Nephrocalcinosis Calcium Antagonists and Kidney

191 Pages·1988·17.53 MB·English

by  Professor Dr. med. Karl-Horst Bichler, Dr. med. Walter Ludwig Strohmaier (auth.), Professor Dr. med. Karl-Horst Bichler, Dr. med. Walter Ludwig Strohmaier (eds.)

Nephrocalcinosis
Calcium Antagonists
and Kidney
Edited by
K.-H. Bichler and W L. Strohmaier
With 107 Figures
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Professor Dr. med. KARL-HoRST BICHLER
Medical Director
Dr. med. WALTER LUDWIG STROHMAIER
Department of Urology
University of Tiibingen
Calwer Str. 7
0-7400 Tiibingen, FRG
ISBN 978-3-642-72859-4 ISBN 978-3-642-72857-0 (eBook)
001 10.1007/978-3-642-72857-0
Library of Congress Cataloging-in-Publication Data. Nephrocalcinosis, calcium antagonists, and
kidney / edited by K.-H. Bichler and W. L. Strohmaier. Includes index.
1. Kidneys - Calcification. 2. Calcium Antagonists therapeutic use. I. Bichler, K.-H. II. Stroh
maier, W. L. (Walter Ludwig), 1957-. [DNLM: 1. Calcium adverse effects. 1. Calcium Channel
Blockers-therapeutic use. 3. Kidney Failure. Acute drug therapy. 4. Nephrocalcinosis drug
therapy. WJ 356 N4388)
RC916.N45 1988 616.6'106.1 dc 19 87-32317
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2122/3130-543210
List of Contributors
You will find the addresses at the beginning of the respective contribution
Bachmann, S. 7 Lang, F. 34
Bichler, K.-H. -113, 126 Lehmann, H. D. 52
Chaimovitz, C. 134 Leonetti, G. 182
Deetjen, P. 34 Nelde, H.-J. 113
Dirks, J. H. 43 Neumayer, H. H. 164
Garthoff, B. 156 Paulmichl, M. 34
Goligorsky, M. S. 134 Rapoport, J. 134
Hertle, L. 156 Sakai, T. 7
Kiryati, A. 134 Strohmaier, W. L. 113, 126
Kol, R. 134 Sutton, R. A. L. 105
Kriz, W. 7, 113 Wagner, K. 164
Laberke, H. G. 67 Yehuda, J. 134
Lach, S. 134 Zanchetti, A. 182
Preface
The effect of calcium antagonists on heart muscle and blood circulation
is the reason that they have found widespread clinical application for
a number of years. Less well known, in contrast, is the effect this group
of substances has on the kidneys, both on kidney cells and the blood flow
through the kidneys. This effect was the subject of a workshop we
organized in Tiibingen in June 1986. Different groups studied the effects
of these substances, especially in animals, on the processing of calcium
by the kidney cells and on blood flow. A possible explanation is that the
calcium antagonists block the influx of calcium through special cell
canals, especially the cells of the distal tubule. It is necessary to test
whether there is a blockade or only a reduction in the passage of calcium.
Our understanding of the effect of calcium antagonists is in large part
based on the results of morphologic, physiologic, and pharmacologic
studies of calcium in the kidneys. The particular processes involved in
nephrocalcinosis are special objects of study with regard to calcium
antagonists. This book presents the results of experimental studies of the
effect of calcium antagonists on nephrocalcinosis and acute renal failure
after ischemia. In this context, the clinician is particularly interested in
the use of calcium antagonists to protect against the kidney in
urolithiasis, in acute renal failure and during kidney transplantation.
The book is thus of interest to urologists and nephrologists as well as
pharmacologists. biochemists, physiologists, and others in research.
Tiibingen, October 1987 K.-H. BICHLER
W. L. STROHMAIER
Contents
Introduction . 1
Fundamentals
Nephron- and Collecting Duct Structure in the Kidney, Rat
S. BACHMANN, T. SAKAl, and W. KRIZ (With 13 Figures) . 7
Cellular Mechanisms of Renal Calcium Transport
F. LANG, M. PAunlIcHL, and P. DEETJEN (With 5 Figures) 34
Factors Influencing Renal Calcium Excretion
J. H. DIRKS. . . . . . . . . . . . . . . . . . . . . 43
Ca2+ Antagonists - Mode of Action and Pharmacodynamics
H. D. LEHMANN (With 7 Figures) . . . . . . . . . . . .. 52
Nephrocalcinosis and Calcium Antagonists
Pathological Anatomy, Etiology, and Pathogenesis
of Nephrocalcinosis
H. G. LABERKE (With 30 Figures) . . . . . . . . . . . . . . 67
Clinical Aspects of Nephrocalcinosis
R. A. L. SUTTON (With 4 Figures) . . 105
Nephrocalcinosis in the Kidney of the Rat on Atherogenic Diet
and the Effect of Calcium Antagonists (Nifedi,p ine)
H.-J. NELDE, K.-H. BICHLER, W. L. STROHMAIER, and W. KRIZ
(With 12 Figures). . . . . . . . . . . . . . . . . . .. 113
Influence of Calcium Antagonists (Nifedipine) on the Excretion
of Calcium and Other Substances Relevant for Stone Formation
in Rats with Nephrocalcinosis (Induced by Atherogenic Diet)
W. L. STROHMAIER and K.-H. BICHLER (With 6 Figures) . . . . 126
The Unique Chemical Composition of Nephrocalcinosis in
Experimental Renal Insufficiency, Disturbances of Cellular Calcium
Metabolism, and Protective Effect of Verapamil Against
Nephrocalcinosis
M. S. GOLIGORSKY, C. CHAIMOVITZ, J. RApOPORT, A. KIRYATI,
S. LACH, R. KOL, and J. YEHUDA (With 19 Figures) . . . . . . 134
x Contents
Calcium Antagonists in Acute Renal Failure and in Hypertension.
Calcium Antagonists in Ischemic Acute Renal Failure
(Improvement of Function and Morphologic Damage by
Nisoldipine)
B. GARTHOFF and L. HERTLE (With 4 Figures). . . . . . 156
Effect of Calcium Antagonist Diltiazem on Acute Renal Failure:
Experiments on Animals and Clinical Studies
K. WAGNER and H.H. NEUMAYER (With 7 Figures) . . .. 164
Renal Function in Hypertensive Patients and Calcium Entry
Blockers
G. LEONETTI and A. ZANCHETTI . 182
Subject Index. . . . . . . . . 187
Introduction
While calcium antagonists have been employed in the treatment of heart and
vascular diseases for some years now, the influence this group of substances has
on the kidney - that is, on the renal cell, the blood flow, and finally the function
ing of the organ - has received little attention. In recent years different groups
have investigated the effect of calcium antagonists on the handling of calcium by
renal cells or on renal function.
As far as the renal cells are concerned, it is necessary to remember that about
50% of the filtered calcium is absorbed along the proximal tubule. The calcium
uptake takes place by means of passive and active transport mechanisms. The
passive transport is through paracellular shunts, and the active transport is de
pendent on the electrochemical gradient for sodium. Permeability plays a vital
role in the proximal tubular part, whereas it is less important in the distal part
and the collecting tubuli. There is much information on the cellular mechanism
in the proximal tubule, yet little is known about that in the distal part. Recent ex
periments on madin-darby-canine kidney cells have led us to suppose that there
are calcium channels which allow for the transcellular transport of calcium. To
all appearances these channels can be blocked by calcium antagonists. Thus alI
round knowledge of the cellular handling of calcium in the kidney is necessary
in order to employ calcium antagonists, in particular to achieve a protective ef
fect. The results with regard to heart and vascular walls suggest that calcium an
tagonists protect against calcifying processes in the tubular cells of the kidney, in
particular in the distal part.
To recognize the influence that this group of substances has on the cells han
dling calcium in the kidney, i.e., the proximal and distal tubular cells, it is neces
sary to consider that these substances produce a blockage of the calcium influx
through specific channels. Thus we can start from the idea that calcium antago
nists influence calcium passage in the distal part of the tubule. We can assume
here that calcium antagonists influence the duration of the periods the calcium
channels are open, this process obviously effecting a slowing-down of the influx
of calcium through these channels. It is less probable that they block the influx
of calcium entirely. Also of consequence to their effect on the tubular cells is their
binding power to the cell membrane (in which the calcium channels are located).
In this context it is necessary to determine whether calcium antagonists influence
the function of the cell membrane.
We have to bear in mind that other factors - e.g., hemodynamics, hormonal
influence, alcalosis, and the effect of vitamin D metabolites - also influence the
effect on the tubular cells. All of these factors influence calcium excretion. Several
Nephrocalcinosis, Calcium Antagonists.
and Kidney
Ed. by K.·H. Bichler and W.L. Strohmaier
~ Springer. Verlag Berlin Heidelberg 1988
Introduction
investigations have demonstrated that renal plasma now is increased by calcium
antagonists. yet that the glomerular filtration rate remains the same. \\Thether
hormonal int1uence has an effect on the renal handling of calcium is still un
known. In this context we have to consider. for example. the effect of the para
thyroid hormone. Of further interest are investigations which demonstrated an
increase in 1.25-D on calcium antagonists (verapamil); other investigations have,
however, shown unchanged vitamin levels.
Apart from an understanding of the physiological processes and the endocri
nological and pharmacological factors, we also have to take into consideration
the morphological situation of those parts of the kidney which handle c:.!lcium.
This is true to understand the normal condition as well as pathological alterations
in connection with calcifying processes and particularly with nephrocalcinosis.
This material is covered in the detailed chapter on the renal morphology. Knowl
edge of the extent to which processes like nephrocalcinosis or the development
of calcium-containing concrements in the kidney or the upper efferent urinary
tract can be influenced by calcium antagonists is of particular interest in clinic:.!l
practice. Specifically, there is the influence on calcifying processes foIlo\ving in
flammatory alterations in the area of the tubule or the interstitium or on calcifi
cations of other origin. With regard to pathologic anatomy, there are different
forms of nephrocalcinosis. Moreover. the clinician discriminates between a
number of syndromes which are accompanied by nephrocalcinotic processes or
are caused by them. Morphologically we discriminate between a primary (meta
static) and a secondary (dystrophic) type of nephrocalcinosis. From the anatomi
cal point of view it is hardly possible to determine predispositions of certain parts
of the kidney to develop calcifications in certain diseases. \Ve can assume, how
ever. that the tubular system is affected by calcifying processes much more often
than other parts. In clinical practice nephrocalcinosis often becomes evident only
when accompanied by an indicating symptom such as nephrolithiasis or. in the
renal tubules, acidosis with hypokalemia. We are interested in the effect of cal
cium antagonists on stone formation and nephrocalcinotic processes. Experimen
tal investigations of nephrocalcinosis induced by the administration of an ather
genous diet showed typical calcifications in the area of the distal tubule. Electron
microscopic examinations demonstrated considerable calcium deposits in the in
terstitium. Pathogenetically different explanations are probable. Noteworthy for
the effect of calcium antagonists in these processes is that a considerably reduced
calcium deposition results in the renal tissue during administration of calcium an
tagonists in an atherogenic diet. Corresponding measurements of calcium excre
tion as well as of the Tamm-Horsfall protein (a sour mucoprotein which is found
mainly in the distal part of the tubule) and citrate content in urine indicate of that
calcium antagonists have a protective effect against nephrocalcinotic alterations
in the kidney. Experimental investigations of nephrocalcinotic processes have
demonstrated that calcium antagonists have a protective effect on the renal pa
renchyma in uremic nephrocalcinosis. Less calcium was accumulated in the tubu
lar cells of rats with verapamil and which had undergone subtotal nephrectomy
than in those which had undergone nephrectomy but had not been given verapa
mil. Obviously, this effect is independent of the parathyroid hormone. so that a
direct effect of verapamil on the tubular cells can be supposed.
Introduction 3
Of particular interest regarding the influence of calcium antagonists are inves
tigations on the effect of this group of substances in acute ischemic renal failure.
Administration of calcium antagonists mitigated ischemically induced functional
impairment of the kidney and ischemically induced calcitications. This is of clini
cal relevance in surgical interventions on the kidney in ischemia (e.g., surgery of
bigger staghorn calculi). Last but not least, calcium antagonists seem to be rele
vant in transplantation medicine. By giving diltiazem in a small number of pa
tients who had undergone renal transplantation it was possible for the function
of the transplant to be improved or the nephrotoxicity of cyclosporin A re
duced.
Fundamentals