When Shaul Massry and Herbert Fleisch asked me to write a foreword for this book, I was honored and eagerly looked forward to reading the many chapters. As they came and I skimmed through them, my mind wandered back to the earliest classic contributions in this field in the late 1920s and early 1930s by Albright and his associates, Greenwald and Gross and Adolph, on the homeostatic regulation of inorganic phosphate and the central role of parathyroid hormone (PTH) in this regulation. They clearly showed the exquisite sensitivity of the renal handling of phosphate to varying dietary and parenteral loads and to changes in the level ofPTH. That two outstanding investigators in the field of divalent ion me tabolism should choose to edit a book solely about the renal handling of inorganic phosphate shows how far we have progressed from these early classics to the recent almost exponential increase in the research and publications related to this subject. Despite this increase, I asked myself, is such a large new monograph, consisting of 13 chapters and 30 distin guished authors, warranted? My reading of these chapters and my learning so much from them convinced me that it is, and my pride was heightened in being asked to write the foreword for this book."

The Fourth International Congress of Peritoneal Dialysis was held in Venice, Italy, June 29 to July 2, 1987. By this time peritoneal dialysis had emerged as a treatment for a substantial fraction of patients with end-stage renal disease and countless numbers of patients with acute renal failure. This treatment is now practiced worldwide and is the life-sustaining treatment for about 40,000 patients with chronic renal failure, representing 15 to 20% of dialysis therapy in about 1000 centers. It is not surprising, therefore, that the number of health professionals engaged in the investigation and the application of the treatment has also grown exponen tially. The First International Symposium on Peritoneal Dialysis, organized by Dr. A. Treviiio-Be cerra in Chapala, Mexico, in 1978, brought together a group of pioneers when continuous ambulatory peritoneal dialysis was in its infancy. In 1981, Dr. G. M. Gahl chaired the Second Symposium, in West Berlin, when the technique and professional interest were growing con siderably. By 1984, when Dr. 1. F. Winchester and I organized the Third Symposium, the pre sented papers exceeded 100 and there were about 1000 attendees. At that time, it was deemed appropriate to form a more organized group and the International Society for Peritoneal Dialy sis was founded. One of the first actions of the Society was to choose from among several applicants Dr."

The kidney, similar to the heart, plays a three-fold role in essential hypertension. First, it participates in the patho genesis of arterial hypertension. Second, it suffers as a target organ of long-standing hypertension, and third, it experiences the effects of antihypertensive therapy. Perhaps most contested at the present time is the involvement of the kidney in the patho genesis of essential hypertension. More than a century ago, William Osler put forward three basic hypotheses about the "genuine contracted kidney. "l 1. "The hypertrophy can be regarded as an effect to overcome a sort of stop-cock action of the vessels when under the influence of an irritating ingredient in the blood greatly contracted and increased the peripheral resistance. " Clearly this hypothesis of an "irritating ingredient" is perhaps the most convincing nowadays, and numerous attempts have been made to identify a specific vasoconstrictive agent in the blood in essential hypertension. 2. "The obliteration of a large number of capillary territories in the kidney materially raised the arterial pressure. An additional factor of dimin ished excretion of water also heightened the pressure within the blood vessel. " Today we know that fluid volume overload in the presence of reduced renal mass seems to be the most likely mechanism accoun ting for renal parenchymal hypertension and, as shown by Guyton's group, for certain forms of experimental hypertension. 3.

This volume emphasizes the comparative approach to under standing vertebrate renal function. I am convinced that this approach is of particular value in understanding both the details of renal function at the cellular and subcellular levels and the renal role in regulating fluid volumes and solute concentrations. My exposure to this approach first occurred during a student research experience in the laboratory of Wilbur H. Sawyer, who also provided an introduction to the works of Homer W. Smith and August Krogh. The importance of this approach was reinforced by doctoral and postdoctoral research in the laboratory of Bodil Schmidt-Nielsen. It has been confirmed through years of personal experience since then. My research and my understanding of renal function have been aided through the years by collaboration and discussion with numerous students and associates. Of particular impor tance in developing my views on comparative renal function, and especially on the relationship of structure to function, has been my long association with my colleague and friend, Eldon J. Braun. Donald S. Farner, who suggested the writing of this volume, provided valuable editorial assistance. Much of my personal research in this area has been supported over the years by grants from the United States National Science Foundation and National Institutes of Health. The writing of this volume was completed while I was in Wiirzburg, Federal Republic of Germany, supported by a Senior U.S. Scientist Award from the Alexander von Humboldt Foundation."

The management of chronic renal failure by dialysis and transplantation has now become an established form of treatment in many parts of the world. However, these forms of treatment have brought with them problems in relation to the selection of patients, economics, clinical problems such as hypertension, encephalopathy, anaemia and renal bone disease, and psychological and social problems. The management of haemodialysis has changed over the years with developments in dialysers, vascular access and the duration of dialysis. Although the overall survival from renal trans plantation has changed little in the past four or five years, there are hopes of improvements in relation to tissue typing and enhancement. Perhaps the most important aspect in the management of chronic renal failure is the multi-disciplinary approach. Nursing and medical staff work closely with dialysis technicians, engineers, dietitians, local authority per sonnel, social workers and with the relatives of the patients. The symposium was planned to draw together representatives from all disciplines involved in the care of patients with chronic renal failure. One of the most relevant sessions was that in which two patients with chronic renal failure described their experience."

In June, 1981, we conducted a two day international symposium in Rome devoted to original scientific presentations on arachidonic acid metabolism in the kidney. Scientists from 20 countries were represented either in the general scientific program or in the poster presentation. This book does not represent the proceedings of this international gathering, but rather the edited manuscripts specifically prepared as sum- maries of the scientific presentations. We feel that the timeliness and originality of the contributions as well as the need for a compilation of existing work on prosta- glandins, thromboxane, and the kidney warrant this publication. The meetings would have been impossible without the generous and substantial support of the Italian government, the National Institutes of Health, United States Public Health Service, and Merck Sharp & Dohme International. Supplementary support was also received from Ciba Geigy S. p. A. , Ente Fiuggi, Farmitalia Carlo Erba S. p. A. , Glaxo Laboratori S. p. A. , Hoechst Italia S. p. A. , Leo Pharmaceutical Products, Pfizer Italiana S. p. A. , Sigm? Tau S. p. A. , Squibb S. p. A. , The Upjohn Company, Wellcome Italia S. p. A. , and Burroughs Wellcome Company. The efficient organization of the symposium was largely attributable to the superb efforts of Elisabeth Mutschlechner and Miki Scarinci of C. K. International, Rome. Linda Goldberg provided expert and invaluable editorial and secretarial assistance in the organization of this book. The book is divided into four major sections comprising: I.

Im Juni 1979 hatte in Dusseldorf ein Symposion uber Diuretika stattgefunden. Behandelt wurden experimentelle und klinische Ergebnisse mit Diuretika, unter anderem mit Diucomb. Ziel des Symposions war, Untersuchungsergebnisse zu referieren und diskutieren. Teilnehmer waren Wissenschaft ler aus der Schweiz, Osterreich, Grossbritannien, USA und der Bundesrepublik Deutschland. Das Material dieses Symposions wurde uberarbeitet, Diskussionen durch einen Redaktionsstab gestrafft. Wir danken Frau J. BOROS fur wertvolle technische Assistenz. Der Springer-Verlag hat uns wiederum sach kundig beraten und ist in grosszugiger Weise unseren Wunschen entgegengekommen Die Herausgeber Inhaltsverzeichnis Einleitung. F. KRUCK . . . . . . . . . . . . . 1 1. Wirkungsmechanismen. Moderation: K. GREEFF . 3 Plasma Concentrations and Comparative Bioavailability of Bemetizide and Triamterene in Combination. L. F. CHASSEAUD . . . . . . . . 5 Pharmakokinetik von Diuretika bei eingeschrankter Nierenfunktion. H. KNAUF und E. MUTSCHLER 14 Diskussion 24 Neue Daten zur Toxizitat von Diuretika. F. LEUSCHNER 26 Diskussion 29 2. Renale Wirkungen. Moderation: O. KRAuPP. . . . . . . . . . . . 33 Die Wirkungsweise diuretischer Substanzen in Abhangigkeit von ihrer re- len Behandlung. P. DEETJEN . . . . . . . . . . . . . . . . . . . 35 Effects of Diuretics on Renal Potassium and Hydrogen Ion Transport. G. GIEBISCH and M. HROPOT . . . . . . . . . . . . . . . . . . . 42 Wirkungen von Diuretika auf den transzellularen Elektrolyttransport der Niere. M. WIEDERHOLT und L. L. HANsEN 53 Diskussion 60 Interaktion zwischen Diuretika und renalem Prostaglandinsystem. H. J. KRAMER, B. STINNESBECK, W. PRIOR und R. DUSING 64 71 Diskussion Untersuchungen zum Wirkungsmechanismus von Acetazolamid und SITS auf den Bikarbonattransport im proximalen Tubulus der Rattenniere."

Recent developments in recombinant DNA technology have led to the large-scale production of human erythropoietin and to the demonstration that it is effective in the treatment of renal and possibly some other anaemias. This has lent a new impetus to studies of the pathophysiology and pharmacology of the hormone which is reflected in this report of the proceedings of a meeting held in Liibeck in June 1988. In 15 papers, all from European centres, the broad topics covered are erythropoietin's physiology and chemistry, the patho- physiology of erythropoiesis and the use of erythropoietin in the treatment of anaemia. Several of the papers include up-to-date reviews of the literature. The field is now expanding rapidly, and this volume, though not comprehensive, usefully points up many areas of recent understanding as well as others of continuing un- certainty. Overall, it contains material likely to be of interest to biochemists and experimental haematologists as well as to phar- macologists, clinical haematologists and nephrologists.

Nitrates have been for many years the cornerstone of cardiovascular therapy for various indications. Not only have nitrates stood the test of time for treatment of chronic stable angina pectoris, but the indications for them have markedly ex panded. They now include all forms of angina pectoris and myocardial ischemia, congestive heart failure and hypertensive emergencies. The beneficial effects of nitrates in all these conditions result from their vasodilatory properties, but it is still unclear whether the central or peripheral effects predominate in the thera peutic mechanism. Recently nitrates have been shown to fulfill the most important requirement for each and every drug - to reduce mortality. A large scale study revealed that isosorbide dinitrate, combined with hydralazine, reduced long-term mortality by 28% in patients with congestive heart failure. This finding will certainly stimulate research on nitrates, and it might be expected that interest in these drugs will markedly increase. The primarily used nitrates in clinical practice are nitroglycerin and the com plex organic nitrates, mainly isosorbide dinitrate. The organic mononitrates are now under clinical investigation, and isosorbide-5-mononitrate (IS-5-MN) appears to be especially promising.

The Department of Continuing Education of Harvard Medical School and members of the faculty of Harvard Medical School held a multidisciplinary course on the management of patients with urologic cancer in the fall of 1982. This course high lighted the multidisciplinary approach to the care of these patients, and outlined the clinical and pathophysiological basis for diagnosis and treatment. The term multidisciplinary was essential to the course in which the disciplines of uro logic surgery, medical oncology, and radiation therapy were each appropriately emphasized. Widespread interest in the contents of this course, and the timely and useful nature of much of the information presented there, has encouraged us to publish, in as rapid a manner as possible, new information and highlights of that course. A camera-ready format was used to allow rapid production, and a variety of disparate styles were maintained from chapter to chapter--some in prose, others in outline. Again, our intent was to disseminate information rapidly and accurately, and to that end, we felt that consistency of style was irrelevant."

Heart and brain interaction is an increasingly vital area of clinical investigation. This is the most comprehensive review of the subject available, presented by internationally recognized authorities in the field. The book offers extensive coverage of cardioembolic stroke, including a brand new contribution on the mechanism of hemorrhagic infarction. Controversial topics such as anticoagulation, combined carotid and coronary surgery and screening for silent coronary disease are covered. Also included are a comprehensive review of the cardiovascular/neurobiological role of the central nervous system in hypertension and sudden death, and a practical approach to the patient with syncope. This integrated, topical presentation makes essential reading for neurologists, cardiologists, internists and anyone caring for patients with stroke or cardiac disease.

Congenital adrenal hyperplasia (CAH) consists of a group of disorders of adrenal steroidogenesis. Each disorder results from an inherited deficiency of one of the several enzymes necessary for normal steroid synthesis. The different enzyme deficiencies produce characteristic patterns of hormonal abnormalities; the clinical symptoms of the different forms of CAH depend on the particular hormones that are deficient or that are produced in excess. The earliest documented description of CAH was by DeCrecchio in 1865 (DeCrecchio 1865). This Neapolitan anatomist described a cadaver having a penis with first degree hypospadias but no externally palpable gonads. Dis- section revealed a vagina, uterus, fallopian tubes, ovaries, and markedly enlarged adrenals. It is interesting that the subject suffered a confusion of sex assignment, being declared a female at birth and a male 4 years later. He conducted himself as a male sexually and socially. Since the original descrip- tion of this case, investigators have unravelled the pathophysiology of the inborn errors of steroidogenesis. 1 Steroidogenesis and Enzymatic Conversions of Adrenal Steroid Hormones A. Steroidogenesis The adrenal synthesizes three main classes of hormones: mineralocorticoids (17-deoxy pathway), glucocorticoids (17-hydroxy pathway), and sex steroids.

Advanced Renal Cell Carcinoma (RCC) cannot be cured by surgery alone. Its resillience to irradiation and chemotherapy demands a new approach to the management of this disease. This book provides an overview of the scientific and clinical developments of RCC, and clarifies the fields ofimmunotherapy and immunobiology. The book contains a compilation of approaches that will enhance the effectiveness of the management of advancedRCC, even in the absence of definitive pre-clinical data. These require additional study and will stimulate the reassessment of preliminary results.Furthermore, preliminary results of already implemented clinical trials withbiological modifiers are presented. Of special interest are the current achievements in the field of immunotherapy using topically and subcutaneously low dosage combinations of cytokines. This concise volume will benefit those seeking a thorough review of the research and the clinical aspects of RCC simultaneously.

The action of diuretics including cellular mechanisms of action, pharmacokinetics, and clinical usage, with much emphasis placed on the most recent findings on the pharmacodynamics of the respective drugs. During the past twenty-five years since volume 14 on Diuretica was published in the Handbook series, the cellular mechanisms of action of diuretics have slowly been unravelled. Today, the role of action within the target cells is known for most of the substances discussed. This has provided a new basis not only for the understanding of drug action but also for secondary effects and interactions. The book represents a comprehensive reference work on the diverse groups of diuretics which are among the most frequently prescribed medications.

The human prostate gland is of undoubted importance in reproductive physiology and is one of the commonest causes of clinical urological problems in the male patient. Despite the wealth of published lit erature relating to the prostate gland surprisingly little is understood about its neural innervation, the influence of pharmacological factors and its precise physiological functions. Indeed, benign disorders of the prostate gland including benign prostatic hyperplasia, bladder neck dyssynergia and inflammatory disorders of the prostate (prostatitis, prostatodynia) although well recognised clinically, are as yet poorly characterised and understood. It was not until the late 1960s that the subject of urodynamics, which for the first time allowed scientific assessment of the function of the lower urinary tract, was introduced. The first section of this book considers recent advances in our understanding of the innervation of the bladder and prostate gland and the changes in bladder function which accompany prostate medi ated bladder outflow obstruction. The clinical consequence of benign prostatic hyperplasia in many patients is bladder outflow obstruction and although the traditional treatment of these conditions is by the use of ablative surgery, in recent years a number of new modalities have been investigated and are reviewed in the second section of the book.

For the last two decades, the topic of chronic renal failure has been dominated by discussions on dialysis and transplantation. As facilities for treating patients with end-stage renal failure have become more readily available, at least in Europe and North America, attention has once again been drawn to conservative measures which may improve both the overall prognosis and the quality of life of patients with renal impairment. Although severe renal failure may be progressive and many patients will ultimately require some form of renal replacement therapy, it is now widely appreciated that distressing symptoms can often be ameliorated by judicious medical treatment. Children as well as, and perhaps to a greater extent than, adults may benefit from such therapy. This volume examines relevant trends in the conservative man agement of both adults and children with chronic renal failure. Each chapter has been written by recognized experts and provides infor mation of clinical relevance for the average clinician. As the overall prognosis for patients with end-stage renal failure improves it is clear the management of patients with relatively stable chronic renal failure is an important topic not only for nephrologists but for all practising clinicians."

Combining principles of contemporary immunology with applications to immunopathology, this up-to-date volume documents new developments in the understanding of the origin of autoimmune diseases. Emphasized are cellular and molecular approaches in both organ-specific and systemic autoimmunity. A comprehensive bibliography, numerous illustrations, and tables make it an invaluable source of information for immunologists, rheumatologists, pathologists, dermatologists, and nephrologists.

A large number of chemical agents are known which affect blood and blood-forming organs. The purpose of this volume is to review the sig- nificant advances made over the past several years regarding such chemical agents. The purification, biological action, and therapeutic implications of several widely used hematopoietic growth factors such as interleukin 3 (IL-3 or multi-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), colony stimu- lating factor (CSF-I or M-CSF), thrombopoietin, and erythropoietin are included in this volume. These factors are important in regulating several hematopoietic cell lines such as neutrophils, monocytes, eosinophils, macrophages, megakaryocytes, platelets, and erythrocytes. People are exposed daily to numerous toxic chemical substances present in our environment which produce a suppression of erythropoiesis, myelo- poiesis, lymphocytopoiesis, and megakaryocytopoiesis. Attempts have been made in this volume to assess the therapeutic role of some of the hematopoietic factors such as erythropoietin in the anemia of end stage renal disease, as well as colony stimulating factors in other hematopoietic abnormalities. In addition, some of the chemical factors in our environment which suppress major hematopoietic lineages stimulated by erythropoietin, macrophage colony stimulating factor, granulocyte colony stimulating factor, interleukin I-alpha, interleukin I-beta, and interleukins 2, 3, 4, 5, 6, 7, and 9 are also included. An updating of the mechanism of action of each of these factors on the major hematopoietic lineages is covered.

The aim of the INTERNATIONAL YEARBOOKS OF NEPHROLOGY is to publish every year a volume to keep nephrologists up to date on all the rapidly changing areas of nephrology. Each volume will be published by the end of each calendar year which corresponds with the annual meeting of the American Society of Nephrology. Each issue of the INTERNATIONAL YEARBOOKS OF NEPHROLOGY will be divided into sections; each section will have different primary focus every year, depending upon what area is of greatest interest at the time. In other words, each annual volume will deal with what is truly current in nephrology. All the authors appointed for the chapters of the INTERNATIONAL YEARBOOKS OF NEPHROLOGY are known experts in the field who will give an objective review of the topic up-dating the readers on the world-wide literature. A crucial point for the success of the INTERNATIONAL YEARBOOKS OF NEPHROLOGY is the list of the references at the end of each chapter. We have asked all authors to provide a complete, accurate and up-to-date list of important references. In order to guarantee the most up-to-date yearbook, very rapid production is mandatory. Rapid publication can be obtained only with camera-ready manuscripts for direct photo-offset reproduction. Thus we have agreed to use photo-offset printing for the series. For the first issue of the series, the INTERNATIONAL YEARBOOK OF NEPHROLOGY 1989, the Editorial Board has focused attention on the latest and most important scientific and clinical advances in nephrology.

Acute renal failure is undoubtedly one of the marize in one volume the recent advances on patho- most interesting and frequent syndromes observed physiology of acute renal failure, the clinical aspects by clinicians. A great number of factors may of the various forms (even those which have been acutely impair renal function, but the pathoge- disregarded in other surveys), the diagnostic tests netic mechanism by which this occurs is fre- available today in our clinical practice, the general quently unknown. Even the pathophysiology of and specific therapeutic measures and (very impor- ischaemic!toxic forms of acute renal failure re- tant, indeed), some useful suggestions for preven- mains controversial despite the huge number of tion. experimental and clinical studies. The contributors have provided clear, complete Medical management of patients with acute renal and up-to-date chapters. I am deeply grateful to failure has greatly improved in recent years, partic- them all. ularly with the use of different types of dialytic I like to express my sincere thanks to Dr. A.J.

Concise, recent data are presented on obstetric problems arising in patients with cardiovascular diseases (not only congenital and acquired valvular heart diseases and hypertension, but also uncommon heart lesions) and on cardiological complications encountered in pregnant women. The goal of the book is to provide obstetricians with necessary cardiological information and cardiologists with essential obstetric information to enable both specialists to make optimal decisions regarding the permissibility of pregnancy, management of pregnancy and labour, or termination of pregnancy, and selection of an adequate form of contraception in women with heart and vascular diseases. Along with recent scientific findings, the book contains practical recommendations for examination diagnosis and treatment that is effective for the mother and safe for the fetus.

After the positive response which followed the first edition of this book 6 years ago, the editors were encouraged to prepare a completely reworked second edition that includes the modern advances in this field. There has been a complete change of diagnostic procedure in the detection of renal tumors, which is now based on sonography, computed tomography, and nuclear magnetic resonance imaging, pushing intravenous urography and angiography completely into the background. Also, new methods of treat ment with radionuclides using embolisation are incorporated. The description of morphological structures forms the basis for under standing and recognising pathology of the kidneys and adrenals. The con tents of pathological morphology could be extended, as we are of the opinion that the detection and therapy of renal and adrenal tumors are derived from different areas of diagnostic science. We are indebted to Springer-Verlag for the excellent book production. On behalf of all the authors, we would like to thank our colleagues and associates for their cooperation in the realisation of this project. The editors hope that this volume will be of interest to radiologists, pa thologists, urologists, pediatrists, and also radiotherapists. Essen, April 1987 EBERHARD LOHR LUTZ-DIETRICH LEDER Table of Contents Pathology of Renal and Adrenal Neoplasms LEDER, L.-D., RICHTER, H.l.

A workshop was organised in order to achieve multi-discipli- nary review of the pathogenesis and management of acute failure, particularly as it occurs and is managed in intensive therapy units. The book deals with the realities and practicalities of this important area of acute medicine. Each chapter is followed by a discussion, so that a concen- sus view is obtained from an international body of experts.

The 1992 International Yearbook of Nephrology is the 4th in a successful series of yearly books updating practising nephrologists and nephrologists-in-training on rapidly changing areas of nephrology. We were encouraged to proceed in our editorial venture by reviews of the previous issues which have appeared in various Nephrology Journals. These reviews have pointed to the successful use of the International Editorial Board, the broad range of topics of current interest which have been covered and the comprehensive and practical nature of the reviews. The principal aim of the Yearbook remains to provide reviews which are more current than those which appear in Nephrology textbooks and which can be in the hands of the readers a few months after the authors have completed the manuscripts. The appointed authors are always experts in the field, who are asked to give an objective review of the topic, up-dating the readers on the world-wide literature and providing them with a complete, accurate and up-ta-date list of important recent references. We have decided to maintain the successful format of the first three issues. Thus, the volume will continue to be divided into sections; each section will continue to have a different primary focus every year, depending upon what is of greatest interest at the time.

Glutamine is a key aminoacid for the synthesis of numerous biologic- ally important compounds in mammalian cells and is a carrier form of ammonia. The advance in knowledge on the metabolic significance of this amino acid is presented in in-depth treatments by experts in this active research field. This includes the enzymology of glutamine synthe- tase and glutaminase activities in different mammalian organs, notably liver, kidney and brain; properties of glutamine transport across bio- logical membranes; role of glutamine metabolism in the liver, with emphasis on the recent discovery of intercellular heterogeneity with respect to enzyme distribution and its functional consequences for ammonia/urea metabolism and pH regulation; renal and intestinal glutamine metabolism; cerebral glutamine/ glutamate interrelationships; skeletal muscle; role of glutamine in cell culture; and finally the clinical aspects, including the new outlook of glutamine antagonists in cancer therapy as well as the role of glutamine in hepatic coma and encephalo- pathy. Some, but not all, of the contributors to this work attended the 48th Conference of the Gesellschaft fur Biologische Chemie on glutamine metabolism held in Gottingen, W. Germany, in September 1983. This conference was supported by the Stiftung Volkswagenwerk, Dr. H. Falk Foundation, Freiburg, and the J. Pfrimmer Co. , Erlangen. The abstracts of the contributions to the conference were published in Hoppe-Seyler's Z. Physiol. Chem. 364,1237-125,6,1983, and this book is not intended as the proceedings of that meeting.