Urinary Stones Diagnosis, Treatment, and Prevention of Recurrence
Albrecht Hesse, Ph.D. Professor of Experimental Urology Department of Urology University of Bonn Sigmund-Freud-Straße 25 DE–53105 Bonn, Germany E-Mail:
[email protected] Harnsteinanalysezentrum Bonn Urinary Stone Analysis Centre Theaterplatz 14 DE–53177 Bonn, Germany E-Mail:
[email protected] Hans-Göran Tiselius, M.D., Ph.D. Professor of Urology Division of Urology Department of Clinical Science, Intervention and Technology Karolinska Institutet Department of Urology Karolinska University Hospital SE–141 86 Stockholm, Sweden E-Mail:
[email protected] Roswitha Siener, Ph.D. Associate Professor of Medical Nutrition Science Department of Urology University of Bonn Sigmund-Freud-Straße 25 DE–53105 Bonn, Germany E-Mail:
[email protected] Bernd Hoppe, M.D. Professor of Pediatrics Head, Division of Pediatric Nephrology Department of Pediatrics University Hospital Cologne Kerpener Straße 62 DE–50924 Cologne, Germany E-Mail:
[email protected]
Urinary Stones Diagnosis, Treatment, and Prevention of Recurrence Albrecht Hesse, Bonn Hans-Göran Tiselius, Stockholm Roswitha Siener, Bonn Bernd Hoppe, Cologne
Foreword by Hibbard E. Williams, Davis, California, USA 36 figures, 16 in color, 2009 3rd revised and enlarged edition
Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Shanghai • Singapore • Tokyo • Sydney
Nachsorge bei Harnstein-Patienten: Ein Leitfaden für die ärztliche Praxis Herausgeber: A. Hesse, A. Jahnen, K. Klocke, A. Nolde, O. Scharrel ISBN 3–334–60832–8 © Gustav Fischer Verlag, Jena, 1994 1. Auflage Urinary Stones: Diagnosis, Treatment, and Prevention of Recurrence Editors: A. Hesse, H.-G. Tiselius, A. Jahnen ISBN 978–3–8055–6346– 8 © Gustav Fischer Verlag, Jena, 1997 1st edition Urinary Stones: Diagnosis, Treatment, and Prevention of Recurrence Editors: A. Hesse, H.-G. Tiselius, A. Jahnen ISBN 978–3–8055–7370–2, e-ISBN 978–3–318–00811–1 © S. Karger AG, Basel, 2002 2nd edition Library of Congress Cataloging-in-Publication Data Nachsorge bei Harnstein-Patienten. English. Urinary stones : diagnosis, treatment, and prevention of recurrence / Albrecht Hesse ... [et al.] ; foreword by Hibbard E. Williams. – 3rd rev. and enl. ed. p. ; cm. Rev. ed. of: Urinary stones : diagnosis, treatment, and prevention of recurrence / Albrecht Hesse, Hans-Göran Tiselius, Andrea Jahnen. 2nd rev. and enl. ed. 2002. Includes bibliographical references and index. ISBN 978-3-8055-9149-2 (soft cover : alk. paper) 1. Urinary organs – Calculi – Handbooks, manuals, etc. I. Hesse, A. (Albrecht) II. Title. [DNLM: 1. Urinary Calculi – Handbooks. WJ 39 N123u 2009a] RC916.N3313 2009 616.6‘22–dc22 2009016407 Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2009 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhard Druck, Basel ISBN 978–3–8055–9149–2 e-ISBN 978–3–8055–9150–8
Contents Foreword Preface to the first edition Preface to the second edition Preface to the third edition Introduction General aspects The emergency stone – Treatment of patients with acute renal colic Standard procedures – Treatment and care of patients with urinary stones Type of stone Calcium oxalate stones Uric acid stones Calcium phosphate stones Struvite stones Cystine stones 2,8-Dihydroxyadenine stones Xanthine stones Ammonium urate stones Appendix Interventional procedures Absorption/loading tests Risk indices Examination under standardized dietary conditions Analytical methods Unusual stone components/artifacts Tables 1–3: Calcium, oxalate and purine contents of foods Tables 4–6: Reference values for children Crystals in the urinary sediment (colored illustrations) References Subject index
VII VIII IX X 1 7 8 21 37 38 66 86 108 124 142 152 160 173 174 178 186 190 192 198 200 206 213 216 227
Foreword Renal stone disease is a most ancient and common affliction of man. Over a seventy-year life span, it is estimated that as many as 15% of some populations will develop renal stones. No age is spared and no country or ethnic group protected from this common clinical problem. Most, but not all, patients who develop a stone will eventually form others. Although very few individuals die as a direct result of stone disease, it does lead to substantial morbidity from pain, urinary tract infections and obstructive uropathy. In the past few decades, substantial progress has been made in understanding the basic pathophysiologic mechanisms of stone disease, which has subsequently led to rational and effective programs for both its treatment and prevention of recurrence. Diagnostic study protocols to identify underlying mechanisms have now become available in most countries, thereby allowing for an accurate categorization of patients with renal stone disease. This handbook to assist physicians in the diagnosis, treatment and prevention of stone disease has been developed by its three editors, each of whom has contributed significantly to our basic understanding of stone disease. Their handbook is oriented toward clinicians and health care professionals to help them quickly and effectively study and treat patients with stone disease and assist them in developing effective approaches to the prevention of further stone development. In addition, it is written in a manner that could make it very useful in explaining to patients the more important aspects of their disease. It is very well organized, making it simple to use as a reference work and its utility is strengthened by an outline format, which facilitates understanding of diagnostic studies and treatment plans. All of the major stone types are discussed in detail, including sections on the less frequent stones, such as those composed of xanthine and 2,8-dihydroxyadenine. Of particular value is the discussion of diagnostic studies to be performed in those patients for whom a stone is not available for analysis, an increasingly common event now that lithotripter use has made it more difficult to recover stones. With our ability to determine more accurately than ever the basic mechanisms of stone formation and, therefore, to develop more effective treatment programs, recurrent stone disease should become less and less common. The editors and authors of this text have made an important contribution to this effort with this handbook which should be of immense help to health care professionals who care for patients with renal stones in efficiently and effectively guiding them through the appropriate diagnostic studies and the development of safe plans for treatment and prevention. Their patients will be ultimate beneficiaries of this text. We are grateful to its editors and authors for such a useful and usable book. Hibbard E. Williams, M.D. Professor and Dean emeritus School of Medicine University of California, Davis, California, USA July 1996
VII
Preface to the first edition During the past 15 years, therapeutic procedures for urinary stone disease have undergone fundamental changes. Alternative methods of lithotripsy have made open surgery superfluous in most countries. Repeated treatment with extracorporeal shock wave lithotripsy (ESWL) is relatively free of side effects and, as a rule, does not interfere with kidney function. However, one should note that these modern methods of therapy serve only to treat the symptoms of the disease – the stone. The actual cause of stone formation – infection, malnutrition, metabolic abnormalities, etc. – frequently remains unnoticed, so that recurrence is bound to occur. With a yearly incidence rate of 0.5% in Europe, the number of recurrences approximates 80%. However, with detailed knowledge of the causes of urinary stone formation, recurrences can largely be prevented. To achieve this goal, there is a need for laboratory diagnostics, including stone and urine analyses. Furthermore, it is necessary to investigate the dietary (nutritional) habits of the patient so that they can be given comprehensive guidelines for their specific kind of stone disease. Finally, the most appropriate post-operative follow-up care must be provided including, if necessary, the use of drugs. The patient should be encouraged to take part in a two-year therapy with regular checks. This may spare the patient further and repeated illness and can reduce the costs of therapy quite considerably. The present book is a manual for physicians in charge who, in the course of practice, encounter urinary stone patients. It provides appropriate diagnostic procedures as well as general advice for recurrence prophylaxis. To start with, there is a survey of outpatient diagnosis and treatment of acute urinary stone disease as it occurs in emergency medicine. If no stone analysis is available, general and unspecific therapeutic measures may be used. If, however, the type of stone is known, the indication as described in the respective chapter should be applied. The layout of the book is arranged so that on the right-hand pages, concise and distinct information is presented, while on the left-hand pages the respective detailed explanation is given. We trust that this book serves as a useful and practical guide to all physicians treating their urinary stone patients. The authors July 1996
VIII
Preface to the second edition The first edition of our book and an unamended reprint stimulated great interest world-wide. Karger Publishers consequently asked us to prepare a second revised edition. We are pleased to comply with this request, and are grateful to the staff of the publishing house for their excellent cooperation. A recent epidemiological survey revealed that 5.5% of all men and 4% of all women in Germany already had urinary stones (prevalence). In the case of men, 10% of those aged 50 or above were stone formers. Acute disorders were recorded in 1.5% of the population in the year 2000 (incidence). The high incidence of this disease makes it clear that modern methods of lithotripsy (ESWL, PNL, URS) have led to the continued disregard of metabolic diagnosis and the prevention of recurrent stone formation. It is in the vital interest of both patients and health economics that prophylactic measures are undertaken for each stone patient in order to prevent recurrences. During the revision of this book due attention has been paid to the current literature (see references) as well as the European and international guidelines on urolithiasis. Certain special methods of metabolic clarification have been supplemented in the appendix. Detailed tables referring to the oxalate, calcium and uric acid content of food have been added. We assume that the reference values for urinary excretion derived from healthy children will help to improve the treatment of children with urinary stones. We trust that this book will prove to be helpful to both doctors and their patients. The authors September 2001
IX
Preface to the third edition ‘Urinary stones are thriving’ – that is certainly not a good slogan! Despite the progress in clinical stone treatment, the incidence of urolithiasis is rapidly increasing. The methods for stone removal – SWL, URS, PNL – have constantly improved, and each method has its preferred application depending on the location and size of the stones involved. However, increasing attention is being paid to the fact that urinary stones less than 1 cm in size can pass spontaneously. A conservative approach with stone expulsion therapy via increased diuresis in combination with physical exercise and – if necessary – medication with -adrenoreceptor antagonists, calcium channel blockers and/or non-steroidal anti-inflammatory agents has proved successful. Expulsion rates of up to 70% have been achieved for stones in this category. In recent years, the guidelines for urinary stone therapy of urological societies (AUA, EAU, DGU) have been updated by expert committees. While the spectrum of available therapeutic methods has remained similar, application of these methods in various countries differs greatly. SWL is still the most important method for active stone removal. Improved flexibility of the instruments and the more widespread use of laser therapy have enhanced the importance of endourologic procedures, also in the treatment of renal stones. The efficiency rates for complete stone removal of staghorn calculi are between 50 (SWL) and 80% (PNL). For ureteral stones, stone-free rates of more than 90% can be achieved with both URS and SWL. However, residual concrements or fragments may often remain in the body after stone removal, and when this material does not pass spontaneously directly after completion of the treatment, it can provide the nucleus for a new stone. From a physico-chemical point of view, no insignificant residual concrements can ever occur when the urine is constantly supersaturated. Regardless of any residual concrements, epidemiological studies have shown that 25% of stone patients are at risk of multiple stone formation. Accordingly, differentiation has been made between high- and low-risk patients in the guidelines. This differentiation is based on the stone case history, the results from the stone analysis, and a basic laboratory diagnostic examination. For the prevention of recurrences in high-risk patients, an elucidation of metabolic risk factors is vital and may be followed by a treatment appropriate for the stone type. Consistent metaphylaxis can prevent more than 50% of recurrences. Patients not only expect to be relieved from symptoms caused by stones, but they also wish to remain free from recurrences. This should be the benchmark against which any therapeutic regimen is measured. In the 3rd edition of Urinary Stones, the recommendations contained in the international and German guidelines relating to urinary stone therapy have been taken into account. Also the latest scientific progress in clinical and laboratory diagnosis, together with dietary therapy and medication, have been included. The current edition also relates more deeply to the specific situation of urolithiasis in childhood. Excellent cooperation with the Karger Verlag has enabled a fundamental revision of the previous edition with the result that state-of-the-art tools are now available for the prevention of recurrences. May everyone applying our recommendations enjoy great success with the treatment of their patients! The authors March 2009
X
Checklist General aspects
Introduction
CaOx
The emergency stone Introduction
Ua
Urinary stones Y belong to the group of biominerals Y are the final product of a multifactorial process
CaP
Y the stone is the symptom, not the disease itself
Symptoms of different abnormalities
Struvite
w
Y occur today with a prevalence of 4–10%, which is steadily increasing
Widespread disease
2,8-DHA
w
Cystine
Y regional differences are important to acknowledge
NH4Urate
Metaphylactic treatment is undoubtedly necessary
Appendix
w
Xanthine
Y the recurrence rate which depends on the stone composition is 50–100% in untreated patients and 10–15% in treated patients
1
Introduction
Formation of urinary stones The biomineralization resulting in a urinary stone has a multifactorial origin in which socio-economic, genetic and constitutional factors as well as diet, pharmacologic treatment and metabolic abnormalities might act in concert. A supersaturation of urine with the stone-forming salt(s) is of fundamental importance and a prerequisite for the necessary precipitation. The solubility of the different stone components depends on the urinary pH and the excretion of other urine constituents. Accordingly, a saturation of urine above the solubility product (SP) and the associated risk of crystallization are determined by the urinary concentration (mmol/l) of the solutes taking part in the crystal formation and the pH. When the SP has been exceeded, the supersaturation is metastable. At this level of supersaturation the crystals can grow and aggregate (agglomerate) but new crystal formation is not possible unless promoted in some way. In order to start the formation of new crystals, the supersaturation has to be further increased to a level termed the formation product (FP). The isolated findings of increased concentrations are not diagnostic for stone disease but might reflect only the concentration capacity of the kidney. Normal values of urine constituents are usually expressed as the total excretion during a 24h period or a fraction of a 24h period. In children the excretion values are normally expressed in mmol and mg/1.73 m2 body surface area/day, or in mmol and mg/kg body weight/day, respectively. In infants and small children spot urines are analyzed and the substance concentration in urine is related to creatinine. Normal values are age-related and additionally given in mmol/24h and in mmol/kg body weight/24h (Appendix, tables 4–6). There is often an overlap in terms of urine supersaturation between stone formers and normal subjects indicating that factors other than the supersaturation have to be considered in the process of stone formation. It is of note, however, that the urine composition obtained from 24h or similar collections might obscure term from peaks of supersaturation. Substances which inhibit the nucleation, growth and aggregation of crystals are thought to play an important role. Furthermore, anatomical and functional abnormalities might contribute either by fixation of crystals or by reducing their excretion. Such a retention of crystals is necessary for the development of a clinically significant crystalline deposit.
Solubility
ammonium urate
uric acid
cystine
phosphate
pH dependence of the urinary solubility of lithogenic substances
2
5
6
7
8
Urinary pH
General aspects
Introduction
CaOx
Formation of urinary stones Profession Mentality
Nutrition Constitution
Climate Race
Inheritance
Metabolic abnormalities
Genetic factors
Ua
Age Sex
Abnormal renal morphology
Disturbed urine flow
Urinary tract infection
CaP
P
excretion of crystallization promoters
pH
excretion of crystallization inhibitors
urinary volume
pH
2,8-DHA
P
Xanthine
Physico-chemical change in the state of supersaturation
P
NH4Urate
Abnormal crystalluria Crystal aggregation Crystal growth
P
Appendix
excretion of stone-forming constituents
Decreased
Cystine
Increased
Struvite
P
Urinary stone
3
Introduction
Location and form of urinary stones Urinary stones occur in all parts of the renal collecting system. The sites of occurrence and formation are not necessarily identical. In the industrialized part of the world, Y 97% of all urinary stones are localized in the: parenchyma (collecting ducts) papilla calices
pelvis pelvis + calices ureter
Y only 3% are found in the bladder and the urethra. The anatomy of the collecting system at the site of stone development is an important determinant for the shape of the stone inasmuch as there frequently is an adaptation to the surrounding structures.
Composition and occurrence of the different crystal phases in urinary stones Urinary stones belong to the group of biominerals. Different inorganic or organic substances with a crystalline or amorphous structure are the major constituents of the stones. Only about 1/3 of all urinary stones has a monomineral composition. There is frequently a structure with layers of varied composition or a homogeneous mixture of different crystal phases. Calcium oxalate is by far the most common stone constituent, and is considered to be the major mineral in at least 70% of all stones. Stone type
Chemical composition
Mineral
Major constituent, % of cases
Oxalates
Calcium oxalate monohydrate Calcium oxalate dihydrate Uric acid Uric acid dihydrate Ammonium urate (mono ammonium urate) Magnesium ammonium phosphate hexahydrate Carbonate apatite Calcium hydrogenphosphate dihydrate Protein Cystine Xanthine 2,8-Dihydroxyadenine Indinavir Silicates Sulfonamides
Whewellite Weddellite Uricite
74.0
Uric acid and urates Phosphates
Protein Genetically determined stones Drug stones
Struvite Dahllite Brushite
11.0 1.0 0.5 5.8 5.0 1.5 0.5 0.5
rare
It is important to consider that the relative distribution of various stone constituents is subject to pronounced geographical variations.
4
General aspects
Introduction
CaOx
Location and shape of urinary stones
Staghorn stone
Pelvic stone
Ua
Calix stone
CaP
Ureteral stone
Cystine
Struvite
Bladder stone
Calcium oxalate monohydrate Calcium oxalate dihydrate
Whewellite Weddellite
Phosphate
Carbonate apatite Calcium hydrogenphosphate dihydrate Tricalcium phosphate Calcium hydroxyl phosphate Magnesium ammonium phosphate hexahydrate
Dahllite Brushite Whitlockite Hydroxyapatite Struvite
Uric acid, Urate
Uric acid Uric acid dihydrate Ammonium urate (mono ammonium urate) Mono sodium urate monohydrate
Uricite – – –
Stones associated with inborn errors of metabolism
L-Cystine
– – –
Xanthine 2,8 -Dihydroxyadenine
Xanthine
Oxalate
NH4Urate
Mineral name
Appendix
Chemical name
2,8-DHA
Composition of the most important stone constituents
5
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
General aspects
CaP Struvite
21 f.
Cystine
H
2,8-DHA
Standard procedures – Treatment and care of patients with urinary stones
Xanthine
8 f.
NH4Urate
H
Appendix
The emergency stone – Treatment of patients with acute renal colic
Ua
CaOx
General aspects
7
General aspects – the emergency stone
The emergency stone Symptoms A urinary stone that obstructs the renal collecting system causes an emergency situation, either as an episode of renal colic or by infection of the obstructed urinary tract.
Renal colic The pain associated with urinary stones can be explained by two mechanisms: 1. Dilatation of the obstructed system with stretching of the pain receptors in the renal pelvis and calices. 2. Local irritation in the wall of the ureter or renal pelvis with edema and release of pain mediators. Differential diagnosis A. Renal colic due to other urologic diseases Y passage of a blood clot Y passage of necrotic tissue Y hydronephrosis caused by pyeloureteral junction (PUJ) obstruction, stricture, compression or abnormal angulation of the ureter B. Other kinds of abdominal pain Y gastrointestinal: appendicitis, terminal ileitis, diverticulitis, cholecystitis, cholelithiasis, duodenal or ventricular ulcerations, pancreatitis, infectious colitis, toxic colon Y vascular: infarction of the kidney, spleen or bowel due to arterial obstruction; aortic aneurysm Y gynecological: ovarian cysts, adnexitis, ectopic pregnancy, endometriosis, ischemia Y others: psoas abscess, retroperitoneal tumors, cardiac infarction, porphyria, intoxication with heavy metals, diabetes mellitus, pheochromocytoma, Addison’s disease C. Children Y symptoms in infants and smaller children may not be colicky abdominal pain, but high fever, vomiting, failure to thrive.
Obstructive pyelonephritis It needs to be emphasized that an obstruction of the renal collecting system is not always associated with renal colic. The combination of flank pain and fever, possibly together with fits of shivering, constitutes an alarming symptomatology. The presence of a urinary tract infection and a dilatation of the renal collecting system demonstrated with ultrasound call for emergency relief of the obstruction. In these cases treatment with antibiotics alone is not sufficient inasmuch as the progressive infection might lead to urosepsis, a condition which has a very high mortality (150%), even with late diversion of urine from the obstructed kidney.
8
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist Emergency stone
Y Clinical signs:
reduced blood pressure, abdominal distension, sparse peristalsis, pain on deep palpation over the stone or most commonly in the costovertebral angle
Y Associated symptoms:
nausea, vomiting, urgency, pollakisuria, oliguria
Ua
very restless Skin: pale, cold perspiration
CaP
Y Patient’s appearance:
With accompanying urinary tract infection:
dysuria, fever, signs of septicemia, anuria
infection, sepsis, anuria
Y Patient’s appearance:
impaired general condition, reduced consciousness
Y Clinical signs:
reduced blood pressure, abdominal distension, sparse or no peristalsis, pain on percussing over the kidney, often only diffuse back or abdominal pain
Y Associated symptoms:
fever, nausea, vomiting
Xanthine
Y Primary symptoms:
2,8-DHA
Symptoms of obstructive pyelonephritis
NH4Urate
w
Where? kidney, urinary bladder, flank, thigh, middle and lower abdomen, urethra, genital tract
Struvite
How? sudden start of attacks of cramp-like pain
colicky pain (not always obvious in infants)
Cystine
Y Primary symptoms:
CaOx
Symptoms of renal colic
Appendix
w
9
General aspects – the emergency stone
Emergency diagnostic work-up Laboratory diagnostics Urine examination Erythrocytes: Microhematuria is a general symptom of urinary stone colic, but may infrequently be absent. Leukocytes and nitrite: Each stone in the urinary tract can cause an obstruction of the urine flow and information on an associated urinary tract infection is required (caution: obstructive pyelonephritis). pH: When clinical presentation, microhematuria and ultrasonography indicate a stone as explanation of the colic, but the plain radiograph is without calcifications, a pH around 5.0 supports the suspicion of a stone composed of uric acid. Blood examination Creatinine: Information on the level of this variable is necessary before administrating intravenous contrast medium, especially in the case of patients with only one kidney or with known reduced renal function. In case of a suspected obstructive pyelonephritis, all those laboratory analyses are indicated that can be of value for the establishment of a correct diagnosis or for the appropriate monitoring of the severity of the disease (caution: acidosis, thrombocytopenia, coagulation abnormalities, renal failure, electrolyte disturbances).
10
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Emergency diagnostics
Culture
Indicates
positive positive positive >7.0 <6.0 ≥105 colonies/ml
urinary tract stone infection (caution: obstructive pyelonephritis) infection infection induced alkalization acid urine; uric acid stone? infection
increased WBC increased increased increased
reduced renal function/obstructed kidney infection infection infection, sepsis
CaP
1. Urine examination Test strips: Erythrocytes Leukocytes Nitrite pH
Finding
Ua
CaOx
Urine and blood examination
Cystine 2,8-DHA Xanthine NH4Urate
Serum creatinine Blood cells Neutrophils CRP, Procalcitonin
Struvite
2. Blood examination
Appendix
w
11
General aspects – the emergency stone
Imaging Ultrasonography is a rather poor technique to demonstrate stones in the ureter, where most stones are located in patients with acute stone colic. As a radiation-free method, its major indication is to show the extent of hydronephrosis as a reflection of the degree of obstruction. Ultrasonography, however, is the method of choice in the pediatric patient with stones and, with the exception of the acute stone in the middle part of the ureter, all other stones are visible for the experienced examiner (also using the twinkling sign, e.g. duplex sonography artefact method). A plain abdominal film of the kidney, ureters and bladder (KUB) is a good method to demonstrate radioopaque urinary tract stones, provided the image quality is not disturbed by intestinal contents. In combination with ultrasonography, KUB might be informative, although the accuracy of this approach is rather low. Plain abdominal film gives valuable information on the number, size, form and position of the stones. This enables an assessment of the probability of spontaneous stone passage (which can be expected in 80% of the cases with stones not larger than 5 mm in diameter). Concrements of minor size, those overlying the bone structures and those composed of radiolucent constituents will escape detection. This method should be avoided in the pediatric patient. Unenhanced helical computerized tomography (CT) is the technique that during recent years has become the primary diagnostic tool in patients with clinical symptoms of acute stone colic. Information is obtained on the presence and size of urinary tract concrements and the morphology and dilatation of the renal collecting system. In combination with a KUB (or just by examining the ‘scout’ image) CT can strongly suggest the presence of uric acid stones, inasmuch as the latter stones are visible on the CT but not on the KUB. The method is very fast and can be accomplished without injection of contrast medium. This means that the examination can be carried out without information on renal function. Intravenous (excretory) urography was previously the standard method for the diagnostic work-up, but today in the majority of cases it is replaced by the much more informative CT. Only when the CT examination is inconclusive or difficult to interpret (for instance in the presence of numerous phleboliths) urography is indicated. Thyroid hormone levels have to be determined beforehand. This method is, however, obsolete in children. Intravenous urography gives more detailed information on the renal collecting system. The grade of obstruction and the current function of the kidney can be assessed by comparing the excretion of contrast medium on the two sides. The intravenous urography should preferably be carried out during a colic-free interval and, if possible, following appropriate intestinal preparation (caution: ruptures of the collecting system, acute renal failure). A normal excretion of contrast medium in an undilated system during an episode of colic makes it likely that the pain has another explanation than a urinary stone. In case of an inconclusive urography, CT might be indicated. Retrograde or antegrade ureteropyelography is useful for establishing a correct diagnosis in silent kidneys with a suspicion of an obstructing ureteral stone (caution: ascending infection). It needs to be emphasized, however, that the choice of imaging method for patients with acute stone colic has to be decided by the imaging procedures that are locally available. Ultrasonography is the method of choice in pediatrics; avoid X-ray examinations!
12
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Emergency diagnostics
Ultrasonography: Issue: Limitation:
Method of choice in pediatrics! Obstruction? Stone in the kidney, in the sub-pelvic or prevesical ureter? Stones in the middle part of the ureter cannot be demonstrated
Ua
Almost all stones can be demonstrated. Morphology and dilatation. Other diseases? No contrast medium.
(Caution: increased serum creatinine; rupture of the renal pelvis) Position of calcifications within the renal collecting system; demonstration of radiolucent stones as filling defects in the contrast; obstruction due to urinary stones; anatomic abnormalities of the kidneys or ureters.
Cystine
i.v. urogram: Issue:
Struvite
Plain abdominal film (KUB): Stones? Size? Position? Issue: Radiolucent stones cannot be demonstrated; stones overlying bone structures are difficult to Limitations: identify; a safe discrimination between stones and calcified opacities outside the collecting system cannot be made.
CaP
CT examination:
CaOx
Imaging
NH4Urate
Xanthine
2,8-DHA
Retrograde, antegrade pyelography: Intracavitary conditions in case of suspicion of a ureteral stone as an explanation of a silent kidney.
Appendix
w
13
General aspects – the emergency stone
Therapy Emergency treatment of a patient with renal colic Renal colic pain is one of the most intense forms of pain that can be experienced. The condition requires prompt symptomatic treatment, an important prerequisite of which is the exclusion of other possible causes. An abdominal source must be excluded, but definite conclusions in this regard usually cannot be made until the patient has been given adequate pain relief. A typical observation in patients with renal colic: H extreme restlessness! Immediate measures for pain relief: H Prostaglandin synthetase inhibitors or spasmoanalgesics are given intramuscularly or intravenously. In case of less intensive pain a suppository might be sufficient. In mild cases: utilization of the viscero-cutaneous reflex by application of heat together with purging. In severe cases: repeated injections or intravenous infusion of spasmoanalgesics. Supportive measures:
anti-edema therapy mobilization
Interventional treatment: Patients with frequently recurring episodes of renal colic or with therapy-resistant pain need some active procedure to accomplish decompression of the renal collecting system. An internal ureteral stent or a percutaneous nephrostomy catheter can usually solve the problem. Otherwise an emergency procedure for stone removal is necessary. Immediate decompression is necessary in patients with bilateral stones, a single kidney or when there is risk of urosepsis.
14
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Renal colic
Ua
I First-line treatment of patients with acute renal colic is subject to considerable variation due to local therapeutic traditions, and whereas a specific pharmacologic agent might be available in one country, in others it is not. The following suggestions therefore only serve as examples of how efficient pain relief can be accomplished.
CaOx
Emergency treatment of renal colic
Initial therapy or
Butylscopolamine bromide Dose: 20–40 mg i.v. or i.m. Preparation: e.g. Buscopan
CaP
Diclofenac sodium Dose: 50 (–75) mg i.m. Preparation: e.g. Voltaren (1–2 ml)
Struvite
I
In patients with lasting pain Butylscopolamine bromide Dose: 40 mg i.v. or i.m.
Cystine
Diclofenac sodium Dose: 75 mg i.m. (do not exceed a daily dose of 150 mg) or
Xanthine
2,8-DHA
Morphine analogues such as: Hydromorphone hydrochloride + atropine sulfate (Dilaudid-Atropine 1 ml s.c.) Ketobemidone hydrochloride (Ketogan 5–7.5 mg i.v.) Methylscopolamine, morphine, atropine (Spasmofen 1–2 ml s.c., i.m. or i.v.) Calcium antagonists (e.g. amlodipine or nifidipine) I If these measures are insufficient, consider active decompression or stone removal.
NH4Urate
I
Appendix
Risk of urosepsis due to infection in an obstructed collecting system or anuria with bilateral stones calls for immediate relief of the obstruction.
Treatment in children Paracetamol: 10–20 mg/kg body weight every 6 hours Tramadol: 0.5–1 mg/kg body weight per dosage up to 8 mg/kg per day (in children 11 year of age) Metamizol: 10–15 mg/kg body weight every 6 hours
15
General aspects – the emergency stone
Methods for stone removal When the acute problems have subsided, the radiographic examination provides a basis for the subsequent management of the patient. Based on the size, form and position of the stone, it is concluded whether a spontaneous passage of the stone can be expected, if the stone can be dissolved or if it requires some kind of active removal.
Facilitation of spontaneous stone passage For stones with a diameter of 5 mm or smaller there is a high likelihood of spontaneous passage. As many as 80% of such ureteral stones might pass, but the time until passage can be as long as 40 days. Continuous administration of diclofenac sodium (50 mg ! 2–3) or paracetamol in pediatric patients (10–20 mg/kg body weight ! 3–4) is useful for prevention of recurrent episodes of stone colic. Alternatively suppositories of spasmoanalgesics can be given. Facilitation of stone passage can be accomplished by ␣-adrenoreceptor antagonists (such as tamsulosin, doxazosin). The effect of this form of treatment has been demonstrated in meta-analyses of results from patients with stones in the distal ureter. Inasmuch as also proximal ureteral stones sooner or later are supposed to take a distal position, there also seems to be a wide indication for ␣-blocking agents in the treatment of such patients. Another option to facilitate stone passage is nifedipine. Because of obstipation, it is frequently necessary to normalize the bowel function by purgatives or enema or both. Normal bowel function is associated with normal ureteral peristalsis. Sharp-edged concrements might cause edema of the ureteral mucosa in which case anti-edema therapy will facilitate stone passage. An increased diuresis can be useful to flush the stone(s) out, and a daily intake of 2–3 liters (or 1.5 liters per m2 body surface area in children) of fluid evenly distributed over the day can be recommended to patients without renal and cardiac insufficiency. It is necessary to follow the intake and outflow of fluid as well as the body weight. An increased intake of fluid should, however, not be started until the acute dilatation of the renal collecting system has subsided and the patient is without pain. Physical activity should be encouraged. It is important that the patient at each voiding passes the urine through a sieve (e.g. Zylosieb쏐 or Urocup쏐) in order to catch the stone for subsequent analysis of its chemical composition.
16
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Stone passage
Facilitation of stone passage CaOx
?
H 80% of all ureteral stones pass spontaneously
CaP
Ua
Y Treatment and/or prevention of episodes of renal colic Diclofenac sodium (Voltaren쏐) Paracetamol Butylscopolamine bromide (Buscopan쏐) ␣-Adrenoreceptor antagonists (tamsulosin or doxazosin; e.g. FlomaxtraTM, UrimaxTM, Alfadil쏐) or Calcium antagonists (e.g. amlodipine or nifidipine) Y Normalization of bowel function
Struvite
Y Anti-edema therapy Diclofenac sodium (Voltaren쏐)
2,8-DHA
Cystine
Y Increased diuresis in the pain-free patient Intake of 2–3 liters (or 1.5 liters per m2 body surface area in children) evenly distributed over the 24h period (even during the night) Suitable beverages: mineral water with a low content of mineral salts; fruit tea, herbal tea, kidney tea, bladder tea Less suitable beverages: coffee, black tea, green tea, undiluted fruit juices Unsuitable beverages: sugar-sweetened soft drinks including cola; ice tea; alcoholic beverages including beer H Beer is not a therapeutic agent
q
Appendix
NH4Urate
Xanthine
Y Physical activity
Until the stone has been delivered, pass the urine through a sieve at each voiding.
17
General aspects – the emergency stone
Limitations of spontaneous passage In the majority of cases, the propensity for spontaneous passage is dependent on the size and the surface character of the stone. More than 80% of stones with a diameter not exceeding 5 mm will pass spontaneously and for stones with a smooth surface, passage can be observed up to a diameter of 9–10 mm. It is thus justified to wait for spontaneous passage of small stones if the ultrasound/radiographic follow-up shows no obstruction or deterioration of kidney function and there are no signs of urinary tract infection. In contrast, a pronounced dilatation of the renal collecting system makes intervention necessary. This treatment has to be undertaken within 7–10 days for stones in the upper ureter and within a few (approx. 2–3) weeks for lower ureteral stones unless the stone moves so that the shape of the collecting system is normalized. For a stone that remains in a fixed position for a longer period of time (up to 4 weeks), active stone removal should be considered. The constant irritation of an impacted stone might cause an inflammatory process, a ‘stone-bite’. Therapeutic measures must immediately be instituted when signs of infection with fever appear in an obstructed collecting system. This is particularly so with ascending, obstructive pyelonephritis, because of the risk of urosepsis. The patient’s experience of pain, tolerance, frequency of episodes of colic as well as his or her profession are factors that affect the compliance with a conservative approach and such factors often change the limits presented above. If a spontaneous passage cannot be achieved, it is necessary to proceed with interventional methods. In pediatrics be aware of compliance issues. However, spontaneous stone passage should also be the primary choice.
18
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Stone passage
CaOx
Limitations of spontaneous stone passage Y Stone diameter >5 mm
Ua
Y Pronounced dilatation of the collecting system with reduced function, due to an impacted stone. Risk of local inflammation (‘stone-bite’) Y Infection in an obstructed collecting system H particularly with ascending, obstructive pyelonephritis
Struvite
CaP
Y Patient’s compliance pain experience, tolerance frequency of colic episodes profession pediatric patient I
Cystine
If spontaneous passage cannot be expected: I
Xanthine
2,8-DHA
H 174 f.
NH4Urate
Active stone removal is necessary
Appendix
w
19
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Standard procedures
H
22 f.
Y Imaging
H
24 f.
Y Biochemical investigations
H
26 f.
H
27 f.
H
28 f.
CaP
Y Medical history
Ua
Stone episodes
Struvite
Biochemical investigations I
Minimal analytic program
Cystine
Y Examination of spot urine samples Y Blood examination
2,8-DHA
Y Stone analysis I
Quality standard Elucidation of the causes of stone formation
Xanthine
Y Examination of 24h urine Y Blood examination
H 190 f.
NH4Urate
Y Dietary history H Metabolic disturbances: Repeated examinations under standardized dietary conditions I
Special investigations Appendix
w
Y Procedures specific for the stone composition Y Loading examinations Y Metabolic studies
H 178 f.
21
General aspects – standard procedures
Careful medical history Common in patients with stones composed of:
22
Current age/Age at first stone: <15 years 15–25 years Fertile women and during pregnancy
Cystine, Struvite, 2,8-DHA, CaOx (PH I/II) Cystine, CaOx Struvite
Profession: Sedentary work, stress, exposure to heat
CaOx
Stone disease in relatives:
Cystine, 2,8-DHA, Xanthine, CaOx
Associated diseases: Disturbances of the metabolism of calcium: pHPT, RTA, Wilson’s disease, medullary sponge kidney (MSK), osteoporosis, immobilization, sarcoidosis, osteolytic metastasis, plasmocytoma, FHHNC (familial hypomagnesemia with hypercalciuria and nephrocalcinosis), Dent’s disease Disturbances of the metabolism of oxalate: Primary hyperoxaluria – type I and II Enteric hyperoxaluria: Crohn’s disease, ulcerative colitis, short bowel syndrome, lack of intestinal oxalate-degrading bacteria (Oxalobacter), intestinal resection, malabsorption, conditions following bariatric surgery Disturbances of the metabolism of uric acid: As a result of cell death: Anemia, neoplastic disorders, intoxication, cardiac infarction, irradiation and treatment with cytotoxic agents As a result of enzyme defects: Primary gout, Lesch-Nyhan syndrome As a result of alterations in the excretion of uric acid: Renal insufficiency, metabolic acidosis
CaOx, CaP
CaOx
Uric acid
Infections: Recurrent urinary tract infections (commonly found in association with anatomic and functional abnormalities of the urinary tract)
Struvite, CaP, Ammonium urate
Medications: Uricosurics, analgesics, vitamin C, anti-epileptic medication
Uric acid, CaOx, CaP
Intoxication: Ethylene glycol
CaOx
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Medical history
CaOx
Schedule for a careful medical history (Explanations on the left page)
Stone analysis: Current stone situation: Plain abdominal film ]
CT ]
Brothers, sisters ]
Yes ] First symptom: First stone: Latest stone: Total number: Number during the last 12 months: By Spontaneous passage ] SWL ] PNL ] Result: Method: IR spectroscopy ]
No ]
Ultrasonography ]
Cystine
URS Open surgery Nephrectomy
Struvite
CaP
Ua
Parents ]
] ] ]
2,8-DHA
Stone removal:
Date of birth: Sex:
X-ray diffraction ]
Xanthine
A history of stone disease in: Associated diseases: Medical treatment for stone prevention: Other forms of medical treatment: Dietary restrictions: Age at:
Body weight:
Intravenous urogram ]
Right Kidney Staghorn Nephrocalcinosis Ureter
] ] ] ]
Left Kidney Staghorn Nephrocalcinosis Ureter
] ] ] ]
Bladder
]
Urethra
]
NH4Urate
Name: Height: Profession:
Appendix
w
]Cave: avoid plain abdominal film and i.v. urogram in pediatric patients
23
General aspects – standard procedures
Imaging Ultrasonography This examination can be repeated frequently without irradiation. Difficulties are, however, encountered for stones in the ureter, and it is not possible to discriminate between calcified and radiolucent stones. Ultrasonography plays an important role in detecting complications such as obstruction with dilatation of the renal collecting system, reduction of renal parenchyma, or for the follow-up of an obstructed kidney during therapy. Ultrasonography is thus less suitable for detailed information on the stone situation. It is, however, the diagnostic tool to be used in pregnant women and children. In all other situations, CT examination without contrast is the superior method.
Radiographic examinations On plain abdominal films of the kidneys, ureters and bladder (KUB), it is usually possible to detect stones with a diameter of 1–2 mm. It is not possible, however, to discriminate between calcifications within and outside the renal collecting system. Radiolucent stones are not visualized. The combination of a KUB film and CT examination can be used to identify radiolucent stones, which in the majority of cases are composed of uric acid. A KUB film is also of great value before interventional procedures because of the similarity to fluoroscopic images. Moreover, the KUB is very useful in the follow-up of patients after extracorporeal shock wave lithotripsy, because on the CT image it can be difficult or impossible to distinguish between gravel and solid stone material. In most other cases the unenhanced CT examination is an excellent procedure that clearly demonstrates the number, size and position of the concrements. At the same time, valuable information is obtained about anatomic abnormalities that might be of importance with respect to the stone formation (horseshoe kidney, double kidney, obstruction of the pelvo-ureteric junction, calix stenosis, ureteral stricture, etc.). The intravenous urogram is necessary for a detailed description of the geometry of the renal collecting system if that kind of information is desirable. Moreover, the intravenous urogram is of great value for the appropriate demonstration of a urothelial tumor. This method is obsolete in children and clearly unnecessary (ultrasound is helpful in most cases – in the rare case where it is not, a MR examination of the kidney and the lower urinary tract is recommended). Grading scale of medullary nephrocalcinosis [Dick et al. 1999]
Grade I Grade II Grade III
24
Mild increase in echogenicity around the border of the medullary pyramids Mild diffuse increase in echogenicity of the entire medullary pyramid Greater, more homogeneous increase in the echogenicity of the entire medullary pyramid
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Imaging
Ultrasonography Limitations:
Necessary in pregnancy and in children Demonstration of radiolucent stones and dilatation of the renal collecting system Inappropriate for the demonstration of some ureteral stones No discrimination can be made between calcified and radiolucent stones
Struvite Cystine 2,8-DHA
1. Plain abdominal film (] avoid in children!) Issue: Y Identification of calcified concrements: H high density: CaOx and CaP stones low density: struvite, mixed and cystine stones H indications for qualitative cystine test (particularly in young patients) Y Demonstration of stones, their size, form and position Limitations: Y Radiolucent stones cannot be identified; neither can extremely small stones or stones shadowed by bone structures. Y No discrimination between calcification within and outside the renal collecting system 2. CT examination Issue: Y Excellent for a detailed description of the stone situation Y No contrast medium necessary Y Detection of radiolucent stones H Uric acid, xanthine, 2,8-dihydroxyadenine, ammonium urate, drug stones 3. Urogram (] obsolete in children!) Issue: Y Detection of radiolucent stones as filling defects H Uric acid, xanthine, 2,8-dihydroxyadenine, ammonium urate, drug stones Y Demonstration of the location of the stones within the renal collecting system Y Demonstration of anatomic abnormalities
CaP
Radiographic examinations
Xanthine
Y
Y Y Y Y
Ua
Issue:
NH4Urate
Y
CaOx
Imaging
Appendix
w
25
General aspects – standard procedures
Biochemical investigations I First examination Minimal program A minimal analytic program should be applied to patients presenting with their first stone. This set of analyses can be carried out in each routine laboratory and comprises a sample of blood serum and a spot urine sample (mid stream). The different variables of interest are summarized on the right page. Information on the pH is important both for the initial evaluation and for subsequent treatment. The measurement of pH as well as the specific gravity of urine is best carried out by the patient, and special equipment is available for this purpose: pH- and density strips and urometer (Zylometer쏐). A standardized urinary sediment might be useful to diagnose hematuria, leukocyturia and crystalluria. When a urinary tract infection is suspected, a quantitative urine culture has to be carried out along with a determination of the sensitivity in case of more than 105 colonies/ml. When cystinuria is suspected or cannot be excluded (family history of stone disease; concrements with a low density on the radiogram, particularly in young patients), a cystine test (Brand’s test, cyanide nitroprusside test) should be carried out. A positive result supports the suspicion. Microscopic examination of urine with demonstration of the typical hexagonal crystals is diagnostic for cystinuria. Typical crystals in the urinary sediment can also occur in other types of stone (see p. 213 f.). Collected stones or crystals need to be analyzed further. Physical methods such as IR spectroscopy or X-ray diffraction should be used (chemical stone analysis is obsolete!) (see p. 192 f.). All children with the first stone event are high-risk patients and should be screened more extensively (see p. 206 f., tables 4–6). Repeated spot urine or 24h urine analysis should give evidence of a possible metabolic background of stone disease, e.g. primary hyperoxaluria or cystinuria.
26
Treatment
Metaphylaxis General aspects
Biochemical investigations
Checklist
Minimal program
CaOx
Minimal analytic program
WBC culture bacteria cystine test Serum calcium
urate creatinine
RTA infection acid urine hematuria infection infection
CaOx, CaP struvite, CaP uric acid all stones struvite, CaP struvite, CaP
>1.010 g/cm3
low fluid intake
all stones
≥105 colonies/ml positive >2.5 mmol/l
>380 mol/l <120 mol/l increased
mucosal lesion infection glomerulonephritis infection infection cystinuria susp. HPT, Williams-Beuren syndrome in infants hyperuricemia hypouricemia disturbed renal function
Struvite
CaOx uric acid uric acid dihydrate struvite cystine apatite brushite 2,8-DHA, NH4-urate all stones
Cystine
envelope, dumb-bell shaped crystals fine crystalline, rectangular crystals whetstone shaped crystals coffin-lid shaped crystals hexagonal plates pseudoamorphous crystals basalt columnar structured crystals brown spherical shaped crystals present
CaP
Ua constantly >5.8 >7.0 ≤5.8 positive positive positive
2,8-DHA
erythrocytes
Common with stones composed of
Xanthine
erythrocytes WBC nitrite Urometer/Strips: density, specific gravity Urinary sediment: crystalluria see Appendix, p. 213 f.
Indicates
struvite, CaP struvite, CaP cystine CaOx, CaP
NH4Urate
Urine (spot urine sample) Test strips: pH value (measured several times a day)
Result
uric acid, CaOx xanthine
Appendix
Examination
Stone analysis: H only with physical methods: IR spectroscopy, X-ray diffraction
27
General aspects – standard procedures
Biochemical investigation II Quality standard General methods for elucidating the causes of stone formation When the existing stone has passed, it is important to start the search for risk factors and mechanism(s) that might have been responsible for the development of the stone. Quality standard under normal dietary conditions: Y Examination of a 24h urine collection (or urine sample collected during any other specified period of time) Y Examination of serum Y Dietary assessment H The patient has to: – collect a 24h urine sample (but analysis of urine should not be carried out until at least 10–20 days have passed after stone passage or removal) – measure a pH profile during the day – complete a diet record H The doctor has to: – give instructions for the appropriate: collection of a 24h urine sample management of test strips, urometer completion of a diet record – provide bottles for urine collection containing an appropriate preservative solution, either: 10 ml of 5% thymol in isopropanol (for a 2 l bottle), or: 20–30 ml of 6 mol/l hydrochloric acid (if uric acid can be omitted from the analytic program) Acidification of urine is necessary in order to prevent precipitation of calcium salts and to prevent oxidation of ascorbic acid to oxalate. If there is reason to suspect a metabolic or dietary abnormality (as a result of the dietary assessment), the biochemical investigation has to be repeated under standardized dietary conditions. H See Appendix, p. 190 f.: Y Examinations under standardized dietary conditions. Y Instructions for collecting a 24h urine sample.
28
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Standard procedures
CaOx
Quality standard Y To be analyzed irrespective of stone composition!
Urate Citrate Oxalate Creatinine* Optional Magnesium Inorganic phosphate Ammonium Cystine
Ua >6.8 g/cm3 l mmol mmol mmol mmol mmol mmol mmol
<3.0 >35 >50 >0.8
mmol mmol mmol mmol
CaP
<5.8 or >1.010 <2.0 >5.0 (>8.0 >4.0 <2.5 >0.5 7–13 13–18
H is defined as hypercalciuria)
Struvite
Compulsory pH (day profile) Density (morning urine) Volume Calcium
Levels at which treatment is justified (per 24h)
women men
Cystine
24h urine variable
2,8-DHA
Urea, sodium, potassium, chloride and phosphate are helpful to assess the dietary habits > = too high; < = too low; * = to check for the completeness of the collection
Optional PTH Blood gases
Reference values for children see H 206 f.
Xanthine
S-Urate S-Phosphate S-Creatinine
2.0–2.5 (1.12–1.32 119–380 0.81–1.29 25–100
mmol/l mmol/l) mol/l mmol/l mol/l
NH4Urate
Compulsory during first examination S-Calcium (ionized calcium)
Normal range
Depending on method pH: 7.35–7.45 pCO2: 35–45 mm Hg / pO2: 80–90 mm Hg HCO3–: 22–26 mmol/l / BE: 8 2 mmol/l
Appendix
Blood
29
General aspects – standard procedures
Evaluation of the results Whenever possible, the results of serum and urine analysis should be considered in view of the stone composition. H Stone composition is known: Procedures for investigation, treatment and metaphylaxis are found in the chapters dealing with the different types of stone. H Stone composition is so far unknown: Further procedures have to be based on the results of urine and serum analysis. One or several urine or serum variables are above or below the reference limits: Y might give a first indication of the stone composition (see table), Y leads to further diagnostic procedures, Y a specific therapy can be added to the general metaphylactic regimen. Further diagnostic procedures Biochemical findings
Procedure
Refer to page
U-Calcium >5 mmol/24h
Dietary assessment Calcium loading in selected patients
184
Dietary assessment
U-Urate >4 mmol/24h pH >6.8 in 24h urine constantly >5.8 in the day profile Reference values for children see
30
冧
Exclude infection When infection is excluded, NH4Cl-loading
H 206 f.
180
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Evaluation of results
CaOx
Evaluation of the results f Stone composition is known: See the specific chapter.
Y Calcium phosphate stone
U-pH in day profile never <5.8 (RTA, infection) U-Calcium d U-Phosphate d S-Calcium d
Y Struvite stone
U-pH >7 (urease-producing bacteria) U-Ammonium d U-Citrate f
Y Cystine stone
U-Cystine d
Y Xanthine stone
S-Urate f
Y Ammonium urate stone
U-pH 6.5–7 (infection) U-Ammonium d U-Phosphate f
CaP
U-pH normal or low U-Calcium d U-Oxalate d U-Citrate f U-Urate d U-Magnesium f
Struvite
Y Calcium oxalate stone
Cystine
U-pH in day profile <6.0 U-Urate d S-Urate d
2,8-DHA
Y Uric acid stone
Xanthine
when:
NH4Urate
Probable stone composition
Ua
f Stone composition is unknown: The results of urine and serum analyses (levels at which treatment is justified see p. 29) together with the radiographic appearance of the stone give valuable clues to stone composition and metabolic abnormalities.
Appendix
w
31
General aspects – standard procedures
Metaphylactic treatment Clearly demonstrated abnormalities of biochemical variables in combination with knowledge of the stone composition provide a basis for methods aimed at reducing the risk of new stone formation. When the stone composition is unknown and the biochemical findings are normal, which is the case in the majority of the patients, general metaphylactic methods should be applied.
Urine dilution The most important therapeutic consideration irrespective of stone composition or the cause of stone formation is a sufficient dilution of urine accomplished by a generous intake of fluid. Experience has shown that urine is sufficiently diluted when the 24h urine flow is maintained at 2–2.5 liters or when the density (specific gravity) is below 1.010 g/cm3. Depending on the environmental temperature and the degree of physical activity, it is usually necessary to drink at least 2 liters to achieve this urine flow. The patient must learn how much to drink. Therefore, the therapy should start with a comparison between the fluid intake and the 24h urine volume and density (urometer or test strips). This necessitates the completion of records until a desired urine flow is obtained. Such records might later be repeated in order to make sure that the fluid intake is sufficient. The intake of fluid should be evenly distributed over the day. It is particularly important to drink before going to bed. Patients with severe stone disease should be encouraged to have nocturia at least once per night. Patients exposed to chronic dehydration, caused by hot and/or dry environments, extensive physical activity or diarrhea, are advised to replace extrarenal fluid losses. The beverages should be urine neutral. This means that urine dilution must be accomplished without changing the urinary pH or the quantitative composition of the urine. It needs to be emphasized that even a careful selection of beverages results in a considerable intake of energy (calories), a fact that has to be particularly considered by overweight patients. When children are not able to achieve a sufficient daily fluid intake of 1–2 liters/m2 body surface area/day, placement of a gastrostomy tube may be necessary in some specific diseases with severe risk of recurrent stones or progressive nephrocalcinosis, e.g. in primary hyperoxaluria or cystinuria.
32
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 2.0 l of urine per day
CaP
Ua
f Fluid intake: at least 2.5 liters/day in adults at least 1.0–2.0 liters/m2 body surface area/day in children f Y How to drink Y Intake evenly distributed over the day Y Intake of a sufficient amount of fluid before going to sleep Y Intake via a gastrostomy tube (if necessary in children)
Struvite
Y Type of beverages H suitable: urine-neutral beverages Y fruit tea, herbal tea, kidney tea, bladder tea Y mineral water with a low content of mineral salts
Cystine
H less suitable: Y coffee, black tea, green tea Y undiluted fruit juices
Appendix
NH4Urate
Xanthine
2,8-DHA
H not suitable: Y all alcoholic beverages, including beer Y sugar-sweetened soft drinks, including cola
33
General aspects – standard procedures
Dietary habits and lifestyle Inappropriate dietary habits and lifestyle play a central role in the pathogenesis of urolithiasis. Western dietary pattern, physical inactivity, mental stress and overweight may contribute to an increased risk of stone formation. A reduction in the risk of stone formation and recurrence rate can already be achieved by appropriate dietary treatment. General dietary metaphylaxis is applicable as basic treatment for all stone patients regardless of stone composition. If no particular abnormalities have been discovered that need special attention, it is usually sufficient to eat a balanced diet in which an energy surplus is avoided. This means that the diet should be composed of natural foodstuffs from all groups of nutrients. Different forms of vegetables, salads and fruits as well as cereals and dairy products should be part of the daily diet. Fresh fruits and vegetables are preferred because of the vitamin reduction that follows storage or cooking. If fresh products are not available, frozen instead of canned food should be chosen. Among products containing cereals, those with a high content of bran are to be preferred (wholegrain bread, porridge oats, müsli) because of their content of minerals and vitamins as well as their contribution to intestinal bulk. It needs to be emphasized, however, that wheat bran is not appropriate because of its high content of oxalate. The intake of meat, meat products, fish and poultry should be limited. Lean meat products should be chosen. In the rich assortment of dairy products, i.e. milk, yoghurt, and cheese, there are several with reduced fat content. Because of their higher content of polyunsaturated fatty acids, plant fats are preferable to fat products from animals. The intake of products with a high sugar or salt content should be avoided. It is important that the dietary intake of foodstuffs is distributed to several meals. Eating should be completed without rush. Overweight and associated dietary patterns are suggested to be significant risk factors for stone formation. Overweight should be reduced but without extreme fasting or high-protein weight-loss diets (e.g. Atkins diet).
34
Biochemical investigations
Treatment
Metaphylaxis
Nutrition
General aspects
Checklist
CaOx
Selection of a balanced mixed diet I Y if possible, select foodstuffs from all food groups
limit:
Y meat, meat products, fish, poultry Y sodium chloride
avoid:
Y fat high in saturated fatty acids Y food products with added sugars
Ua
fresh fruits, vegetables and salads wholegrain products low-fat dairy products plant fat
CaP
Y Y Y Y
Struvite
prefer:
Y avoid energy surplus
Cystine
Y distribute the intake of food to several meals
2,8-DHA
Lifestyle Y Reduce overweight
Xanthine
Y Practice physical activity Y Avoid sweating and other forms of fluid loss Y Reduce stress
NH4Urate
Y Allow for sufficient sleep
Appendix
w
35
General aspects
Type of stone
H
86 f.
Struvite stones
H 108 f.
Cystine stones
H 124 f.
2,8-Dihydroxyadenine stones
H 142 f.
Xanthine stones
H 152 f.
Ammonium urate stones
H 160 f.
CaP
Calcium phosphate stones
Struvite
66 f.
Cystine
H
2,8-DHA
Uric acid stones
Xanthine
38 f.
NH4Urate
H
Appendix
Calcium oxalate stones
Ua
CaOx
Type of stone
37
Type of stone – calcium oxalate stones
Calcium oxalate stones Introduction Calcium oxalate stones are the most frequent urinary stones of all. 70–75% of all stones contain calcium oxalate. Men are afflicted two times more frequently than women; people aged 30–50 years run the highest risk. Calcium oxalate stones develop as a multifactorial process in which an imbalance between crystallization-driving and -inhibiting forces plays a fundamental role. Dietary factors might be of great importance in stone development. Inborn errors of metabolism as well as acquired metabolic disorders are important contributing factors. So are most certainly also subepithelial calcifications (Randall’s plaques), and it is of note that a large fraction of calcium oxalatecontaining stones also contain calcium phosphate. Calcium oxalate occurs in two different forms. Whewellite (CaOx monohydrate; COM) is compact and of brown or black color. Its formation is favored by high urinary oxalate concentrations. However, high concentrations of calcium and magnesium result in weddellite (CaOx dihydrate; COD) stone formation. Weddellite crystals are of light yellow color and during lithotripsy they disintegrate much more easily than whewellite stones. The recurrence risk is considered higher for COD than for COM stones.
38
Calcium oxalate stones
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Weddellite (COD)
Whewellite (COM)
U-volume f
U-pH f
U-urate d
Inhibitory activity f
Hyperabsorption Ox, Ca
HPT, RTA
Cystine
U-citrate f U-magnesium f U-macromolecules f
Nutrition Ox d, Ca d, Purine d, Protein d
U-oxalate d
U-calcium d
2,8-DHA
Fluid intake f Fluid losses d
Xanthine
Sex = > R Climate Age
Struvite
Frequency: 70–75% Develop as a result of a multifactorial process
Lithogenic potential d
NH4Urate
Y Y
CaP
Ua
CaOx
Calcium oxalate stones
Appendix
Supersaturation with CaOx
Crystalluria
Ox = Oxalate CaOx = Calcium oxalate
Calcium oxalate stone
39
Type of stone – calcium oxalate stones
Specific notes for CaOx stone disease see General aspects, page
Medical history
22 f.
Lifestyle: Overweight, lack of physical activity, stress Pathophysiologic factors: Disturbances in the metabolism of calcium, oxalate and uric acid
Imaging
24 f.
Radiograms with calcifications Ultrasonography: Echogenic structures
Minimal program Urine analysis: pH low Envelope and dumb-bell shaped crystals in the sediment
26 f. 213 f.
Serum analysis: Calcium 12.5 mmol/l (5.0 meq/l) or normal Uric acid 1380 mol/l (6.4 mg/100 ml) or normal
Establishment of the diagnosis by stone analysis: CaOx stone (whewellite, weddellite)
40
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
>2.5 mmol/l
H
Exclude HPT
H
42 f.
Urate
>380 mol/l
H
Diet
H
56 f.
H
Medication
H
62 f.
Struvite
Calcium
CaP
Ua
Serum analysis
H
52 f.
Density
>1.010 g/cm3
H
Urine dilution
H
52 f.
Calcium
>5.0 mmol/24h
H
Diet
H
54 f.
Medication
H
58 f.
Diet
H
56 f.
Medication
H
64 f.
Diet
H
56 f.
Medication
H
62 f.
Diet
H
56 f.
Medication
H
62 f.
Oxalate
Urate
Citrate
>0.5 mmol/24h
>4.0 mmol/24h
<2.5 mmol/24h
H
H
H
Magnesium
<3.0 mmol/24h
H
Medication
H
58 f.
pH
>6.8
H
Exclude RTA
H
46 f.
Treat RTA
H
48 f.
Reference values for children see H 206 f.
2,8-DHA
Urine dilution
Xanthine
H
NH4Urate
<2 l/24h
Appendix
Volume
Cystine
24h urine analysis
41
Type of stone – calcium oxalate stones
Biochemical investigations Serum analysis Calcium Disturbances in calcium metabolism result in hypercalciuria or hypercalcemia or both. The combination of high serum and urine values is observed in only 3–5% of patients, and the levels are usually parallel. The serum concentration of calcium is usually strictly controlled within the narrow limits of 2.0 and 2.5 mmol/l (4.0–5.0 meq/l). Ionized serum/plasma calcium is usually between 1.15–1.30 mmol/l. Suspicion of hyperparathyroidism (HPT) Additional diagnostic procedures in patients with hypercalcemia Increased serum concentrations of calcium raise the suspicion of primary HPT (but can also be seen with osteolytic malignant processes and in renal failure). It is therefore necessary to measure the serum concentration of parathyroid hormone. Serum phosphate (low in primary HPT) and alkaline phosphatase (sometimes high in primary HPT) are also indicators of a disturbed metabolism of calcium. The analysis of ionized serum calcium is very helpful in diagnosis of HPT. Urate Disturbances in urate metabolism are sometimes considered to be of pathognomonic importance for the formation of calcium oxalate stones. It might therefore be worthwhile to be attentive to an increased serum level of urate: 1380 mol/l (6.4 mg/100 ml). It is of note that an increased serum or plasma urate concentration parallels increased levels of creatinine.
42
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Serum analysis
CaOx
Calcium 12.5 mmol/l I
Suspicion of pHPT Ua
f Further diagnostic procedures
Normal range
Findings
Calcium Phosphate PTH Ionized calcium
2.0–2.5 mmol/l 0.84–1.45 mmol/l depends on method 1.15–1.3 mmol/l
always increased decreased or normal increased increased
Struvite
Variable
CaP
f
Cystine
f Ultrasonography (scintigraphy; CT; MR)
The diagnosis of pHPT is established
Xanthine
w
2,8-DHA
f
Urate 1380 mol/l (16.4 mg/100 ml)
NH4Urate
f
Appendix
The diagnosis of hyperuricemia is established
43
Type of stone – calcium oxalate stones
Analysis of urine 24h urine Numerous factors influence the formation of calcium oxalate stones. Therefore, it is important that the relevant components of the 24h urine are carefully analyzed according to the principles for the quality standard (see p. 28 f.). The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190 f.) Note: Analysis of urate and pH cannot be carried out in acidified urine samples. Another preservative should be used such as 10 ml of 5% thymol in isopropanol or 30 ml of 0.3 mol/l sodium azide (for 24h urine collections). Calcium The excretion of calcium is particularly interesting inasmuch as increased values are observed in up to 56% of patients with calcium oxalate stone disease, and particularly in recurrent stone formers. Hypercalciuria is defined as an excretion of 68 mmol of Ca per 24h, but it is justified to start calcium reduction therapy even at a 24h excretion of 5 mmol (children: 10.1 mmol/kg body weight/24h). Oxalate Increased excretion of oxalate can be demonstrated in 20–50% of patients with calcium oxalate stone disease. A high oxalate excretion is associated with a high risk of recurrent stone formation. It is therefore essential that oxalate is analyzed in this group of patients. The intestinal oxalate absorption rate can be determined through the [13C2]oxalate absorption test (see p. 178 f.). Urate Urate might contribute to the formation of stones because high concentrations of urate lead to decreased solubility of calcium oxalate. The occurrence of increased urate excretion varies between different populations but figures between 20 and 60% have been reported. Citrate and magnesium Citrate and magnesium are the two most important inhibitors of crystallization that can be influenced by therapy. A low excretion of citrate which is associated with a high risk of stone formation has been demonstrated in up to 50% of all patients with calcium oxalate stone disease. The analysis of citrate is an important part of the quality standard.
44
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Urine analysis
Calcium
H
28 f.
H
46 f.
Ua
I Part of the quality standard particularly relevant: calcium, oxalate, urate, citrate, magnesium, pH
CaOx
24h urine collection
≥8mmol/24h
≥0.5 mmol/24h
Struvite
Oxalate
CaP
H Hypercalciuria Therapy is justified at a level of 5 mmol/24h
H Hyperoxaluria ≥4 mmol/24h
Cystine
Urate
H Hyperuricosuria Citrate
≤2.5 mmol/24h
Magnesium
2,8-DHA
H Hypocitraturia ≤3 mmol/24h
The pH day profile does not show any values below 5.8 H Exclude RTA
NH4Urate
pH
Xanthine
H Hypomagnesuria
Appendix
Reference values for children see H 206 f.
45
Type of stone – calcium oxalate stones
Diagnosis of renal tubular acidosis (RTA) Although the formation of CaOx stones is very little affected by variations within the physiological pH range, a low pH is probably associated with an increased risk of CaOx crystallization. A disturbed renal acidification is, however, associated with a pronounced reduction in urinary citrate. Measurement of pH values during the 24h period is, however, recommended to check the acidifying capacity of the kidney. Day profile of pH H Following careful instructions on how to use pH strips, the patient is advised to record the pH at each voiding during one 24h period. (Has the patient normal color vision?) In the routine laboratory, measure pH with a glass electrode. A pH remaining at a level above 5.8 supports the suspicion of renal tubular acidosis (RTA). When an infection with urease-positive bacteria has been excluded, the diagnosis of RTA is established with an NH4Cl-loading (the procedure is described in the Appendix, p. 180 f.). Pathophysiology RTA results from a disturbed secretion of H+-ions in the renal tubuli. There are too few H+-ions available for an adequate bicarbonate reabsorption in exchange of acid anions. Instead, chloride ions are reabsorbed and a hyperchloremic metabolic acidosis develops which can result in a resorption of apatite from the bone and hence a mobilization of calcium. The increased calcium load is filtered through the glomeruli giving concentrations in the tubular urine that exceed the maximal reabsorption rate, whereby increased quantities of calcium are excreted in urine. In addition to recurrent urinary stone formation, nephrocalcinosis is frequently observed in these patients. Two forms of RTA are recognized: proximal RTA and distal RTA. Only the distal RTA is of importance for stone formation. A complete form of distal RTA occurs in 0.5% of stone formers. The milder form of acidification defect without acidosis that can be demonstrated in 3–5% of all patients with urinary stone disease is called incomplete distal RTA.
46
Complete dRTA
Incomplete dRTA
Blood pH f Plasma HCO3– f S-Chloride d U-Calcium d U-Phosphate d U-Citrate f
Blood pH normal Plasma HCO3– normal S-Chloride normal U-Calcium d U-Phosphate normal U-Citrate f
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diagnosis of RTA
CaOx
Day profile of pH during several days f
pH never !5.8 Ua
f Exclude a urinary tract infection f
CaP
Further diagnostic procedures
Struvite
f
Ammonium chloride loading Procedure
H 180 f.
Cystine
f Interpretation of the result: H No RTA
2,8-DHA
pH is reduced to 5.4 pH is not reduced below 5.4 f
normal
f
f
complete dRTA
incomplete dRTA
NH4Urate
low
Xanthine
Plasma HCO3– and blood pH
Appendix
Blood gas analysis:
47
Type of stone – calcium oxalate stones
Treatment Stone removal CaOx stones cannot be dissolved. In case of a stone without symptoms, there are no absolute indications for stone removal. However, stone removal should be considered as a method to prevent future episodes of renal colic. Metaphylactic procedures are indicated to prevent stone growth. This is particularly important in the substantial group of stone formers with residual fragments following modern procedures for stone disintegration. Small ureteral stones can be expected to pass spontaneously. Stones should always be removed in patients with symptoms and complications and when stone growth can be expected.
Treatment of primary hyperparathyroidism In 80% of patients, the cause of pHPT is an autonomous adenoma of the parathyroid glands, in 15% hyperplasia and in 5% a carcinoma. In all these situations, the treatment of choice is parathyroidectomy. Surgery results in cure of more than 90% of these patients.
Treatment of RTA A complete RTA is so uncommon that these patients should be managed at centers with particular experience with this disease. The disturbance can only be treated symptomatically. Despite the alkaline urinary pH, it is necessary to correct the metabolic acidosis with alkaline citrate or sodium bicarbonate. In the case of hypokalemia, substitution with electrolytes is necessary. The excretion of the H+-ions can be specifically influenced by the diuretic agent ethycrinic acid. In patients with stone disease, RTA is usually incomplete.
Treatment of urinary tract infection See the chapter on struvite stones, p. 108 f.
48
H 174 f.
Ua
Oral chemolysis impossible Removal of symptom-free stones is not compelling Stone removal should be undertaken in patients with symptoms and complications Consider stone removal as a method to prevent complications
CaOx
Stone removal H H H H
CaP
Treatment of pHPT Surgery necessary
Struvite
f After surgery 90% of the patients will be recurrence free
Complete RTA H Treatment if possible at specialized centers Therapy
Y
2,8-DHA
Y
Cystine
Treatment of RTA
H 190 f.
Incomplete RTA
Xanthine
f Alkalization Y
Potassium citrate Dosage: 5–12 g/day (14–36 mmol/day) in adults (0.1–0.15 g/kg body weight in children) divided into 2–3 doses
NH4Urate
?
Metaphylaxis
Treatment
Treatment of urinary tract infection
Appendix
?
Biochemical investigations
General aspects
Checklist
H 114 f.
49
Type of stone – calcium oxalate stones
Metaphylactic treatment Metaphylactic measures should be directed towards any abnormalities that have been recorded in urine composition in order to reduce the risk of recurrent stone formation.
Long-term goal To decrease the excretion of substances with lithogenic properties. To increase the excretion of substances with inhibitory properties. Because of the multifactorial process involved in the development of calcium oxalate containing stones, a urine dilution evenly distributed over the day as well as general metaphylactic measures are particularly important. This is especially the case in those patients whose urine composition has not shown any apparent metabolic abnormalities.
General measures It is important to reduce overweight but without extreme fasting. Y Normal weight: BMI (body mass index) 18.5–25.0 kg/m2 BMI = body weight in kg/height in m2 A sufficient amount of physical activity helps the weight reduction and has a positive influence on the function of the renal collecting system. Extreme losses of fluid due to excessive sweating or the use of purgatives should be avoided or compensated by additional intake of fluid. H All relevant serum and urine variables should be checked regularly: Serum: calcium, urate, creatinine 24h urine: pH, calcium, oxalate, urate, citrate, magnesium, creatinine
50
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Long-term goal CaOx
w
Ua
Y Sufficient urine dilution at least 2.0 l of urine/24h density (spec. weight) ^1.010 g/cm3
CaP
Y Low excretion of lithogenic substances calcium !5 mmol/24h oxalate !0.5 mmol/24h urate !4 mmol/24h
Struvite
Y High excretion of inhibitory substances citrate 12.5 mmol/24h magnesium 13 mmol/24h
Cystine
Y Urine pH 6.5–7.0 in the day profile Reference values for children see H 206 f.
2,8-DHA
General measures
Xanthine
Y Reduction of body weight (aim at the normal body weight without extreme fasting) Y Sufficient physical activity Y Avoid excessive losses of fluid (e.g. sauna, sun-baths, extreme exercise, purgatives)
NH4Urate
Y Reduce stress Y Allow for sufficient sleep Y Regular checks of G serum and urine variables
Appendix
w
51
Type of stone – calcium oxalate stones
Urine dilution The most important metaphylactic measure is sufficient urine dilution. This is especially important if no metabolic abnormalities have been recorded. The goal should be a production of at least 2–2.5 l of urine every day. Depending on the extent of physical activities and the surrounding temperature, the amount of fluid necessary to drink is at least 2.5 l/day (1–2 l per m2 body surface area in children). This intake of fluid should be evenly distributed over the day. It is a good habit to drink again before or after each voiding. It is also important to drink before going to sleep at night to avoid urine concentration during the sleeping period. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before each voiding
Type of beverages Alkalizing beverages should be preferred because they increase urine pH and the excretion of citrate (inhibition of crystallization d) Y Mineral water rich in hydrogen carbonate and with a moderate content of calcium at least 1,500 mg HCO3–/l, max. 150 mg Ca/l Y Citrus juices have a substantial content of energy (around 400 kcal/l) and should be diluted before ingestion. Urine-neutral beverages: They dilute urine without affecting its composition. Limited amounts: Coffee should be consumed in moderation, because caffeine induces hypercalciuria, affects hydration and may aggravate hypertension. In addition, black and green tea might contain considerable quantities of oxalate. Milk contains calcium, animal protein and phosphate. Unsuitable beverages: Sugar-sweetened beverages affect the excretion of calcium. Alcoholic beverages increase the excretion of urate and bring about an acidification of urine.
52
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 2.0 l of urine per day f
Ua
Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children f
Type of beverages CaP
H preferable: alkalizing beverages Y mineral water rich in HCO3– and not high in Ca Y citrus juices (diluted with water)
Struvite
H also suitable: urine-neutral beverages Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
2,8-DHA
Cystine
H suitable in limited amounts: Y coffee Y black tea, green tea Y milk
Appendix
NH4Urate
Xanthine
H unsuitable: Y sugar-sweetened soft drinks, including cola Y all alcoholic beverages
53
Type of stone – calcium oxalate stones
Diet Patients with calcium oxalate stone disease should eat a balanced diet in which natural products from all food groups ought to be included. Certain points need particular attention: Protein intake It is recommended that the intake of protein should be restricted to 0.8 g/kg body weight/day. This goal can usually be achieved if the intake of meat, fish or sausages is reduced to 150 g/day. On 3 days per week meat and meat products should be avoided. The daily intake of protein can be estimated from the excretion of urea by the following formula: Gram protein = (24h urea [mmol] ! 0.18) + 13 Calcium intake General recommendation for healthy subjects and patients: 1,000–1,200 mg Ca/day (25–30 mmol Ca/day) The intake of calcium can be controlled by the selection of milk and dairy products, which are the most important foodstuffs containing calcium. A reduction of calcium is only necessary in patients with hypercalciuria (1 8 mmol/ 24h). An intestinal hyperabsorption occurs in about 30% of patients. A normal varied diet without milk products contains about 500 mg of calcium. The remaining 500–700 mg have to be added as milk or other dairy products. H It is important to inform the patients about the calcium content of different dairy products. The following basic rule can be applied: H The harder the cheese, the higher is its content of calcium. To be preferred:
Allowed in limited amounts:
mg Ca/100 g (mmol/100 g) Milk Yoghurt Cream Harzer, Mainzer
120 (3) 120 (3) 80–90 (2–2.3) 125 (3.1)
mg Ca/100 g (mmol/100 g) Soft cheese Brie, Camembert
400 (10) 400–600 (10–15)
To be avoided: mg Ca/100 g (mmol/100 g) Hard cheese: Gouda, Edamer Emmentaler Parmesan
800 (20) 1,200 (30) 1,300 (32.5)
See also Table 1 for the Ca content of dairy products H 200 It is important to emphasize that the daily intake of calcium should not be below the recommendations given above. A further reduction in dietary calcium leads to a negative calcium balance with loss of bone tissue and an increased intestinal absorption of oxalate. Salt intake (sodium chloride) A high ingestion of sodium chloride may promote urinary calcium excretion. Salt intake should therefore be limited to no more than 6 g/day. It is important to be aware of hidden sources of salt.
54
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
CaOx
Balanced mixed diet With consideration of the following points f
Ua
Protein intake
CaP
Y restrict intake of protein to 0.8 g/kg bogy weight/day H max. 150 g of meat, meat products or fish/day H restrict meat and meat products to max. 4 meals/week
Calcium intake
Struvite
Y 1,000–1,200 mg (25–30 mmol) of calcium per day (not more) f Y 500 mg (12.5 mmol) of calcium per day H is the normal content of a mixed diet without milk products
In patients with intestinal hyperoxaluria a higher Ca intake is indicated but has to be carefully guided!
Inform the patients of the calcium content of the most important milk products
H 200 f.
Example of milk products providing 500 mg (12.5 mmol) of calcium per day: 180 mg (4.5 mmol) Ca 80 mg (2 mmol) Ca 240 mg (6 mmol) Ca 500 mg (12.5 mmol) Ca
170 ml milk 250 g yoghurt
200 mg (5 mmol) Ca 300 mg (7.5 mmol) Ca
NH4Urate
150 g yoghurt 100 g fresh cheese 60 g Brie
500 mg (12.5 mmol) Ca
Appendix
q
Xanthine
2,8-DHA
Cystine
f Y 500–700 mg (12.5–17.5 mmol) of calcium per day H has to be covered with dairy products
Salt intake Y max. 6 g sodium chloride/day
55
Type of stone – calcium oxalate stones
Oxalate intake Up to 50% of the urinary oxalate is derived from the diet, the remainder comes from endogenous sources. An increased absorption of oxalate (110%) has been demonstrated in 46% of patients with calcium oxalate stone disease (p. 178). Some foods, particularly vegetables, contain very high concentrations of oxalic acid and can result in a significant increase in the urinary excretion of oxalate. It is wise to avoid these foodstuffs. mg oxalate/100 g
mmol oxalate/100 g
Rhubarb 1,235 13.7 Mangold 874 9.7 Sorrel 1,391 15.5 Spinach 1,959 21.8 Sesame 3,800 42.2 Wheat bran 457 5.1 Almonds 383 4.3 Cocoa 567 6.3 H Reduce the intake of chocolate Tea leaves 375–1,450 4.2–16.1 H The oxalate content of black tea depends on the amount of tea leaves and the steeping duration. See also Table 2 for the oxalate content of foods H 201 f. Purine intake Assuming that an increased excretion of urate increases the risk of calcium oxalate stone formation, it might be reasonable to pay attention to the intake of purine-rich foodstuffs. Intake of meat and sausages should be restricted to no more than 150 g/day. Innards and some kinds of fish with an extremely high content of purines should be avoided. (For further information on dietary purine, see the chapter on uric acid stones, p. 82 and Table 3, p. 204 f.) Vegetables, salads, fruits and cereal products Fruits and vegetables display an anti-lithogenic effect due to their high contents of water, potassium and magnesium. Fruits and vegetables have an alkalizing effect and may increase urinary citrate excretion. Increasing buffering capacity by increasing fruit and vegetable intake with a balanced diet counteracts the acidity generated by the dietary protein, reduces calciuria and consequently improves calcium balance. Furthermore, wholegrain cereals and cereal products should be preferred. Oxalate-rich foodstuffs should be avoided.
56
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
CaOx
Balanced mixed diet With consideration of the following points f
Ua
Oxalate intake
CaP
Y Foodstuffs with an extremely high content of oxalic acid: H avoid: spinach, rhubarb, mangold and sorrel H restrict: cocoa, black tea, nuts and black chocolate
Purine intake
Struvite
Y Foodstuffs rich in purine: H restrict: meat, meat products and fish (max. 150 g/day), legumes, including soy products, beer
Cystine
Y Foodstuffs extremely rich in purine: H avoid: viscera, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork
Vegetables, salads, fruits and cereal products
NH4Urate
Xanthine
2,8-DHA
consume a variety of vegetables, salads, fruits and wholegrain products each day wholegrain products are e.g. wholegrain bread, porridge oats, müsli and rice avoid oxalate-rich foodstuffs prefer raw foods
Appendix
Y Y Y Y
57
Type of stone – calcium oxalate stones
Medical treatment Risk factor: Hypercalciuria Limit for starting therapy: 5–8 mmol Ca/24h (10.1 mmol/kg body weight/24h in children). If the excretion of calcium cannot be reduced below 5 mmol/24h by dietary means, medical treatment can be indicated. The recommended approach is an alkalization of urine. Y Treatment with alkaline citrate Effect: Increased urinary pH, mild metabolic alkalosis H Inhibition of the intracellular metabolism of citrate H Increased excretion of citrate (increased inhibition of crystallization) H Mild decreased excretion of calcium Contraindications: Recurrent urinary tract infections, renal insufficiency, metabolic alkalosis and hyperkalemia. Pure calcium phosphate stones are also a relative contraindication, but patients with brushite stones might benefit from treatment with alkaline citrate. Side effects: Infrequent gastrointestinal disturbances Alternative: Sodium bicarbonate H Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate H Use capsules soluble in the small intestine Y Treatment with magnesium In patients with a high urinary pH and a sufficient excretion of citrate, there is no indication for alkalization. In such cases magnesium might be a therapeutic alternative. Effects: The complex between magnesium and oxalate formed in the intestine counteracts the absorption of oxalate. The MgOx complex formed in urine has a higher solubility than CaOx. Contraindications: Renal insufficiency Caution: Complexes of Mg-citrate might be formed instead of Ca-citrate and Mg-oxalate. Recent research has shown that even K-Mg-citrate is efficient in the treatment of patients with hyperoxaluria. Y Treatment with a dietary fiber preparation If treatment with alkali is impossible, administration of a fiber preparation is an alternative. Effect: Reduced absorption of calcium from the diet Contraindications: Intestinal obstruction Side effects: Transient meteorism
58
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
CaOx
Calcium excretion 5–8 mmol/24h When dietary measures are insufficient I
Y
Ua
Alkalization
Alkaline citrate 5–12 g (14–36 mmol) citrate per day of which 7–10 mmol citrate should be administered in the evening. (If the compliance is bad, give a single evening dose of 6 g.) (Dosage in children: 0.1–0.15 g/kg body weight/day) Preparations: Potassium citrate, sodium-potassium citrate, potassium-magnesium citrate e.g. Urocit-K, Blemaren N, Polycitra-K
CaP
Dosage:
4.5 g/day (3 capsules with 500 mg ! 3) Sodium bicarbonate (capsules soluble in small intestine) Caution: Na increases hypercalciuria
Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate, e.g. in Crohn’s disease and short bowel syndrome. Reduction in intestinal oxalate absorption
Magnesium
Xanthine
Y
Dosage: 200–400 mg/day (8.25–16.5 mmol/day) Preparations: Magnesium citrate, magnesium oxide, magnesium hydroxide
Fiber preparation 15 g/day
NH4Urate
Dosage:
Appendix
Y
Cystine
Sodium bicarbonate Dosage: Preparation:
2,8-DHA
Y
Struvite
or
59
Type of stone – calcium oxalate stones
Risk factor: Hypercalciuria (cont.) 68 mmol Ca/24h makes medical treatment necessary: Y Treatment with thiazides Effect: Increases the reabsorption of calcium in the distal tubules – the excretion of calcium is significantly reduced. Additional measures: Potassium supplements, blood pressure control, sodium chloride restriction Contraindications: Gout, hypotension, hypokalemia, acute glomerulonephritis Side effects: Hypotension, hyperuricemia (be careful in patients with gout), reduced glucose tolerance (be careful in patients with diabetes mellitus), erectile dysfunction, hypocitraturia secondary to hypokalemia. It is essential that the loss of potassium that follows treatment with thiazides is compensated for by administration of a potassium salt. In this regard potassium citrate is an excellent alternative, but potassium chloride can also be used as a less expensive choice. The additional benefit of potassium citrate should, however, be taken into account. The loss of effect during long-term thiazide treatment is most certainly caused by hypokalemic hypocitraturia. Also magnesium losses can occur during thiazide treatment. The following compound can be used as an alternative to thiazides, but it needs to be emphasized that the experience with this drug is limited and its usefullness controversial: Y Orthophosphate Effect: Increases the excretion of pyrophosphate (inhibition of crystallization increases), reduces excretion of calcium Contraindications: Phosphate stones, urinary tract infection, hypertension, gastrointestinal diseases, hypernatremia Side effects: The long-term use can result in diarrhea and other intestinal disturbances as well as a risk of phosphate stone formation. Orthophosphate should not be chosen unless thiazide treatment is impossible.
60
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
CaOx
Calcium excretion 68 mmol/24h Primary therapeutic choice:
Potassium citrate 750–1,000 mg ! 2 (7 mmol ! 2) Analysis of serum or plasma concentrations of potassium and magnesium is an important part of the follow-up. In children:
Modified Shol’ Solution Cystine
Y
冧
Y Na-K-citrate effervescent tablets (e.g. Blemaren H 8.8 mmol citrate/tablet (= 30 ml modified Shol’ Solution)
2,8-DHA
Sodium citrate 150 mmol/l (= 44.1 g/l) 0.3 mol/l (0.3 mmol/ml) citrate Potassium citrate 150 mmol/l (= 48.7 g/l) Dosage: 1–2 ml/kg/day = 0.6 mmol/kg/day
N)
Xanthine
Possible alternative: Y
CaP
25–50 mg/day in adults (increase the dose slowly) 0.5–1.0 mg/kg body weight/day in children Preparation: Hydrochlorothiazide Also bendroflumethiazide in a dose of 5 mg/day can be chosen (2.5 mg ! 2 or 5 mg ! 1) H Please observe the indications and possible side effects and use it only in patients with a pronounced hypercalciuria. Additionally given potassium citrate is helpful.
Ua
Thiazide Dosage:
Struvite
Y
Orthophosphate 1–2 g three times daily in adults 25–30 mg/kg body weight/day in children Preparation: K-/Na-Phosphate (Contraindications and side effects see left page)
NH4Urate
Dosage:
Appendix
Use orthophosphate in patients with decreased tolerance for thiazides.
61
Type of stone – calcium oxalate stones
Risk factor: Hypocitraturia Citrate forms a soluble complex with calcium, favored by a high urinary pH. Moreover citrate counteracts growth and aggregation of CaOx crystals. Citrate also prevents precipitation of CaOx in calcium phosphate mixed stones (cave: U-pH 16.8). In situations with a low excretion of citrate the formation of CaOx crystals is facilitated. A particularly low excretion of citrate can be anticipated during the night and in the early morning as a result of the normal circadian rhythm. The simultaneous low pH thereby further augments the risk of CaOx stone formation. When the citrate excretion cannot be sufficiently increased by dietary measures, medical treatment is indicated. Y Treatment with alkaline citrate Effect: Increased urinary pH, mild metabolic alkalosis H Inhibition of intracellular metabolism of citrate H Increased excretion of citrate (the inhibition of CaOx crystal formation is increased) H Mild decreased excretion of calcium (Contraindications and side effects see p. 58, risk factor hypercalciuria) Alternative: Sodium bicarbonate H Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate H Use capsules soluble in small intestine Risk factors: Hyperuricosuria/hyperuricemia The renal excretion of urate is also considered as a possible risk factor of CaOx stone formation. An increased concentration of urate results in reduced solubility of CaOx and might be associated with an increased risk of CaOx crystallization. It has been observed that calcium oxalate stone formers in some geographic areas have higher serum and/or urine concentrations of urate than normal subjects. In cases where the urate excretion cannot be reduced to a level below 4 mmol/24h by means of a reduced intake of purine-rich food, medical therapy might be indicated. Y Treatment with allopurinol Effect: See chapter on uric acid stones, p. 84 f. Side effects: A high dose of allopurinol can result in the formation of xanthine stones
62
Biochemical investigations
Metaphylaxis
Treatment
Medication
General aspects
Checklist
CaOx
Citrate excretion !2.5 mmol/24h When an increased intake of plant foodstuffs and alkalizing beverages is insufficient
5–12 g (14–36 mmol) citrate distributed over the day (up to a pH of 7.0) of which 7–10 mmol citrate should be administered in the evening. In cases of bad compliance give 6 g (18 mmol citrate) as an evening dose (Dosage in children: 0.1–0.15 g/kg body weight/day) Potassium citrate, sodium potassium citrate, potassium magnesium citrate e.g. Urocit-K, Blemaren N, Polycitra-K or Shol’ Solution in small infants and children (see p. 61)
CaP
Preparation:
Ua
Alkaline citrate Dosage:
Struvite
f Y
or
Sodium bicarbonate Dosage: Preparation:
4.5 g/day (3 capsules with 500 mg ! 3) Sodium bicarbonate (capsules soluble in small intestine) Caution: Na increases hypercalciuria
Cystine
Y
2,8-DHA
H Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate.
Xanthine
Urate excretion 14 mmol/24h When a purine-restricted diet is insufficient f Alkalization
H
58 f.
Allopurinol Dosage:
Preparation:
if S-urate >380 mol/l and U-urate >4 mmol/24h 100 mg/day if only U-urate >4 mmol/24h (1–3 mg/kg body weight/day in children) Allopurinol 300 mg/day
Appendix
Y
NH4Urate
+
63
Type of stone – calcium oxalate stones
Risk factor: Hyperoxaluria 1. Secondary hyperoxaluria a) Enteric hyperoxaluria. The most common reason for enteric hyperoxaluria is the insufficient complex formation between calcium and oxalate seen in Crohn’s disease, conditions following bariatric surgery, pancreatic insufficiency and other diseases with malabsorption. The high intestinal concentration of fatty acids results in binding of calcium with ensuing lack of calcium for oxalate complex formation. Increased absorption of oxalate can also be the result of an insufficient intake of calcium. A reduced occurrence of intestinal oxalate-consuming bacteria (Oxalobacter formigenes) is another factor to consider. Hyperabsorption of oxalate might also occur for unknown reasons (oxalate absorption test, see Appendix, p. 178 f). b) Other causes of secondary hyperoxaluria Y intoxication with ethylene glycol and methoxyflurane Y ingestion of large doses of ascorbic acid (more than 2–4 g/day) Therapeutic possibilities: Y calcium administration (in patients with a low Ca excretion): Diet rich in calcium or calcium salt preparations (Cave: calcium salt preparations may contain vitamin D! Hence, calcium absorption and therefore calcium excretion may increase!). Neither diet nor calcium salt preparations are recommended in childhood. Y magnesium administration (complex-formation with oxalate) Y administration of alkaline citrate Y reduced intake of fat Y administration of MCT fat (medium chain fatty acids). This form of treatment can be attempted in patients with maldigestion or malabsorption of fat. MCT fats are absorbed without lipolysis and without the need of bile acids. The formation of calcium-soaps is thereby counteracted. MCT fats should be gradually increased. 2. Primary hyperoxaluria (Type I and II) H These patients should preferably be treated in specialized centers. In primary hyperoxaluria endogenous production of oxalate is increased, which leads to massive hyperoxaluria and hence recurrent urolithiasis or progressive nephrocalcinosis. Y administration of pyridoxine (vitamin B6): pyridoxine is an essential cofactor of all body aminotransferases. In PH I administration of vitamin B6 may lead to enhancement of AGT activity and thus lesser endogenous oxalate production. Pyridoxine is started with 5 mg/kg body weight/day, in order to exclude or demonstrate pyridoxine responsiveness (130% reduction of urinary oxalate excretion). If no response is reached, dosage will be increased stepwise to 20 mg/kg body weight/day. A trial of at least 3–6 months is warranted in all PH I patients to prove or disprove B6 responsiveness. Pyridoxine does not help in PH II, and in secondary hyperoxaluria. Y alkaline citrate: increased excretion of citrate results in increased inhibition of CaOx crystallization (recent results have indicated a much better prognosis in patients treated with alkaline citrate). Y the intake of calcium must be sufficient (in children age-dependent: 600–1,200 mg/day). A high intestinal concentration of calcium brings about a reduction of intestinal hyperabsorption of oxalate. Y magnesium forms a soluble complex with oxalate and is a therapeutic alternative to alkaline citrate.
64
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
CaOx
Oxalate excretion 10.5 mmol/24h Secondary hyperoxaluria Therapeutic possibilities:
Ua
Calcium 500 mg/day (12.5 mmol/day) or more, taken together with meals (the urinary Ca excretion should be monitored) Preparations: Calcium effervescent tablets Cave: vitamin D-containing calcium supplements (hypercalciuria)
Magnesium
Y
MCT fats
Struvite
Dosage: 200–400 mg/day (8.25–16.5 mmol/day) Preparations: Magnesium citrate, magnesium oxide, magnesium hydroxide in patients with maldigestion or malabsorption of fat
Cystine
Primary hyperoxaluria H best treated in specialized centers Therapeutic possibilities: Y
Pyridoxine (Vit. B6) Dosage:
Preparation: Y
Pyridoxine is started with 5 mg/kg body weight/day If no response is reached, dosage will be increased stepwise to 20 mg/kg body weight/day (see left page) Pyridoxine
Magnesium Dosage: Adults: as above. Children: 6 mg (0.25 mmol) per kg body weight/day Preparations: as above
Alkaline citrate
NH4Urate
Y
Appendix
Dosage: Children: 0.10–0.15 g/kg body weight/day Preparations: Potassium citrate, sodium-potassium citrate, potassium-magnesium citrate, Shol’ Solution (see p. 58 f. and 61 f.) Y
2,8-DHA
Y
CaP
Dosage:
Xanthine
Y
Sufficient intake of calcium
65
Type of stone – uric acid stones
Uric acid stones Introduction Up to 15% of urinary stones are composed of uric acid. Most patients with uric acid stones are in an advanced period of life, with the majority of patients aged more than 60 years. Younger uric acid stone formers are often obese. Men fall ill two to four times more frequently than women. At physiologic pH values, urate is the end-product of purine metabolism, which is converted to poorly soluble uric acid at pH values !6.5 after renal excretion. As uric acid stones are formed only in an acid urine, the individual diet might be an important risk factor in uric acid stone formation. A diet rich in protein and purines with a high consumption of alcoholic beverages results in increased uric acid excretion and a low urinary pH value. 20–40% of gout patients subsequently form uric acid stones. These patients suffer from overproduction of uric acid which results in hyperuricosuria. Together with low urinary pH values, the risk for uric acid stone formation is increased. It needs to be emphasized that patients with ileostomy more commonly form uric acid stones than calcium oxalate stones because of the combined low pH and small urine volume and also because the colon seems to be important for the excessive oxalate absorption in enteric hyperoxaluria. Uric acid dihydrate is a special modification, which is formed in very acid urine (pH ! 5.5). Uric acid stones are the only type of stone that can be dissolved by medical agents. This chemolytic treatment is successful in 90% of uric acid stone patients.
66
Biochemical investigations
Checklist
Treatment
Metaphylaxis General aspects
Uric acid stones
Ua
CaOx
Uric acid stones
Uric acid
CaP Struvite Cystine
low urine pH + high concentration of uric acid
high urine pH + high concentration of urate + cation
f
f
High ion-activity product of uric acid
High ion-activity product of a urate salt (NH4, Na or K)
Uric acid stone
Urate stone
2,8-DHA
Y
Xanthine
Y
Occurrence: 3–15% Formed in acid urine Different from urate stones
NH4Urate
Y
Uric acid dihydrate
H 160 f.
Appendix
Y radiolucent Y susceptible to medicinal dissolution
67
Type of stone – uric acid stones
Specific notes for uric acid stone disease see General aspects, page
Medical history
22 f.
Pathophysiologic factors Metabolic abnormalities Pharmacologic influence on the excretion of uric acid
Imaging
24 f.
Radiolucent stone on plain films Visible on helical CT examination Contrast defect on the urogram Ultrasonography: Structure with a high density and a typical echo
Minimal program Urine analysis: pH constantly !6.0 Crystals with whetstone appearance or with right angles; fine crystalline ‘brick-meal’ in the sediment
26 f.
213 f.
Serum analysis: Urate 1380 mol/l (6.4 mg/100 ml)
Establishment of the diagnosis by stone analysis: Uric acid and/or uric acid dihydrate stone
68
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
H
Diet
H
82 f.
Medication
H
84 f.
CaP
>380 mol/l (6.4 mg/100 ml)
Struvite
Urate
Ua
Serum or plasma analysis
H
Urine dilution
H
80 f.
Density
>1.010 g/cm3
H
Urine dilution
H
80 f.
pH
in day profile <6.0
H
Diet
H
82 f.
H
Medication
H
84 f.
H
Diet
H
82 f.
Medication
H
84 f.
Urate
>4.0 mmol/24h
2,8-DHA
<2 l/24h
Xanthine
Volume
Cystine
24h urine analysis
Appendix
NH4Urate
Reference values for children see H 206 f.
69
Type of stone – uric acid stones
Biochemical investigations Serum or plasma analysis Urate The serum concentration of urate varies in women between 119 and 375 mol/l (2.0–6.3 mg/100 ml) and in men between 155 and 404 mol/l (2.6–6.8 mg/100 ml). Blood pH is slightly alkaline and the risk of precipitation is determined by the solubility of sodium urate. The solubility limit at pH 7.4 and a temperature of 37 ° C is 380 mol/l (6.4 mg/100 ml). Values above 380 mol/l are therefore considered as hyperuricemia in both men and women and require therapeutic measures. The mean serum urate concentration is markedly higher in about 25% of patients with uric acid stones compared with normal subjects.
70
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Serum analysis
CaOx
Urate 1380 mol/l (6.4 mg/100 ml) f
Hyperuricemia established Ua
f
CaP
Medical treatment necessary
Urate 300–380 mol/l in repeated analyses
Struvite
f
Appendix
NH4Urate
Xanthine
2,8-DHA
Cystine
Suspicion of latent hyperuricemia as a result of high dietary purine intake
71
Type of stone – uric acid stones
Urine analysis The most important determinants of uric acid stone formation are the urinary pH and the concentration of urate. The lower the pH and the higher the urate concentration, the greater is the risk of uric acid precipitation. The reason for an extremely low urinary pH needs to be carefully examined. Urinary pH (spot urine) Day profile of pH H Following careful instructions on how to use pH strips, the patient is advised to record the pH at each voiding during one 24h period. (Has the patient normal color vision?) In the routine laboratory, measure pH with a glass electrode. A urine pH constantly below 6.0 is often associated with a reduced excretion of ammonia. The explanation for such a condition is a reduced intrarenal enzymatic metabolism of glutamine. 24h urine As a part of the quality standard (p. 28), the diagnosis of hyperuricosuria is of great importance. The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190 f.) In order to enable measurement of urinary pH, the urine should be collected in bottles without acid. Suitable preservatives are thymol or sodium azide (see p. 190). (for calculation of the ion-activity product of uric acid, see p. 186)
72
Treatment
Metaphylaxis General aspects
Biochemical investigations
Checklist
Urine analysis
CaOx
Spot urine: pH constantly !6.0 f
Ua
Suspect a constantly acid urine
CaP
pH day profile f
pH constantly <6.0 Struvite
f
Cystine
Establishes the diagnosis of acid urine
24h urine collection
Urate
28 f.
Xanthine
H
Part of the quality standard particularly relevant: Urate
2,8-DHA
f
≥4.0 mmol/24h (672 mg/24 h) H Hyperuricosuria
206 f.
NH4Urate
H
Appendix
Reference values for children see
73
Type of stone – uric acid stones
Treatment Stone dissolution (chemolysis) Stones composed of uric acid are the only type of stone that can be dissolved by medicinal agents administered orally or parenterally. A stone-free state by means of such chemolytic treatment can be obtained in about 90% of patients. The required duration of the treatment depends on the size and purity of the stone as well as on the diuresis.
Supportive measures Such measures are necessary under certain conditions. Unilateral or bilateral ureteral obstruction by uric acid stones or gravel requires insertion of ureteral catheters, stents, or percutaneous nephrostomy catheters. The surface area of the concrement can be significantly increased by extracorporeal shock wave lithotripsy, whereby the chemolytic process can be accelerated. In the presence of a percutaneous track, it is also possible to carry out the chemolysis by local application of an alkaline solution.
Chemolysis Uric acid stones develop at high concentrations of urate in acidic urine. The stone dissolution can be attained by: 1. Increase of urinary pH H urine alkalization 2. Decrease of urate excretion 3. Urine dilution. 1,800
°
1,600 1,400
Large amounts of urate can be held in solution by increasing the urinary pH. Alkalization can be accomplished by alkalizing medications and beverages. The latter are an important part of treatment which at the same time brings about a dilution of the urine. The dosage of alkalizing agents is determined by the pH response and it is necessary for the patient to carry out a continuous control of the urinary pH.
Uric acid (mg/l)
1. Urine alkalization
1,200 Stone development
1,000 800
Stone dissolution
•
600 400 200 0
•
4.5
•
5
5.5 pH
6
6.5
Solubility of uric acid as a function of pH
74
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Chemolysis
Stone dissolution CaOx
?
CaP Struvite
How should the oral chemolysis be carried out? 1. Alkalization of urine f aim at a pH of 7.0–7.2
Cystine
f Medicinal agents
Dosage: Depending on pH Preparations: Sodium-potassium citrate, potassium citrate, e.g. Uralyt U, Blemaren N, Polycitra-K, Urocit-K
or
Y
Sodium bicarbonate Dosage: Preparation:
Depending on pH Sodium bicarbonate
2,8-DHA
Alkaline citrate
Xanthine
Y
Beverages
NH4Urate
Y Mineral water with a high concentration of bicarbonate ( 11,500 mg HCO3–/l) Y Citrus juices (diluted with water; be aware of the energy content)
Appendix
w
Ua
H Uric acid stones can be dissolved H Success rate: 90% H Supportive interventional measures: Y at unilateral or bilateral obstruction Y lithotripsy (SWL) to increase the surface area of the solid material
75
Type of stone – uric acid stones
2. Reduction of urate excretion A reduced excretion of urate is accomplished by inhibiting the endogenous production of urate and by decreasing the intake of purine-containing foodstuffs. Treatment with allopurinol Effect: Inhibition of the endogenous production of urate. Instead of converting hypoxanthine to xanthine and this further to urate, xanthine oxidase catalyzes the metabolism of allopurinol to oxypurinol. Contraindications: Reduced dosage in patients with renal insufficiency. Pregnancy and liver diseases are relative contraindications. Side effects: Increased excretion of xanthine (formation of xanthine stones has, however, been observed only with the extreme doses used in the treatment of patients with Lesch-Nyhan syndrome); changes in blood cell formation; hypersensitivity reactions; interaction with anticoagulants and antihistaminics.
Adenine Guanine f f Hypoxanthine – – – – – – – – – – – – – – – – – – – – – H Xanthine – – – – – – – – – – – – – – – – – – – – – H Urate U U
Xanthine oxidase f f f Allopurinol – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – H Oxypurinol
Reduced intake of purines In order to decrease the substrate necessary for uric acid formation, the intake of purines needs to be reduced. To avoid the development of lactaciduria and thereby a disturbed excretion of urate, alcohol abstinence is recommended.
3. Urine dilution The goal should be a urine dilution of at least 2.0–2.5 l/24h, achieved by a fluid intake of at least 2.5 l/day. The ideal beverage is alkalizing mineral water (11,500 mg HCO3–/l).
76
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Chemolysis
2. Reduction of urate excretion f
Ua
Goal: !4.0 mmol urate/24h !0.12 mmol/kg body weight/24h in children f
Y
CaP
Medication
Allopurinol if S-urate >380 mol/l and U-urate >4.0 mmol/24h 100 mg/day if only U-urate >4.0 mmol/24h 1–3 mg/kg body weight/24h in children Preparation: Allopurinol
Struvite
300 mg/day
Cystine
Dosage:
H uricosuric agents increase the excretion of urate and are contraindicated
2,8-DHA
Diet Y foodstuffs with a low content of purines ( H see Diet, p. 82, and Table 3 on the purine content of foods, p. 204 f.)
3. Urine dilution
Xanthine
f Goal: at least 2.0 l of urine/24h
NH4Urate
Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children
Type of beverages
Appendix
preferably: alkalizing beverages Y mineral water rich in bicarbonate (11,500 mg HCO3–/l) Y citrus juices (diluted with water; be aware of the energy content)
77
Type of stone – uric acid stones
Metaphylactic treatment Methods aimed at dissolving uric acid stones also have a preventive effect against new crystal precipitation and therefore: Therapy = Metaphylactic treatment As a long-term objective, it is important to change living and dietary habits so that the need of medication can be reduced or even eliminated. In any case, the basic disease should always be considered and treated appropriately.
General measures Reduction of overweight is particularly important in cases of uric acid stone formation. Weight reduction should, however, be accomplished without extreme fasting, because this can lead to an increased excretion of uric acid. Y Normal weight: BMI (body mass index) 18.5–25.0 kg/m2 BMI = body weight in kg/height in m2 In addition to an adaptation of the energy intake, sufficient physical activity is necessary. Great losses of fluid due to extreme sweating or the use of laxatives must be avoided or compensated by additional intake of fluid. The risk of new stone formation increases markedly with a reduction in pH and therefore it is necessary to check the urinary pH level regularly. H All relevant serum and urine variables should be checked regularly: Serum: urate Urine: pH, urate
78
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Long-term goal CaOx
w
Y Increased pH (6.5–6.8)
Ua
Y Reduced excretion of urate ! 4.0 mmol/24h ! 0.12 mmol/kg body weight/24h in children
Struvite
General measures
Cystine
Y Reduction of body weight (aim at normal body weight without extreme fasting) Y Sufficient physical activity Y Avoid excessive losses of fluid (sauna, sun-baths, extreme exercise, use of laxatives)
2,8-DHA
Y Reduce stress Y Allow for sufficient sleep
NH4Urate
Xanthine
Y Regular control of: G serum and urine variables
Appendix
w
CaP
Y Sufficient urine dilution at least 2.0 l/24h at least 1.0–2.0 l/m2 body surface area/24h in children
79
Type of stone – uric acid stones
Urine dilution The most important metaphylactic measure is a sufficient dilution of urine. The daily intake of fluid should be at a level that results in at least 2.0 l of urine. Depending on the degree of physical activity and surrounding temperature, it is necessary to drink at least 2.5 l/day, evenly distributed over the day. It is wise to drink again before or after each voiding. In order to counteract high urine concentrations that occur during the sleeping period, it is also important to drink just before going to bed. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding
Type of beverages Alkalizing beverages are preferable since they increase the urinary pH: Y Mineral water rich in hydrogen carbonate (11,500 mg HCO3–) Y Citrus juices have a considerable energy content (approx. 400 kcal/l) H if possible, dilute them before ingestion Also useful are urine-neutral beverages: They dilute urine without affecting its composition. Unsuitable beverages: Alcoholic beverages (especially beer) increase the urate excretion and acidify the urine.
80
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 2.0 l of urine per day
Ua
f Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children f
Type of beverages CaP
H preferable: alkalizing beverages Y HCO3– -rich mineral water Y citrus juices (diluted with water)
Struvite
H also suitable: urine-neutral beverages Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
Cystine
H suitable in limited amounts: Y coffee Y black tea, green tea
Appendix
NH4Urate
Xanthine
2,8-DHA
H unsuitable: Y all alcoholic beverages (especially beer) Y sugar-sweetened soft drinks, including cola
81
Type of stone – uric acid stones
Diet Patients with uric acid stones do not need to follow a strict dietary regimen, but it is important that the food has a low purine content (max. 500 mg of uric acid/day or 3 mmol/day). Products from plants usually have a lower content of purine than animal products and have an alkalizing effect. In contrast, meat and fish have an acidifying effect due to their protein composition. Purine content of some foodstuffs: Uric acid
Meat Skin-free fish Neck sweet bread Liver Kidneys Poultry skin Herring with/without skin
Uric acid
mg/100 g
mmol/100 g
150 150 900 230–360 220–255 300 320/180
0.9 0.9 5.4 1.4–2.1 1.3–1.5 1.8 1.9/1.1
Chick peas Lentils Soy beans Sardines Anchovies Sprats
mg/100 g
mmol/100 g
160 200 350 350 160 500
1.0 1.2 2.1 2.1 1.0 3.0
See also Table 3 on the purine content of foods H 204 f. The diet is best composed of vegetables, salads, fruits, cereal products, eggs and dairy products. Furthermore, wholegrain cereals and cereal products should be preferred. It should be noted that alternative dietary components (e.g. soy products) are not purine free (see table below). In particular, products which are enriched with yeast to give taste contain considerable quantities of purine. Compare:
Soy beans Soy-knackwurst Tofu Buckwheat Whole-meal noodles
Uric acid
Uric acid
mg/100 g
mmol/100 g
220 100 70 150 50
1.3 0.6 0.4 0.9 0.3
H H
White beans Knackwurst
H H
Wheat Regular noodles
mg/100 g
mmol/100 g
180 110
1.1 0.7
90 30
0.5 0.2
It is recommended that the intake of protein should be restricted to 0.8 g/kg body weight/day. This goal can usually be achieved if the intake of meat, fish and sausages is reduced to 150 g/day. On 3 days/week meat and meat products should be avoided.
82
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
CaOx
Balanced mixed diet With consideration of the following points f
Ua
Purine intake Y restrict dietary products rich in purine H meat, meat products and fish (max. 150 g/day), legumes, including soy products
Struvite
Y prefer dietary products with a low content of purine H vegetables, salads, fruits, cereal products, eggs and dairy products
CaP
Y avoid dietary products extremely rich in purine H innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork
H ovo-lacto-vegetarian diet
Cystine
Caution: alternative dietary regimens which have a high content of purines.
Protein intake
NH4 Urate
Xanthine
Important general rule: Avoid excesses!
Appendix
w
2,8-DHA
Y restrict intake of protein to 0.8 g/kg bogy weight/day H max. 150 g of meat, meat products or fish per day H restrict meat and meat products to max. 4 meals per week
83
Type of stone – uric acid stones
Medical treatment Neutralization of urine Y Treatment with alkaline citrate or sodium bicarbonate Effect: Increases urinary pH by adjusting the acid-base balance Contraindications: Recurrent urinary tract infections, hypertension (control!), phosphate stones, renal insufficiency, metabolic alkalosis, hyperkalemia Side effects: Infrequent gastrointestinal disturbances Long-term administration of K-citrate or Na-K-citrate particularly to patients with reduced renal function can lead to hyperkalemia. In such cases a Ca-citrate preparation might be useful. H The regular intake of alkalizing beverages can enable a reduced dosage of alkaline citrate or sodium bicarbonate. The effects should be monitored by repeated measurements of the urinary pH. Reduction of uric acid excretion Y Treatment with allopurinol Effect: see p. 76 Contraindications: Be careful treating patients with reduced renal function. Relative contraindications: Pregnancy, liver disease Side effects: Increased excretion of xanthine (formation of xanthine stones has, however, been observed only with the extreme doses used to treat patients with Lesch-Nyhan syndrome); changes in blood cell formation; hypersensitivity reactions; interaction with anticoagulants and antihistaminics
84
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
Alkaline citrate Dosage: Preparations:
According to pH 6.5–6.8 Sodium potassium citrate, potassium citrate, e.g. Uralyt U쏐, Blemaren쏐 N, Urocit-K쏐, Polycitra-K쏐
Ua
f Y
CaOx
Urinary pH constantly ^6.0
or
Sodium bicarbonate Dosage:
CaP
Y
According to pH 6.5–6.8
Y
Struvite
with reduced renal function:
Calcium citrate Dosage:
According to pH 6.5–6.8
Cystine
H Dose reduction is possible with a generous intake of alkalizing beverages.
Allopurinol Dosage:
if S-urate >380 mol/l and U-urate >4.0 mmol/24h 100 mg/day if only U-urate >4.0 mmol/24h (1–3 mg/kg body weight/day in children) 300 mg/day
Xanthine
Y
2,8-DHA
Urate excretion 14.0 mmol/24h
Appendix
NH4 Urate
H Dose reduction is possible with a low purine diet.
85
Type of stone – calcium phosphate stones
Calcium phosphate stones Introduction Two different kinds of calcium phosphate stones occur depending on the urinary pH value. Carbonate apatite and other calcium phosphate/apatite stones develop in alkaline urine (pH 1 6.8) with high calcium and low citric acid concentrations. Inasmuch as calcium oxalate stones develop under similar conditions, carbonate apatite and calcium oxalate stones often occur as mixed stones. However, brushite stones (calcium hydrogen phosphate) develop in urine with a pH in the range of 6.5–6.8 and high concentrations of calcium and phosphate. When the pH value increases up to 6.8, brushite converts into carbonate apatite. Brushite stones grow rapidly with a correspondingly very high recurrence rate. So strong prophylactic treatment is highly important in brushite stone formers. Brushite stones are very hard, therefore disintegration by lithotripsy is more difficult than for other calcium stones.
86
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
Calcium phosphate stones
Y
Occur in different forms
Carbonate apatite (Dahllite) and other calcium phosphates/apatites
Cystine
w
Dahllite
Struvite
Brushite
CaP
Ua
CaOx
Calcium phosphate stones
Xanthine
Brushite (Calcium hydrogen phosphate dihydrate)
NH4 Urate
Occurrence: 1.5% are monomineral stones 0.5% are mixed stones most commonly together with a small fraction of CaOx Y brushite stones most commonly occur in a monomineral form
Appendix
w
2,8-DHA
Occurrence: 32% of all stones are mixed stones with different fractions of carbonate apatite 4.8% are monomineral stones Y most common in alkaline or infected urine Y occur together with CaOx or struvite
87
Type of stone – calcium phosphate stones
Specific notes for calcium phosphate stone disease see General aspects, page
Medical history
22 f.
Immobilization; infections in the urinary tract/other organs Pathophysiologic factors: Disturbances in the metabolism of calcium and phosphate Unexplained back pain H A renal stone as an accidental finding
Imaging
24 f.
Radiodense stones, sometimes of staghorn type Widespread intratubular calcifications and multiple stones Ultrasonography: Structure with a high density and a typical echo
Minimal program
26 f.
Urine analysis: pH 1 6.8 Test strips: sometimes positive for leukocytes and nitrite; pseudo-amorphous crystals in the sediment
冧
H Carbonate apatite/Whitlockite
pH 6.5–7.2 Test strips: negative for leukocytes and nitrite; pillar-like crystals in the sediment
冧
H Brushite
Serum analysis: Calcium sometimes 12.5 mmol/l (5.0 meq/l)
Establishment of the diagnosis by stone analysis: Carbonate apatite, brushite and other phosphates/apatites
88
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
>2.5 mmol/l
H
Exclude HPT (also refer to the chapter on CaOx stones)
H
42 f.
CaP
Calcium
Ua
Serum or plasma analysis
102 f.
Density
>1.010 g/cm3
H
Urine dilution
H
102 f.
Calcium
>8.0 mmol/24h
H
Diet
H
104 f.
Medication
H
106 f.
(also refer to the chapter on
H
54 f.
CaOx stones)
H
58 f.
Diet
H
104 f.
(chapter on struvite stones)
H
120 f.
Medication
H
106 f.
Phosphate >35 mmol/24h
H
Citrate
<2.5 mmol/24h
H
Exclude RTA
H
94 f.
pH
in 24h urine >6.8
H
Exclude infection
H
92 f.
or
Treat infection
H
96 f.
in day profile never <5.8
Exclude RTA
H
94 f.
Treat RTA
H
98 f.
Reference values for children see H 206 f.
Cystine
H
2,8-DHA
Urine dilution
Xanthine
H
NH4 Urate
<2 l/24h
Appendix
Volume
Struvite
24h urine analysis
89
Type of stone – calcium phosphate stones
Biochemical investigation Serum analysis Calcium The serum concentration normally varies within narrow limits: 2.0–2.5 mmol/l (4.0–5.0 meq/l). Repeated measurements above 2.5 mmol/l indicate that the patient might be suffering from primary hyperparathyroidism. Osteolytic malignancies and renal insufficiency are other possible reasons for a high serum calcium. Suspicion of hyperparathyroidism For further diagnostic procedures in patients with hypercalcemia, see the chapter on calcium oxalate stones (p. 42 f.).
Urine analysis Urinary pH (spot urine) The most common causes of calcium phosphate stone formation are disturbances in the calcium phosphate balance, renal tubular acidosis (RTA), and urinary tract infection. In all these conditions, urinary pH is a major determinant for the crystallization of calcium phosphate. Carbonate apatite and other calcium phosphates/apatites These stones form in alkaline urine with an optimal pH above 6.8. In case of urinary tract infection with urease-producing microorganisms, struvite is another component of the precipitate. Thereby the pH usually increases to levels above 7.0. Carbonate apatite and other calcium phosphates/apatites are commonly mixed with CaOx. These stones are usually not associated with an infection, and the admixture of calcium phosphate occurs as a result of physiologic circadian pH variations during the development of the stone. Brushite stones These stones form in a mildly acid urine (brushite is stable in the pH interval 6.5–6.8). Infections are not relevant in brushite stone formation, which indicates that they form in sterile urine. Most commonly brushite occurs in monomineral form or mixed with only small amounts of CaOx. There is a very high recurrence rate in patients who have formed brushite stones. For the formation of other types of calcium phosphate stones, the optimal pH is above 6.8, and it is necessary to exclude both an infection and the possible presence of RTA.
90
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Serum/ Urine analysis
CaOx
Calcium 12.5 mmol/l f
Suspicion of pHPT
H
42 f.
H
48 f.
CaP
Treatment necessary
Ua
f
Struvite
Spot urine: pH 16.8 f
Exclude urinary tract infection f
Cystine
If no infection f
Appendix
NH4 Urate
Xanthine
2,8-DHA
Exclude RTA
91
Type of stone – calcium phosphate stones
Urine analysis (cont.) 24h urine The analysis of calcium, phosphate, citrate and pH is an important part of the quality standard (p. 28 f.). The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed. (for detailed instructions how to collect urine, see p. 190 f.) In order to enable measurement of urinary pH, the urine should be collected in bottles without acid. Suitable preservatives are thymol or sodium azide (see above). For interpretation of the phosphate excretion, it is important to emphasize its strong relationship to the dietary intake. A high consumption of meat and other foodstuffs rich in phosphate results in a high excretion of phosphate (see p. 104 H dietary history!). Protein intake can be checked by urea analysis. Low citrate levels occur in renal tubular acidosis (RTA), and in all patients without a urinary tract infection, it is necessary to exclude RTA.
Bacteriology (Diagnosis of a urinary tract infection) 1. Test strips: The demonstration of leukocytes or a positive nitrite reaction in freshly voided urine always means that a urinary tract infection is present. (Caution: inappropriate storage or preservation of the urine can result in a false-positive nitrite reaction). 2. Determination of the number of bacteria: This can be accomplished with a simplified culturing procedure. 3. Determination of the bacterial strain/resistance pattern: This is necessary when more than 105 bacterial colonies/ml have been detected. The presence of urease-producing bacterial strains is particularly important because of the pronounced alkalization resulting from urease activity. The most important urease-producing bacterial strains are: Proteus, Klebsiella, Pseudomonas, Providencia, Staphylococci and Serratia.
92
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Urine analysis
H
58 f.
≥8 mmol/24h H Hypercalciuria Therapy is initiated at a level of 5 mmol/24h
Phosphate
28 f.
CaP
Calcium
H
Ua
f Part of the quality standard particularly relevant: calcium, phosphate, citrate and pH
CaOx
24h urine collection
≥35 mmol/24h
Citrate
Struvite
H Hyperphosphaturia Caution: diet-dependent excretion of phosphate ≤2.5 mmol/24h
Cystine
H Hypocitraturia
Xanthine
Diagnosis of a urinary tract infection
NH4 Urate
H 1. Test strips: Leukocytes, positive nitrite reaction H 2. Number of bacteria: 6105 colonies/ml H 3. Bacterial strain/resistance pattern/urease activity
Appendix
w
2,8-DHA
Reference values for children see H 206 f.
93
Type of stone – calcium phosphate stones
Diagnosis of renal tubular acidosis (RTA) Within the physiological pH range, formation of CaP stones is strongly affected by pH variations. Measurement of pH values during the 24h period is, therefore, recommended to check the acidifying capacity of the kidney. Day profile of pH H Following careful instructions on how to use pH strips, the patient is advised to record the pH at each voiding during the 24h period. (Has the patient normal color vision?) In the routine laboratory, measure pH with a glass electrode. A pH remaining at a level above 5.8 supports the suspicion of renal tubular acidosis (RTA). When an infection with urease-positive bacteria has been excluded, the diagnosis of RTA is established with an NH4Cl loading (the procedure is described in the Appendix, p. 180 f.). Pathophysiology RTA results from a disturbed secretion of H+-ions in the renal tubuli. There are too few H+-ions available for an adequate bicarbonate reabsorption in exchange of acid anions. Instead, chloride ions are reabsorbed and a hyperchloremic metabolic acidosis develops which can result in a resorption of apatite from the bone and hence a mobilization of calcium. The increased calcium load is filtered through the glomeruli giving concentrations in the tubular urine that exceed the maximal reabsorption rate, whereby increased quantities of calcium are excreted in urine. In addition to recurrent urinary stone formation, nephrocalcinosis is frequently observed in these patients. Two forms of RTA are recognized: proximal RTA and distal RTA. Only the distal RTA is of importance for stone formation. A complete form of distal RTA occurs in 0.5% of stone formers. The milder form of acidification defect without acidosis that can be demonstrated in 3–5% of all patients with urinary stone disease is called incomplete distal RTA.
94
Complete dRTA
Incomplete dRTA
Blood pH f Plasma HCO3– f S-Potassium f S-Chloride d U-Calcium d U-Phosphate d U-Citrate f
Blood pH normal Plasma HCO3– normal S-Potassium normal S-Chloride normal U-Calcium d U-Phosphate normal U-Citrate f
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diagnosis of RTA
When a urinary tract infection has been excluded
92 f.
CaOx
H
pH day profile
Ua
f
pH never !5.8 f
CaP
Exclude a urinary tract infection f
Struvite
Further diagnostic procedures f
Cystine
Ammonium chloride loading H 180 f.
Procedure f
pH is reduced to 5.4 pH is not reduced below 5.4
2,8-DHA
Interpretation of the result: H No RTA
Plasma HCO3– and blood pH low
normal
f
f
complete dRTA
incomplete dRTA
NH4 Urate
Blood gas analysis:
Xanthine
f
Appendix
w
95
Type of stone – calcium phosphate stones
Treatment Stone removal Calcium phosphate stones can grow rapidly. In the case of brushite stones, the recurrence rate might be very high. At the time of diagnosis, the stones have usually reached a size that makes spontaneous passage unlikely. In all patients stone removal should be considered. For stones associated with urinary tract infection, it is essential to remove all stone material to eradicate the infection. Irrespective of how the stones are removed, these patients need a careful follow-up.
Treatment of urinary tract infection In the presence of a urinary tract infection, it is essential to initiate antibiotic therapy along with the complete stone removal: 1. Antibiotics should be selected according to the resistance pattern. Y trimethoprim + sulfamethoxazole in children 1. 3rd-generation cephalosporins Y cephalosporins 2. trimethoprim/sulfamethoxazole Y ciprofloxacin 3. aminopenicillins Y norfloxacin Y gyrase inhibitors If the kidney contains residual fragments or stones and the infection cannot be eradicated, long-term low dose antibiotic treatment can be considered: Y nalidixic acid Y nitrofurantoin 2. Acidification of urine H pH ! 6.2 3. Dilution of urine to reduce the concentration of bacteria (see p. 102 f.)
Treatment of primary hyperparathyroidism In 80% of cases, the cause of pHPT is an autonomous adenoma in the parathyroid glands, in 15% hyperplasia and in 5% a carcinoma. In all these situations, the treatment of choice is parathyroidectomy. Surgery results in cure of more than 90% of these patients.
96
Treatment
Metaphylaxis
Rapid stone growth Oral chemolysis not possible Reduced growth by acidification Frequent recurrences Multiple stones Nephrocalcinosis Complete stone removal particularly in association with urinary tract infection
H 174 f.
CaP
H H H H H H H
CaOx
Stone removal
Ua
?
Biochemical investigations
General aspects
Checklist
Y
Struvite
Treatment of a urinary tract infection Antibiotics
Cystine
(see left page) Y Acidification with
Y
Urine dilution
Depending on pH 3 ! 200–500 mg/day Consider intermittent administration of ammonium chloride once or twice a week
2,8-DHA
Dosage:
Xanthine
Chemolysis of rest fragments
Ammonium chloride
Treatment of pHPT Surgery
Appendix
?
Y
Y
NH4 Urate
or Y L-Methionine Depending on pH Dosage: 3–6 ! 500 mg/day (1–2 tablets 3 times daily)
f After surgery 90% of patients will be recurrence free
97
Type of stone – calcium phosphate stones
Treatment of RTA A complete dRTA is so uncommon that patients should be managed at centers with particular experience with this disease. The disturbance can only be treated symptomatically. Independent of the urinary pH, it is necessary to correct the metabolic acidosis with alkaline citrate or sodium bicarbonate. Sodium bicarbonate should be reserved for patients with decreased tolerance for alkaline citrate. In patients with hypokalemia substitution with electrolytes is necessary. The excretion of the H+-ions can be specially influenced by the diuretic agent ethycrynic acid. In patients with stone disease, dRTA is usually incomplete. These patients should also be given alkaline citrate. For patients with calcium phosphate stones formed as a result of incomplete RTA, a short-term course of acidification with the aim of stone or stone fragment dissolution might occasionally be useful, provided the pharmacological regimen results in a lowering of the urinary pH. If such a therapy is started, it is essential to follow the acid-base status of the patient, since metabolic acidosis can develop. Long-term acidification is, however, discouraged.
98
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Treatment of RTA
Y
CaOx
Treatment of RTA Complete RTA
Incomplete RTA
CaP
Y
Ua
H Should if possible be treated in specialized centers Therapy: Y Reduce metabolic acidosis Y Electrolyte substitution (hypokalemia) Y Increase excretion of hydrogen ions Preparation: Potassium citrate
f
Potassium citrate
Y
18–36 mmol/day in adults, divided into 2–3 doses (0.1–0.15 g/kg body weight/day in children)
Cystine
Dosage:
Sodium bicarbonate Dosage: Preparation:
4.5 g/day (3 capsules with 500 mg ! 3) Sodium bicarbonate (capsules soluble in small intestine) Caution: Na increases hypercalciuria.
2,8-DHA
Y
Struvite
Alkalization
Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate.
Xanthine
Acidification Stone dissolution
NH4 Urate
L-Methionine pH ! 6.2
Only as short-term treatment
Appendix
Y
99
Type of stone – calcium phosphate stones
Metaphylactic treatment Inasmuch as pure carbonate apatite and other calcium phosphates/apatites are rare, knowledge of the other stone constituents is highly important for an efficient metaphylactic treatment. If CaOx presents as a major constituent, refer to the treatment described in the chapter on calcium oxalate stones. If the stone formation is the result of an infection, struvite is the most common crystal copartner. Until the infection has been completely eradicated, refer to the treatment described in the chapter on struvite stones. Brushite stones are in most cases monomineral and associated with an extremely high recurrence rate. When a urinary tract obstruction has been excluded, the metaphylactic treatment must be directed mainly towards a sufficient dilution of urine. Following the exclusion of hypercalciuria and hyperphosphaturia, a detailed analysis of urine variables is necessary.
General measures A generous intake of fluid and avoidance of excessive fluid losses are of importance in achieving a sufficient dilution of urine. Sauna, sun-bathing, extreme sport activities and use of laxatives should be avoided. Since infection plays an important role in the stone formation, prevention of infection is important. Y Avoid cooling the kidneys, bladder region and feet. A high pH is a good indicator of an infection; these patients should regularly measure their urinary pH. If it increases, they should get prompt therapy. The formation of CaP stones can also be the result of immobilization. In addition to increased excretion of calcium and phosphate caused by bone resorption, the reduced urine flow and the chronic infection frequently seen in these patients can facilitate the precipitation of calcium phosphates. Physical activity is therefore an important part of the metaphylactic program. H All relevant serum and urine variables should be regularly checked: Serum: calcium, potassium, creatinine (possibly blood-gas analysis) Urine: pH, calcium, potassium, citrate, nitrite (urine culture and resistance pattern)
100
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Metaphylactic treatment CaOx
w
Ua
H Carbonate apatite stones are commonly mixed stones Y detailed information on the other stone constituent(s) is essential Y decide on measures directed towards the other stone constituent(s)
CaP
H Brushite stones commonly have a monomineral structure Y a high recurrence rate Y specific measures based on a detailed diagnostic work-up
Struvite
General measures Y Sufficient urine dilution (see next page)
Cystine
Y Prevention of infection Y Check the urinary pH
2,8-DHA
Y Sufficient physical activity also in immobilized patients Y Reduction of body weight (aim at the normal body weight without extreme fasting) Y Reduce stress
Xanthine
Y Allow for sufficient sleep
NH4Urate
Y Regular control of G serum and urine variables
Appendix
w
101
Type of stone – calcium phosphate stones
Urine dilution The most important metaphylactic measure for all types of stones is sufficient urine dilution. Increased urine flow not only counteracts new crystal formation, but also flushes bacteria out of the collecting system. The goal should be a production of at least 2.5 l of urine per day. Depending on the extent of physical activities and surrounding temperature, the amount of fluid necessary to drink is at least 2.5 l/day. This intake of fluid should be evenly distributed over the day. It is a good habit to drink again before or after each voiding. It is also important to drink before going to sleep at night to prevent high urine concentration during the sleeping period. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) H During sleeping period: drink before going to bed and drink again before or after each voiding In order to check a sufficient urine dilution, the urine density should be regularly measured using a urometer or test strips. With a density of more than 1.010 g/cm3, the fluid intake has to be increased (if possible).
Type of beverages Urine acidifying and urine-neutral beverages should be preferred: Y Mineral water with a low content of calcium and bicarbonate max. 500 mg HCO3–/l, max. 150 mg Ca/l Y Juice from cranberries has an acidifying and bacteriostatic effect (due to the high energy content, it is recommended to drink these beverages in diluted form H 1 l of cranberry juice contains 480 kcal!)
102
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 2.5 l of urine per day
Ua
f Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children f
Type of beverages
Struvite
CaP
H preferable: acidifying and urine-neutral beverages Y mineral water poor in HCO3– and not high in Ca Y cranberry juice (diluted with water) Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
Cystine
H in limited amounts: Y coffee Y black tea, green tea Y milk
Appendix
NH4Urate
Xanthine
2,8-DHA
H unsuitable: Y citrus juices Y HCO3– -rich, Ca-rich mineral water Y sugar-sweetened soft drinks, including cola Y all alcoholic beverages
103
Type of stone – calcium phosphate stones
Diet There is no need for people with CaP stones to follow a strict dietary regimen; they should eat a balanced mixed diet composed of various constituents: No pure vegetarian diet: – Vegetables, fruits and their products have an alkalizing effect so the intake of citrus fruits and their juice should be restricted. – Foodstuffs of animal origin have an acidifying effect. Calcium intake An excessive intake of calcium should be avoided in order to minimize the risk of increased excretion of calcium (see chapter on Calcium oxalate stones, p. 54 f.) H 500 mg (12.5 mmol) of Ca/day as milk or dairy products preferable: yoghurt, fresh cheese small amounts: soft cheese (Brie, Camembert, etc.) avoid: hard cheese (Emmentaler, Gouda, etc.) Protein intake A high protein content of the diet increases the renal excretion of calcium. A reduced intake of protein is therefore recommended. H max. 150 g/day of meat, fish or sausages On 3 days per week meat and meat products should be avoided. Phosphate intake It is particularly important for patients with hyperphosphaturia to reduce the consumption of meat. In addition, foodstuffs with a high content of phosphate should be avoided (see also p. 120). Hard cheese, legumes and nuts have a high content of phosphate and also a relatively high content of calcium. Restricted intake of these products will thus contribute to a reduced excretion of both phosphate and calcium. Dietary fiber The generally desirable high intake of dietary fiber is attained by the consumption of wholegrain products as well as vegetables, salads and fruits.
104
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
CaOx
Balanced mixed diet
Ua
With consideration of the following points f Y no pure vegetarian diet Y citrus fruits and juices in small amounts H
54 f. and Table 1 200
CaP
Y moderate intake of calcium H preferred: yoghurt, fresh cheese H avoid: hard cheese
Y in case of hyperphosphaturia H in addition to a restricted consumption of meat, avoid foodstuffs with an extremely high content of phosphate: hard cheese, processed cheese, legumes, nuts, cocoa, liver.
Cystine
Y consume a variety of vegetables, salads, fruits and wholegrain products each day
Struvite
Y moderate intake of protein H max. 150 g/day of meat, fish or sausages
Appendix
NH4Urate
Xanthine
2,8-DHA
Y use food with adequate energy intake H to avoid overweight
105
Type of stone – calcium phosphate stones
Medical treatment Reduction of calcium excretion (see the chapter on Calcium oxalate stones, p. 58 f.) Medical treatment is usually necessary in patients with calcium excretion 18 mmol/24h (10.1 mmol/kg body weight/ day in children). Treatment with alkali in order to increase urinary citrate is not appropriate for these patients. Y Treatment with thiazides Contraindications: Hypotension, hypokalemia, acute glomerulonephritis, gout Side effects: Hypotension, hyperuricemia (be careful in patients with gout), reduced glucose tolerance (caution: patients with diabetes mellitus), erectile dysfunction, hypocitraturia secondary to hypokalemia Y Due to the risk of severe side effects, thiazides should be used only in cases of pronounced hypercalciuria. In patients with brushite stones thiazides are mostly indicated. Y Treatment with dietary fiber preparations As an alternative to thiazides, treatment with dietary fiber preparations is possible. In patients with brushite stones, simultaneous acidification is indicated. (see also p. 58) Acidification of urine When a complete RTA has been excluded, a reduction of the urinary pH to 5.8–6.2 is desirable especially in patients with a pH above 6.5 and stone fragments. Y Acidification with L-methionine or ammonium chloride Effect: see p. 122 The dosage is adjusted according to the pH measurements made daily by the patient. The patient is advised to get in touch with the physician in case of pronounced changes. Due to adaptation of the body’s acid-base balance, treatment with ammonium chloride might be more efficient if given intermittently in a high dose once or twice a week. Reduction of phosphate excretion A resistant hyperphosphaturia (135 mmol of phosphate/24h) might necessitate a reduction of the excretion of phosphate. Y Treatment with aluminum hydroxide (consider only in adults) Effect: Inhibits the intestinal absorption of phosphate by forming an insoluble aluminum-phosphate complex Side effect: Gastrointestinal disturbances Y Treatment with Sevelamer (Renagel쏐) or calcium-containing phosphate binders in children
106
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
Thiazide Preparation:
1–2 ! 25 mg/day (slowly increased dosage) 0.5–1.0 mg/kg body weight/day in children Hydrochlorothiazide
Ua
Dosage:
H Please observe the indications and possible side effects (potassium substitution if necessary) and use it only in patients with a pronounced hypercalciuria! H In most cases it is indicated in patients with brushite stones!
Struvite
Urinary pH constantly 16.2
Cystine
Y L-Methionine Dosage: pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2) or
Ammonium chloride Dosage:
pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2) Consider intermittent administration of ammonium chloride once or twice a week.
2,8-DHA
Y
Xanthine
H Contraindication: complete RTA H The solubility of brushite increases with pH <6.2
NH4Urate
Phosphate excretion 135 mmol/24h In therapy-resistant cases
Aluminum hydroxide (consider only in adults) Dosage:
Y
Appendix
Y
CaP
Y
CaOx
Calcium excretion 18 mmol/24h
3 ! 2.2–3.5 g/day
Sevelamer (Renagel쏐) or calcium-containing phosphate binders in children
107
Type of stone – struvite stones
Struvite stones Introduction Struvite stones are always caused by a urinary tract infection with urease-producing microorganisms (Proteus, Providentia, Klebsiella, Pseudomonas, Ureaplasma). Struvite stone formers are two times more frequently female than male. Stones in infants are mostly composed of struvite, whereby especially boys are afflicted. Urinary tract infection results in high ammonium concentrations and pH values of 17.0. Under these conditions the solubility of phosphates is reduced which results in struvite and carbonate apatite crystallization. So struvite stones often occur mixed with carbonate apatite stones. In struvite stone disease a high urinary volume is of great importance to wash out the bacteria and to decrease the supersaturation of phosphates. Besides the specific infection treatment, acidification (L-methionine) is very important to prevent relapses.
108
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
Struvite stones
CaOx
Struvite stones
NH4+ d
pH d
fluid intake f
Citrate f
Urine volume f
2,8-DHA
urea-splitting bacteria
Xanthine
Y>0
Supersaturation MgNH4PO4 ⴢ 6 H2O
NH4Urate
Sex
Cystine
Frequency: 4–6% Caused by infections with urease-producing bacteria Formation optimum at an alkaline pH
Crystalluria
Appendix
Y Y Y
Struvite
CaP
Ua
Magnesium-ammonium-phosphate-hexahydrate stones
Struvite stone
109
Type of stone – struvite stones
Specific notes for struvite stone disease see General aspects, page
Medical history
22 f.
Possibly diffuse back pain H Diagnosis of a stone by chance Infection of the urinary tract and other organs Condition after urological operation Age/sex Children up to 5 years Women in fertile age, during pregnancy
Imaging
24 f.
Moderately radiopaque Frequently staghorn calculus Often multilayered morphology on plain films Possibly urine flow obstruction Chronic inflammatory changes Anatomical abnormalities Ultrasonography: Structure with a high density and a typical echo
Minimal program Urine analysis: pH 17.0 Test strip: leukocyte detection, nitrite positive Sediment with coffin-lid like crystals
26 f.
213 f.
Establishment of the diagnosis by stone analysis: Struvite stone
110
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
Ua
Serum or plasma analysis
CaP
Normal values one or both kidneys affected: Creatinine possibly increased >380 mol/l (6.4 mg/100 ml)
H
risk of ammonium urate stone formation
H
160 f.
Struvite
Urate
H
118 f.
Urine density
>1.010 g/cm3
H
Urine dilution
H
118 f.
pH
in day profile constantly >7.0
H
Exclude infection
H
112 f.
Treat infection
H
114 f.
Acidification therapy
H
122 f.
Ammonium
≥50 mmol/24h
H
Treat infection
H
114 f.
Phosphate
≥35 mmol/24h
H
Diet
H
120 f.
Medication
H
122 f.
2,8-DHA
Urine dilution
Xanthine
H
NH4Urate
<2 l/24h
Appendix
Volume
Cystine
24h urine analysis
Reference values for children see H 206 f.
111
Type of stone – struvite stones
Biochemical investigations Urine analysis Urinary pH (spot urine) Under physiologic conditions, struvite stones form only in the presence of urease-producing microorganisms. The enzyme urease splits urea, causing the formation of ammonium and bicarbonate, which are responsible for an increased urinary pH. For diagnosis and during therapy the control of pH is particularly important. Day profile of pH H Following careful instructions on how to use pH strips, the patient is advised to record the pH at each voiding during one 24h period. (Has the patient normal color vision?) In the routine laboratory, measure pH with a glass electrode. 24h urine Of the optional urine analyses of the quality standard (see p. 28), the measurement of ammonium and phosphate is particularly important. The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190) In order to enable measurement of urinary pH the urine should be collected in bottles without acid. Suitable preservatives are thymol or sodium azide (see above).
Bacteriology (Diagnosis of a urinary tract infection) 1. Test strips: The demonstration of leukocytes or a positive nitrite reaction in freshly voided urine always means that a urinary tract infection is present. (Caution: Inappropriate storage or preservation of the urine can result in a false-positive nitrite reaction.) 2. Determination of the number of bacteria: This can be accomplished with a simplified culturing procedure. 3. Determination of the bacterial strain/resistance pattern: This is necessary when more than 105 bacterial colonies/ml have been detected. The presence of urease-producing bacterial strains is particularly important because of the pronounced alkalization resulting from urease activity. The most important urease-producing bacterial strains are: Proteus, Klebsiella, Pseudomonas, Providencia, Serratia and Staphylococci. Demonstration of ureaplasma requires a special culture medium.
112
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Urine analysis
CaOx
pH day profile f
pH constantly 17.0 Ua
f
typical with urinary tract infection H
46 f.
H
28 f.
CaP
(keep in mind: RTA)
Ammonium
Cystine
f Part of the quality standard particularly relevant: ammonium, phosphate
Struvite
24h urine collection
≥50 mmol/24h
Phosphate
2,8-DHA
Hyperammoniuria ≥35 mmol/24h
NH4Urate
Diagnosis of a urinary tract infection H 1. Test strips: Leukocytes; positive nitrite reaction H 2. Number of bacteria: 6105 colonies/ml H 3. Bacterial strain/resistance pattern/urease activity
Appendix
w
Xanthine
Hyperphosphaturia Caution: diet-dependent excretion of phosphate
113
Type of stone – struvite stones
Treatment Stone removal Since struvite stones contain bacteria, and the number of bacteria on the stone surface increases despite antibiotic therapy, the eradication of a urinary tract infection is only possible after complete stone removal. This is accomplished either with standard surgical procedures or by combining SWL and chemolysis. Cave SWL: Recurrence of UTI, urosepsis!
Elimination of a urinary obstruction If the infection is caused by a urinary obstruction, a simultaneous surgical removal of the stones and the obstruction is necessary.
Treatment of the urinary tract infection Struvite stones can grow rapidly to a large size and can continue to develop as long as the causative infection has not been completely eradicated. Therefore, long-term antibiotic therapy is necessary: 1. Antibiotics should be selected according to their resistance pattern Y trimethoprim + sulfamethoxazole in children 1. 3rd-generation cephalosporins Y cephalosporins 2. trimethoprim/sulfamethoxazole Y ciprofloxacin 3. aminopenicillins Y norfloxacin Y gyrase inhibitor If the kidney contains residual fragments or stones and the infection cannot be eradicated, long-term low dose antibiotic treatment can be considered: Y nalidixic acid Y nitrofurantoin 2. Acidification of urine H pH <6.2, prophylaxis of infection and chemolysis of rest fragments 3. Dilution of urine to reduce the concentration of bacteria (see p. 118 f.)
114
Treatment
Metaphylaxis
Ua
Complete stone removal absolutely necessary Percutaneous chemolysis with acid solutions possible In case of disturbances of urination attributable to anatomic abnormalities: Elimination of urinary obstruction and simultaneously Indication for stone removal
H
174 f.
CaP
H H H H H
CaOx
Stone removal
Struvite
Treatment of a urinary tract infection Determination of resistance! Y
Antibiotics
Y Acidification with Dosage:
Y
Depending on pH 3–6 ! 500 mg/day (1–2 tablets 3 times daily)
Y
Ammonium chloride Dosage: 3 ! 200–500 mg/day (to pH 5.8–6.2) Consider intermittent administration of ammonium chloride once or twice a week.
Chemolysis of rest fragments Urine dilution
NH4Urate
Y
or
Xanthine
Y L-Methionine
2,8-DHA
Cystine
(see left page)
Appendix
?
Biochemical investigations
General aspects
Checklist
115
Type of stone – struvite stones
Metaphylactic treatment The most important prerequisite for an effective metaphylaxis is a complete removal of the stone caused by infection and a correction of any obstructions of the urine flow. H Residual concrements not only hinder recovery, but inevitably result in relapse of stone formation. Occasionally it has been reported that well-disintegrated stone fragments (after SWL) are sterilized by long-term treatment with antibiotics.
General measures As struvite stones generally result from a urinary tract infection, it is most important to prevent infections in these patients. H Avoid: cooling the kidneys, bladder region and feet (take notice particularly during pregnancy) A high pH is a good indicator of an infection; these patients should regularly measure their urinary pH in order to get prompt therapy if there is an increase. Excessive fluid loss due to sauna, sun-bathing, extreme exercise or abuse of laxatives should be avoided. The formation of these stones is also promoted by immobilization. In addition to increased excretion of calcium and phosphate as a result of osteolysis, a reduced urine flow with chronic infection stimulates stone formation. H All relevant serum and urine variables should be regularly checked: Serum/plasma: creatinine Urine: pH, leukocytes, erythrocytes, nitrite (possibly a urine culture with assessment of the resistance pattern)
116
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Metaphylactic treatment CaOx
w
Prerequisite: Complete removal of all concrements
Ua
f
General measures
Struvite
Y Prevention of infections Y Check the urinary pH
Cystine
Y Sufficient urine dilution (see next page) (avoid excessive fluid loss) Y Regular and sufficient physical activity also in immobilized patients
2,8-DHA
Y Reduction of body weight (aim at normal body weight without extreme fasting) Y Reduce stress Y Allow for sufficient sleep
NH4Urate
Xanthine
Y Regular control of G serum and urine variables
Appendix
w
CaP
effective metaphylaxis possible
117
Type of stone – struvite stones
Urine dilution The most important metaphylactic measure for all types of stones is a sufficient urine dilution. This measure not only prevents new stone formation, but also promotes the elimination of crystals and bacteria. The goal should be a production of at least 2–2.5 l of urine per day (1–2 l per m2 body surface area in children). Depending on the extent of physical activity and the surrounding temperature, the amount of fluid necessary to drink is at least 2.5 l/day. This intake of fluid should be evenly distributed over the day. It is a good habit to drink again before or after each voiding. It is also important to drink before going to sleep at night to prevent high urine concentration during the sleeping period. Therefore, in addition to the intake of other fluids: H During day-time: drink 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and again before or after each voiding To check sufficient urine dilution, the urine density should be measured regularly with a urometer or with test strips. With a density of more than 1.010 g/cm3, fluid intake has to be increased if possible.
Type of beverages Acidifying and neutral beverages should be preferred: Y Mineral water with a low content of bicarbonate (max. 500 mg HCO3–/l) Y Juice from cranberries has an acidifying and bacteriostatic effect (due to the high energy content, it is recommended to drink these beverages in diluted form H 1 l cranberry juice contains 480 kcal)
118
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 2.0 l of urine per day
Ua
f Fluid intake: at least 2.5 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children f
Type of beverages
Struvite
CaP
H preferable: acidifying and neutral beverages Y mineral water poor in HCO3– Y cranberry juice (diluted with water) Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
Cystine
H suitable in limited amounts: Y coffee Y black tea, green tea
Appendix
NH4Urate
Xanthine
2,8-DHA
H unsuitable: Y citrus juices (alkalizing) Y HCO3– -rich mineral water (1500 mg HCO3–/l) Y sugar-sweetened soft drinks, including cola Y all alcoholic beverages
119
Type of stone – struvite stones
Diet For people with struvite stones, a balanced mixed diet is recommended, and the food should be as natural as possible. No pure vegetarian diet: – Vegetables, fruits and their products cause alkalization. Citrus fruits and their juices, in particular, cause intensive alkalization and thus counteract acidification of urine. Such products should be consumed only in limited quantities. – Foodstuffs of animal origin cause acidification. The energy content of the diet should be adequate to prevent overweight. Lean dairy and meat products should be chosen. Because of their higher content of polyunsaturated fatty acids, plant fats are preferable to fat products from animals. The intake of products with high sugar content should be avoided. The dietary intake of foodstuffs should be distributed over several meals. Phosphate intake With high phosphate excretion, meat consumption should be limited. The following products with a particularly high phosphate content should be avoided. Phosphorus
Processed cheese Emmental cheese Gouda, Tilsit cheese Kidney beans Lentils (dried) Soy beans
Phosphorus
mg/100 g
mmol/100 g
944 860 500, 570 429 412 591
30 28 16, 18 14 13 19
Peanuts Almonds Brazil nuts Cocoa powder Liver (pork)
mg/100 g
mmol/100 g
410 500 600 740 350–360
13 16 19 24 11–12
Dietary fiber intake There should be a sufficiently high intake of dietary fibers to prevent obstipation. This can be accomplished by preferring wholegrain products and a regular intake of vegetables, salads and fruits.
120
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
Ua CaP Struvite Cystine 2,8-DHA Xanthine
Y
NH4Urate
Y Y
With consideration of the following points f no pure vegetarian diet citrus fruits and juices in small amounts adequate energy intake H to avoid overweight consume a variety of vegetables, salads, fruits and wholegrain products each day in case of hyperphosphaturia: H limited intake of meat total max. 150 g meat, fish or sausages/day foodstuffs with extremely high phosphate content G avoid: hard cheese, processed cheese, legumes, nuts, cocoa, liver
Appendix
Y Y Y
CaOx
Balanced mixed diet
121
Type of stone – struvite stones
Medical treatment Treatment of a urinary tract infection (see p. 114 f.) Check of pH: pH 16.2 f Acidification of urine Struvite stones grow only in an alkaline urine; thus, after chemolysis of rest fragments new stone formation can be avoided in acidic urine. (Control of acid-base metabolism. No long-term therapy in children!) Y Acidification with L-methionine Effect: The metabolism of sulfurous amino acids produces sulfate and protons H pH decreases. Y Acidification with ammonium chloride Effect: Modulation of the acid-base metabolism The dosage depends on urinary pH (aim at a pH of 5.8–6.2), which should be monitored daily by the patient (in case of unacceptable changes in the pH level, get in touch with a physician). Due to adaptation of the body’s acid-base balance, treatment with ammonium chloride might be more efficient if given intermittently in a high dose once or twice a week. Reduction of phosphate excretion In resistant cases with proven hyperphosphaturia (135 mmol phosphate/24h; see laboratory diagnosis), a reduced phosphate excretion might be necessary. Y Treatment with aluminum hydroxide Effect: Inhibition of intestinal phosphate absorption by formation of insoluble aluminum-phosphate salts Side effects: Gastrointestinal disturbances Y Treatment with Sevelamer (Renagel쏐) or calcium-containing phosphate binders in children
122
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
Long-term infection therapy!
H
CaOx
Urine pH constantly 16.2 114 f.
Ua
Y L-Methionine Dosage: pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2) or
Ammonium chloride
H
pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2) Consider intermittent administration of ammonium chloride once or twice a week.
CaP
Dosage:
Contraindication: complete RTA Struvite
Y
Cystine
Phosphate excretion 135 mmol/24h In therapy-resistant cases
Aluminum hydroxide
Xanthine
Sevelamer (Renagel쏐) or calcium-containing phosphate binders in children
NH4Urate
Y
3 ! 2.2–3.5 g/day
2,8-DHA
Dosage:
Appendix
Y
123
Type of stone – cystine stones
Cystine stones Introduction Cystine stones are caused by an inborn, heritable renal defect. The tubular reabsorption of the amino acids cystine, arginine, lysine and ornithine is reduced; even though only cystine is poorly soluble. Stone formation might occur already in infancy, although the first manifestation mostly occurs in the second decade of life. The habitual diet may promote stone formation. Low urinary dilution and a high intake of animal protein as well as sodium chloride increase the urinary excretion of cystine. In cystine stone disease a high urinary volume (13.5 l/24h) is very important. Particularly during the night 1.5 l urine should also be achieved. By alkalization the urinary pH value should be increased up to 7.5–8.0. Treatment with Tiopronin (Thiola쏐, Captimer쏐, Acadione쏐) and/or ascorbic acid results in decreased cystine excretion.
124
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
Cystine stones
Cystine 2,8-DHA Xanthine NH4Urate
Y Y
Frequency: 1–2% Caused by an autosomal recessive hereditary transport defect of the amino acids cystine, lysine, arginine and ornithine Need a lifelong consistent treatment One of the few kinds of stone where the stone constituent always is excreted in an increased quantity
Appendix
Y Y
Struvite
CaP
Ua
CaOx
Cystine stones
125
Type of stone – cystine stones
Specific notes for cystine stone disease see General aspects, page
Medical history
22 f.
Cystinuria or less well-diagnosed stone disease in family Age at the first manifestation Infancy or 15–20 years
Imaging
24 f.
Radiograph with weak, milk-glass like shadows Indication for qualitative cystine test H Family screening Ultrasonography: Structure with a high density and a typical echo
Minimal program Urine analysis: Sediment with hexagonal, plain crystals pH normal
26 f.
213 f.
Establishment of the diagnosis by cystine test: Positive stone analysis: Cystine stone
126
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
Ua
Serum analysis H
28 f.
H
Urine dilution
H
134 f.
Cystine
>0.8 mmol/24h
H
Diet
H
136 f.
Medication
H
Urate
>0.5 mmol/24h
>4.0 mmol/24h
H
H
H
(also refer to the chapter CaOx stones) Diet
H
54 f.
Medication
H
58 f.
Diet
H
56 f.
Medication
H
64 f.
(also refer to the chapter CaOx stones)
NH4Urate
Oxalate
>8.0 mmol/24h
(also refer to the chapter Uric acid stones) Diet
H
82 f.
Medication
H
84 f.
Reference values for children see H 206 f.
127
Appendix
Calcium
138 f.
Cystine
<3 l/24h
2,8-DHA
Volume
Xanthine
24h urine analysis
Struvite
CaP
Normal values
Type of stone – cystine stones
Biochemical investigations Urine analysis 24h urine 1. Quantitative cystine analysis A quantitative cystine analysis is necessary to determine the appropriate treatment. This is only possible by a special amino acid analysis. The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190) In order to enable measurement of urinary pH the urine should be collected in bottles without acid. A suitable preservative is thymol. For the determination of cystine and cysteine 2 ml of 5% SSA is added to 2 ml of urine after collection. Urinary cystine values: Normal: 0.17–0.33 mmol/24h (40–80 mg/24h) Homozygous: often 1 4.16 mmol/24h (1,000 mg/24h) Start of treatment: 60.8 mmol/24h (192 mg/24h) Limit of solubility: 1.33 mmol/l (320 mg/l) at pH 6.0 For childhood values see tables 4–6, p. 206 ff. 2. Analysis according to the quality standard In addition to cystinuria, accompanying metabolic anomalies like hypercalciuria, hyperoxaluria and hyperuricosuria might occur. Of the optional urine analyses in the quality standard (see General aspects, p. 28), the measurement of calcium, oxalate and urate is particularly important.
128
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Urine analysis
CaOx
24h urine collection f Quantitative cystine analysis ≥0.8 mmol/24h (192 mg/24h)
Ua
Cystine
H start of therapy
54 f.
H
56 f.
H
82 f.
Cystine 2,8-DHA
≥0.5 mmol/24h H see chapter CaOx stones
Urate
H
≥8.0 mmol/24h H see chapter CaOx stones
Oxalate
28 f.
≤4.0 mmol/24h H see chapter Uric acid stones
Xanthine
Calcium
H
Struvite
Part of the quality standard particularly relevant: Calcium, oxalate, urate
CaP
In case of diagnosed cystinuria, arrange a family screening!
Appendix
NH4Urate
Reference values for children see H 206 f.
129
Type of stone – cystine stones
Bacteriology (Diagnosis of a urinary tract infection) Since urine alkalization is an important therapeutic measure, a urinary tract infection has to be excluded. 1. Test strips: The demonstration of leukocytes or a positive nitrite reaction in freshly voided urine always means that a urinary tract infection is present. (Caution: Inappropriate storage or preservation of the urine can result in a false-positive nitrite reaction.) 2. Determination of the number of bacteria: This can be accomplished with a simplified culturing procedure. 3. Determination of the bacterial strain/resistance pattern: This is necessary when more than 105 bacterial colonies/ml have been detected.
Treatment Stone removal Although the solubility of cystine steeply increases with a pH above 7.0, medical litholysis can only rarely be achieved. Without infection, alkalization therapy can support SWL treatment. The indication for stone removal depends on whether complaints or complications are evident. Cystine stones are sometimes difficult to disintegrate sufficiently by SWL. Auxiliary procedures are generally necessary but it should be noted that inserted catheters can become encrusted rather quickly. A controlled treatment with SWL and chemolytic irrigation with THAM solutions [tris-hydroxymethyl-aminomethane] and acetylcysteine might sometimes be successful.
130
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diagnosis of a urinary tract infection CaOx
w
Ua
H 1. Test strips: Leukocytes, positive nitrite reaction H 2. Number of bacteria: 6105 colonies/ml H 3. Bacteria strain/resistance pattern/urease activity
174 f.
Xanthine
2,8-DHA
Cystine
Without a consistent metaphylaxis stone relapse is unavoidable.
NH4Urate
q
Oral chemolitholysis only rarely possible H Complaints or complications are an indication for stone removal After diagnosis and stone removal, respectively, immediate therapy is necessary Attempts with chemolysis after SWL may be successful
Struvite
H H H H
CaP
Stone removal
Appendix
?
131
Type of stone – cystine stones
Metaphylactic treatment Cystinuria is an inborn metabolic disease and a rigorous lifelong therapy is necessary. The following therapeutic possibilities should be considered: 1. Reduction of the cystine concentration by extensive urine dilution, 2. A reduction of cystine excretion by a diet with relatively low protein and sodium content, 3. Increased solubility of cystine by urine alkalization and 4. Medicinal reduction of the urinary concentration of cystine with sulfide-containing compounds. In selected cases ascorbic acid can be used to decrease urinary cystine.
mg/ml 1,000 800 600 400
The solubility of cystine is considerably dependent on pH. Between 5.0 and 7.0 only 160–320 mg (0.7–1.3 mmol) cystine/l are soluble, while with pH 17.0 the solubility increases steeply. Thus, the goal has to be a steady high pH level of 7.5–8.0. Presupposition: free of infection!
200 0 5
6
7
8
pH
General measures The patient-monitored control of pH is important for a successful alkalization therapy. Since the high pH makes it impossible to detect a pH increase caused by an infection, every attempt must be made to prevent infections. Excessive fluid loss due to sauna, sun-baths, extreme exercise or intake of laxatives must be avoided. H During the lifelong treatment, a close control of the relevant serum and urine parameters is necessary: Serum: creatinine, urate Urine: volume, urine density (dilution sufficient?), cystine (dose of drugs adequate?), pH (alkalization sufficient?), nitrite (infection?), calcium, phosphate (keep in mind: risk of phosphate stone formation with high pH), oxalate (very important during ascorbic acid therapy), urate (accompanying metabolic disease possible)
132
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
136 f.
H
138 f.
H
140 f.
Ua
H
CaP
134 f.
General measures
Cystine
Y Prevention of infections Y Regularly check the urinary pH
2,8-DHA
Y Sufficient urine dilution (see next page) (avoid excessive fluid loss) Y Regular and sufficient physical activity Y Avoid excessive losses of fluid (e.g. sauna, sun-baths, extreme exercise, laxatives)
Xanthine
Y Reduction of body weight (aim at normal body weight without extreme fasting) Y Reduce stress Y Allow for sufficient sleep Y Regular control of G serum and urine variables
NH4Urate
w
H
Struvite
1. Extensive urine dilution H reduced concentration of cystine 2. Diet with a low content of sodium and without excessive protein intake H reduced excretion of cystine 3. Urine alkalization H increased cystine solubility (only after exclusion of a urinary tract infection!) 4. Ascorbic acid or sulfide containing preparations H medicinal reduction of urinary cystine concentration
CaOx
Therapeutic possibilities
Appendix
w
133
Type of stone – cystine stones
Urine dilution Extensive urine dilution is necessary for a successful metaphylaxis in patients with cystine stone disease. To remain below the critical limit of 1.3 mmol cystine/l (300 mg/l), with a cystine excretion of 1 4.2 mmol/24h (1,000 mg/24h), the mean urine volume must be at least 3.5 l/day. Depending on the extent of physical activity and the surrounding temperature, the amount of fluid needed varies between 3.5–4.0 l/day. This intake of fluid should be evenly distributed over the 24h period, thus also during the night hours. It is a good habit to drink again before or after each voiding. Therefore, in addition to the intake of other fluids: H During day-time: drink 2.5 dl every hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding
Type of beverages Since the solubility of cystine increases clearly with a rising pH, the fluid requirement should mainly be satisfied with alkalizing beverages. Alkalizing beverages should be preferred: Y Mineral water rich in bicarbonate at least 1,500 mg HCO3–/l, max. 500 mg Na/l Y Citrus juices (450 kcal/l)
134
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
General aspects
Checklist
CaOx
Goal: Urine dilution H at least 3.5 l of urine per day
Ua
f Fluid intake: at least 3.5–4.0 l/day in adults at least 1.5–2.0 l/m2 body surface area advisable for infants and young children (age !10 years), for older children see recommendations for adults evenly distributed over the 24h period f
CaP
Type of beverages
Struvite
H preferable: alkalizing beverages Y mineral water rich in HCO3– (sodium content as low as possible) Y citrus juices (diluted with water)
Cystine
H also suitable: urine-neutral beverages Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
2,8-DHA
H suitable in limited amounts: Y coffee Y black tea, green tea
Appendix
NH4Urate
Xanthine
H less suitable: Y sugar-sweetened soft drinks, including cola Y all alcoholic beverages
135
Type of stone – cystine stones
Diet Protein intake Since cystine is formed during the metabolism of methionine, a diet with a low content of this amino acid would be effective. Unfortunately, such a diet seriously reduces the quality of life. Thus, the person who develops cystine stones should choose a balanced mixed diet with relatively low protein content which should not exceed 0.8 g protein/kg body weight/day. H Protein-rich foodstuffs should be consumed only in limited quantities: meat, fish, sausages, eggs, hard cheese, nuts and legumes (esp. soy beans). A mainly vegetarian diet has a relatively low protein content and brings about an alkalization. Vegetables, salads, fruits and cereals should form the major content of the diet. In children, the requirements of iron and iodine may not be sufficiently satisfied with such a diet and they should be given 1–2 meat meals and 1 fish meal weekly. Sodium intake Cystine excretion increases with high sodium intake and therefore the sodium chloride content of the diet should be limited. This can be accomplished by preferring fresh foodstuffs and by restricting the use of salt during cooking. Processed food such as fast food, canned foods, pickled and smoked products sometimes contain very large quantities of sodium chloride and therefore should be avoided. Change in Na content of several foodstuffs by industrial processing mg sodium/100 g (mmol/100 g) mushrooms, fresh peas, fresh milk
136
8 (0.3) 2 (0.1) 48 (2.1)
mg sodium/100 g (mmol/100 g) H H H
canned canned hard cheese
319 (13.9) 236 (10.3) 420–860 (18.3–37.4)
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Diet
CaOx
Balanced mixed diet With consideration of the following points f
Ua
Protein intake Y protein-rich foodstuff only in limited quantities H meat, fish, sausages, eggs, cheese, legumes
CaP
Y prefer foodstuff with a low protein content H fruits (esp. citruses) vegetables, salads vegetarian diet cereals
Cystine
Children: do not completely exclude meat and fish from diet H important for iron and iodine supply
2,8-DHA
Sodium intake
Xanthine
Y restrict the sodium chloride content of the diet H avoid: additional salt during the meal canned foods smoked and pickled foods
NH4Urate
Y consume a variety of vegetables, salads, fruits and wholegrain products each day
Appendix
q
Struvite
冧
137
Type of stone – cystine stones
Medical treatment Alkalization of urine As the solubility of cystine increases with a pH above 7.5, alkalization of the urine is a successful kind of treatment. Y Alkaline citrate Effect: Increases urinary pH by modulating acid-base metabolism Contraindication: Recurrent urinary tract infection, severe hypertension, renal insufficiency, metabolic alkalosis, hyperkalemia Side effects: Gastrointestinal discomfort Caution: Risk of phosphate stone formation Alternative: Sodium bicarbonate H Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate H Use capsules soluble in small intestine Reduction of cystine concentration Y ␣-Mercaptopropionylglycine (Tiopronin; Thiola쏐, Captimer쏐, Acadione쏐) Indication: Cystine excretion of more than 3.0–3.5 mmol/24h = 720–840 mg/24h Effect: Transformation of cystine to one molecule cysteine and one molecule cysteine + drug Side effects: (Sharply reduced compared with the previously used D-penicillamine) up to 20% of patients might develop dysgeusia, gastritis, dermatosis, nephrotic syndrome (NS) Regular check of serum and urine values!
138
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
CaOx
Goal: urine pH 17.5 Only when the patient is free from a urinary tract infection
Alkaline citrate Ua
Y
Dosage:
According to pH H the patient has to measure the pH throughout the day! spread the dose over the day Preparations: e.g. Polycitrat-K쏐, Urocit-K쏐, Blemaren쏐 N
Sodium bicarbonate Dosage:
According to pH H the patient has to measure the pH throughout the day! spread the dose over the day Caution: Na increases hypercalciuria
Struvite
Y
CaP
or
Cystine
Y Use sodium bicarbonate only in patients with decreased tolerance for alkaline citrate.
Y
2,8-DHA
Cystine excretion 13.0 (3.5) mmol/24h ␣-Mercaptopropionylglycine
Xanthine
Dosage: Begin slowly with 250 mg/day according to cystine excretion, increase up to 1–max. 2 g/day H Loses efficacy during long-term therapy (tachyphylaxis)! Increase the dose if necessary according to the cystine excretion. Do not exceed the maximum dose!
Appendix
NH4Urate
Notice side effects (see left page)! If necessary stop treatment immediately!
139
Type of stone – cystine stones
Medication Reduction of cystine concentration (cont.) Y Treatment with ascorbic acid Indication: Cystine excretion !3.0–3.5 mmol/24h , 720–840 mg/24h H The frequency of stone formation, urine volume, etc. determine the lower or upper limit for ascorbic acid therapy. Effect: Changing of the redox balance between cystine and cysteine to the well-soluble cysteine (p. 196). Side effects: Increased excretion of oxalate possible (check regularly!) Caution: Control of therapy by routine analysis of cystine is not possible. Normally cystine and cysteine are assessed together as total cystine because in the presence of oxygen, cysteine is oxidized back to cystine. Separate measurement of cystine and cysteine is only possible by special analysis (Birwé et al., 1991).
140
Biochemical investigations
Treatment
Metaphylaxis
Medication
General aspects
Checklist
NH4Urate
Xanthine
2,8-DHA
Cystine
Struvite
CaP
Dosage: 3–5 g/day H Check the urinary pH, goal: pH 17.5 H Use ascorbic acid effervescent tablets, because they support alkalization; pure ascorbic acid might result in acidification! H In case of use of pure ascorbic acid, urinary pH should be adjusted to 17.5 with alkaline citrate
Ua
Ascorbic acid
Appendix
Y
CaOx
Cystine excretion !3.0 (3.5) mmol/24h
141
Type of stone – 2,8-dihydroxyadenine stones
2,8-Dihydroxyadenine stones Introduction Normally 2,8-dihydroxyadenine (2,8-DHA) does not occur as a metabolic product. Caused by an autosomal, recessive hereditary defect of adenine phosphoribosyl transferase, adenine cannot be converted to AMP. Alternative adenine is oxidized to 2,8-DHA by the enzyme xanthine oxidase. This complete enzyme defect causes stone formation already in infancy. The symptoms are easy to confuse with uric acid stone disease. Thus a special diagnostic procedure in children with stone disease is always indicated. Xanthine oxidase can be inhibited by allopurinol, so that 2,8-DHA excretion decreases drastically. Thus, with a regular drug intake the risk of a new stone formation can be minimized.
142
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
2,8-Dihydroxyadenine stones
Cystine 2,8-DHA Xanthine NH4Urate
Y Y
Occurrence: very rare Caused by an autosomal recessive hereditary defect of the enzyme adenine phosphoribosyl transferase Lifelong consistent treatment is necessary Can easily be confused with uric acid stones
Appendix
Y Y
Struvite
CaP
Ua
CaOx
2,8-Dihydroxyadenine stones
143
Type of stone – 2,8-dihydroxyadenine stones
Specific notes for 2,8-dihydroxyadenine stone disease see General aspects, page
Medical history
22 f.
Possibly diffuse abdominal pain Progressive renal insufficiency Stones in family history (possibly falsely diagnosed as uric acid stones) Age at the first manifestation Mostly in infancy
Imaging
24 f.
Radiolucent Contrast defect on the urogram H Confusion with uric acid stones Ultrasonography: Structure with a high density and a typical echo
Minimal program Urine analysis: pH value normal Sediment with circular, brown crystals
26 f.
213 f.
Serum analysis: Urate normal
Establishment of the diagnosis only possible by stone analysis: 2,8-Dihydroxyadenine stone
144
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition
Ua
(in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
Serum analysis
CaP
Urate normal
<2 l/24h
H
Urine dilution
H
148 f.
Density
>1.010 g/cm3
H
Urine dilution
H
148 f.
H
Diet
H
150 f.
Medication
H
150 f.
Cystine
Volume
Struvite
24h urine analysis
Xanthine NH4Urate Appendix
demonstrated
2,8-DHA
2,8-Dihydroxyadenine:
145
Type of stone – 2,8-dihydroxyadenine stones
Biochemical investigations Origin of 2,8-dihydroxyadenine Adenine which originates from purine metabolism is normally retransformed to AMP by the enzyme adenine phosphoribosyl transferase (APRT). With a defect of APRT, adenine is oxidized to 2,8-dihydroxyadenine, a reaction catalysed by the enzyme xanthine oxidase. The following substances are excreted in the urine at high concentrations: adenine, hydroxyadenine, 2,8-dihydroxyadenine, hypoxanthine; but only 2,8-dihydroxyadenine is poorly soluble.
Urine analysis 24h urine Normally no 2,8-dihydroxyadenine is excreted in urine and its presence is a confirmation of the APRT defect. In addition to the obligatory analysis of the quality standard (see p. 28 f.), the measurement of 2,8-dihydroxyadenine is necessary. The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190)
Measurement of APRT activity The extent of this enzyme defect is determined by assessing the enzyme activity in the erythrocyte lysate. After blood transfusion, a correct diagnosis is impossible. Normal: 24.7 8 4.8 nmol adenine/mg Hb/h Homozygous: grave or complete loss of activity Heterozygous: moderate loss of activity H no clinical symptoms (for example: members of families with homozygous affected children)
146
Biochemical investigations
Treatment
Metaphylaxis
CaOx
General aspects
Checklist
Origin of 2,8-dihydroxyadenine // APRT defect
adenine
Ua
AMP {
{
xanthine oxidase
{
CaP
P 8-hydroxyadenine xanthine oxidase
Cystine
Struvite
P 2,8-dihydroxyadenine
24h urine collection 28 f.
2. Quantitative analysis of 2,8-dihydroxyadenine
H 196
2,8-DHA
H
Xanthine
1. According to the quality standard
Erythrocyte lysate f
NH4Urate
Measurement of APRT activity
Appendix
f Stone formation in cases of homozygous disease with complete or partial enzyme deficiency
147
Type of stone – 2,8-dihydroxyadenine stones
Treatment Stone removal The size of 2,8-dihydroxyadenine stones varies from gravel to staghorn calculi; thus, spontaneous stone passage is sometimes possible but interventional measures might be necessary. The latter is dependent on whether complaints or complications are evident or can be expected. A chemical dissolution of 2,8-dihydroxyadenine is impossible under physiological conditions. In any case, metaphylactic measures should be started immediately. The poor solubility of 2,8-dihydroxyadenine not only results in stone formation, but might also lead to a progressive renal failure because of nephrocrystallosis.
Metaphylactic treatment Urine dilution In addition to the treatment with allopurinol (see next pages), an improved urine dilution is the most important metaphylactic measure. The goal should be a production of at least 2.5 l urine/day. Depending on the extent of physical activities and the surrounding temperature, the amount of fluid needed is at least 3.0 l/day (1–2 l/m2 body surface area in children). As the 2,8-dihydroxyadenine excretion shows a characteristic diurnal variation, with excretion peaks during the night and early morning hours, the fluid intake has to be evenly distributed over the 24h period to ensure an adequate urine flow during the sleeping periods. It is a good habit to drink again before or after each voiding. Thus, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding To check sufficient urine dilution, the urine density should be regularly measured with a urometer or test strips. With a density of more than 1.010 g/cm3, the fluid intake has to be increased.
148
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
174 f.
Ua
H 2,8-Dihydroxyadenine stones are insoluble H Indication for stone removal H – complaints and complications – if metaphylactic therapy cannot prevent stone growth or new stone formation
CaOx
Stone removal
CaP
Goal: Urine dilution H at least 2.5 l of urine per day
NH4Urate
Xanthine
2,8-DHA
Cystine
Struvite
f Fluid intake: at least 3.0 l/day in adults at least 1.0–2.0 l/m2 body surface area/day in children evenly distributed over the 24h period
Appendix
?
General aspects
Checklist
149
Type of stone – 2,8-dihydroxyadenine stones
Diet Since 2,8-dihydroxyadenine originates from purine metabolism, a reduction of dietary purine is desirable. As shown in the chapter on uric acid stones (see p. 82 f.), an ovo-lacto-vegetarian diet has a low content of purine and is thus the ideal kind of nutrition for adults. For children, the supply of proteins, iron and iodine might be insufficient with such a diet. Thus, 1–2 meals with meat and 1 meal with fish should be given weekly. In any case, food with an extremely high content of purine should be avoided.
Medical treatment Reduction of 2,8-dihyroxyadenine excretion The transformation of adenine to 2,8-dihydroxyadenine is catalyzed by the enzyme xanthine oxidase. This enzyme is inhibited by administration of the hypoxanthine analogue allopurinol (see Uric acid stones, p. 76 f.). Y Treatment with allopurinol Effect: ‘Diversion’ of the xanthine oxidase activity from the transformation of adenine to 2,8-dihydroxyadenine to the transformation of allopurinol to oxypurinol Control of efficacy: – 2,8-dihydroxyadenine excretion decreased to a minimum – adenine excretion increased Side effects: Formation of xanthine or oxypurinol concrements possible; changes in blood count; hypersensitivity reactions; interaction with anticoagulants and antihistaminics Increase of 2,8-dihydroxyadenine solubility The solubility of 2,8-dihydroxyadenine is very poor in a pH range of 4.8 to 8.0, increasing only with pH values exceeding 9.0. Therefore, alkalization is not a clinically feasible alternative.
150
Biochemical investigations
Metaphylaxis
Treatment
Diet/Medication
General aspects
Checklist
CaOx
Balanced mixed diet With consideration of the following points f
meat, meat products and fish (max. 150 g/day), legumes, including soy products innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork
Children: do not completely exclude meat and fish from the diet
Struvite
H important for the supply of protein, iron, iodine
Allopurinol Dosage:
5–10 mg/kg body weight/day adults: 300–600 mg/day
2,8-DHA
Y
Cystine
Reduction of 2,8-dihydroxyadenine excretion
NH4Urate
Xanthine
H Find the optimum (= minimum) dose by measuring the excretion of unmetabolized allopurinol
Appendix
q
82 f.
CaP
Y restrict: Y avoid:
H
Ua
Purine intake (see also Uric acid stones)
151
Type of stone – xanthine stones
Xanthine stones Introduction Xanthine stones are absolutely rare. They are caused by an inborn defect of xanthine oxidase. Xanthine cannot be oxidized to uric acid, so that the excretion of hypoxanthine and xanthine increases. Xanthine is only poorly soluble, which results in xanthine stone formation. A drug therapy to dissolve xanthine stones is not available. Consequently a high dilution day and night is the most important measure in xanthine stone disease. An ovo-lacto-vegetarian diet to increase the urinary pH value and to decrease xanthine excretion is also indicated.
152
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
Xanthine stones
Cystine NH4Urate
Xanthine
2,8-DHA
Occurrence: very rare Caused by an autosomal recessive hereditary defect of the enzyme xanthine oxidase Lifelong consistent treatment is necessary Can easily be confused with uric acid stones
Appendix
Y Y Y Y
Struvite
CaP
Ua
CaOx
Xanthine stones
153
Type of stone – xanthine stones
Specific notes for xanthine stone disease see General aspects, page
Medical history
22 f.
Stones in family history Treatment with high doses of allopurinol Lesch-Nyhan disease Chemotherapy of malignant diseases Age at the first manifestation Mostly in infancy
Imaging
24 f.
Radiolucent Contrast defect on the urogram H Confusion with uric acid stones Ultrasonography: Structure with a high density and a typical echo
Minimal program
26 f.
Serum analysis: Urate markedly decreased !119 mol/l (2 mg/100 ml)
Establishment of the diagnosis only possible by stone analysis: Xanthine stone
154
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition
Ua
(in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
Serum analysis <119 mol/l (<2 mg/100 ml)
CaP
Urate
158 f.
Urine density
>1.010 g/cm3
H
Urine dilution
H
158 f.
Xanthine
>40 mol/24h
H
Diet
H
158 f.
Hypoxanthine
>70 mol/24h
Cystine
H
2,8-DHA
Urine dilution
Xanthine
H
NH4Urate
<2 l/24h
Appendix
Volume
Struvite
24h urine analysis
155
Type of stone – xanthine stones
Biochemical investigations Serum analysis The striking and most important diagnostic finding is the markedly decreased serum level of urate. This is caused by the lack of activity of xanthine oxidase, which catalyzes the transformation of hypoxanthine to xanthine and xanthine to urate. GMP
K
guanosine f guanine K
inosine P hypoxanthine P xanthine P urate
J
adenosine J AMP
J
xanthine oxidase
J
xanthine oxidase
Urine analysis 24h urine In addition to the analysis of the quality standard (see p. 28 f.), assessing the 24h excretion of xanthine and hypoxanthine is essential for a correct diagnosis. The patient has to collect a complete 24h urine sample. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190) Treatment with high doses of allopurinol in case of Lesch-Nyhan disease and with chemotherapy in malignant diseases can also lead to decreased serum levels of uric acid and an increased xanthine excretion with a risk of xanthine stone formation. To confirm the diagnosis of a primary xanthinuria, other medical reasons must be excluded.
156
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Serum/ Urine analysis
CaOx
Urate markedly decreased !119 mol/l (!2 mg/100 ml)
Ua
Normal value 119–380 mol/l (2.0–6.4 mg/100 ml)
H
2. Quantitative determination of xanthine and hypoxanthine
H
Xanthine
28 f. 196
Struvite
f 1. According to the quality standard
CaP
24h urine collection
very much increased
Hypoxanthine
Cystine
normal value <40 mol/24h Caution: high doses of allopurinol may also cause xanthinuria
normal or increased
NH4Urate
Xanthine
Arrange a family screening
Appendix
w
2,8-DHA
normal value <70 mol/24h
157
Type of stone – xanthine stones
Treatment Stone removal Chemolitholysis of xanthine stones is not possible. The symptoms caused by xanthine stones are less pronounced; therefore, at the time of diagnosis the stones often have reached a size which necessitates interventional measures. Because of the inborn error of metabolism with a risk of rapid stone growth, the aim should always be a complete surgical removal of all stones.
Metaphylactic treatment At present, there are no possibilities for medical treatment of primary xanthinuria. Treatment with allopurinol is not successful. An increased urine dilution is particularly important.
Urine dilution More than 2.5 l of urine should be excreted daily. The daily fluid intake should be 3 l for adults and 1.5–2 l for children. Since extremely high concentrations of xanthine might occur during the sleeping period, the fluid intake should be evenly distributed over the 24h period. It is a good habit to drink again before or after each voiding. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding
Diet Since xanthine originates from purine metabolism, a reduction of the dietary intake of purine is indicated. An ovolacto-vegetarian diet has a low purine content (see p. 82 f.) and is thus ideal for adults. In children, the requirements of protein, iron and iodine may not be sufficiently satisfied with such a diet. Thus, 1–2 meat meals and 1 fish meal should be given weekly. Foodstuff with extremely high purine content should always be avoided.
158
Biochemical investigations
Treatment
Metaphylaxis Urine dilution/ Diet
H Xanthine stones are insoluble H Indication for stone removal H – complaints and complications – if metaphylactic therapy cannot prevent stone growth and new stone formation
CaOx
Stone removal
174 f.
Ua
?
CaP
Goal: urine dilution H at least 2.5 l of urine per day
Cystine
Struvite
f Fluid intake: adults 3 l/day, children 1.5–2 l/day evenly distributed over the 24h period
Adults: a diet with a low purine content meat, meat products and fish (max. 150 g/day), legumes, including soy products innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork
2,8-DHA
Y restrict: Y avoid:
Xanthine
Children: do not completely exclude meat and fish from diet
NH4Urate
H important for the supply of protein, iron, iodine
Appendix
q
General aspects
Checklist
159
Type of stone – ammonium urate stones
Ammonium urate stones Introduction Ammonium urate stones are very rare in industrial countries, and are normally caused by an infection with ureasesplitting bacteria (see also struvite stones). In developing countries ammonium urate stones occur endemically, especially in children. The reason for stone formation is an unbalanced diet with mainly rice and an insufficient intake of phosphate from milk and meat products. Caused by the low urinary phosphate buffer capacity, the transformation of glutamine to ammonium is increased. A low pyrophosphate and a high urinary pH and urate excretion result in ammonium urate stone formation. Comparable reasons for stone formation in developed countries might be anorexia nervosa, laxative abuse or an unbalanced vegetarian diet. In this case, the main therapeutical measure is a change in dietary habits.
160
Checklist
Biochemical investigations
Treatment
Metaphylaxis General aspects
Ammonium urate stones
Cystine 2,8-DHA Xanthine NH4Urate
Y Y Y
Frequency: 0.5% A rarity in industrial countries; endemic in countries with unbalanced nutrition (e.g. India, South East Asia) In contrast to uric acid stones: grow only with pH 16.5 Caused mostly by infections Often mixed with struvite
Appendix
Y Y
Struvite
CaP
Ua
CaOx
Ammonium urate stones
161
Type of stone – ammonium urate stones
Specific notes for ammonium urate stone disease see General aspects, page
Medical history
22 f.
Possibly abdominal pain because of urinary tract infection Unbalanced vegetarian diet Phosphate malnutrition; abuse of laxatives; anorexia nervosa
Imaging
24 f.
Radiolucent Contrast defect on the urogram H Confusion with uric acid stones H Radiopaque stones: H Struvite as a component Ultrasonography: Structure with a high density and a typical echo
Minimal program Urine analysis: pH 1 6.5 Test strip: possibly nitrite positive Sediment with spherical shape crystals with radial beam structure
26 f.
213 f.
Serum analysis: Urate possibly increased 1380 mol/l (16.4 mg/100 ml)
Establishment of the diagnosis by stone analysis: Mono-ammonium urate stone
162
192 f.
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
CaOx
Quick reference with known serum and urine composition (in case of unclear findings, first episode of stone, etc.: consider the following pages on diagnostic work-up)
Potassium
H
Diet
H
170 f.
Medication
H
170 f.
CaP
>380 mol/l (6.4 mg/100 ml)
Hypokalemia (normal 3.5–5.5 mmol/l)
Struvite
Urate
Ua
Serum or plasma analysis
H
168 f.
Density
>1.010 g/cm3
H
Urine dilution
H
168 f.
pH
>6.5
H
Exclude infection
H
166 f.
Treat infection
H
168 f.
Diet
H
170 f.
Medication
H
170 f.
Exclude infection
H
166 f.
Urate
>4 mmol/24h
H
Ammonium
>50 mmol/24h
H
Phosphate Sodium Potassium
obviously decreased decreased decreased
(normal: 16–48 mmol/24h) (normal: 150–220 mmol/24h) (normal: 30–90 mmol/24h)
Reference values for children see H
2,8-DHA
Urine dilution
Xanthine
H
NH4Urate
<2 l/24h
Appendix
Volume
Cystine
24h urine analysis
206 f.
163
Type of stone – ammonium urate stones
Biochemical investigations Serum or plasma analysis Urate An ammonium urate crystallization caused by increased urate excretion might be the result of hyperuricemia. This demands adequate therapeutic measures and makes clarification imperative. Potassium In patients with ammonium urate stones, hypokalemia is not rare. Thus, in addition, the serum potassium level should be determined.
Urine analysis Urinary pH value (spot urine sample) Ammonium urate stones can develop in slightly acid, sterile urine as well as in alkaline, infected urine. Day profile of pH H Following careful instructions on how to use pH strips, the patient is advised to record the pH at each voiding during the 24h period. (Has the patient normal color vision?) In the routine laboratory, measure pH with a glass electrode. Results: pH 17.0: Suggests an infection with urea-splitting (urease-producing) microorganisms (most frequent reason in industrial countries). Because of the high pH with a simultaneously high urate excretion, proportionally high ion-activity products (supersaturations) of uric acid are formed. Together with ammonium from the urea breakdown, ammonium urate is formed. pH between 6.5 and 7.0: Suggests that the reason is a decreased urinary phosphate buffer capacity. For compensation, additional ammonium is excreted. With a simultaneously increased urate excretion, the development of ammonium urate stones is possible even without urinary tract infection.
164
Biochemical investigations
Treatment
Metaphylaxis General aspects
Checklist
Serum/ Urine analysis
CaOx
Urate 1380 mol/l (16.4 mg/100 ml) f
Ua
Hyperuricemia
CaP
Potassium decreased (normal 3.5–5.5 mmol/l) f
Struvite
Hypokalemia
2,8-DHA
f reason: reduced phosphate excretion (clarify) + increased urate excretion
Xanthine
f reason: infection (clarify) + increased urate excretion
NH4Urate
f pH 6.5–7.0
Appendix
f pH constantly 1 7.0
Cystine
pH day profile
165
Type of stone – ammonium urate stones
Urine analysis 24h urine The formation of ammonium urate in infected urine is particularly promoted by increased excretion of urate and ammonium. In case of stone formation in slightly acidic, sterile urine, a reduced phosphate excretion is typical. This is mostly the result of a very unbalanced diet with low phosphate and protein content (the main reason in Third-world countries, e.g. South East Asia; in industrial countries: unbalanced vegetarian diet, laxative abuse, anorexia nervosa). As part of the quality standard (see p. 28), the measurement of urate, ammonium and phosphate is particularly important. In addition, the sodium and potassium excretion should be determined. Decreased levels are found in ammonium urate stone formers. The patient has to collect a complete 24h urine. H Detailed instructions how to collect the sample are essential: Y the first portion of urine in the morning is discarded and the time noted Y collect all urine during the following 24h in the bottle Y the last voiding should be made at the same time as the collection was started on the previous day Y if possible, store the urine in a cool place and bring it to analysis as soon as possible after the collection has been completed (for detailed instructions how to collect urine, see p. 190) For the analysis of urate and pH, the urine collection should be carried out in bottles without acid. Preferable preservatives are thymol or sodium azide (see above).
Bacteriology (Diagnosis of a urinary tract infection) In industrial countries, an infection with urea-splitting microorganisms is the main reason for the development of ammonium urate stones. Thus, ammonium urate is often mixed with struvite. 1. Test strips: The demonstration of leukocytes or a positive nitrite reaction in freshly voided urine always means that a urinary tract infection is present. (Caution: Inappropriate storage or preservation of the urine can result in a false-positive nitrite reaction.) 2. Determination of the number of bacteria: This can be accomplished with a simplified culturing procedure. 3. Determination of the bacterial strain/resistance pattern: This is necessary when more than 105 bacterial colonies/ml have been detected. The presence of urease-producing bacterial strains is particularly important because of the pronounced alkalization resulting from the urease activity. The most important urease-producing bacterial strains are: Proteus, Klebsiella, Pseudomonas, Providencia, Serratia and Staphylococci or Ureaplasma urealyticum.
166
Treatment
Metaphylaxis General aspects
Biochemical investigations
Checklist
Urine analysis
CaOx
24h urine collection f Part of the quality standard particularly relevant: Urate, ammonium, phosphate
28 f.
Ua
H
≥50 mmol/24h
Phosphate
very much decreased (normal 16–48 mmol/24h)
Sodium
decreased (normal 150–220 mmol/24h)
Potassium
decreased (normal 30–90 mmol/24h)
NH4Urate
Diagnosis of a urinary tract infection H 1. Test strips: Leukocytes, positive nitrite reaction H 2. Number of bacteria: 6105 colonies/ml H 3. Bacterial strain/resistance pattern/urease activity
Appendix
w
206 f.
Xanthine
Reference values for children see H
Struvite
Ammonium
Cystine
≥4 mmol/24h
2,8-DHA
Urate
CaP
Determine also: Sodium, potassium
167
Type of stone – ammonium urate stones
Treatment Stone removal Chemolitholysis of ammonium urate stones is not possible. Depending on the size of the stone, it might either pass spontaneously or require intervention. The latter is particularly necessary in the case of complaints or complications. Alternatively, the stone can be left in the kidney with regular follow-up.
Treatment of a urinary tract infection When an infection is the basis of ammonium urate stone formation, long-term antibiotic therapy is indispensable: 1. Antibiotics should be selected according to resistance patterns Y trimethoprim + sulfamethoxazole in children 1. 3rd-generation cephalosporins Y cephalosporins 2. trimethoprim/sulfamethoxazole Y ciprofloxacin 3. aminopenicillins Y norfloxacin Y gyrase inhibitors If a kidney contains residual fragments or stones and the infection cannot be eradicated, long-term low dose antibiotic treatment can be considered: Y nalidixic acid Y nitrofurantoin 2. Acidification of urine H pH !6.2 3. Dilution of urine to reduce the concentration of bacteria (see below)
Metaphylactic treatment Urine dilution As with all kinds of stones, the most important metaphylactic measure is a sufficient urine dilution in order to reduce the concentration of stone-forming substances and to wash out bacteria. The goal should be the production of at least 2.0 l of urine/day. The amount of fluid needed to drink is at least 2.5 l/day. This intake of fluid should be evenly distributed over the day. It is a good habit to drink again before and after each voiding. Urine-neutral beverages should be preferred. Therefore, in addition to the intake of other fluids: H During day-time: drink at least 2.5 dl every second hour (approx. 2 cups or 2 small glasses) During sleeping period: drink before going to bed and drink again before or after each voiding
168
Biochemical investigations
Treatment
Metaphylaxis
Urine dilution
CaOx
Stone removal
Ua
H Ammonium urate stones are not soluble H Indication for stone removal H 174 f. – in case of complaints or complications – if metaphylactic therapy cannot prevent stone growth and new stone formation
Struvite
H see left page H see next page
Cystine
1. Antibiotics 2. Acidification with L-methionine or ammonium chloride 3. Urine dilution
CaP
Treatment of urinary tract infection
Goal: Urine dilution H at least 2.0 l of urine per day
2,8-DHA
f Fluid intake: at least 2.5 l/day in adults at least 1–2 l/m2 body surface area in children f
Xanthine
Type of beverages
NH4Urate
H preferable: urine-neutral beverages Y kidney tea, bladder tea, herbal tea and fruit tea Y mineral water with a low content of minerals
Appendix
?
General aspects
Checklist
169
Type of stone – ammonium urate stones
Diet Purine intake Since the formation of ammonium urate stones is promoted by an increased urate excretion, a reduction of the dietary purine intake is necessary. As specified in the Uric acid chapter (see p. 82 f.), an ovo-lacto-vegetarian diet has a low purine content and thus is ideal. The intake of meat and meat products should be limited to a maximum of 150 g/day. Products with extremely high purine content should be avoided completely. Phosphate intake If the stone formation is caused by an obviously low phosphate excretion as a result of an extremely unbalanced diet, a change of nutrition to a balanced diet is absolutely necessary. Laxative abuse should be diagnosed and stopped; in the case of anorexia nervosa special therapy is necessary.
Medical treatment Acidification of urine In the case of pH 16.8 after eradication of infection, an acidification therapy is indicated. Y Acidification with L-methionine Effect: The dissimilation of sulfurous amino acids produces sulfate and protons H pH decreases Y Acidification with ammonium chloride Effect: Modulation of the acid-base metabolism Consider intermittent administration of ammonium chloride once or twice a week. Reduction of urate excretion When it is impossible to reduce the urate excretion below 4 mmol/24h by changing the diet to a low purine content, a medical therapy is indicated. Y Treatment with allopurinol Effect, contraindications, side effects: see chapter Uric acid stones, p. 76 f.
170
Biochemical investigations
Treatment
Metaphylaxis
Diet/Medication
General aspects
Checklist
CaOx
Balanced mixed diet With consideration of the following points f
CaP Struvite
Reduced phosphate excretion H notice unbalanced diet
H
Notice infection therapy! or
Y
114 f.
Ammonium chloride Dosage: pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2)
Xanthine
Y L-Methionine Dosage: pH dependent 3 ! 200–500 mg/day (to pH 5.8–6.2)
Cystine
Urine pH constantly 16.2
Urate excretion 14.0 mmol/24h Allopurinol Dosage:
if S-urate >380 mol/l and U-urate >4 mmol/24h 100 mg/day if only U-urate >4 mmol/24h (1–3 mg/kg body weight/day in children) 300 mg/day
NH4Urate
Y
Appendix
q
meat, meat products and fish (max. 150 g/day), legumes, including soy products innards, sardines, anchovies, sprats, mackerel, skin from fish, poultry and pork
2,8-DHA
Y restrict: Y avoid:
Ua
Purine intake (see also Uric acid stones)
171
General aspects
Appendix
H
186 f.
Examination under standardized dietary conditions
H
190 f.
Analytical methods
H
192 f.
Unusual stone components/artifacts
H
198 f.
Tables 1–3: Calcium, oxalate and purine contents of foods
H
200 f.
Tables 4–6: Reference values for children
H
206 f.
Crystals in the urinary sediment (colored illustrations)
H
213 f.
CaP
Risk indices
Struvite
178 f.
Cystine
H
2,8-DHA
Absorption/loading tests
Xanthine
174 f.
NH4Urate
H
Appendix
Interventional procedures
Ua
CaOx
Appendix
173
Appendix – interventional procedures
Interventional procedures Extracorporeal shock-wave lithotripsy (SWL) During SWL treatment, disintegration is accomplished by focussing extracorporeally induced shock waves on the stone. The shock-wave sources might be electrohydraulic, electromagnetic or piezoelectric. Today most devices use electromagnetic sources. The shock waves are transmitted into the body through water, focused by a reflector or acoustic lens system, and the energy is released by reflection at the surface of the stone. The absorption of this energy is the basis for the disintegrating power. Demands on modern lithotripters: Y high efficiency (high energy density at the stone) with optimum focus (no damage to the surrounding tissues) and minimal pain (possible to complete the treatment with mild analgo-sedation) Y combined ultrasonographic and fluoroscopic imaging Indications: Y 80% of all stones: SWL mono-therapy Y 90% of all stones: SWL together with auxiliary measures Restrictions: Y spontaneous passage of fragments must be possible Y a urinary obstruction (below the stone) needs to be surgically corrected Y large staghorn stones (combination with PNL or chemolysis) Y avoidance in PH types I and II and in accompanying nephrocalcinosis Success rate: Y 60–75% of the stone patients are free of stones after 3 months; for ureteral stones the stone-free rate is above 90%. Attendant measures: Y Prevention of new aggregation by alkalization therapy, if the kind of stone indicates it (not with phosphate and ammonium urate stones) and urinary infection can definitely be excluded. In patients with residual gravel appropriate recurrence-preventive measures should be considered.
174
Loop extraction Under cytoscopic and preferably fluoroscopic control, a special ureteral catheter is inserted beyond the stone up to the renal pelvis where it is closed to form a loop (Zeiss loop catheter). In successful cases, the peristaltic activity of the ureter expels the catheter together with the stone. This passive extraction might occasionally take several days. The stone can also be extracted with a little basket, but such a procedure should only be carried out with a ureteroscope. Both Zeiss loop and basket extractions are only applicable for stones with diameters not greater than 5–6 mm.
CaP Appendix
NH4Urate
Indication: Y Distal ureteral stones which remain in position despite a size that should enable spontaneous passage.
Struvite
Complications: Y Ureter lesions or perforation up to 10%, most of which heal without complications with internal ureteral stenting. Y The development of late strictures is possible.
Cystine
Indication: Y Particularly in the case of impacted stones, but in the hands of an experienced endoscopist, the technique can be used for all ureteral stones. There is a high success rate and a low complication rate with ureteral stones. Both URS and SWL are considered as acceptable alternatives for removal of ureteral stones at all levels of the ureter.
2,8-DHA
An endoscope (semirigid or flexible), the diameter of which is adapted to the lumen of the ureter is inserted transurethrally into the ureter up to the stone under visual and radiographic control. General or regional anesthesia is usually necessary. The stone is extracted intact or disintegrated by mechanical vibration, by laser or by shock waves (electrohydraulic ultrasound). Today the most efficient technique to disintegrate ureteral stones has been reported with Holmium-YAG-laser devices.
Xanthine
Ureterorenoscopy (URS)
Ua
CaOx
General aspects
Interventional procedures
175
Appendix – interventional procedures
Percutaneous nephrolithotomy (PNL) Under regional or general anesthesia and with ultrasonographic or fluoroscopic control, the kidney is punctured and a track established through the renal parenchyma. Following dilatation to 20–30 Fr, a nephroscope can be introduced. The stone is extracted intact or disintegrated under vision by mechanical vibration or shock waves (electrohydraulic ultrasound or laser lithotripsy). The fragments can subsequently be removed with forceps or by suction. Indication: Y renal stones or occasionally proximal ureteral stones, particularly those with a diameter exceeding 20–25 mm Y in case of SWL failure Y for removal of disintegrated stones after SWL Y in combination with SWL in case of a large staghorn stone Y in case of urinary tract obstruction below the stone (infundibular stenosis, ureteral stenosis)
Retrograde intrarenal stone surgery (RIRS) Retrograde intrarenal stone surgery has been introduced for removal of stones in the renal pelvis or calices. The procedure is accomplished by a flexible ureteroscope and forceps or a laser device. The technique requires specific expertise but might be useful for removal of, for instance, stones in the caliceal diverticula as well as stone material residing in the lower calix.
176
Open surgery
Cystine
Open surgery has been abandoned almost completely due to the modern techniques SWL, URS and PNL.
CaP
Uric acid is the only salt that is very well soluble in alkaline urine. Alkalization can be attained by agents given orally or intravenously. The pH levels necessary for dissolving other kinds of stone can only be reached in vitro or in situ with irrigation through percutaneously or transurethrally inserted catheters. The risks of these methods are either local irritation of the mucosa or systemic effects if the solution is inappropriately used. Chemolitholysis is indicated for removal of residual gravel following SWL of stones caused by infection (soluble in acid solutions) and of uric acid and cystine stones (soluble in alkaline solutions). Solutions used for dissolution of uric acid stones are THAM (tris-hydroxymethyl-aminomethane; 0.3 or 0.6 mol/l). These solutions can also be used for contact dissolution of cystine stone material. In the latter case a combination with 2% acetylcysteine (0.12 mol/l in an alkaline solution, pH 8.5) might be successful. For infection stones the greatest chemolytic experience has been obtained with hemiacidrin (Renacidin쏐, 10%) or Suby’s solution.
Struvite
Chemolitholysis
Ua
CaOx
General aspects
Interventional procedures
Appendix
NH4Urate
Xanthine
2,8-DHA
Indication: Y stone removal with the simultaneous treatment of a urinary tract obstruction Y when all other options have been unsuccessful, particularly in case of acute obstructive pyelonephritis Y for removal of large staghorn stones
177
Appendix – absorption/loading tests
Absorption/loading tests [13C2]Oxalate absorption test* Hyperoxaluria is one of the most important risk factors for urinary stone formation. A small increase in oxalate easily results in exceeding the calcium oxalate formation product. Depending on the method of measurement and the definition of the upper normal limit, up to 46% of calcium oxalate stone patients exhibit hyperoxaluria. Hyperoxaluria can result from endogenous production, from excessive oxalate content of the diet or from intestinal hyperabsorption. For a causal therapy, it is important to discriminate between endogenous and absorptive hyperoxaluria. The [13C2]oxalate absorption test allows reliable determination of intestinal oxalate absorption. Because of the use of a stable isotope, this test may be repeated as often as required. Study design for the oxalate absorption test The assessment of oxalate absorption is performed under standardized conditions: 2,400 ml of liquid is distributed evenly over the day. Standard diet on the test days consists of normal foodstuffs; it contains 2,400 kcal, 93 g protein, 350 g carbohydrates, 96 g fat, 800 mg (20 mmol) calcium, 750 mg (31 mmol) magnesium and 63 mg (0.7 mmol) oxalate per day. Normal values: adults !10% (von Unruh et al., 2003; Voss et al., 2006) children !18.6% (Sikora et al., 2008)
* Von Unruh et al. (1998).
178
General aspects
Absorption/ loading tests
CaOx
[13C2]Oxalate absorption test
8 a.m.
Intake of 33.8 mg [13C2]oxalic acid as 50 mg of di-Na-salt in a capsule, soluble in gastric juice Breakfast Urine collection (+15 ml HCl, 25%) Lunch Urine collection (+15 ml HCl, 25%) Urine collection (+30 ml HCl, 25%)
9 a.m. 8 a.m. to 2 p.m. 2 p.m. 2 p.m. to 8 a.m. 8 p.m. to 8 a.m.
CaP
Day 2:
Median
Range
Median
Range
Women (n = 60) Men (n = 60) Total (n = 120)
6.80 7.75 6.85
1.7–20.0 1.8–18.5 1.7–20.0
Women (n = 60) Men (n = 60) Total (n = 120)
8.80 9.85 9.45
2.7–23.5 1.8–27.1 1.8–27.1
Girls (n = 12) Boys (n = 23) Total (n = 35)
9.6 10.6 10.4
1.9–18.6 4.3–26.2 1.9–26.2
Girls (n = 27) Boys (n = 33) Total (n = 60)
14.1 17.0 15.3
1.7–37.7 2.6–32.8 1.7–37.7
Xanthine
CaOx stone patients
NH4Urate
Healthy subjects
2,8-DHA
The quantitative determination of the [13C2]oxalate excreted in the urine fractions of Day 2 was performed by gas chromatography-mass spectroscopy. Adhering to the standardized conditions – especially the liquid supply and the supply of calcium and magnesium – the following values were determined:
Struvite
Urine collection (+30 ml HCl, 25%) Urine collection (+30 ml HCl, 25%)
Cystine
8 a.m. to 8 p.m. 8 p.m. to 8 a.m.
As borderline for an increased risk an absorption of 10% was defined. 46% of the calcium oxalate stone patients (n = 120) and 28% of the volunteers (n = 120) had an oxalate absorption of ≥10%.
179
Appendix
Day 1:
Ua
Procedure
Appendix – absorption/loading tests
Ammonium chloride loading test To demonstrate renal tubular acidosis (RTA) A urinary pH that over several days never falls below 5.8 in the day profile raises the suspicion of a latent RTA. Pathogenesis The reason for RTA is an insufficient secretion of H+-ions in the distal tubule. Also few H+-ions are available for the bicarbonate in exchange of acid anions. Instead, more chloride anions are reabsorbed, and this results in a hyperchloremic metabolic acidosis. A metabolic acidosis always causes a breakdown of apatite with increased mobilization of calcium and phosphate from the bone tissue. Thus, RTA always implies a great risk of calcium phosphate as well as of calcium oxalate stone formation. A proximal and a distal form of RTA is known. Only distal RTA is important for stone formation. The complete distal form is found in 0.5% of patients with stone disease. A limited acidification capacity without acidosis, the incomplete form of RTA, occurs in 3–5% of all stone patients.
180
Complete dRTA
Incomplete dRTA
Blood pH f Plasma HCO3– f S-Chloride d U-Calcium d U-Phosphate d U-Citrate f
Blood pH normal Plasma HCO3– normal S-Chloride normal U-Calcium d U-Phosphate normal U-Citrate f
General aspects
Absorption/ loading tests
CaOx
Ammonium chloride loading test
Ua
f pH never decreases below 5.8 in diurnal profile (exclude urease-positive infection!) f Demonstration of RTA NH4Cl loading test (see next page)
CaP
f Result pH falls to 5.4 pH does not fall below 5.4
Struvite
H no RTA
f
Cystine
Blood gas analysis f 7.35–7.45 35–45 mm Hg 80–90 mm Hg 22–26 mmol/l 8 2 mmol
2,8-DHA
: : : : :
low
normal
f
f
complete RTA
incomplete RTA
Xanthine
Plasma HCO3– and blood pH
NH4Urate
Result
pH pCO2 pO2 HCO3– BE
Appendix
normal values:
181
Appendix – absorption/loading tests
Ammonium chloride loading test The test can be carried out on an ambulatory basis. Y laboratory instruments: pH-meter – glass electrode (do not use test strips) Number of NH4Cl tablets or capsules per kg body weight (, 0.1 g NH4Cl/kg body weight) Body weight, kg
Number of tablets
Body weight, kg
Number of tablets*
40–41 42–44 45–47 48–51 52–54 55–57 58–61 62–64
12 13 14 15 16 17 18 19
65–67 68–70 71–74 75–77 78–80 81–84 85–87 88–90
20 21 22 23 24 25 26 27
* 1 tablet/capsule , 300 mg NH4Cl
182
General aspects
Absorption/ loading tests
Y
CaOx
Ammonium chloride loading test Material for the patient
9 a.m.
collect urine into first collecting bottle H drink 150 ml*
10 a.m.
collect urine into second collecting bottle H drink 150 ml*
11 a.m.
collect urine into third collecting bottle H drink 150 ml*
12 noon
collect urine into fourth collecting bottle H drink 150 ml*
1 p.m.
Struvite
breakfast + NH4Cl tablets H drink 150 ml*
Cystine
8 a.m.
CaP
Procedure
2,8-DHA
Y
Ua
NH4Cl tablets (number see opposite page) 5 small (0.5 l) collecting bottles (number the bottles!)
collect urine into fifth collecting bottle H lunch
Xanthine
* fruit tea or mineral water poor in HCO3– f Y
Immediately bring all collecting bottles to the laboratory Measure the pH value in all samples
Appendix
Y
NH4Urate
f
183
Appendix – absorption/loading tests
Calcium loading test* Hypercalciuria is the most frequent biochemical abnormality in patients with stone disease. When stone formation continues despite normal calcium intake or medical treatment, a special diagnostic work-up might be indicated. With the calcium loading test, three types of hypercalciuria can be distinguished. 1. Absorptive hypercalciuria: Excessive calcium absorption from the intestine. After exceeding the renal resorption maximum, the excessive calcium supply results in hypercalciuria: type I: independent of Ca intake type II: only with increased Ca intake 2. Renal hypercalciuria: Pathologically decreased Ca reabsorption in the distal tubules H renal leak. The renal Ca loss stimulates the production of parathyroid hormone leading to secondary hyperparathyroidism (HPT). 3. Resorptive hypercalciuria: Excessive bone reabsorption and increased intestinal Ca absorption because of primary hyperparathyroidism. If no metabolic disorder is discovered and the hypercalciuria cannot be assigned to one of these types, the disorder is called idiopathic hypercalciuria. This occurs in approximately 20% of the afflicted patients. If necessary, the test can be carried out on an ambulatory basis, but since the result highly depends on a correct handling of the samples, it is advisable to do it as an in-patient examination. The urinary excretion of substances of importance for stone formation is influenced by the diet. Since metabolic disorders may be concealed, simulated or enhanced by the individual diet, the calcium loading test should be performed under standardized dietary conditions.
* Modified according to Pak et al. (1975) and Heller et al. (2007).
184
General aspects
Absorption/ loading tests
Y
CaOx
Calcium loading test Material for the patient
Y
Ca-poor diet (no milk products) 6 p.m. last meal 8 p.m. 300 ml Ca-poor water 11 p.m. 300 ml Ca-poor water
second day:
7 a.m. 7–9.00 a.m.
Struvite
first day:
CaP
Procedure
Cystine
urination, 600 ml Ca-poor water first urine collecting period (blank value) collect urine into first collecting bottle 9 a.m. breakfast (1 sandwich, butter, jam, 2 cups of fruit tea) + 1,000 mg Ca tablets 9.00 a.m.–1 p.m. second urine collecting period (loading value) collect urine into second collecting bottle 11 a.m. 300 ml Ca-poor water
2,8-DHA
Y
Ua
2 (1 l) collecting bottles (numbered) 1.5 l Ca-poor water 1,000 mg Ca (effervescent tablets)
Analyses Calcium and creatinine are measured in first and second urine sample.
Xanthine
Interpretation of the result
normal absorptive hypercalciuria renal/resorptive hypercalciuria
blank value
loading value
up to 0.337 up to 0.337 ≥ 0.338
up to 0.563 ≥ 0.564 ≥ 0.564
NH4Urate
Divide: Ca (mmol/l)/creatinine (mmol/l)
Appendix
Y
renal hypercalciuria: cAMP increased resorptive hypercalciuria: parathyroid hormone increased k HPT
185
Appendix – risk indices
Risk indices Ion-activity product indices* Estimates of the ion-activity products of calcium oxalate and calcium phosphate The precipitation of calcium oxalate (CaOx) and calcium phosphate (CaP) is determined by the level of supersaturation with the respective salt. In order to get an idea of the level of supersaturation, information on the ion-activity product (AP) is necessary. Ion-activity products can be obtained from advanced calculation with computerized systems following analysis of a large number of urine variables. Two simplified indices are presented below by means of which approximate estimates of the ion-activity products of CaOx and CaP can be derived from the analysis of calcium, oxalate, citrate, magnesium, phosphate and pH. Moreover the volume is measured and expressed in liters. The urine variables used in the formulas should be in mmols excreted during the collection period. The APCaOx index approximately corresponds to 108 ! APCaOx and the APCaP index to 1015 ! APCaP. APCaOx and APCaP are the ion-activity products of CaOx and CaP as derived from calculations with the EQUIL2 program. Thereby fixed values were used for variables not included in the indices. The estimates of AP are valid in case the latter urine variables do not deviate too much from their fixed values. In order to avoid errors that might be due to samples with urine volumes that do not reflect the normal situation, standardized estimates have been formulated in which the 24h urine volume is set to 1.5 liters. Because it is often difficult to get a reliable assessment of pH in a long-term urine collection, the standardized APCaP index has the pH set to 7.0. In the clinical work-up an APCaOx index of !1.5–1.7 and an APCaP index of !50 should be the aim of treatment.
* Tiselius et al. (1997/2001).
186
General aspects
Risk indices
CaOx
Ion-activity products of CaOx, CaP and uric acid A ⴢ Calcium0.84 ⴢ Oxalate
APCaOx index =
Ua
Citrate0.22 ⴢ Magnesium0.12 ⴢ Volume1.03 B ⴢ Calcium1.07 ⴢ Phosphate0.70 ⴢ (pH – 4.5)6.8
APCaP index =
CaP
Citrate0.20 ⴢ Volume1.31
6
8
12
16
18
20
24
Factor A Factor B (! 10–3)
6.3 5.1
4.5 4.3
3.7 3.9
3.2 3.6
2.7 3.2
2.3 3.0
2.2 2.9
2.1 2.8
1.9 2.7
Cystine
4
Formula for estimating the ion-activity product of uric acid (APHU). APHU =
Curate ⴢ 10–pH ⴢ 0.53 (1 + 1.63 ⴢ 105 ⴢ 10–pH)
Appendix
NH4Urate
In this formula Curate is the concentration of urate. The solubility (SP) and formation (FP) products of uric acid are 2 ⴢ 10 –9 (mol/l)2 and 5 ⴢ 10 –9 (mol/l)2, respectively.
2,8-DHA
2
Xanthine
Collection period (h)
Struvite
Factors A and B are determined according to the duration of the collection period and take the following values:
187
Appendix – risk indices
Calcium oxalate crystallization risk – the BONN Risk Index (BRI) The BONN Risk Index is a successfully applied strategy in the evaluation and monitoring of the risk of calcium oxalate formation (Laube et al., 2000, 2004). This index is determined by in vitro crystallization experiments in samples of unprepared native urine. Method The determination of the BRI requires first the collection of a 24h urine without the addition of any preservatives. During the collection period, the urine should be stored at +4 ° C. When urine collection is complete, the urine’s calcium ion concentration, [Ca2+], has to be determined by a conventional calcium-selective electrode. To a well-stirred 200-ml aliquot of the 24h urine, 0.04 N ammonium oxalate solution is added step-by-step (0.25 ml/step; 1 step/min) until precipitation of calcium oxalate begins. This moment can be simply detected by an in-line laser probe or a dip-in photometer ( = 620 nm), as the number of suspended particles dramatically increases at this moment. The [Ca2+] measurement and the crystallization experiment have to be performed at a sample temperature of 37 ° C. From the [Ca2+] and the amount of ammonium oxalate added at the moment of detected crystallization (Ox2–), the BRI can be simply obtained by calculating BRI = [Ca2+]/(Ox2–). A BRI ; 1 l–1 is the best value to separate samples of stone formers and healthy persons, i.e., the overlap between both groups is minimized. Therefore, samples indicated by a BRI 1 1 l–1 are assumed to be ‘at risk’, whereas samples showing a BRI ^ 1 l–1 are assumed to be at ‘moderate risk’, or, samples with very low values ‘without risk’. Conclusion The particular advantage of the BRI approach is the fact that all urinary components contribute their individual effects in their native ratio to the experiment. Thus, BRI is an excellent marker of an imbalance between promoters and inhibitors at an individual level. In the case of an observed crystallization risk, the urine should be biochemically investigated in order to clarify, for example, the metabolic reasons for the enhanced risk. In comparison, the calculation of, for example, the relative supersaturation out of a biochemical data set provides a helpful strategy to evaluate an individual treatment scheme as the urinary concentrations of the major lithogenic constituents, which are the focus of therapeutic measures, are combined in a meaningful and easy-to-interpret manner.
188
General aspects
Risk indices
CaOx
Calcium oxalate crystallization risk – the BONN Risk Index (BRI) 2.5
‘high risk’
1.0
BRI = 1/l
‘low’ to ‘no risk’
0.5
CaP
1.5
Struvite
Ionized calcium (mmol/l)
2.0
Ua
Best-fit hyperbola (r = 0.88) Urines of healthy subjects, n = 157 Urines of stone formers, n = 139
BRI = 32.9/l
BRI = 0.044/l
0 Amount of titrated ammonium oxalate at the beginning of crystallization (mmol)
Mean and standard deviation of [Ca2+] and (Ox2–) values obtained from 24h urine samples of stone formers and healthy subjects. The [Ca2+] and (Ox2–) values are significantly (p ! 0.001) and highly hyperbolically (r = 0.87) related. Samples plotted on a line through the origin show the same BRI as is calculated as the quotient of [Ca2+] and (Ox2–). Circles indicate the maximum (32.9 l–1) and minimum (0.044 l–1) BRI values observed from a stone former and a healthy subject.
Appendix
NH4Urate
Short description Y Collection of a 24h urine, without preservatives (storage at +4 ° C) Y Determination of [Ca2+] with a calcium-selective electrode Y Triggering of calcium oxalate precipitation by addition of ammonium oxalate solution Y Detection of that moment with an in-line laser probe or a dip-in photometer; evaluation of (Ox 2–) Y Calculation of BRI = [Ca2+]/(Ox2–) ] BRI ` 1 l–1: sample ‘at risk’ ] BRI ^ 1 l–1: sample at ‘low risk’
2,8-DHA
Cystine
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0
Xanthine
0
189
Appendix – examination/diet
Examination under standardized dietary conditions The urine excretion of substances of importance for stone formation is influenced by the diet. Thus, metabolic disorders may be concealed, stimulated or enhanced. Since the examination under standardized dietary conditions needs an exact handling, it is necessary to do it on an in-patient basis. To clarify the metabolic situation, the patient should collect one or two 24h urine samples with their individual diet (control urine). Afterwards, one urine sample should be collected after 3 days on a standardized diet (standardized diet urine). During this period the metabolism is adapted to a steady state, so that abnormalities attributable to the diet are eliminated or at least minimized. By comparing the composition of the control urine and the standardized diet urine sample, it is possible to detect those abnormalities that depend on dietary habits. A recording of the diet should be carried out at the same time. Collection of a 24h urine Y Material for the patient: Two 2.5 l collecting bottles per day For urine preservation fill 10 ml of 5% thymol in isopropanol into each bottle. Y Collecting instructions 1. On the day of urine collection, void as usual after getting up in the morning and discard the urine. Note the time! 2. After that, all urine should be collected in the bottle (also during the night). Urinate before each defecation, so that no urine is lost. Always store the collecting bottles in a cool place! 3. At exactly the same time on the next morning, urinate and collect the urine for the last time. 4. When the collection is completed, bring the urine immediately to the laboratory.
190
General aspects
Examination/ Diet
Ua H
28 f.
H
28 f.
CaP
f 24h urine under individual diet H recording of the diet f Analyses according to the quality standard
CaOx
Control urine
Standardized diet urine
Struvite
f Three days standardized diet
f Analyses according to the quality standard
Cystine
f On the fourth day, collection of a 24h urine sample under the standardized diet
2,8-DHA
Interpretation of the results
184 f.
H Ammonium chloride loading test
H
180 f.
H [13C2]Oxalate absorption test
H
178 f.
H BONN Risk Index (BRI)
H
188 f.
NH4Urate
H
Appendix
H Calcium loading test
Xanthine
1. Normalization of abnormal urine variables under the standardized dietary conditions: H inappropriate dietary habits (arrange a contact with a dietitian) 2. No change of abnormal urine variables under the standardized dietary conditions: H indicates metabolic disorders! (further clarification by loading tests)
191
Appendix – analytical methods
Analytical methods Analysis of urinary stones Based on the guidelines for treatment and recurrence prevention of urolithiasis, the first measure after stone removal is analysis of the concrements (Straub et al., 2005; Tiselius et al., 2008). A specific diagnostic evaluation as well as successful prevention of recurrent stones should always be based on a valuable stone analysis. Different methods have been used for stone analysis, however, only a few meet the criteria for use in a routine laboratory and its accompanying quality control. Hence, only the last two of the following methods are recommended for stone analysis: – Chemical analysis – Microscopy – Scanning electron microscopy – X-ray diffraction – Infrared spectroscopy The chemical methods show a significant error rate and are not able to distinguish between different mineralogical phases. The exact microscopic examination of stone grain specimens requires very highly qualified laboratory personnel. For scanning electron microscopy very expensive equipment is required and the analysis is time-consuming. Hence, this method needs further research efforts. On the basis of the crystalline structure of the stone substances, a very exact stone analysis is obtained by X-ray diffraction (Hesse et al., 2005; Euler et al., 2008). However, the equipment is also very expensive and substances without a crystalline structure, such as proteins and amorphous phosphates, are not ascertained. Infrared spectroscopy is the most widely used method for stone analysis. Based on the different molecular structures of the stone substances, typical absorption spectra in the infrared spectrum range result, which correspond to a finger print of each single substance. More than two thirds of all urinary stones are composed of more than one substance, which can clearly be distinguished with this method (Hesse et al., 2005). Infrared spectroscopy equipment with the latest technology (FTIR-ATR) only needs a very tiny amount of a substance for analysis (!1 mg) and enables very fast and accurate analysis. For evaluation, reference spectra or a computed spectra library can be applied (Hesse and Sanders, 1988). Because of the necessary equipment stone analysis should be performed in qualified centers where adequate documentation for scientific evaluation can also be carried out (see figure on p. 193).
192
Urinary Stone Analysis Center Bonn
Patient name and date of birth (address)
CaOx
General aspects
Analytical methods
harnsteinanalysezentrum bonn
Ua
Prof. Dr. rer. nat. A. Hesse * Dr. med. R. M. Schaefer Dr. med. Ph. Lossin * Prof. Dr. med. D. Bach
Theaterplatz 14, D - 53177 Bonn - Bad Godesberg Phone: +49 228 95737 16 * Fax: +49 228 95737 21
CaP
Sender/Stamp/Date
no
Stone Lab
Sample received on:
Sample-No.:
Date of stone passage dd.mm.yy
Result in weight-%
Stone removal
Whewellite Weddellite Carbonatapatite (Dahllite) Brushite Struvite Uric acid (Uricit) Uric acid dihydrate Ammonium urate Cystine
spontaneous
operative
conservative
chemolitholytic
instrumental
lithotryptic
kidney right
kidney left
ureter right
ureter left
bladder
urethra
yes
no
Localization
Core-Shell-Analysis *Additional comments:
No. of stones/ gravel
overall
Stone colour white yellow black brown
=1 =2 =3 =4
core
shell
Cystine
other*
yes
2,8-DHA
urinary stone
Recurrence:
Stone surface green = 5 beige = 6 grey = 7
Xanthine
Type of stone:
Struvite
To fill in by the SENDER:
rough =1 smooth = 2 bizarre = 3
stone analysis by infrared spectroscopy
Appendix
stone analysis by infrared spectroscopy
NH4Urate
Date/Signature:
193
Appendix – analytical methods
In addition to routine analytic methods (Ca, Mg, uric acid, creatinine), some special methods are necessary. In the following, the most important of these methods are described.
Oxalate Method 1: Principle:
Enzymatic with oxalate oxidase (Sigma-Kit) Transformation of oxalate to carbon dioxide and hydrogen peroxide by oxalate oxidase. In the presence of peroxidase, hydrogen peroxide reacts with 3-methyl-2-benzothiozolinon and 3-dimethylamino benzoic acid forming an indamine dye-stuff. The intensity of the color as determined photometrically at 590 nm is directly proportional to the concentration of oxalate.
Method 2: Principle:
Ion chromatographic After separation from other constituents, oxalate is quantified on an anion exchange column by means of a conductivity detector. Robertson, W.G., Scurr, D.S., Smith, A., Orwell, R.L. (1982) The determination of oxalate in urine and urinary calculi by a new ion-chromatographic technique. Clin. Chim. Acta 126: 91–99
Literature:
Method 3: Principle:
Literature:
194
HPLC-enzyme-reactor An in-line enzyme reactor containing immobilized oxalate oxidase which converts oxalate to hydrogen peroxide is used. Hydrogen peroxide is analyzed with high sensitivity by amperometric detection. The determination limit for the method is 1.5 mol/l, the mean recovery in urine is 102%. Hönow, R., Bongartz, D., Hesse, A. (1997) An improved HPLC-enzyme-reactor method for the determination of oxalic acid in complex matrices. Clin. Chim. Acta 261: 131–139
Urine and plasma glycolate, oxalate, sulfate, phosphate and citrate
Literature:
CaP
Inorganic phosphate
Literature:
Phosphate-molybdate reaction Reaction of phosphate with molybdate by forming molybdenum blue. The color intensity is proportional to the concentration of phosphate and is determined photometrically at 578 nm. Anner, B., Moosmayer, M. (1975) Rapid determination of inorganic phosphate in biological systems by highly sensitive photometric method. Analyt. Biochem. 65: 305
Appendix
Method: Principle:
Struvite
Enzymatic with citrate lyase Transformation of citrate by citrate lyase to oxaloacetic acid and acetate. In the presence of malate dehydrogenase, oxaloacetic acid and its decarboxylation product pyruvate are reduced to L-malate and L-lactate by NADH+H+. The required amount of NADH which is proportional to the concentration of citrate is determined photometrically at 340 nm. Moellering, H., Gruber, W. (1966) Determination of citrate with citrate lyase. Anal. Biochem. 17: 369–376 Welshman, S.G., McCambridge, H. (1973) The estimation of citrate in serum and urine using a citrate lyase technique. Clin. Chim. Acta 46: 243–246
Cystine
Method: Principle:
2,8-DHA
Citric acid
Xanthine
Literature:
Combined ion-chromatographic method Urine and plasma glycolate, oxalate, sulfate, phosphate and citrate concentration is simultaneously measured with an ion-chromatography system. Hoppe, B., Kemper, M.J., Hvizd, M.G., Sailer, D.E., Langman, C.B. (1998) Simultaneous determination of oxalate, citrate and sulfate in children’s plasma with ionchromatography. Kidney Int. 53: 1348–1352
NH4Urate
Method: Principle:
Ua
CaOx
General aspects
Analytical methods
195
Appendix – analytical methods
Ammonium Method: Principle: Literature:
Ion-selective electrode Determination of ammonium in strong alkaline milieu as ammonia. Classen, A., Weber, A., Miersch, W., Liappis, N., Hesse, A. (1987) Measurement and importance of ammonium concentration in urine of patients with urolithiasis. (Messung und Bedeutung der Ammoniumkonzentration im Harn bei Urolithiasis-Patienten.) Lab. Med. 11(4): 165–166
Xanthine, 2,8-Dihydroxyadenine Method: Principle: Literature:
High performance liquid chromatography (HPLC) Separation of purines, e.g. xanthine and 2,8-DHA, on C18-phase with sodium-phosphate-buffer. Hesse, A., Thon, A., Classen, A., Birwé, H. (1988) Diagnostic and therapy-control of inborn metabolic disorders by high performance liquid chromatography: 2,8-Dihydroxyadeninuria, Xanthinuria. Chromatographia 25: 205–209
Cystine/Cysteine Method 1: Principle: Literature:
Method 2:
Literature:
196
Amino acid analyzer Separation on ion exchange columns, detection with ninhydrine reaction. H only the total sum of cystine and cysteine is assessed. Liappis, N. (1973) Sex specific differences of urinary free amino acids in adults. (Geschlechtsspezifische Unterschiede der freien Aminosäuren im Harn von Erwachsenen.) Z. Clin. Chem. Clin. Biochem. 11(7): 297–285 High performance liquid chromatography H determination of both cystine and cysteine is possible; important to follow the treatment of patients with cystinuria. Birwé, H., Hesse, A. (1991) High-performance liquid chromatographic determination of urinary cysteine and cystine. Clin. Chim. Acta 199: 33–42
Appendix – unusual stones/artifacts
Unusual stone components/artifacts Drug stones During therapeutic measures, urinary stones may form as a result of the transformation of certain active drug components to insoluble metabolites. Y Chemotherapeutic agents Sulfamethoxazole and sulfadiazine are transformed into the poorly soluble metabolites N4 -actetyl-sulfamethoxazole or N4 -acetyl-sulfadiazine, respectively. These constituents have been found as the only stone components. Indinavir sulfate is a protease inhibitor of human immunodeficiency virus (HIV). Based on clinical trials the incidence of indinavir-associated urolithiasis is 3–14%. Y Analgesics Mefenamic acid is excreted in urine in glucoronic form. Concrements with 20% of mefenamic acid have been described. Y Antacids Antacids made of magnesium trisilicates may lead to the development of SiO2-containing concrements after long-time use.
Inappropriate handling of sample material Improper storage of stone material can result in its transformation to other compounds. Newberyite: (Magnesium-hydrogenphosphate-trihydrate) may form if struvite stones are kept in formalin. Dittmarite: (Magnesium-ammonium-phosphate-monohydrate) may form during the ageing process of struvite. Protein: Coagulum, fibrin
198
CaOx
General aspects
Unusual stones/ Artifacts
Artifacts
CaP Struvite
Paraffin, wax, material of suppositories Grain of seed Suture material, gauze Lead bullets Origin of artifacts Y unintentional material mix-up: e.g. instead of a dropped urinary stone, a piece of mud or plaster has been picked up. Y intentional artifacts: material brought along by the patient themselves (may be a completely different material than listed in the table above) Important: For identification and correct classification of unusual urinary stones or of artifacts, an exact stone analysis with physical methods (infrared spectroscopy, X-ray diffraction) is absolutely necessary. With chemical analyses, unusual stone components such as pharmaceutical agents and their metabolites might be impossible to discover.
Appendix
* Cave: Regular intake of silicate-containing drugs (see Drug stones, p. 198) may lead to the formation of silicate stones in vivo. Likewise calcite stones may form at high urinary pH values (18.0). In animals, silicate- and calcium carbonate-containing concrements often occur in specific species (Hesse and Neiger, 2009).
Cystine
Tridymite (quartz) – Gypsum Calcite, aragonite, vaterit
2,8-DHA
Silicon dioxide* Cholesterin (biliary calculus) Calciumsulfate-dihydrate Calcium carbonate*
Xanthine
Mineralogical name
NH4Urate
Chemical name
Ua
Relatively often, the following compounds are found as artifacts:
199
Appendix – tables
Tables Table 1: Calcium content of foods (mean, mg/100 g) I. Up to 150 mg Ca/100 g Butter Cream Sour cream Curd, cottage cheese Milk Yoghurt Ice cream
20 90 100 90 120 120 150
II. 150–400 mg Ca/100 g Evaporated milk Camembert/brie 60–70% fat 45% fat
250 300 400
III. Over 400 mg Ca/100 g Ewe’s cheese Chester, Edam, Gouda, Tilsit Hard cheese Emmental Parmesan Parmesello Powdered milk Milk protein concentrate 60% protein 80% protein Conversion factor (calcium): mg ! 0.02495 = mmol
200
600 800 1,200 1,300 1,600 900 1,900 1,400
General aspects
Tables
Oxalate content
CaOx
Table 2: Oxalate content of foods (mean, mg/100 g)* Sample
Soluble
Total
Ua
mg/100 g
6.8 2.6 16.2 54.2 13.9 36.9 1.4
Struvite
6.8 0.9 15.7 1.9 1.5 16.3 1.1
Cystine
3.5 6.8 6.8 29.2 295.4 2.4 72.1 20.5 21.6 27.0 1.7 23.0 3.1 7.5 8.5 1.8 4.9 18.9 19.8 0.3
2,8-DHA
1.8 1.9 0.7 0.9 138.9 1.5 7.1 3.3 3.2 3.1 0.6 2.4 0.5 0.5 0.3 0.2 0.9 3.4 4.9 0.3
Xanthine
Apple, Granny Smith, raw Apricot, raw Banana, raw Bramble, raw Carambola, raw Cherry, sweet, raw Elderberry, black, raw Fig, raw Gooseberry, red, raw Gooseberry, green, raw Grape, green, raw Kiwi fruit, raw Lemon, raw Lime, raw Mandarin, raw Orange, raw Pineapple, preserved, without sugar Raspberry, raw Red current, raw, red Watermelon, raw
CaP
I. Fruits
Appendix
Artichoke, boiled Asparagus, boiled Aubergine, raw Bean, preserved, white Bean, kidney, red Beet root, boiled Broccoli, boiled
NH4Urate
II. Vegetables and salads
* Hönow, R. and Hesse, A. (2002); Siener et al. (2006a, b).
201
Appendix – tables
Sample
Soluble
Total mg/100 g
II. Vegetables and salads Carrot, raw Leek, raw Lentil, dried Linseed, ground coarsely Mangold, raw Olive, green, canned Olive, black, canned Potato, boiled Potato, chips Radish, raw, red Rhubarb, raw Rice, raw Spinach, raw Tomato, raw Tomato ketchup
9.0 9.4 1.9 7.2 327 1.2 1.6 12.8 45.8 1.4 380 12.8 1,029 3.6 3.3
17.8 17.0 13.3 7.7 874 45.7 13.9 24.3 47.0 1.7 1,235 12.8 1,959 8.5 7.7
III. Beverages Apple juice, 100% Carrot juice, 100% Cherry juice, 100% Cranberry juice, 100% Grapefruit juice, 100% Grape juice, red, 100% Lemon juice, 100% Orange juice, 100% Pineapple juice, 100% Tomato juice, salted, filtered Black tea, 1.75 g/200 ml, 5 min, 70°C Camomile tea, 1.5 g/200 ml, 5 min, 70°C Fennel tea, 3.5 g/200 ml, 5 min, 70°C Fruit tea, 3 g/200 ml, 5 min, 70°C
202
0.19 2.8 1.17 0.4 0.12 1.2 0.3 0.1 1.4 3.6 4.0 0.3 1.3 0.6
0.9 4.6 1.17 0.4 0.12 2.1 0.6 0.2 1.4 4.1 – – – –
General aspects
Tables
Oxalate content Soluble
Total
CaOx
Sample
mg/100 g
6.3 0.6 1.0 – – 0.6 0.4
– – 1.1 567 0.05 – 0.4
60.0 76 90.8 2.4 26.8 41.2 22.3
159 136 623 28.5 55.7 85.2 182
89.9 82.2 26.0 35.9 36.8 10.5 123 11.8 7.1 131.2
383.3 143.0 90.8 167.4 56.5 26.4 3,800 24.5 37.9 457.4
CaP
Green tea, 1.75 g/200 ml, 5 min, 70°C Peppermint tea, 1.25 g/200 ml, 5 min, 70°C Beer Cacao powder, oil removed Coke, Coca-Cola Coffee, 30 g/l Milk, 1.5% fat
Ua
III. Beverages
Cystine 2,8-DHA
Dill, raw Parsley, leaves Pepper, black, ground Pepper, white, ground Peppermint, leaves Sage, leaves Thyme, dried
Struvite
IV. Spices and herbs
NH4Urate Appendix
Almond, slices Buckwheat Crisp bread Hazel nut, chopped Pistachio, chopped Rolled oats, whole corn Sesame seed, dried Sunflower seed, peeled Wholemeal bar, with chocolate Wheat bran
Xanthine
V. Nuts and cereals
Conversion factor (oxalate): mg ! 0.01111 = mmol
203
Appendix – tables
Table 3: Purine content of foods (mg uric acid/100 g) Over 150 mg uric acid/100 g Cereals Buckwheat
150
Pulses Peas, green Lentils, dried Soy beans
150 200 220
Meat Veal Beef, fillet Pork, fillet Game
150 150 170 150–170
Poultry Chicken roasted Leg Skin
160 300
Innards Veal
Beef Pork
Kidney Liver Neck sweet bread (thymus gland) Liver Kidney Liver
Wolfram, G. (2006)
204
210 260 900 360 255 300
General aspects
Tables
CaOx
Purine content
190 320 200 260 170 180 350
CaP
Fish Herring, without skin with skin Trout, with skin Anchovies Salmon Tuna in oil Sardines in oil
Ua
Over 150 mg uric acid/100 g
Appendix
NH4Urate
Xanthine
2,8-DHA
Cystine
Struvite
Conversion factor (uric acid): mg ! 0.0059485 = mmol
205
Appendix – tables
Table 4: Reference values for urinary excretion and molar creatinine ratios (solute:creatinine) of specific urinary lithogenic and stone inhibitory substances in children Parameter Age
Ratio solute:creatinine
Urinary excretion
Calcium <12 months 1–3 years 3–5 years 5–7 years >7 years
mol/mol <2.2 <1.5 <1.1 <0.8 <0.6
g/g 0.8 0.53 0.4 0.3 0.21
<0.1 mmol/kg body weight (<4 mg/kg body weight)
Oxalate 0–6 months 7–24 months 2–5 years 5–14 years >16 years
mmol/mol <325–360 <132–174 <98–101 <70–82 <40
mg/g 260–288 110–139 80 60–65 32
<0.5 mmol/1.73 m2/24h (<45 mg/1.73 m2/24h)
Cystine <1 month 1–6 months >6 months
mmol/mol <85 <53 <18
mg/g 180 112 38
<10 years: <55 mol (13 mg)/1.73 m2/24h >10 years: <200 mol (48 mg)/1.73 m2/24h
Urate
mol/mol
g/g
1.5 1.3 1.0 0.6 0.4
2.2 1.9 1.5 0.9 0.6
Excretion substantially higher throughout childhood than in adults <70 mol (1.29 mg)/kg body weight/24h <65 mol (1.1 mg)/kg body weight/24h <65 mol (1.1 mg)/kg body weight/24h <55 mol (0.9 mg)/kg body weight/24h <55 mol (0.9 mg)/kg body weight/24h
<1 year 1–3 years 3–5 years 5–10 years >10 years
206
General aspects
Tables
Urinary excretion
Citrate 0–5 years >5 years
mol/mol >0.12–0.250 >0.08–0.15
Males: >1.9 mmol/1.73m2/24h >0.61 mg/kg body weight/24h Females: >1.6 mmol/1.73m2/24h >0.47 mg/kg body weight/24h
g/g 0.20–0.42 0.14–0.25
CaP
Ratio solute:creatinine
Struvite
Parameter Age
Ua
CaOx
Reference values
Appendix
NH4Urate
Xanthine
2,8-DHA
Cystine
Normal values do show regional variations. As the values given are derived from different studies mostly performed in industrialized countries, the urinary calcium/creatinine ratio especially must be carefully interpreted. For citrate, there are relatively few studies on normal values in children. Therefore a range for normal molar ratios is given. In addition, differences in analysis have to be kept in mind, when comparing normal levels. Recommendation: Use these normal values as a guideline, but also look for regional reference values [Leumann et al., 1990, 1997; Hoppe et al., 1997, 2008; de Santo et al., 1992; Brodehl et al., 1988; Payne, 1998, Stapleton and Nash, 1983; see tables on p. 208 f.].
207
Appendix – tables
Table 5: Reference values for urine variables in children according to age. Values are mmol/24h, mean (2 SEM)* Age groups (years) –1 R =
208
n = 16 n = 34
2–3
4–6
7–9
10–12
13–15
22 29
34 72
31 60
35 82
15 43
Volume (ml) R =
351 (141) 280 (50)
472 (115) 560 (120)
568 (100) 520 (60)
666 (121) 610 (60)
653 (106) 750 (70)
1,172 (326) 930 (120)
pH value R =
6.74 (0.34) 6.80 (0.36)
6.87 (0.36) 6.73 (0.30)
6.50 (0.19) 6.45 (0.16)
6.33 (0.22) 6.27 (0.17)
6.38 (0.19) 6.38 (0.12)
6.37 (0.32) 6.41 (0.14)
Sodium R =
13.0 (7.1) 11.3 (4.1)
38.7 (8.9) 35.6 (7.5)
60.4 (9.8) 56.4 (9.0)
69.3 (14.5) 79.2 (10.6)
71.4 (16.1) 91.0 (11.1)
124.8 (50.3) 111.3 (15.2)
Potassium R =
10.2 (4.1) 11.7 (3.1)
18.9 (5.2) 18.9 (3.6)
22.3 (3.2) 26.8 (4.2)
34.2 (7.7) 32.4 (6.1)
28.0 (4.6) 38.7 (4.2)
50.5 (13.3) 45.7 (5.9)
Calcium R =
0.24 (0.14) 0.28 (0.10)
0.78 (0.26) 1.16 (0.41)
1.02 (0.20) 1.37 (0.25)
1.43 (0.36) 2.53 (0.50)
1.58 (0.41) 2.50 (0.37)
1.71 (0.63) 2.36 (0.63)
Magnesium R =
0.32 (0.18) 0.33 (0.09)
1.07 (0.32) 1.32 (0.25)
1.62 (0.36) 1.82 (0.26)
2.25 (0.48) 2.62 (0.43)
1.91 (0.45) 2.74 (0.27)
2.50 (0.52) 2.80 (0.36)
Chloride R =
8.6 (5.5) 13.1 (5.0)
39.7 (8.1) 34.6 (5.8)
53.8 (8.8) 54.6 (8.4)
66.6 (14.1) 76.3 (8.4)
65.1 (12.5) 81.5 (9.4)
110.3 (41.1) 101.9 (15.0)
General aspects
Tables
CaOx
Reference values
–1
7–9
10–12
13–15
22 29
34 72
31 60
35 82
15 43
CaP
n = 16 n = 34
4–6
3.9 (1.6) 5.1 (1.3)
6.7 (1.6) 7.8 (1.3)
9.3 (1.3) 11.5 (1.5)
12.8 (2.3) 16.2 (3.0)
13.3 (2.3) 19.5 (2.2)
20.6 (5.1) 22.4 (2.9)
Sulfate R =
1.9 (0.8) 2.4 (0.7)
5.6 (1.5) 6.0 (1.0)
8.1 (1.1) 9.7 (1.2)
11.0 (2.1) 13.6 (1.7)
11.8 (1.7) 15.6 (1.5)
19.8 (5.3) 17.6 (2.3)
Urate R =
0.36 (0.15) 0.38 (0.08)
0.77 (0.16) 0.94 (0.16)
0.99 (0.14) 1.24 (0.19)
1.46 (0.26) 1.48 (0.18)
1.45 (0.26) 2.08 (0.21)
2.47 (0.65) 2.53 (0.41)
Oxalate R =
0.028 (0.011) 0.082 (0.018)
0.119 (0.030) 0.144 (0.035)
0.150 (0.037) 0.187 (0.034)
0.196 (0.05) 0.188 (0.020)
0.214 (0.092) 0.235 (0.026)
0.262 (0.093) 0.307 (0.051)
Citrate R =
0.30 (0.15) 0.34 (0.10)
0.52 (0.16) 0.62 (0.13)
0.74 (0.13) 0.96 (0.17)
1.11 (0.33) 1.21 (0.17)
1.00 (0.19) 1.56 (0.17)
1.22 (0.46) 1.74 (0.26)
Creatinine R =
0.32 (0.17) 0.61 (0.15)
1.46 (0.29) 1.83 (0.29)
2.49 (0.34) 2.96 (0.36)
3.94 (0.74) 4.63 (0.65)
4.80 (0.71) 5.93 (0.56)
5.53 (1.47) 7.78 (1.19)
Cystine
Struvite
Phosphate R =
NH4Urate
Xanthine
2,8-DHA
R =
2–3
Ua
Age groups (years)
Appendix
* Hoppe, B. et al. (1997).
209
Appendix – tables
Table 6: Reference values for urinary variables in children according to age. Values are mmol/kg/24h, mean (2 SEM), for numbers see table 5 Age groups (years)
210
–1
2–3
4–6
7–9
10–12
13–15
Sodium R =
2.05 (0.38) 1.68 (0.44)
2.57 (0.57) 2.40 (0.49)
3.10 (0.49) 2.73 (0.42)
2.42 (0.46) 2.68 (0.32)
2.04 (0.47) 2.33 (0.27)
2.58 (1.20) 2.14 (0.30)
Potassium R =
1.99 (1.03) 1.92 (0.44)
1.20 (0.28) 1.34 (0.30)
1.14 (0.17) 1.29 (0.21)
1.24 (0.28) 1.10 (0.18)
0.76 (0.11) 1.01 (0.12)
1.03 (0.28) 0.87 (0.12)
Calcium R =
0.043 (0.025) 0.050 (0.014)
0.054 (0.018) 0.080 (0.026)
0.054 (0.012) 0.080 (0.012)
0.052 (0.014) 0.090 (0.018)
0.043 (0.011) 0.060 (0.009)
0.034 (0.013) 0.040 (0.012)
Magnesium 0.045 (0.018) R 0.059 (0.016) =
0.071 (0.020) 0.088 (0.013)
0.082 (0.018) 0.088 (0.013)
0.081 (0.018) 0.071 (0.008)
0.051 (0.012) 0.071 (0.008)
0.051 (0.012) 0.054 (0.072)
Chloride R =
1.21 (0.55) 1.95 (0.52)
2.63 (0.51) 2.38 (0.42)
2.80 (0.50) 2.64 (0.41)
2.33 (0.48) 2.61 (0.27)
1.84 (0.36) 2.09 (0.24)
2.58 (0.95) 1.96 (0.30)
Phosphate R =
0.72 (0.25) 0.87 (0.20)
0.45 (0.10) 1.52 (0.09)
0.48 (0.07) 0.55 (0.08)
0.46 (0.08) 0.53 (0.07)
0.36 (0.06) 0.50 (0.05)
0.42 (0.11) 0.43 (0.06)
Sulfate R =
0.31 (0.10) 0.39 (0.11)
0.38 (0.10) 0.40 (0.06)
0.41 (0.06) 0.47 (0.06)
0.38 (0.06) 0.46 (0.05)
0.32 (0.05) 0.46 (0.05)
0.41 (0.11) 0.34 (0.05)
Urate R =
0.068 (0.018) 0.070 (0.012)
0.052 (0.011) 0.060 (0.009)
0.050 (0.007) 0.060 (0.009)
0.053 (0.010) 0.050 (0.006)
0.041 (0.007) 0.050 (0.005)
0.051 (0.014) 0.050 (0.008)
General aspects
Tables
CaOx
Reference values
7–9
10–12
13–15
Oxalate R =
0.007 (0.003) 0.017 (0.006)
0.008 (0.002) 0.010 (0.002)
0.007 (0.002) 0.009 (0.001)
0.007 (0.002) 0.007 (0.001)
0.006 (0.003) 0.006 (0.001)
0.005 (0.002) 0.006 (0.001)
Citrate R =
0.056 (0.023) 0.058 (0.016)
0.033 (0.009) 0.043 (0.011)
0.038 (0.007) 0.046 (0.008)
0.040 (0.011) 0.041 (0.005)
0.027 (0.005) 0.040 (0.004)
0.025 (0.009) 0.033 (0.005)
Creatinine R =
0.049 (0.028) 0.098 (0.018)
0.098 (0.042) 0.119 (0.015)
0.126 (0.046) 0.142 (0.018)
0.138 (0.069) 0.155 (0.016)
0.129 (0.053) 0.153 (0.014)
0.114 (0.062) 0.146 (0.022)
Sulfate Uric acid Oxalic acid Citric acid Creatinine
1 mmol = 92.06 mg 1 mmol = 168.11 mg 1 mmol = 126.07 mg 1 mmol = 192.12 mg 1 mmol = 113.12 mg
Xanthine
1 mmol = 22.99 mg 1 mmol = 39.10 mg 1 mmol = 40.08 mg 1 mmol = 24.31 mg 1 mmol = 35.45 mg 1 mmol = 94.97 mg
NH4Urate
Sodium Potassium Calcium Magnesium Chloride Phosphate
Appendix
Factors of conversion:
Struvite
4–6
Cystine
2–3
2,8-DHA
–1
CaP
Ua
Age groups (years)
211
General aspects
Sediment illustrations
Ua
CaOx
Crystals in the urinary sediment
Y Sediment analysis is an integral part of urinary examination. Y Crystals only form when the urine is supersaturated with the relevant substances.
Y Some forms of crystalluria are also physiological and do not cause urolithiasis: calcium oxalates, calcium phosphates and uric acid.
Appendix
NH4Urate
Xanthine
Y A definitive diagnosis can be obtained through the analysis of crystals by infrared spectroscopy (method of stone analysis).
Struvite
Y Struvite crystals indicate urease-producing microorganisms, but are no reliable indication of struvite urolithiasis (secondary infection of urine by other types of stone is possible!).
Cystine
Y Typical crystals are a reliable indication in genetically determined urolithiasis: cystine, 2,8-dihydroxyadenine, xanthine and calcium oxalate stones in primary hyperoxaluria.
2,8-DHA
Y It is therefore important to carry out the sediment analysis correctly and immediately (fresh urine in the morning).
CaP
Y Various crystals can provide an indication of the composition of the stones.
213
Appendix – sediment illustrations 1 Uric acid (fine crystals)
5 Ammonium urate
2 Uric acid (crystalline plates)
6 Cystine
3 Uric acid dihydrate (barrel plates)
7 2,8-Dihydroxyadenine
4 Uric acid dihydrate (rhomboidal plates)
8 Brushite, monocrystals resembling basalt columns
214
Sediment illustrations 13 Weddellite/Whewellite
10 Whewellite (dumb-bell shaped)
14 Struvite
11 Whewellite (elliptical and dumb-bell shaped)
15 Struvite aggregated with carbonate apatite
12 Whewellite (stretched oval shape)
16 Struvite with pseudoamorphous Ca-phosphate (polarized light)
Appendix
NH4Urate
Xanthine
2,8-DHA
Cystine
Struvite
CaP
Ua
CaOx
General aspects
9 Weddellite (dipyramids), Whewellite (dumb-bell)
215
References
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216
de Santo, N.G., Di Iorio, B., Capasso, G., Paduano, C., Stamler, R., Langman, C.B., Stamler, J. (1992) Population based data on urinary excretion of calcium, magnesium, oxalate, phosphate and uric acid in children from Cimitile (southern Italy). Pediatr. Nephrol. 6: 149–157
Struvite
Dick, P.T., Shuckett, B.M., Tang, B., Daneman, A., Kooh, S.W. (1999) Observer reliability in grading nephrocalcinosis on ultrasound examinations in children. Pediatr. Radiol. 29: 68–72
CaP
Curhan, G.C., Willett, W., Rimm, E.B., Stampfer, M.J. (1993) A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N. Engl. J. Med. 328: 833–838
Ua
CaOx
General aspects
References
Cystine
Euler, H., Bastian, H.P., Bastian, P.J., Lümmen, G. (2008) Qualitative and quantitative analysis of urolithiasis with the Rietveld method (X-ray diffraction). Urologe 47: 1472–1480
2,8-DHA
Heimbach, D., Jacobs, D., Müller, S.C., Hesse, A. (2000) Improving cystine stone therapy: an in vitro study of dissolution – comparison of natural and artificial stones. Urology 55: 17–21
Hess, B., Mauron, H., Ackermann, D., Jaeger, P. (1999) Effects of a ‘common sense diet’ on urinary composition and supersaturation in patients with idiopathic calcium urolithiasis. Eur. Urol. 36: 136–143
217
Appendix
Heller, H.J., Zerwekh, J.E., Gottschalk, F.A., Pak, C.Y.C. (2007) Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria. Kidney Int. 71: 808–815
NH4Urate
Xanthine
Heimbach, D., Jacobs, D., Müller, S.C., Hesse, A., Zhong, P., Preminger, G.M. (1999) How to improve lithotripsy and chemolitholyse of brushite-stones: an in vitro study. Urol. Res. 27: 266–271
References
Hesse, A. (2009) Urinary stones. In Lang, F. (ed): Encyclopedia of Molecular Mechanisms of Disease, vol. 3. Berlin, Springer, pp. 2144–2147. Hesse, A., Brändle, E., Wilbert, D., Köhrmann, K.U., Alken, P. (2003) Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000. Eur. Urol. 44: 709–713 Hesse, A., Heimbach, D. (1999) Causes of phosphate stone formation and the importance of metaphylaxis by urinary acidification. World J. Urol. 17: 308–315 Hesse, A., Kruse, R., Geilenkeuser, W.J., Schmidt, M. (2005) Quality control in urinary stone analysis: results of 44 ring trials (1980–2001). Clin. Chem. Lab. Med. 43: 298–303 Hesse, A., Neiger, R. (2009) A Colour Handbook of Urinary Stones in Small Animal Medicine. London, Manson Publishing Ltd. Hesse, A., Sanders, G. (1988) Atlas of Infrared Spectra for the Analysis of Urinary Concrements. Stuttgart, Georg Thieme Hesse, A., Schneeberger, W., Engfeld, S., von Unruh, G.E., Sauerbruch, T. (1999) Intestinal hyperabsorption of oxalate in calcium oxalate stone formers: application of a new test with [13C2]oxalate. J. Am. Soc. Nephrol. 10 (suppl. 14): S329–S333 Hollingsworth, J.M., Rogers, M.A., Kaufman, S.R., Bradford, T.J., Saint, S., Wie, J.T., Hollenbeck, B.K. (2006) Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 368: 1171–1179
218
Hönow, R., Hesse, A. (2002) Comparison of extraction methods for the determination of soluble and total oxalate in foods by HPLC-enzymereactor. Food Chem. 78: 511–521
Struvite
Hoopes, R.R., Jr., Shrimpton, A., Knohl, S.J., Hueber, P., Hoppe, B., Matyus, J., Simkes, A., Tasik, V., Thoenshof, B., Suchy, S.F., Nussbaum, R.L., Scheinman, S.J. (2005) Dent’s disease with mutation in OCRL1. Am. J. Hum. Gen. 76: 260–267
CaP
Holmes, R.P., Goodman, H.O., Assimos, D.G. (2001) Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 59: 270–276
Ua
CaOx
General aspects
References
Cystine
Hoppe, B., Beck, B., Gatter, N., von Unruh, G., Tischer, A., Hesse, A., Laube, N., Kaul, P., Sidhu, H. (2006) Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney Int. 70: 1305–1311
Xanthine
2,8-DHA
Hoppe, B., Hesse, A. (2009) Primary hyperoxalurias. In Lang, F. (ed): Encyclopedia of Molecular Mechanisms of Disease, vol. 2. Berlin, Springer, pp. 917–919.
NH4Urate
Hoppe, B., Jahnen, A., Bach, D., Hesse, A. (1997) Urinary calcium oxalate saturation in healthy infants and children. J. Urol. 158: 557–559
Appendix
Hoppe, B., Leumann, E. (2004) Diagnostic and therapeutic strategies in hyperoxaluria: a plea for early intervention. Nephrol. Dial. Transplant. 19: 39–42 Hoppe, B., Leumann, E., von Unruh, G., Laube, N., Hesse, A. (2003) Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria. Front. Biosci. 8: e437–e443
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Ua
Marangella, M., Vitale, C., Bagnis, C., Bruno, M., Ramello, A. (1999) Idiopathic calcium nephrolithiasis. Nephron 81 (suppl. 1): 38–44
Osther, P.J., Grenabo, L., Haraldsson, G., Holmberg, G., Lindell, O., Mogensen, B., Schultz, A., Ulvik, N.M. (1999) Metabolic evaluation and medical management of upper urinary tract stone disease. Guidelines from the Scandinavian Cooperative Group for Urinary Stones. Scand. J. Urol. Nephrol. 33: 372–381
2,8-DHA
Pak, C.Y.C., Kaplan, R.A., Bone, H., Townsend, J., Woters, O. (1975) A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. New Engl. J. Med. 292: 497–500
Cystine
Norman, R.W. (2001) Metabolic evaluation of stone disease patients: a practical approach. Curr. Opin. Urol. 11: 347–351
Struvite
CaP
Muldowney, F.P., Freaney, R., Moloney, M.F. (1982) Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int. 22: 292–296
Xanthine
Pak, C.Y.C., Peterson, R., Poindexter, J.R. (2001) Adequacy of a single stone risk analysis in the medical evaluation of urolithiasis. J. Urol. 165: 378–381
NH4Urate
Pak, C.Y.C., Resnick, M.I. (2000) Medical therapy and new approaches to management of urolithiasis. Urol. Clin. North Am. 27: 243–253
Appendix
Payne, R.B. (1998) Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann. Clin. Biochem. 35: 201–206
221
References
Preminger, G., Tiselius, H.G., Assimos, D.G., Alken, P., Buck, C., Gallucci, M., Knoll, T., Lingeman, J.E., Nakada, S.Y., Pearle, M.S., Sarica, K., Türk, C., Wolf, J.S., Jr. (2007) 2007 guideline for the management of ureteral calculi. J. Urol. 178: 2418–2434 Preminger, G., Tiselius, H.G., Assimos, D.G., Alken, P., Buck, C., Gallucci, M., Knoll, T., Lingeman, J.E., Nakada, S.Y., Pearle, M.S., Sarica, K., Türk, C., Wolf, J.S., Jr. (2007) 2007 guideline for the management of ureteral calculi. Eur. Urol. 52: 1610–1631 Rivers, K., Shetty, S.D., Menon, M. (2000) When and how to evaluate a patient with nephrolithiasis. Urol. Clin. North Am. 27: 203–213 Robertson, W.G. (1998) Medical management of urinary stone disease. Eur. Urol. Update Ser. 7: 139–144 Santos-Victoriano, M., Brauhard, B.H., Cunningham, R.J. (1998) Renal stone disease in children. Clin. Pediatr. 37: 583–599 Siener, R. (2006) Impact of dietary habits on stone incidence. Urol. Res. 34: 131–133 Siener, R., Ebert, D., Nicolay, C., Hesse, A. (2003) Dietary risk factors for hyperoxaluria in calcium oxalate stone formers. Kidney Int. 63: 1037–1043 Siener, R., Glatz, S., Nicolay, C., Hesse, A. (2004) The role of overweight and obesity in calcium oxalate stone formation. Obes. Res. 12: 106–113
222
Ua
Siener, R., Hesse, A. (2002) The effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects. Eur. Urol. 42: 289–296
CaOx
General aspects
References
CaP
Siener, R., Hesse, A. (2003) The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation. Eur. J. Nutr. 42: 332–337
Struvite
Siener, R., Hesse, A. (2005) Recent advances in nutritional research on urolithiasis. World J. Urol. 23: 304–308
Cystine
Siener, R., Hesse, A. (2009) Hypocitraturia. In Lang, F. (ed): Encyclopedia of Molecular Mechanisms of Disease, vol. 2. Berlin, Springer, pp. 969–970.
Xanthine
2,8-DHA
Siener, R., Heynck, H., Hesse, A. (2001) Calcium-binding capacities of different brans under simulated gastrointestinal pH conditions. In vitro study with 45Ca. J. Agr. Food Chem. 49: 4397–4401 Siener, R., Hönow, R., Seidler, A., Voss, S., Hesse, A. (2006) Oxalate contents of species of the Polygonaceae, Amaranthaceae and Chenopodiaceae families. Food Chem. 98: 220–224
Siener, R., Jahnen, A., Hesse, A. (2004) Influence of a mineral water rich in calcium, magnesium and bicarbonate on urine composition and the risk of calcium oxalate crystallization. Eur. J. Clin. Nutr. 58: 270–276
223
Appendix
NH4Urate
Siener, R., Hönow, R., Voss, S., Seidler, A., Hesse, A. (2006) Oxalate content of cereals and cereal products. J. Agr. Food Chem. 54: 3008–3011
References
Siener, R., Schade, N., Nicolay, C., von Unruh, G.E., Hesse, A. (2005) The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients. J. Urol. 173: 1601–1605 Sikora, P., Glatz, S., Beck, B.B., Stapenhorst, L., Zajaczkowska, M., Hesse, A., Hoppe, B. (2003) Urinary NAG in children with urolithiasis, nephrocalcinosis or risk of urolithiasis. Pediatr. Nephrol. 18: 996–999 Sikora, P., Roth, B., Kribs, A., Michalk, D.V., Hesse, A., Hoppe, B. (2003) Hypocitraturia is one of the major risk factors for nephrocalcinosis in very low birth weight (VLBW) infants. Kidney Int. 63: 2194–2199 Sikora, P., von Unruh, G.E., Beck, B., Feldkötter, M., Zajaczkowska, M., Hesse, A., Hoppe, B. (2008) [13C2]oxalate absorption in children with idiopathic calcium oxalate urolithiasis or primary hyperoxaluria. Kidney Int. 73: 1181–1186 Stapleton, F.B., Nash, D.A. (1983) A screening test for hyperuricosuria. J. Pediatr. 102: 88–90 Straub, M., Strohmeier, W.L., Berg, W., Beck, B., Hoppe, B., Laube, N., Lahme, S., Schmidt, M., Hesse, A., Koehrmann, K.U. (2005) Diagnosis and metaphylaxis of stone disease. Consensus concept of the national working committee on stone disease for the upcoming German urolithiasis guideline. World J. Urol. 23: 309–323 Taylor, E.N., Stampfer, M.J., Curhan, G.C. (2004) Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J. Am. Soc. Nephrol. 15: 3225–3232 Tekin, A., Tekgul, S., Atsu, N., Sahin, A., Ozen, H., Bakkaloglu, M. (2000) A study of the etiology of idiopathic calcium urolithiasis in children: hypocitraturia is the most important risk factor. J. Urol. 164: 162–165
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References
Ua
Tiselius, H.G. (1996) Solution chemistry of supersaturation. In Coe, F.L., Favus, M.J., Pak, C.Y.C., Parks, J.H., Preminger, G.M. (eds): Kidney Stones: Medical and Surgical Management. Philadelphia, Lippincott-Raven, pp. 33–64
CaP
Tiselius, H.G. (1997) Risk formulas in calcium oxalate urolithiasis. World J. Urol. 15: 176–185
2,8-DHA
Tiselius, H.G. (2001) Possibilities for preventing recurrent calcium stone formation: principles for the metabolic evaluation of patients with calcium stone disease. BJU Int. 88: 158–168
Cystine
Struvite
Tiselius, H.G. (2000) Metabolic evaluation and therapy. Curr. Opin. Urol. 10: 545–549
Xanthine
Tiselius, H.G. (2002) Medical evaluation of nephrolithiasis. Endocrinol. Metab. Clin. North Am. 31: 1031–1050 Tiselius, H.G. (2003) Epidemiology and medical management of stone disease. BJU Int. 91: 758–767
Appendix
NH4Urate
Tiselius, H.G. (2004) Recurrence prevention in patients with urinary tract stone disease. Scient. World 4: 35–41 Tiselius, H.G. (2005) Aetiological factors in stone formation. In Oxford Textbook of Clinical Nephrology, ed 3. Oxford, Oxford University Press, pp. 1201–1223
225
References
Tiselius, H.G. Alken, P., Buck, C., Gallucci, M., Knoll, T., Sarica, K., Türk, C. (2008) Guidelines on Urolithiasis. Arnhem, European Association of Urology, ISBN-13: 978–90–79754–09–0 Tiselius, H.G., Hellgren, E., Andersson, A., Borrud-Ohlsson, A., Eriksson, I. (1999) Minimally invasive treatment of infection staghorn stones with shock wave lithotripsy and chemolysis. Scand. J. Urol. Nephrol. 33: 286–290 Von Unruh, G.E., Langer, M.A., Paar, D.W., Hesse, A. (1998) Mass spectrometric-selected ion monitoring assay for an oxalate absorption test applying [13C2]oxalate. J. Chromatogr. B 716: 343–349 Von Unruh, G.E., Voss, S., Sauerbruch, T., Hesse, A. (2004) Dependence of oxalate absorption on the daily calcium intake. J. Am. Soc. Nephrol. 15: 1567–1573 Voss, S., Hesse, A., Zimmermann, D.J., Sauerbruch, T., von Unruh, G.E. (2006) Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [13C2]oxalate absorption test. J. Urol. 175: 1711–1715 Wolfram, G. (2006) Hyperurikämie und Gicht. In Adam, O. (ed): Ernährungsmedizin in der Praxis. Balingen, Spitta Yagisawa, T., Hayashi, T., Yoshida, A., Okuda, H., Kobayashi, H., Ishikawa, N., Goya, N., Toma, H. (1999) Metabolic characteristics of the elderly with recurrent calcium oxalate stones. BJU Int. 83: 924–928
226
General aspects
Subject index
Blood gas analysis 46, 47, 180, 181 BONN Risk Index, calcium oxalate crystallization 188, 189 Brushite, see Calcium phosphate stones
NH4Urate
Xanthine
2,8-DHA
Cystine
Struvite
CaP
Calcium food content 200 urine reference values 29, 206, 208, 210 Calcium citrate, uric acid stone management 85 Calcium loading test indications 184 technique 185 Calcium oxalate stones BONN Risk Index 188, 189 dietary treatment diet 54–57 general measures 50, 51 long-term goal 50, 51 urine dilution 52, 53 formation 39 forms 38, 39 hypercalciuria management 58–61 hyperoxaluria management 64, 65 hyperparathyroidism management 48, 49 hyperuricosuria management 62, 63 hypocitraturia management 62, 63 imaging 40 ion-activity product 186, 187 laboratory findings serum 41–43 urine 41, 44, 45 minimal analytic program 40 prevalence 38, 39 renal tubular acidosis diagnosis 46, 47 treatment 48, 49 urinary tract infection treatment 48, 49
Ua
Antegrade ureteropyelography 12, 13 Artifacts 199 Ascorbic acid, cystine stone management 140, 141
Appendix
Adenine phosphoribosyl transferase, assay 146 Alkaline citrate cystine stone management 138, 139 hypercalciuria management 58, 59, 61–63 hyperoxaluria management 65 hypocitraturia management 62, 63 renal tubular acidosis management 98, 99 uric acid stone management 84, 85 Allopurinol ammonium urate stone management 170, 171 calcium oxalate stone management 62, 63 2,8-dihydroxyadenine stone management 150, 161 hyperuricosuria management 62, 63 uric acid stone management 76, 77, 84, 85 Aluminum hydroxide calcium phosphate stone management 106, 107 struvite stone management 122, 123 Ammonium chloride ammonium urate stone management 170, 171 calcium phosphate stone management 106, 107 loading test 180–183 struvite stone management 122, 123 Ammonium, determination 196 Ammonium urate stones dietary treatment diet 170, 171 urine dilution 168, 169 imaging 162 laboratory analysis blood 163, 164 urine 163–167 medical history 162 medical treatment 170, 171 minimal analytic program 162 overview 160, 161 prevalence 161 stone removal 168, 169 urinary tract infection diagnosis 166, 167 treatment 168, 169
CaOx
Subject index
227
Subject index
Calcium phosphate stones dietary treatment diet 104, 105 general measures 100, 101 urine dilution 102, 103 forms 87 ion-activity product 186, 187 laboratory findings blood 89–91 urine 89–92, 95 medical history 88 medical treatment 106, 107 minimal analytic program 88 prevalence 87 renal tubular acidosis diagnosis 94, 95 pathophysiology 94, 95 treatment 98, 99 treatment hyperparathyroidism 96, 97 stone removal 96, 97 urinary tract infection diagnosis 92, 93 treatment 96, 97 Chemolitholysis, principles 177 Chloride, urine reference value in children 208–210 Citrate, see also Alkaline citrate citric acid, determination 195 urine reference values 29, 207, 209, 211 Computed tomography advantages and limitations 24, 25 emergency stone findings 12, 13 Creatinine emergency stone findings 10, 11 urine reference values 29, 209, 211 Cysteine, determination 196 Cystine, urine reference values 29, 206 Cystine, determination 196 Cystine stones dietary treatment
228
diet 136, 137 general measures 132, 133 urine dilution 134, 135 imaging 126 laboratory findings blood 127 suspected cases 31 urine 127–129 medical history 126 medical treatment 138–141 minimal analytic program 126 overview 124, 125 prevalence 125 stone analysis 192 stone removal 130, 131 urinary tract infection diagnosis 130, 131 Dahlite, see Calcium phosphate stones Dietary treatment ammonium urate stones diet 170, 171 urine dilution 168, 169 calcium oxalate stones diet 54–57 general measures 50, 51 urine dilution 52, 53 calcium phosphate stones diet 104, 105 general measures 100, 101 urine dilution 102, 103 cystine stones diet 136, 137 general measures 132, 133 urine dilution 134, 135 2,8-dihydroxyadenine stones diet 150, 151 urine dilution 148, 149 lifestyle modification 34, 35 struvite stones diet 120, 121
Ua Cystine
Struvite
CaP
Infrared spectroscopy, stone analysis 26, 192 Intravenous urography advantages and limitations 24, 25 emergency stone findings 12, 13
2,8-DHA
Hypercalciuria management in calcium oxalate stones 58–61 management in calcium phosphate stones 106, 107 Hyperoxaluria management in calcium oxalate stones 64, 65 primary types 64, 65 secondary forms 64, 65 Hyperparathyroidism diagnosis 42, 43 treatment 48, 49, 96, 97 Hyperuricosuria management in ammonium urate stones 170, 171 management in calcium oxalate stones 62, 63 Hypocitraturia, management in calcium oxalate stones 62, 63
Xanthine
Grading, medullary nephrocalcinosis 24
NH4Urate
Emergency stones imaging 12, 13 laboratory findings 10, 11 renal colic treatment children 15 overview 14, 15 pain management 14, 15 stone passage facilitation of spontaneous passage 16, 17 limitations 18, 19 symptoms 8, 9 Extracorporeal shock-wave lithotripsy, principles 174
Fiber, hypercalciuria management 58, 59 Formation, urinary stones ammonium urate stones 160, 161 calcium oxalate stones 38, 39 calcium phosphate stones 86, 87 cystine stones 124, 125 2,8-dihydroxyadenine stones 142, 143 overview 2, 3 struvite stones 108, 109 uric acid stones 66, 67 xanthine stones 152, 153
Appendix
general measures 116, 117 urine dilution 118, 119 uric acid stones diet 82, 83 general measures 78 urine dilution 76–81 urine dilution, general aspects 32, 33 xanthine stones diet 158, 159 urine dilution 158, 159 2,8-Dihydroxyadenine stones dietary treatment diet 150, 151 urine dilution 148, 149 imaging 144 laboratory findings blood 145 urine 145–147 medical history 144 medical treatment 150, 151 minimal analytic program 144 overview 142, 143 stone analysis 192 stone removal 148, 149 Dittmarite, formation in stored stones 198 Drug stones 198
CaOx
General aspects
Subject index
Kidney, ureter and bladder, plain abdominal film advantages and limitations 24 emergency stone findings 12, 13
229
Subject index
Lifestyle modification, metaphylactic treatment 34, 35 Location, urinary stones 4, 5 Loop extraction, stones 175 Magnesium hypercalciuria management 58, 59 hyperoxaluria management 65 urine reference values 29, 208, 210 Medical history, stone evaluation ammonium urate stones 162 calcium oxalate stones 40 calcium phosphate stones 88 cystine stones 126 2,8-dihydroxyadenine stones 144 overview 22, 23 struvite stones 110 uric acid stones 68 xanthine stones 154 ␣-Mercaptopropionylglycine, cystine stone management 138, 139 Methionine ammonium urate stone management 170, 171 calcium phosphate stone management 106, 107 struvite stone management 122, 123 Minimal analytic program ammonium urate stones 162 calcium oxalate stones 40 calcium phosphate stones 88 cystine stones 126 2,8-dihydroxyadenine stones 144 first stone 26, 27 struvite stones 110 uric acid stones 68 xanthine stones 154 Newberyite, formation in stored stones 198 Obstructive pyelonephritis, symptoms 8, 9 Orthophosphate, hypercalciuria management 60, 61
230
Oxalate food content 56, 57, 201–203 urine reference values 29, 206, 209, 211 Oxalate absorption test study design 178 technique 179 Oxalate stones, see Calcium oxalate stones Oxalobacter formigenes 64 Percutaneous nephrolithotomy, principles 176 pH solubility dependence of lithogenic substances 2, 132 urine reference values 29, 208 Phosphate stones, see also Calcium phosphate stones chemical composition 4, 5 laboratory findings in suspected cases 31 stone analysis 192 Phosphate, urine reference values 29, 209, 210 Potassium citrate, see Alkaline citrate Potassium, urine reference values 29, 208, 210 Prevalence, urinary stones ammonium urate stones 161 calcium oxalate stones 38, 39 calcium phosphate stones 87 cystine stones 125 overview 1 struvite stones 109 uric acid stones 66, 67 Primary hyperoxaluria 64, 65 Purine, food content 82, 204, 205 Pyridoxine, hyperoxaluria management 64, 65 Quality standard, stone evaluation 28, 29 Recurrence, urinary stones rate 1 risk factors 20 Renal colic differential diagnosis 8, 9
Ua CaP Struvite
Thiazide diuretics calcium oxalate stone management 60, 61 calcium phosphate stone management 106, 107 hypercalciuria management 60, 61
Xanthine
2,8-DHA
Cystine
Ultrasonography advantages and limitations 24, 25 emergency stone findings 12, 13 Urate stones, see also Ammonium urate stones chemical composition 4, 5 laboratory findings in suspected cases 31 Urate, urine reference values 29, 206, 209, 210 Uric acid stones dietary treatment diet 82, 83 general measures 78, 79 urine dilution 76–81 formation 66, 67 imaging 68 ion-activity product 186, 187 laboratory findings blood 69–71 suspected cases 31 urine 69, 72, 73 medical history 68 minimal analytic program 68 prevalence 66, 67 treatment alkaline citrate 84, 85 allopurinol 76, 77, 84, 85 calcium citrate 84, 85
NH4Urate
Sediment, crystal illustrations 213–215 Sevelamer calcium phosphate management 106, 107 struvite stone management 122, 123 Sites, urinary stones 4, 5 Sodium bicarbonate cystine stone management 138, 139 hypercalciuria management 58, 59 hypocitraturia management 62, 63 renal tubular acidosis management 98, 99 uric acid stone management 84, 85 Struvite stones dietary treatment diet 120, 121 general measures 116, 117 urine dilution 118, 119 formation 108, 109 imaging 110 laboratory findings blood 111 suspected cases 31 urine 111–113 medical history 110 medical treatment 122, 123 minimal analytic program 110
prevalence 109 stone removal 114, 115 urinary tract infection pathogens 108, 112 diagnosis 112, 113 treatment 114, 115 Sulfate, urine reference values in children 209, 210 Surgery, stone removal 177
Appendix
emergency treatment children 15 overview 14, 15 pain management 14, 15 symptoms 8, 9 Renal tubular acidosis ammonium chloride loading test 180–183 diagnosis 46, 47, 94, 95 pathophysiology 46, 47, 94, 95 treatment 48, 49, 98, 99 Retrograde intrarenal stone surgery 176 Retrograde ureteropyelography, emergency stone findings 12, 13 Risk factors, urinary stones 3
CaOx
General aspects
Subject index
231
Subject index
Uric acid stones (continued) chemolysis 74, 75 sodium bicarbonate 74, 75, 84, 85 Urinary tract infection diagnosis 92, 93, 130, 131, 166, 167 struvite stones diagnosis 92, 93, 112, 113 pathogens 108 treatment 114, 115 treatment 48, 49, 96, 97, 114, 115, 168, 169 Urine dilution, dietary treatment ammonium urate stones 168, 169 calcium oxalate stones 52, 53 calcium phosphate stones 102, 103 cystine stones 134, 135 2,8-dihydroxyadenine stones 148, 149 overview 32, 33 struvite stones 118, 119 uric acid stones 76–81 xanthine stones 158, 159 Urine examination ammonium urate stones 163–167 calcium oxalate stones 41, 44, 45 calcium phosphate stones 89–95 collection 190, 191
232
cystine stones 127–129 2,8-dihydroxyadenine stones 145–147 emergency stone findings 10, 11 reference values 29, 206–211 sediment crystal illustrations 213–215 struvite stones 111–113 uric acid stones 69, 72, 73 xanthine stones 155–157 Ureterorenoscopy, principles 175 Xanthine stones dietary treatment diet 158, 159 urine dilution 158, 159 imaging 154 laboratory findings blood 155–157 suspected cases 31 urine 155–157 medical history 154 minimal analytic program 154 overview 152, 153 stone analysis 192 stone removal 158, 159 X-ray diffraction, stone analysis 26, 192
