Nephrol Dial Transplant (1996) 11: 71.7-720
Nephrology
Dialysis
Transplantation
Historical Note
(Section Editor: J. S. Cameron)
Carl Ludwig: the discoverer of glomerular filtration
John M. Davis, Klaus Thurau and Dieter Haberle
Institute of Physiology, University of Munich, Germany
Introduction
mechanism of filtration itself, however, precedes this
by 90 years and takes us to Marburg, a small university
town on the banks of the river Lahn in central
Germany.
The year 1995 saw the 100th anniversary of the death
of a most remarkable scientist—Carl Friedrich
Wilhelm Ludwig (born 23 December 1816, died 23
April 1895, Fig. 1). Only few scientists today recall the Carl Ludwig
name of Ludwig, and of those who do, even fewer will
recall the context, and yet modern biological and Ludwig was born in 1816 in Witzenhausen on the river
biomedical science owes an immeasurable debt to this Werra in the Electorate of Hesse, Germany, into an
man. Why then, has Ludwig been largely forgotten,
when contemporaries such as Virchow, Ehrlich,
Helmholtz and Pasteur are still remembered? The
reason is probably as trite as it is true. As Zimmer
recently expressed it [1], his numerous inventions (such
as the kymograph, the blood flow meter, the blood gas
pump, etc.) were so timely and his findings so self
evident, that they passed rapidly into the anonymous
mass of accepted knowledge. On the other hand, the
controversy touched off by his revolutionary scientific
philosophy — the prime reason for our debt to him —
continued for many decades and undoubtedly became
so broad and diffuse, that by the time the validity of
this philosophy was generally accepted, its origins were
no longer clear. Nor was Ludwig the man to publicise
the role he had played and so, with the passing of
Ludwig and the 'first generation' of his students (by
the 1920s) whatever connection there still existed was
broken and lost. It was perhaps a happy accident that
the epochal study, which signalled the start of a
revolution in the philosophy and practice of biomedical
science, was concerned with renal function; but this
study is the reason for renal physiologists and nephrologists to hold Carl Ludwig in particular respect.
Although the kidney's glomerular filtration rate
(GFR) is a circulatory, rather than a uniquely renal,
phenomenon, its intimate relations with, and linkage
to specific downstream tubular functions are the
reasons for its central position in renal medicine as
'the' marker of renal function for the 50 years or more
since the discovery of methods for its measurement in
the 1920s and 30s [2-4]. The identification of the
Correspondence and offprint requests to: J. M. Davis, Institute of
Physiology, University of Munich, Pettenkoferstrasse 12, D-80336
Munich, Germany.
Fig. l.Carl Friedrich Wilhelm Ludwig (1816-1895). A photographic
portrait from 1886.
© 1996 European Dialysis and Transplant Association-European Renal Association
718
enlightened, liberal, middle-class family of modest
means. He was the third of eight children of a retired
cavalry Rittmeister (captain), then employed in the
financial administration of the prince elector. He began
his medical studies in Marburg in 1835, from whence
he was rusticated after a political scandal in 1836. He
spent the following semesters at Erlangen and Bamberg
in Bavaria until he was permitted to return to Marburg
where he took his doctorate in 1839. He spent time
with the physicist Bunsen and the physiologist Nasse
in the latter's physiological laboratory in the Dept. of
Anatomy, where he (Ludwig) was appointed 2nd
Prosector. After his habilitation (see below) and with
the help of Ludwig Fick, the elder brother of Ludwig's
life-time friend Adolf, he was appointed 1st Prosector
in 1843 and to an extraordinary chair in physiology in
1846. In all these years he still defended his liberal
principles strongly, so that the call to the chair of
physiology in Zurich in 1848, the year of revolution in
Germany, came at a very welcome time. Not particularly happy in Switzerland, he accepted appointment
to the corresponding chair at the 'Josephinum' in
Vienna in 1855 from whence he made his final move
to the chair in Leipzig in 1865.
J. M. Davis et al.
thesis, he rewrote and published it in German as well,
to make it, as he put it, available to the wider medical
community. Although some components appear in a
different order and some aspects have been emphasized
more in one version than in the other, or are expressed
differently, the versions appear generally comparable,
given the grammatical economy of Latin, although
there are inconsistencies in numbers and units. Since
both appeared within a few months of each other they
must be regarded as equivalent. Ludwig's previous
doctoral thesis was of no great scientific moment. For
further biographical and other details the reader is
referred to other publications [1,6,7] and the references
cited therein.
Carl Ludwig's philosophy and his concept of
glomerular filtration
We accept today as self-evident that physiological
functions are the expression of universal, meaningfully
ordered, physicochemical processes that, for that very
reason, can be analysed and understood by recourse
to the theoretical and experimental methods of physics
and chemistry. This approach, which in retrospect was
so successful, was in fact the real and revolutionary
Carl Ludwig's thesis and habilitation
innovation in Ludwig's 1842 hypothesis that saw urine
formation as the result of a simple biophysical process
In the autumn of 1842, then a 26-year-old physician of ultrafiltration in the glomeruli and was an unprecedand 2nd Prosector in the physiological laboratory of ented departure from the views current at the time.
the University of Marburg's Department of Anatomy,
Physiology in that period was a system of natural
Ludwig published his first major scientific work, a philosophy based on vitalism, divine revelation and
24-page treatise reporting the results of experiments other metaphysical notions. Experimentation using
carried out to elucidate the mechanism of urine forma- physical methods, although in use in physiological
tion [5]. This was published in Latin and was entitled investigation since Stephen Hales' (1677-1761) famous
'Z)e viribus physicis secretionem urinae adjuvantibus' measurement of arterial blood pressure, and indeed
(On the physical forces that promote the secretion of assigned a central position by workers like Francois
urine) and only recently has become available in the Magendie (1783-1855) and Johannes Muller
international literature [6]. This document not only (1801-1858), was still questioned as being sufficient or
enunciated principles which are still valid today but, appropriate means of gaining insight into the processes
as noted in the introduction, marked the beginning of of life. In order to realize his scientific ideas, Ludwig
a revolution in scientific philosophy and procedure.
thus had to challenge these traditional philosophies by
Ludwig presented the thesis to obtain his habilitation, the adoption of this new Weltanschauung. In this he
a senior degree in German universities for which there was soon joined by three other scientific 'revolutionaris no English equivalent. This degree conferred on the ies' and students of Johannes Muller: Emil du Boisholder the title of 'Privatdozent', the nearest equivalent Reymond, Hermann von Helmholz, and Ernst Wilhelm
to which is the position of 'Reader' in English and von Briicke, and was supported by the newly emerging
Commonwealth universities, the right to hold lecture esteem in which physics was held, together with the
courses and to receive the attendance fees from the writings of scientific naturalists like Karl Vogt, Jakob
students enrolled in the courses. It was also the prere- Moleschott, and Ludwig Buchner. These researchers
regarded the living organism as a type of machine, in
quisite for appointment as Professor.
Until about the turn of the century, the faculties of which physicochemical processes were responsible for
most German universities required such theses to be all the phenomena of life and which, for that very
written in Latin. However, even at the time when reason, could be investigated solely by physicochemical
Ludwig was writing (1842), the modern languages had methods. Characteristic of this new approach are the
already largely replaced Latin in academic discourse following words of Ludwig, taken from the introducin the natural sciences. As he makes clear in his preface, tion to his 'Textbook of human physiology', published
Ludwig recognized the difficulties of antiquated Latin in Zurich in 1852:
in coping with contemporary science, and the diffi- 7n accordance with this experience, it is concluded that
culties of contemporary scientists in coping with Latin. all the phenomena of the animal body are the conThus, shortly after submitting and publishing the Latin sequence of simple attractions and repulsions (between
Carl Ludwig: the discoverer of glomerular filtration
719
a limited number of chemical atoms) such as can be models, and from the analysis of these experiments he
observed when these elementary components collide.1 was able to predict the hydrostatic pressure and flow
This conclusion will be irrefutable, when it is proven,profiles in the vascular bed of the kidney (Fig. 2).
with mathematical precision, that the above mentioned 4. The chemical composition of urine and blood
elementary conditions are so ordered, with respect to was, by that time, sufficiently well known to lead to
direction, time and mass, in the animal body that all thethe recognition of the fact that urine is not a product
accomplislunents of the living or dead organism must, of the kidney's own chemical activity, but rather that
of necessity, follow from their interactions.' [8]
the principal components of urine are present already
Given both Ludwig's materialist-mechanist view of in blood. Conversely, it was apparent also that some
life on the one hand, and on the other the circumstance substances, such as urea, are excreted at far higher
of his initial employment at the Marburg Anatomical concentrations than at those present in blood. Thus it
Institute under the direction of Hermann Nasse where followed that, if these substances entered urine solely
his first tasks were concerned with the structure of by glomerular filtration, as Ludwig proposed, a subrenal vasculature, it is no surprise that he was the stantial fraction of filtered solvent must have been
first — albeit more intuitively than experimentally — reabsorbed through the tubular walls back into the
to understand correctly the mechanism of filtrate blood.
formation and reabsorption. At the same time he
5. Finally, and probably of more fundamental
possessed the appropriate strength of character to importance than any of these facts, Ludwig applied
present these considerations in such a way that they strictly the principle of considering seriously only such
assumed rapidly a central position in contemporary theory as could be experimentally investigated with the
scientific discussion.
methods of physics and chemistry, The correctness of
Ludwig based his concepts of renal function on the such theory was then assessed according to its physicofollowing observations, gained from the literature and mechanistic plausibility (Ludwig's mechanistic parafrom his own experiments during the period from his digm). This principle enabled him to reject other
appointment at Marburg in 1841 to the publication of theories on the origin of urine, for example, the vitalist
his Habilitation dissertation in 1842 [5] and his two- view or the view put forward by Johannes Miiller in
his textbook (1834) [10] that regarded the kidney as a
volume text book in 1852 and 1856 [8,9].
1. Blood is a protein-containing solution; in addi- gland, and ascribed the responsibility for urine formation, ^proteins have a substantial chemical affinity for tion to the renal nerves. Ludwig's strict application of
water and many aqueous solutions (and to some extent his mechanistic philosophy had doubtlessly been furalso for fats).' Ludwig carried out a variety of experiments on the reabsorption of concentrated and diluted
urine by blood through semipermeable membranes.
He found that thefluidcomponents of blood 'penetrate
the intact vascular walls. This process, termed secretion,
is opposed by a further process, reabsorption.' He
thought this secretion through 'thierische Haute'
(animal membranes) occurred through minute openings, and that the passage of fluid through these
openings did not lead to any change in the fluid's
composition. However, this did not hold for proteincontaining solutions, since the rate of filtration of such
solutions through animal membranes diminished with
time, presumably because (as he put it) the pores
B
gradually clog up. Furthermore the rate of filtration
rose with increasing blood pressure. Using sheep intestine as a model membrane, he studied both these
phenomena with defibrinated serum at various hydrostatic pressures.
2. From his dye injection experiments with the
anatomist Biinger in Marburg, Ludwig was well aware
of the structure of the renal vascular system, in particular of the two capillary beds, the glomerular and the
peritubular, connected in series.
3. By this time the laws of hydraulics applied to
symmetrically branched tubes were well known. Using
these laws, Ludwig performed experiments using Fig. 2. A. (top) Ludwig's representation of the renal microvasculature
1
Ludwig defines the elementary components of which all liveing
organisms are composed as atoms, electricity, and luminferous
aether, with which he also equates warmth.
including the capillary beds of the glomerulus (left) and the peritubular network (right); (bottom) representation off the relative total
cross-sectional areas of the different vascular segments (a afferent
arteriole, e efferent arteriole, g glomerulus, v venule). B.
Representation of the pressure profile across the capillary bed
720
ther consolidated during his period as an Assistant in
Bunsen's laboratory at Marburg. Considering this and
the anatomical structure of the glomerulus, it is in no
way surprising that even at this early stage he was able
to speculate that the process of glomerular filtration
might be regulated by the contraction of the muscular
walls of the afferent or efferent arterioles, with the
consequent slowing of blood flow. He regarded the
filtration part of his hypothesis as the most plausible
and firmly based. The different compositions of blood
and urine suggested to him, at least for a time, that
only reabsorptive and diffusive processes occurred in
the renal tubules, that is, reabsorption of the fluid
filtered in the glomerulus and diffusive transport of the
other urinary components.
It would, of course, be wrong to suggest that
Ludwig's genius was immediately recognized and
acclaimed, and the scientific philosophy of the 'organic
physicists', as they were called, universally welcomed
and accepted. The 'vitalists' vigorously opposed the
new mechanist philosophy and, although in general on
the retreat over the second half of the last century,
they were not entirely without success, as the subsequent history of the development of the concept of
glomerular filtration shows. It took a further 80 years
or more for the correctness of Ludwig's views to be
recognized.
The following considerations are relevant. Ludwig's
1842 hypothesis [5] was a 'complete' explanation of
renal function, namely filtration at the glomerulus
followed by reabsorption, powered by 'endosmosis',
along the nephron. It must rapidly have become clear
to Ludwig that his passive reabsorption mechanism
was unable to explain all aspects of renal excretion,
and he turned his attention to more rewarding and
fruitful areas. At the same time the vitalists, led by a
further student of Johannes Miiller, Rudolf Heidenhain
in Breslau, recognized this inadequacy and used this
as the grounds to reject Ludwig's hypothesis in toto.
For this Heidenhain called extensively on William
Bowman's study [11], published practically simultaneously with Ludwig's thesis, in which the function of
the glomerulus was recognized or, more accurately,
derived intuitively from its microscopic structure.
Although termed the 'Bowman-Heidenhain' hypothesis, Bowman's contribution was the solitary study,
and the leading protagonist was indeed Heidenhain
[12]. Given the lack of experimental evidence to the
contrary—Ludwig never returned to the kidney—
Heidenhain's view of renal function, with secretion by
the tubule as the central mechanism with the glomerulus secreting a little fluid to provide the solvent, held
the upper hand, although as textbooks of the period
show, Ludwig was not completely forgotten.
The tables began to turn at the turn of the century.
In 1896 the English physiologist Ernest Starling
(1866-1927) published his description of the formation
of tissue fluid [13], invoking essentially the same
mechanism as that proposed 50 years earlier by Ludwig
for glomerular filtration. In 1906, Rudolf Metzner,
J. M. Davis et al.
Professor of Physiology in Basel, Switzerland and a
former student of Ludwig in Leipzig, published a
unified hypothesis which recognized correctly the threecomponent (glomerular filtration, tubular reabsorption
and secretion) model of renal function that we accept
today [14]. Of interest is the fact that this theory of
Metzner's appeared 20 years before the publication of
the famous monograph on the formation of urine by the
Scottish pharmacologist Arthur Cushny [15] who is
generally but in view of the foregoing, undeservedly
accepted as the 'father' of the 'modern' theory of urine
formation. The final evidence for the correctness of
Ludwig's views on filtration was, of course, delivered
by the first micropuncture experiments of Wearn and
Richards in the 1920s [16] and subsequent measurements of glomerular capillary pressure [16-19].
References
1. Zimmer HG. Carl Ludwig: the man, his time, his influence.
Pfliigers Arch 1996; (Suppl) (in press)
2. Rehberg P Brandt. Studies on kidney function. I. The rate of
filtration and reabsorption in the human kidney. Biochem J
1926; 20: 447-460
3. Rehberg P Brandt. Studies on kidney function. II. The excretion
of urea and chloride analysed according to a modified filtration
reabsorption theory. Biochem J 1926; 20: 461-480
4. Shannon JA, Smith HW. The excretion of inulin, xylose and
urea by normal and phlorizinized man and dog. J Clin Invest
1935; 14: 393-401
5. Ludwig C. De viribus physicis secretionem urinae adjuvantibus.
Elwert, Marburg, 1842
6. Davis JM, Gottschalk CW, Haberle DA, Thurau K. Carl
Ludwig's revolutionary concept of renal function. Kidney Int
1994; 46 (Suppl 46)
7. Thurau K, Davis JM, Haberle DA. Renal blood flow and
dynamics of glomerular filtration: evolution of a concept from
Carl Ludwig to the present day. In: Gottschalk CW, Berliner
RW, Giebisch GH (eds) Renal physiology. Men and ideas.
American Physiological Society, Bethesda: 1987: pp 31-61
8. Ludwig C. Lehrbuch der Physiologie des Menschen vol 1 .Winter,
Heidelberg: 1852
9. Ludwig C. Lehrbuch der Physiologie des Menschen vol 2.Winter,
Leipzig: 1856
10. Miiller J. Handbuch der Physiologie vol l.Holscher, Koblenz
(various volumes, sections and editions): 1833; 1834; 1837
11. Bowman W. On the structure and use of the Malpighian bodies
of the kidney with observations on the circulation through that
gland. Phil Trans R Soc Lond [B] 1842; 132: 57-80
12. Heidenhain R. In: Hermann L. (ed) Handbuch der Physiologie
vol 5, part 1. Vogel, Leipzig: 1883: pp. 279-373
13. Starling EH. Physiological factors involved in the causation of
dropsy. Lancet 1896; 1: 1267-1270; 1331-1334; 1407-1410
14. Metzner K. Die Absonderung und Herausbeforderung des
Harnes. In: Nagel W. (ed) Handbuch der Physiologie des
Menschen vol 2, part l.Vieweg. Braunschweig: 1906: pp. 207-335
15. Cushny AR (1917, 1926) The secretion of the urine. Longmans
Green, London
16. Wearn JT, Richards AN. Observations on the composition of
glomerular urine with particular reference to the problem of
reabsorption in the renal tubules. Am J Physiol 1924; 71: 209-227
17. Hayman JM. Estimations of afferent arteriole and glomerular
capillary pressures in the frog kidney. Am J Physiol 1927;
79: 389-409
18. Pappenheimer JR, Renkin EM, Borrero LM. Filtration,
diffusion and molecular sieving through peripheral capillary
membranes. A contribution to the pore theory of capillary
permeability. Am J Physiol 1951; 167: 13-46
19. Brenner BM, Troy JL, Daugharty TM. The dynamics of glomerular ultrafiltration in the rat. J Clin Invest 1971; 50: 1776-1780