystalline) DG Gibbs energy change DGhet Gibbs energy change for heterogeneous nucleation DGhom Gibbs energy change for homogeneous nucleation DGs Gibbs energy change for production of new crystal surface DGv Gibbs energy change for production of new crystal volume DGcrit Gibbs energy change for production of a critical nucleus g growth rate J.P. Kavanagh Department of Urology, University Hospital of South Manchester, Manchester, UK e-mail: firstname.lastname@example.com I ionic strength J nucleation rate k growth rate constant ksp solubility product k Boltzmann constant FP formation product L particle size Lcrit size of critical nucleus M strength factor of aggregation bridge ML metastable limit N Avogadro's number n growth rate reaction order pKa -log (acid dissociation constant) r radius rcrit radius of critical nucleus R gas constant Ragg aggregation rate Rcoll aggregate collision rate Rcon aggregate consolidation rate Rdisp aggregate dispersion rate S supersaturation ratio T absolute temperature vm molecular volume (x) concentration of species x P.N. Rao et al. (eds.), Urinary Tract Stone Disease, DOI 10.1007/978-1-84800-362-0_3, © Springer-Verlag London Limited 2011 17 J.P. Kavanagh 18 [x] activity of species x z valency a volume shape factor b surface shape factor g activity coefficient gSs interfacial energy (between substratum and solution phase) gcs interfacial energy (between crystal and solution phase) gSc interfacial energy (between substratum and crystal phase) q contact angle m0 chemical potential at the standard state m chemical potential Dm thermodynamic driving force s relative supersaturation t induction time F reaction affinity (positive form of Dm) F/N reaction affinity per molecule j heteronucleation factor Y aggregation efficiency factor Subscripts c eq s S crystals equilibrium solution substratum 3.1 Introduction Stones in the urinary tract are usually predominantly crystalline and the exceptions (rare matrix stones) will not be considered in this chapter. Crystallization is a physicochemical process involving a change of phase and this has been extensively written about elsewhere, either as a subject in its own right1,2 or with particular attention to urinary/biomineral crystallization.3–7 The intention of this chapter is to introduce the important concepts and their theoretical background, concentrating on relevance to stones but without attempting to encompass the whole of the crystallization field. In particular, crystal morphology and how modifiers (often urinary macromolecules) of crystallization act will barely be touched upon. Whatever the chemical nature and wherever in the urinary system that uro-crystallization takes place, it is an absolute requirement that there is sufficient free energy to drive the reaction. This only occurs when the solution is supersaturated; that is, the concentration of the crystallizing species in the solution is higher than its solubility in that solution. For all those rare components that make up only 1% or 2% of stones (e.g., the metabolically derived cystine, xanthine, dihydroxyadenosine, or drug-induced stones such as indinavir), supersaturation with the relevant species is absent from the urine of the general population and is only found in those who form these stones. In these cases the presence of supersaturation is sufficient to explain the consequent stone disease.7 Similarly, urine is normally undersaturated with struvite, and this only forms stones when supersaturation is developed by the action of ureasplitting bacteria. By contrast, the more common stone components, calcium oxalate (CaOx), calcium phosphate (in the form of carboxy- or hydroxyapatite), and, to a lesser extent, uric acid are often found at supersaturated levels in the urine of healthy people.7 It follows that, while supersaturation is an essential requirement for stone formation, it is possible for persistently supersaturated urine to be produced without any ill effects. In part, this is achieved by crystallization inhibitors, but it also reflects the fundamental physical chemistry of crystallization, where the energy barrier to be overcome for initiation of crystallization is greater than that required to sustain it. The most important crystallization processes are crystal nucleation, crystal growth, and crystal aggregation. Nucleation is the first stage and involves the formation of small crystal nuclei. These will be made up of only a small number of atoms (some tens or hundreds) and therefore contribute a negligible amount toward the total crystal mass or volume. Crystal growth is the incorporation of molecules or ions from solution into the crystal lattice and is the most important contributor to the total mass and volume. Aggregation is the bringing together and consolidation of individual crystals into a polycrystalline body. Although this may involve a small amount of incorporation of material from solution, it can be thought of as essentially a redistribution of the volume with little change in mass. All three of these processes are dependent on the degree of supersaturation. 3.2 Supersaturation 3.2.1 Different States of Saturation Different degrees of saturation are recognized (Fig. 3.1). A solute is undersaturated if it is in solution below its solubility, and in this case further solute, when added in Supersaturation ratio, S unstable/ spontaneous crystallization Relative supersaturation, σ metastable σ=0 S=1 stable/solid dissolves S=0 σ = −1 Fig. 3.1 Different regions of saturation can be distinguished (Reprinted with kind permission from Springer Science+Business Media7) 3 Physicochemical Aspects of Uro-crystallization and Stone Formation crystalline form, will dissolve. At the point when no more solid will dissolve, the solution is in equilibrium with the crystals and is saturated. In this state, the chemical potential of the substance in solution (ms) is equal to the chemical potential of the crystals (mc). If a saturated solution, in equilibrium with crystals, is cooled (lowering the solubility or decreasing mc) or evaporated (with the aim of increasing the solute concentration and thereby increasing ms) then the crystals will grow (taking solute from the solution) and maintain an equilibrium position with ms and mc matched. Conversely, if the saturated solution in equilibrium with crystals is heated or diluted, then some of the crystals will dissolve, again preserving the balance between the chemical potentials. At first sight, it might be thought that a supersaturated solution should not be attainable because any means used to generate a chemical potential difference between the solution and solid phase will be resisted by crystallization to the equilibrium condition. It is, however, possible to produce a supersaturated solution by cooling or evaporating an undersaturated solution (which, of course, will not contain any crystals). This is because the chemical energy required for crystallization to begin (nucleation) is greater than that needed to maintain crystallization, once crystals are already present. As long as the solution remains free of crystals then a supersaturated state can persist. As soon as crystals are introduced, or a nucleation event takes place, then these crystals will grow until the equilibrium condition is reached. This relatively stable supersaturated condition is described as being metastable. Another way to produce a supersaturated solution is to mix two solutions of soluble salts, each of which contains one part of an insoluble salt (for example, sodium oxalate and calcium chloride); if both of these are sufficiently concentrated then CaOx will immediately begin to crystallize when they are mixed. This is because the high supersaturation formed is sufficient to induce spontaneous nucleation. It is also possible to mix less concentrated solutions of two soluble salts to produce a metastable (supersaturated) solution of calcium oxalate. Forming supersaturated and crystallizing solutions of calcium oxalate in this way is a common experimental method,8,9 but it is not how urine becomes supersaturated. In the urinary tract, supersaturation is achieved largely by water removal, which gradually increases the solution concentration. 3.2.2 Supersaturation Equations The extent of supersaturation can be expressed in a number of ways, all involving the concentration of the crystallizing species in the solution