Uremic Toxins E-Book

Toshimitsu Niwa

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley-Interscience Series on Mass Spectrometry
• Sprache: Englisch

Seitenzahl: 666

Veröffentlichungsjahr: 2012

Beschreibung

Reviews all the latest basic and clinical research findings With contributions from leading international experts in the field, this book is dedicated to all facets of uremic toxins research, including low molecular weight solutes, protein-bound solutes, and middle molecules. Moreover, it covers everything from basic mass spectrometry research to the latest clinical findings and practices. Uremic Toxins is divided into three sections: * Section One, Uremic Toxins, explores the definition, classification, listing, and mass spectrometric analysis of uremic toxins * Section Two, Selected Uremic Toxins, describes key uremic toxins, explaining chemical structures, metabolism, analytical methods, plasma levels, toxicity, clinical implications, and removal methods. Among the uremic toxins covered are indoxyl sulfate, asymmetric dimethylarginine, PTH, ß2-microglobulin, and AGEs * Section Three, Therapeutic Removal of Uremic Toxins, describes how uremic toxins can be removed by hemodialysis, peritoneal dialysis, and oral sorbent All chapters are based on the authors' thorough review of the literature as well as their own personal laboratory and clinical experience. References at the end of each chapter provide a gateway to the literature in the field. Reviewing all the latest basic and clinical research findings, Uremic Toxins will help bench scientists in nephrology advance their own investigations. It will also help clinicians take advantage of the latest tested and proven treatments for the management of chronic kidney disease.

Leseprobe

Contents

Cover

Wiley Series on Mass Spectrometry

Title Page

Copyright

Preface

Contributors

Section 1: Uremic Toxins

Chapter 1: Uremic Toxins: AN Integrated Overview of Definition and Classification

1.1 Introduction

1.2 Definition of a Uremic Toxin

1.3 Classification of Uremic Toxins by Physicochemical Characteristics

1.4 Classification of Uremic Toxins According to Pathobiological Processes Underlying Accumulation

1.5 The Relationships of Uremic Toxins to the Pathobiology of Uremia

1.6 Clinical Manifestations of Uremia and the Role of Tropisms

1.7 Conclusion

References

Chapter 2: Classification and A List of Uremic Toxins

2.1 Introduction

2.2 Classification of Uremic Retention Solutes

2.3 Listing and Identification of Uremic Retention Solutes

2.4 Method

2.5 Results

2.6 Conclusion

References

Chapter 3: Analysis Of Uremic Toxins With Mass Spectrometry

3.1 Liquid Chromatography/Mass Spectrometry (LC/MS)

3.2 Capillary Electrophoresis/Mass Spectrometry (CE/MS)

3.3 Gas Chromatography/Mass Spectrometry (GC/MS)

3.4 Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS)

References

Section 2: Selected Uremic Toxins

Chapter 4: Indoxyl Sulfate

4.1 Chemical Structure and Molecular Weight

4.2 Metabolism and Biology

4.3 Quantification Methods

4.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

4.5 Toxicity and Clinical Relevance

4.6 Therapeutic Methods to Remove The Toxins

4.7 Conclusion

References

Chapter 5: p-Cresyl Sulfate

5.1 Chemical Structure and Molecular Weight

5.2 Metabolism and Biology

5.3 Quantification Method

5.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

5.5 Toxicity and Clinical Relevance

5.6 Therapeutic Methods to Remove the Toxins

5.7 Conclusion

References

Chapter 6: 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropionic Acid

6.1 Chemical Structure and Molecular Weight

6.2 Metabolism and Biology

6.3 Quantification Method

6.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

6.5 Toxicity and Clinical Relevance

6.6 Therapeutic Methods to Remove the Toxins

References

Chapter 7: Phenylacetic Acid

7.1 Chemical Structure and Molecular Weight

7.2 Metabolism and Biology

7.3 Quantification Methods

7.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

7.5 Toxicity and Clinical Relevance

7.6 Therapeutic Methods to Remove the Toxins

References

Chapter 8: Homocysteine and Hydrogen Sulfide, Two Opposing Aspects in the Pathobiology of Sulfur Compounds in Chronic Renal Failure

8.1 Homocysteine

8.2 Hydrogen Sulfide

References

Chapter 9: Guanidino Compounds

9.1 Chemical Structure and Molecular Weight

9.2 Metabolism and Biology

9.3 Quantification Methods

9.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

9.5 Toxicity and Clinical Relevance

9.6 Therapeutic Methods to Remove the Toxins

9.7 Conclusion

References

Chapter 10: Asymmetric Dimethylarginine

10.1 Chemical Structure and Molecular Weight

10.2 Metabolism and Biology

10.3 Quantification Method

10.4 Plasma/Serum Levels In Uremic Patients And Healthy Subjects

10.5 Toxicity and Clinical Relevance

10.6 Therapeutic Methods to Remove the Toxins

References

Chapter 11: Nicotinamide Metabolites

11.1 Chemical Structure and Molecular Weight

11.2 Metabolism and Biology

11.3 Quantification Method

11.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

11.5 Toxicity and Clinical Relevance

11.6 Therapeutic Methods to Remove the Toxins

11.7 Conclusion

References

Chapter 12: Dicarbonyls (Glyoxal, Methylglyoxal, and 3-Deoxyglucosone)

12.1 Chemical Structure and Molecular Weight

12.2 Metabolism and Biology

12.3 Quantification Method

12.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

12.5 Toxicity and Clinical Relevance

12.6 Therapeutic Methods to Remove the Toxins

References

Chapter 13: Glucose Degradation Products in Peritoneal Dialysis

13.1 Chemical Structure and Molecular Weight

13.2 Metabolism and Biology

13.3 Quantification Method

13.4 Levels in PD Fluids

13.5 Toxicity and Clinical Relevance

13.6 Technological Methods to Avoid or Remove the Toxins in PD Fluids

References

Chapter 14: Dinucleoside Polyphosphates

14.1 Chemical Structure and Molecular Weight

14.2 Metabolism and Biology

14.3 Quantification Methods

14.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

14.5 Toxicity and Clinical Relevance

14.6 Therapeutic Methods to Remove the Toxins

Acknowledgment

References

Chapter 15: Parathyroid Hormone

15.1 PTH: Structure and Physiology

15.2 Action of PTH

15.3 Measurement of PTH in Blood

15.4 The Toxic Effects of PTH in CKD

15.5 Acute Effects of PTH on Cytosolic Calcium

15.6 Chronic Effect of PTH on Tissue Calcium and Cytosolic Calcium

15.7 Effect of PTH on Phospholipids of Cell Membrane

15.8 Mechanisms Responsible for the PTH-Induced Rise in ([Ca2+])i in CRF

15.9 Role of PTH-Mediated Elevation in [Ca2+]i in the Genesis of the Uremic Syndrome

15.10 Management of Secondary Hyperparathyroidism in CRF

References

Chapter 16: β2-Microglobulin

16.1 Chemical Structure and Molecular Weight

16.2 Metabolism and Biology

16.3 Quantification Methods

16.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

16.5 Toxicity and Clinical Relevance

16.6 Therapeutic Methods to Remove the Toxins

References

Chapter 17: Cytokines

17.1 Chemical Structure and Molecular Weight

17.2 Metabolism and Biology

17.3 Quantification Method

17.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

17.5 Toxicity and Clinical Relevance

17.6 Therapeutic Methods to Remove the Toxins

References

Chapter 18: Free Immunoglobulin Light Chains

18.1 Chemical Structure and Molecular Weight

18.2 Metabolism and Biology

18.3 Quantification Methods

18.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

18.5 Toxicity and Clinical Relevance

18.6 Therapeutic Methods to Remove the Toxins

18.7 Conclusion

References

Chapter 19: Advanced Glycation Endproducts (AGEs)

19.1 Chemical Structure and Molecular Weight

19.2 Metabolism and Biology

19.3 Quantification Method

19.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

19.5 Toxicity and Clinical Relevance

19.6 Therapeutic Methods to Remove the Toxins

References

Chapter 20: Oxidized Albumin

20.1 Chemical Structure and Molecular Weight

20.2 Metabolism and Biology

20.3 Quantification Methods

20.4 Plasma/Serum Levels in Uremic Patients and Healthy Subjects

20.5 Toxicity and Clinical Relevance

20.6 Therapeutic Methods to Remove the Toxins

References

Section 3: Therapeutic Removal of Uremic Toxins

Chapter 21: Therapeutic Removal of Uremic Toxins by Hemodialysis

21.1 Hemodialysis

21.2 Solute Clearance by Hemodialysis

21.3 Solute Sequestration and Volume of Distribution

21.4 Application of Mass Spectrometry

References

Chapter 22: Therapeutic Removal of Uremic Toxins by Peritoneal Dialysis

22.1 Introduction

22.2 Solute and Fluid Transport in Peritoneal Dialysis

22.3 Removal of Uremic Toxins During PD

22.4 The Evaluation of Peritoneal Membrane Transport

22.5 The Assessment of PD Adequacy

22.6 Conclusion

Acknowledgment

References

Chapter 23: Therapeutic Removal of Uremic Toxins by Oral Sorbent

23.1 What is an Oral Sorbent AST-120?

23.2 Experimental Effects of AST-120 on Chronic Kidney Disease (CKD)

23.3 Clinical Effects of AST-120 on CKD

23.4 Experimental Effects of AST-120 on Cardiovascular Disease (CVD)

23.5 Clinical Effects of AST-120 on CVD

23.6 Experimental Effects of AST-120 on Bone Disease in CKD

23.7 Conclusion

References

Index

Wiley Series on Mass Spectrometry

Series Editors

Dominic M. Desiderio

Departments of Neurology and Biochemistry

University of Tennessee Health Science Center

Nico M. M. Nibbering

Vrije Universiteit Amsterdam, The Netherlands

A complete list of the titles in this series appears at the end of this volume.

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Uremic toxins / edited by Toshimitsu Niwa.

p. ; cm. – (Wiley Series on mass spectrometry)

Includes bibliographical references and index.

ISBN 978-1-118-13513-6 (cloth)

I. Niwa, Toshimitsu, II. Series: Wiley Series on massspectrometry.

[DNLM: 1. Uremia–metabolism. 2. Uremia–therapy. 3. Kidney Failure, Chronic–physiopathology. 4. Kidney Failure, Chronic–therapy. 5. RenalDialysis–methods. 6. Toxins, Biological–metabolism. WJ 348]

616.6′35–dc23

2012015255

Preface

This book is the first one that covers all aspects of uremic toxins. Many books on nephrology have been published in the past. A few books have mentioned uremic toxins briefly, but none of these books covered the whole topics of uremic toxins.

Uremic toxins include low-molecular weight solutes, protein-bound solutes, and middle molecules. In recent years, usage of mass spectrometry has dramatically increased in the research of uremic toxins. Based on analysis of these uremic toxins, the pathogenesis of uremic symptoms is being elucidated to prevent and manage the symptoms. Thus, a growing knowledge on uremic toxins should be compiled to one book.

This book covers (1) definition, classification, listing, and mass spectrometric analysis of uremic toxins; (2) description of selected uremic toxins including their chemical structures, metabolism, analytical methods, plasma levels, toxicity and clinical implication, and removal methods; and (3) therapeutic removal of uremic toxins by hemodialysis, peritoneal dialysis, and oral sorbent.

The worldwide eminent specialists on uremic toxins have contributed to this book. I am greatly indebted to them for their efforts, without which this book could not have been produced.

I sincerely hope that this book will be received by readers, and will facilitate them to easily get the information on uremic toxins for their research and clinical management of chronic kidney disease patients.

I wish to give special thanks to Ms. Kiwako Mori for her invaluable assistance. I am also appreciative of the continued support of the publishers.

Toshimitsu Niwa, MD, PhD

Department of Advanced Medicine for Uremia

Nagoya University Graduate School of Medicine

Nagoya, Japan

Contributors

Björn Anderstam, PhD, Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, KFC Novum, Lab 606, Karolinska Institutet, Stockholm, Sweden

Pavel Aronov, PhD, Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Palo Alto, CA, USA

Maurizio Bruschi, Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Genova, Italy

Giovanni Candiano, Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Genova, Italy

Gerald Cohen, Priv.- Doz. Mag. Dr., Medizinische Universität Wien, Univ. Klinik für Innere Medizin III, Abteilung für Nephrologie und Dialyse, Währinger Gürtel 18-20, Vienna, Austria

Malgorzata Debowska, PhD, Researcher, Department for Mathematical Modelling of Physiological Processes, Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland

Peter Paul De Deyn, MD, PhD, Professor, Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Rita De Smet, MSc, Department of Internal Medicine, Renal Division, Ghent University Hospital, Ghent, Belgium

Sunny Eloot, PhD, Professor, Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Gent, Belgium

Elvia García-López, MD, PhD, Researcher, Divisions of Baxter Novum and Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

Fumitake Gejyo, MD, PhD, President, Niigata University, Niigata, Japan

Sabrina Gensberger, Food Chemistry Department of Chemistry and Pharmacy-Emil Fischer Center, University of Erlangen-Nürmberg, Erlangen, Germany

Gian Marco Ghiggeri, MD, PhD, Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Genova, Italy

Richard J. Glassock, MD, MACP, Professor Emeritus, Department of Medicine, Geffen School of Medicine, UCLA Los Angeles, CA, USA

Griet LRL Glorieux, MSc, PhD, Nephrology Division, Department of Internal Medicine, Ghent University Hospital, Gent, Belgium

Walter H. Hörl, Univ.- Prof. Dr. Dr. FRCP, Medizinische Universität Wien, Univ. Klinik für Innere Medizin III, Abteilung für Nephrologie und Dialyse, Währinger Gürtel 18-20, Vienna, Austria

Diego Ingrosso, MD, PhD, Department of Biochemistry and Biophysics “F. Cedrangolo”, School of Medicine and Surgery, Second University of Naples, Naples, Italy

Joachim Jankowski, PhD, Professor, Charité, Experimental Nephrology and Hypertension, Berlin, Germany

Vera Jankowski, PhD, Priv.-Doz., Charité, Experimental Nephrology and Hypertension, Berlin, Germany

Junichiro James Kazama, MD, PhD, Associate Professor and Director, Division of Blood Purification Therapy, Niigata University Medical and Dental Hospital, Niigata, Japan

Bengt Lindholm, MD, PhD, Adjunct Professor, Division of Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, K56, Stockholm, Sweden

Hiroki Maruyama, MD, PhD, Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan

Shaul G. Massry, MD, Professor Emeritus, Department of Medicine, Keck School of Medicine University of Southern California, Los Angeles, CA, USA

Timothy W. Meyer, MD, Professor, Department of Medicine, VA Palo Alto HCS and Stanford University, Palo Alto, CA, USA

Ichiei Narita, MD, PhD, Professor, Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan

Nathalie Neirynck, MD, Department of Internal Medicine, Renal Division, Ghent University Hospital, Ghent, Belgium

Toshimitsu Niwa, MD, PhD, Professor, Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan

Alessandra F. Perna, MD, PhD, Associate Professor, First Division of Nephrology, Department of Cardio-thoracic and Respiratory Sciences, Second University of Medicine, Naples, Italy

Monika Pischetsrieder, PhD, Professor, Food Chemistry Department of Chemistry and Pharmacy-Emil Fischer Center, University of Erlangen-Nürmberg, Erlangen, Germany

Anneleen Pletinck, Department of Internal Medicine, Renal Division, Ghent University Hospital, Gent, Belgium

Naila Rabbani, PhD, Protein Damage and Systems Biology Research Group, Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospital, Coventry, UK

Jaroslav Racek, MD, PhD, DSc, Professor, Head Institute of Clinical Biochemistry and Hematology Medical Faculty Charles University, Pilsen, Czech Republic

Boleslaw Rutkowski, MD, PhD, DSc, Professor, Department of Nephrology, Transplantation and Internal Medicine, Medical University in Gdansk, Gdansk, Poland

Przemyslaw Rutkowski, MD, PhD, Department of General Nursing, Medical University in Gdansk, Gdansk, Poland

Laura Santucci, Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Genova, Italy

Eva Schepers, MBioScE, PhD, Department of Internal Medicine, Renal Division, Ghent University Hospital, Ghent, Belgium

Anna Schulz, MSc, Charite, Experimental Nephrology and Hypertension, Berlin, Germany

Tammy L. Sirich, MD, Department of Medicine, VA Palo Alto HCS and Stanford University, Palo Alto, CA, USA

Miroslaw Smogorzewski, MD, Associate Professor of Medicine, Division of Nephrology Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Peter Stenvinkel, MD, PhD, Professor, Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, K56, Stockholm, Sweden

Vladimir Teplan, MD, PhD, DSc, Professor, Vice-head, Department of Nephrology, Institute for Clinical and Experimental Medicine and Head, Chair of Nephrology, Institute for Postgraduate Medicine, Videnska, Prague, Czech Republic

Paul J. Thornalley, PhD, Professor, Protein Damage and Systems Biology Research Group, Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospital, Coventry, UK

Raymond Vanholder, MD, PhD, Professor, Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Gent, Belgium

Jacek Waniewski, PhD, Professor, Department for Mathematical Modelling of Physiological Processes, Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland

Suguru Yamamoto, MD, PhD, Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan

Section 1

Uremic Toxins

Chapter 1

Uremic Toxins: AN Integrated Overview of Definition and Classification

Richard J. Glassock and Shaul G. Massry

1.1 Introduction

As the overall function of the kidney declines in the course of chronic kidney disease (CKD) a wide variety of solutes, normally dependent on glomerular filtration, tubular secretion or renal metabolism for elimination, gradually accumulate in the body fluid compartments. Some of these solutes have biological effects that result in the malfunction of various cell types and organ systems. When these biological effects are sufficient to evoke clinically recognizable disturbances, the “uremic syndrome” is said to be present and the offending molecules are designated “uremic toxins”.1,2 These uremic toxins exhibit a broad array of physicochemical characteristics and have very diverse pathobiological effects at the cellular level.1,2 A complete characterization of the catalogue of uremic toxins would be very useful in the design of approaches for their removal by dialysis; for ways to enhance their removal by nondialytic methods; for creation of interventions to prevent/mitigate their formation; for synthesis of inhibitors of their adverse effects on cells and organ systems—all directed at subjects with advancing CKD or end-stage renal disease (ESRD). The analysis of the issues surrounding uremic toxicity requires a useful definition and synthesis of a classification of uremic toxins. This brief essay attempts to provide a succinct approach to classification of uremic toxins, derived form a review of the current literature on the subject.1

1.2 Definition of a Uremic Toxin

In order to define a uremic toxin, one must first define the syndrome of uremia itself. Almost 35 years ago, the late Jonas Bergstrom gave a definition of the uremic syndrome that is just a valid today as it was then.3 He stated that the uremic syndrome is a “toxic syndrome caused by severe glomerular deficiency associated with disturbances in tubular and endocrine functions of the kidney. It is characterized by the retention of toxic metabolites, associated with changes in the volume and composition of the body fluids and an excess or deficiency of various hormones.” This very broad definition allows the uremic syndrome to embrace the retention of solutes due to failure of renal excretion (glomerular and/or tubular insufficiency) and hormonal surfeits or deficiencies arising from the disturbances wrought by kidney disease itself, such as enhanced endogenous production or impaired degradation of potential injurious solutes.

From this description of the uremic syndrome, it is clear that uremic toxins must be defined via a connection between the putative toxic substance and one or more of the pathophysiological attributes of the uremic syndrome. Making this connection requires that a series of criteria be fulfilled. These criteria are called the Massry/Koch postulates—so-called because they are a derivative of Koch's postulates for defining a pathogenetic organism as developed by one of the coauthors of this essay (SM) about a quarter century ago.4 The requirements for an “authentic” uremic toxin are as follows:

(i) The toxin must be identified and characterized as a unique chemical entity.

(ii) Quantitative analysis of the toxin in biological fluids must be possible.

(iii) The level of the putative toxin must be elevated in biological fluids of subjects with the uremic syndrome.

(iv) A relationship between the level of the putative toxin in biological fluids and one or more of the manifestations of the uremic syndrome must be present.

(v) A reduction in the levels (or total body burden) of the putative toxin in biological fluids must result in some measurable amelioration of uremic manifestations.

(vi) Administration of the putative toxin to achieve levels similar to that observed in the uremic syndrome must reproduce the uremic manifestations in otherwise normal animals or man (in vitro demonstration of cellular toxicity alone is insufficient to meet this criterion).

A seventh criterion could be added to this list; namely, that a consistent and plausible pathobiologic mechanism should be able to explain the linkage between the putative toxin and the uremic manifestation (e.g., cellular toxicity, inhibition of signal transduction, metabolic perturbations). These postulates are difficult to apply directly to those disturbances that are part and parcel of the uremic syndrome but that emanate from surfeits or deficiencies of certain hormones or biologically active peptides (e.g., erythropoietin, calcitriol) consequent to the loss of renal mass in CKD. Nevertheless, these postulates are quite useful for the definition of uremic toxins resulting from retention of solutes normally excreted by the kidney and substances that arise in enhanced levels endogenously (from excessive synthesis or impaired degradation) as kidney disease progresses to symptomatic uremia (e.g., parathyroid hormone).

The demonstration of a linkage between a specific putative uremic toxin and a clinical manifestation of uremia can be a formidable task, as the symptoms and signs of “uremia” are extraordinarily diverse.5 The ability of a specific putative toxin to elaborate a clinical manifestation is governed by a panoply of factors (see Table 1.1). These complicate enormously the task of identifying “authentic” uremic toxins as they require longitudinal in addition to cross-sectional analysis, body fluid compartmental studies, and the influence of naturally occurring inhibitors and promoters. Some toxins may also exhibit “tropism” for specific cellular types or organ systems (e.g., neurotropism) (see below).

Table 1.1 Factors Influencing the Toxicity of Substances Accumulating in Uremia.

(1) The rapidity of changes in the levels in biological fluids(2) Fluctuations in levels over time (time averaged vs. peak levels)(3) Penetration into sites of action(4) Intrinsic toxicity versus dependency of metabolism to more (or less) toxic compounds(5) Distribution in body fluids (protein binding, lipophilicity, hydrophilicity)(6) Presence and activity of naturally occurring inhibitors or promoters(7) Rate of metabolism at active sitesReproduced with permission of Ref. [1].

1.3 Classification of Uremic Toxins by Physicochemical Characteristics

A classification of putative uremic toxins according to their physicochemical characteristics (molecular mass, polarity, protein binding, chemical structure) has been the time-honored and most popular approach.1,2 In this schema, uremic toxins are categorized into four nonoverlapping categories; namely (i) polar, water soluble, nonprotein bound, low molecular mass (<500 Da); (ii) polar, water soluble, protein bound, low molecular mass (<500 Da); (iii) middle molecular mass (>500 and <3000–12,000 Da), nonprotein bound; (iv) high molecular mass (>3000–12,000 Da), nonprotein bound.1,2 The work of the European Uremic Toxin Work Group (EUTox) has been invaluable in creating a uniform approach to classifying uremic toxins, and have pointed out the necessity for standardized schema for analysis of their in vitro effects and the enormous difficulties posed by variability in reported concentrations of putative toxins.2 In their landmark review in 2003, the EUTox group created an encyclopedic listing of uremic retention solute (90 total), 68 of which were <500 Da molecular mass, 10 had a molecular mass of >500–12,000 Da, and 12 had molecule mass of >12,000 Da. Twenty-five of the retention solutes were protein bound, all but two had molecular mass of <500 Da. The concentration of these putative toxins in biological fluids ranged broadly from ng/L to g/L. Of all the toxins identified almost 40% were either “middle” molecules or were protein bound. The development of large-scale, rapid capillary electrophoresis-mass spectrometry analysis of body fluids has greatly enhanced the ability to identify and characterize potential uremic toxins.6–9

Inorganic substances (H2O, Na+, K+, H+, Mg2+, PO42−, Ca2+, SO4) and trace metals (Al, Cr, Si, Pb) can also qualify as uremic toxins. For example, retention of sodium chloride and water can evoke disastrous consequences on the cardiovascular system in CKD and ESRD and contribute markedly to organ dysfunction (left ventricular hypertrophy), morbidity (hypertension and congestive heart failure) and mortality (sudden cardiac death).10 Also, acidosis (retention of H+ ion) can wreak havoc in many cell and organ systems.

Although many potential uremic toxins have elevated plasma concentrations due to impairment of renal excretion, many are also associated with increased synthesis or impaired degradation of normal substances produced endogenously (e.g., parathyroid hormone). It must be emphasized that the plasma concentrations of putative uremic retention solutes are very poorly correlated with the prevailing level of glomerular filtration rate (GFR),11 and the plasma levels of each specific solute may have a unique association with the level of GFR.11 These observations add emphasis to a neglected phenomenon well recognized in the aglomerular kidney of marine teleosts (anglerfish),12 specifically that the tubules represent an important site for elimination of putative toxic by-products of metabolisms. This phenomenon was pointed out in an elegant essay by Jerome Lowenstein in 2011.12

Thus, residual activity of transport systems in tubules of diseased kidneys (specifically the organic anion transporters [OAT] in the proximal tubule) may have important influence on the concentration of toxins at low levels of GFR. This phenomenon gives rise to the notion that enhanced expression of the OAT might be able to limit the accumulation of uremic toxins even with advanced loss of GFR.13

The low molecular mass solutes (<500 Da) have attracted a great deal of attention over many years. Urea (a low molecular mass, nonprotein-bound solute) has been used as a “surrogate” for authentic uremic toxins, although its intrinsic toxicity is greatly limited to very, very high plasma concentrations seldom achieved even in advanced uremia.14 The evidence that urea per se functions as an authentic uremic toxin is very weak.14 Nevertheless, its spontaneous degradation to isocyanate can lead to the “carbamylation” of serum and tissue proteins, such as albumin or hemoglobin.

Protein-bound uremic toxins are of great theoretical and practical importance.15–18 Such protein binding may greatly limit the ability of diffusive or convective dialysis therapies to remove the compound efficiently, and this explain the limitations of extra-corporeal therapies using membranes of low molecular mass “cutoff” for the treatment of uremia. Displacement of the uremic toxin from its protein-binding site might be a very attractive way of enhancing uremic solute removal by dialysis.15–18 The most well studied of the protein-bound uremic solutes include p-cresyl sulfate and indoxyl sulfate.19–24 Both of these uremic solutes originate in the colon from the action of resident bacteria—thus, there is an important contribution of the colon to the uremic state,25 leading to the potential for treatment of uremia by oral adsorbents.26 Other protein-bound uremic solutes include asymmetric dimethylarginine (ADMA), homocysteine, pentosidine, deoxyglucosone, derivatives of nucleosides, and advanced glycation end products.27,28 ADMA appears to accumulate in uremia more as a result of disturbed renal metabolism that from impaired renal excretion.27,28 It is noteworthy that the R2 values of ADMA levels in relationship to eGFR is only 0.167 (the R2 value to creatinine is 0.737).11 Uric acid and other nucleotide derivatives are emerging as important candidates for low molecular mass uremic toxins.29–31

Middle molecules (>500–12,000 Da) have been regarded as important in the uremic syndrome and its response to dialysis treatment, ever since the seminal observations leading up to the “middle molecule hypothesis” were made by Babb and Scribner 40 years ago.32 As noted above, EUTox identified about 10 such middle molecule uremic toxins in their survey.2 These compounds are often glucuronide conjugates, polypeptides (such as β2-microglobulin), carbohydrate derivatives, advanced glycation or oxidation end products, or polypeptide hormones (such as parathyroid hormone or its fragments).2,33–37 These compounds may exert their toxic effects via engagement of other intermediary processes. The high molecular mass (>12,000 Da) nondialyzable toxins have been less well characterized, but include cytokines, chemokines, Ig light chains, complement factors, advanced glycation or oxidation end products, inhibitor proteins, chemotaxis-inhibiting peptides.2

1.4 Classification of Uremic Toxins According to Pathobiological Processes Underlying Accumulation

The uremic toxins classified by their intrinsic physicochemical properties can accumulate in body fluid compartments though a number of distinct mechanisms. A Type I mechanism represents the accumulation in body fluids of toxic substances normally produced endogenously by metabolic processes largely as a result of reduced renal excretory capacity. A Type II mechanism is a surfeit of toxic substances in body fluids as a result of excess endogenous production or impaired degradation (or both) but not necessarily due to reduced renal excretory capacity. A Type III mechanism is the accumulation of toxic substances in biological fluids from exogenous sources by virtue of reduced renal excretory capacity often combined with continued dietary consumption. A Type IV mechanism is a deficiency or reduced activity of substances normally produced endogenously as a result of decreased synthesis, enhanced degradation, or biological inhibition. Combinations of more than one pathobiological process are possible. For example, urea is a uremic toxin that arises because of a combination of Type I and Type III processes—excessive accumulation due to impaired renal excretion and continued production due to exogenous (dietary) consumption of protein as a precursor of urea. It is helpful to keep this classification of the processes underlying accumulation of uremic toxins when approaching a patient with the uremic syndrome.

1.5 The Relationships of Uremic Toxins to the Pathobiology of Uremia

In recent years, a new concept has emerged that the uremic syndrome is strongly associated with a state of “chronic inflammation” and enhanced “oxidative stress” manifested by an increase in “positive” acute phase reactant proteins (such as CRP, IL-6, fibrinogen, ferritin, and serum amyloid A protein) and a reduction in “negative” acute phase reactant proteins (albumin, transferrin, prealbumin).38,39 The proposed origins of this inflammatory state include (1) an imbalance between pro- and anti-inflammatory factors; (2) underlying organ-based chronic inflammation (occult infection [periodontal disease, infected vascular access, vulnerable atherosclerotic plaques], kidney inflammation associated with basic disease); (3) exposure to inflammatory promoters (endotoxin-contaminated dialysate, bioincompatible membranes). No doubt in individual patients, multiple factors explain the presence of an inflammatory state.

Certain candidate uremic toxins, such as uric acid or ADMA, may be potent promoters of inflammation, and in turn inflammation can lead to the generation of uremic toxins, such as advanced oxidation products via the generation and inadequate scavenging of toxic oxygen radicals.40,41 Indoxyl sulfate, a putative uremic toxin, can also promote further progression of renal disease by activating harmful mediators such as transforming growth factor-β (TGF-β).42 Thus, the accumulation of uremic toxins may also exert a positively reenforcing action on the basic process of tissue and organ damage, in addition to their effect on manifestations of the uremic syndrome per se.42

The “toxicity” of ADMA has also emerged as an important element in new concepts of the pathobiology of uremic toxicity.40,41 This methylated amino acid is highly protein bound, and its concentration in plasma is elevated in uremia. The elevation is predominantly caused by the inhibition of its major kidney-derived metabolizing enzyme (dimethylarginine dimethylaminohydrolase-1; DDAH-1) rather than by markedly decreased renal excretion. ADMA, along with uric acid, is a potent inhibitor of endothelial cell nitric oxide synthase (eNOS).40,41 Impaired eNOS and reduced nitric oxide production by endothelial cells may lead to vasoconstriction, elevated blood pressure, and vascular damage. Oxidative stress associated with uremia may also impair the effectiveness of DDAH-1, proving a link between endothelial cell dysfunction and inflammation in uremia. DNA methylation and repair may also be adversely affected by putative uremic toxins.43,44 These some retention uremic solutes (such as homocysteine and its metabolites) could have profound effects on gene expression and epigenetics.43,44

Thus, the pathobiology of uremic toxicity needs to be viewed as a complex, dynamic, interacting system of effector, promoter, and inhibitory molecules occurring in a situation of reduced renal excretory capacity, impaired defensive ability, and superimposed deficiency states. The cumulative adverse effects on cellular and organ system function will depend on the balance of these factors.

1.6 Clinical Manifestations of Uremia and the Role of Tropisms

The clinical manifestations of uremic toxicity are broad and diverse. As pointed out previously every organ systems in the body can be affected. Each individual uremic toxin may have its own unique profile of “tropisms.” That is, each toxin may have a preferential action on only one system (monotropic) or act on only a few systems (oligotropic). Most uremic toxins studied so far have effects on multiple systems (pleiotropic), perhaps by interference with very fundamental common pathways of cellular behavior (elevated cytosolic calcium, nitric oxide synthesis, DNA methylation and repair, defense against oxidative stress), such as exemplified by parathyroid hormone, uric acid, and other derivatives of purine nucleotides and ADMA. However, some toxins (such as guanidino compounds) may exhibit relative specificity for certain organ systems (hematopoiesis, neuronal function, bone metabolism, endothelial cell integrity).45 Elucidation of the “tropic” behavior of individual toxins is an important element in their full characterization and classification.

1.7 Conclusion

An exposition of uremic toxicity requires an integrative analysis of the physicochemical properties of putative toxins (molecular size, protein binding), an understanding of the pathobiological processes responsible for their formation and accumulation, and a mechanistic view of how they alter fundamental cellular and organ behavior. A consideration of both glomerular filtration and tubular secretion is essential for the proper understanding of levels of putative uremic toxins in the body fluids in CKD and ESRD. An explanation of how individual or groups of toxins lead to clinical manifestations of uremia requires a consideration of tropism (monotropic, oligotropic, and pleiotropic toxins). This “multidimensional” integration allows for a better understanding of the complexity and the potential for mapping of the important elements of uremic toxicity. The long-term importance of better understanding of the chemical basis of uremia is to aid the development of better and more rational methods of treatment including ablation of organ sources of putative toxins, or the medical suppression of the activity of such organs, reduction of exogenous sources of toxic precursors, reduction in (colonic) absorption of putative toxins, enhancement of extra-renal removal of toxins (intra- or extra-corporeal), supplementation for replacement of deficiencies, suppression of toxic effects at the cellular level, replacement of renal tissue or its products.46,47 Dialytic therapy of uremic toxicity is just one small part of the overall picture of uremia.

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Chapter 2

Classification and A List of Uremic Toxins

Nathalie Neirynck, Rita De Smet, Eva Schepers, Raymond Vanholder, and Griet Glorieux

2.1 Introduction

Retention of uremic solutes starts from the moment kidney function declines, evolving in the progressive dysfunction of virtually every organ system. The clinical picture is the uremic syndrome. The kinetics of this retention process are, however, far from clear. Although during the last few years an immense progress has been made in the identification and quantification of uremic solutes, a large number of retention solutes remain unidentified. The presence of an indefinite number of posttranslational modifications of retention solutes, as a result of oxidation, glycation, cysteination, as well as of several other chemical processes, with each of these structural variants possibly exerting a pathophysiologic impact that differs from the mother compound, hampers the process of mapping the uremic retention solutes even more. Although many compounds and/or their functional role remain unknown, further identification and classification is compulsory before a targeted and possibly also tailored treatment will be possible.