A 2000-year history of nephrology: 10 enduring scientific landmarks

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Contribution 1: the understanding that
the kidneys are the sourCe of urine
Galen of Pergamum (131-201 ad), On the Natural
Faculties and the Usefulness of the Parts of the
Body, ca. 150-200 ad
Against the backdrop of Aristotle who held that diseases
can be understood through an understanding of different
humors, there arose the remarkable Galen of Pergamum (1).
Galen was a Greek physician who spent time in Alexandria
and moved to Pergamum to become physician to the gladi-
ators, a fact which must have advanced his understanding
of human anatomy and surgery considerably! Galen’s ideas
held sway in Western medicine for a millennium and a half.
He was the very first “experimentalist” in the modern sense
of the word, and he devised the first notion of a system of
human physiology (2).
Although Galen’s system of physiology was fundamen-
tally flawed, it persisted as a dogma because no other ex-
perimentalist arose to refute it on the basis of hard obser-
vations. Galen pointed out that every butcher is aware of
the fact that the kidneys are connected to the bladder by
the ureters. He further pointed out that people who suffer
from dysuria or retention of urine experience pain in the
loins, which points to a connection between bladder and
kidneys. This simple fact, says Galen, clearly refutes the
“ingenuity” of Asclepiades (1
st
century bc), who believed
that the bladder is a sponge or a piece of wool that ab-
sorbs vapors formed from ingested fluid and converts it
Department of Biomedical Sciences Cedars-Sinai Me-
dical Center and University of California, Los Angeles,
California - USA
Leon G. Fine
A 2000-year history of nephrology: 10 enduring
scientific landmarks
ORIGINAL ARTICLE
DOI: 10.5301/jn.5000364
introduCtion
As interesting as a continuous and complete coverage of
an area of evolving scientific thought may be, it is equally
intriguing to attempt to pluck out of this history, a small
number of contributions which have held up over time
and which have allowed a field to lurch forward in a way
which appears to be understandable. This analysis of 2
thousand years in the history of nephrology attempts to
do just that. By nephrology is meant the field which en-
compasses the structure and function of the kidney, its
role in homeostasis, its diseases and the attempts by the
medical profession to prevent, cure and manage such
diseases.
Events which are recent tend to assume an exaggerated
importance which could wane substantially over the pas-
sage of time. So, in looking back over 2 millennia to decide
what constitutes an “enduring contribution,” it is surpris-
ingly easier to judge older contributions than newer ones.
Accordingly, less coverage is devoted to the more recent
contributions.
Ten seminal contributions are presented, which have
moved the field of nephrology forward in a substantial
way. A few intervening events are included where ap-
propriate. What emerges, somewhat disturbingly, is that
nothing of real substance may occur over large spans of
time, despite much industry and activity and many pub-
lications. Each step is characterized in this history as an
“understanding” so that the evolution of the ideas has
continuity.

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into fluid. Galen was incredulous that the “Compact and
impervious nature of the bladder” with “two strong coats”
was not apparent to seemingly observant people: “Why
do vapors not pass through the peritoneum and the dia-
phragm by this analogy and fill the whole abdominal cav-
ity and thorax with water?” “How does one explain the
fact,” he asked, “that when the bladder is filled with water
or tied at its neck and squeezed all round, it does not let
anything out but retains its contents? Does this not refute
the idea of inlets via the ureters?” (2).
To answer this question, Galen experimented on a living
animal, in perhaps the first well-devised renal physiology
experiment described. In Book I, chapter 13, of On the
Natural Faculties (1), he wrote:
Now the method of demonstration is as follows. One has
to divide the peritoneum in front of the ureters, then secure
these with ligatures, and next, having bandaged up the
animal, let him go (for he will not continue to urinate). After
this, one loosens the external bandages and shows the
bladder empty and the ureters quite full and distended –
in fact almost on the point of rupturing; on removing the
ligature from them, one then plainly sees the bladder be-
coming filled with urine.
When this has been made quite clear, then, before the
animal urinates, one has to tie a ligature round his penis
and then to squeeze the bladder all over; still nothing
goes back through the ureters to the kidneys. Here, then,
it becomes obvious that not only in a dead animal, but
in one which is still living, the ureters are prevented from
receiving back the urine from the bladder. These obser-
vations having been made, one now loosens the ligature
from the animal’s penis and allows him to urinate, then
again one ligatures one of the ureters and leaves the
other to discharge into the bladder. Allowing, then, some
time to elapse, one now demonstrates that the ureter
which was ligatured is obviously full and distended on
the side next to the kidneys, while the other one – that
from which the ligature has been taken – is itself flaccid,
but has filled the bladder with urine (1).
In these simple experiments, Galen showed that fluids
cannot pass through the wall of the bladder, and that
urine enters via the ureters but cannot reflux back into
them.
To the question “How is the urine formed in the kidneys
and how is it propelled to the bladder?” Galen responded
with 2 alternatives: either the kidneys “attract” urine, or
the veins exert a propulsive action on the kidneys. He
pointed out that if the latter alternative were true, not only
urine but also the whole of the blood would be squeezed
into the kidneys. Because this does not occur, he con-
cluded that the kidneys exert their own attraction on
urine. Furthermore, he says:
If the kidneys are like sieves and readily let the thinner se-
rous portion [i.e., urine] through and keep out the thicker
portion, then the whole of the blood contained in the vena
cava must go to them just as the whole of the urine is
thrown into the filters. Thus it is that, if the blood-serum has
to percolate through the kidneys, the whole of the blood
must come to them and not merely one part of it (1).
Remarkably, here we hear an idea raised 2 thousand years
ago which suggests that the blood may be filtered into a
thick and a thin component.
Before leaving Galen, this insight of his is worthy of consid-
eration:
The amount of urine passed every day shows clearly
that it is the whole of the fluid drunk which becomes
urine, except that which comes away with the dejec-
tions or passes off as sweat or insensible perspiration.
This is most easily recognized in winter in those who are
doing no work but are carousing, especially if the urine
be thin and diffusible; these people rapidly pass almost
the same quantity as they drink (1).
Galen concluded that function of the kidneys is to “re-
duce the blood of its watery portion.”
Nothing much was added to the ideas of Galen over
the ensuing millennium. The Middle Ages saw physi-
cians assigning diagnoses and prognoses according to
the color and appearance of the urine, a practice called
uroscopy. Elaborate schemes and diagrams supported
such practices in the literature.
Contribution 2: the understanding
that
blood CirCulates in a Continuous
CyCle through the organs and tissues
William Harvey (1578-1657), An Anatomical
Disquisition on the Motion of the Heart and
the Blood in Animals, 1628
One thousand five hundred years elapsed between the
writings of Galen and those of William Harvey. Harvey
did not write about the kidneys, nor did he write about

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the body fluids. So why include him here? What is the
process whereby a single individual establishes a new
paradigm in science? How did Harvey arrive at a realiza-
tion which changed the fundamental understanding of
how the human body works?
The simple answer is that the revolution in thought which
Harvey led was so profound that no history of medicine,
in any field, can be written without including the under-
standing that blood circulates through the organs and
delivers its constituents to such organs (3). Harvey’s
magnum opus, the De Motu Cordis was published in
1628 (4). One has to remember that physiology in the
1600s was still derived from Galen. Overturning this was
no mean feat, which is why it took Harvey a decade from
the time of his understanding of the circulation, to will-
ingly publish his “new concept of the heart’s movement
and function of the blood’s passage around the body.” It
took a further 25 years for his peers to accept his con-
clusions!
Perhaps part of his genius lay in understanding how to
establish the facts. For, first and foremost, Harvey was
an experimentalist. His knowledge of parts of the body
came only by comparing animals of different species,
whether winged, terrestrial or aquatic, viviparous or
oviparous. He almost certainly engaged in the dissec-
tion of many species. But not only did he dissect dead
animals, he vivisected them too. It was his vivisections
that lay at the heart of his ability to understand function.
But there were other unique attributes which Harvey
undoubtedly possessed. Not only did he learn from all
species, but he understood that much could be learned
from studying development. His experimental method,
furthermore, employed interventions including ligatures,
inflation techniques and injections, many of which were
entirely novel in concept. Finally, he was able to think
quantitatively, the oft-quoted example being his calcula-
tion of cardiac output from the product of stroke volume
and pulse rate. This led to his conclusion that the only
way this large volume of blood could be accommodated
was not by formation and destruction but by constant
recirculation.
Let it not be thought that Harvey was an iconoclast who
brushed aside everything from the past. He subscribed to
the conventional idea that the main function of the heart
was the distribution of heat. Only later did he see the
blood as the vehicle for this process. He also accepted
that the function of the lungs was to deliver blood to
the heart in order to relieve it of its excess heat. In this
scheme, the heart acted to distribute heat, and the lungs
acted to cool the instrument of the heart – i.e., the blood.
Furthermore, he never denied the notion that the lungs
concoct blood and “spirit,” as do the heart and liver, and
following Aristotle, he equated warmth with perfection
and related this to the nobility of animal species. He also
believed in the attractive power of parts of the body.
What did Harvey discover? The dogma at the time was
that blood ebbs and flows in the great veins connected
to the right side of the heart, with some blood percolat-
ing through the septum. There it combined with “spirit”
(pneuma) and was turned into arterial blood, which was
then distributed to all parts. While the passage of blood
from the right ventricle through the lungs to the left ven-
tricle may have been feasible due to the porous nature
of the lungs, this same concept was not intuitively ap-
plied to the greater circulation – blood was also thought
to ebb and flow in the arteries.
By direct observation in living animals, Harvey observed
that, upon contraction (systole), the heart lifts upward
to strike the chest, becoming harder and paler. He con-
cluded that the size of the ventricle decreases and that
“blood flows out as the heart erects.” He proved this
by making an incision in the ventricle from which blood
spurted. What had previously been inferred, Harvey
confirmed by experimentation, including observations
on cold-blooded animals with slower heart rates which
allowed for more precise measurement.
Essentially Harvey established with certainty (i) that ven-
tricular systole (and not diastole) causes the apex beat,
(ii) that ventricular systole corresponds to arterial dias-
tole (expansion) and (iii) that blood flows from right ven-
tricles to left ventricles through the lungs.
Blood delivered from the heart enters the kidneys
via its arteries and leaves via its veins. (Harvey did
not explicitly address the kidneys.) What its func-
tions are in this context was left for others to discov-
er. Harvey’s disciples and followers in England gradu-
ally came to realize that blood contains a constituent
which is essential for life and that this constituent
enters it via the lungs. It took another century for Joseph
Priestley to discover oxygen. No attention was paid to
the kidneys!
In addition to these fundamental discoveries, Harvey
created a method for conducting biological experiments
which endured for centuries. The essential points of his
method were (i) phrase a pertinent question, (ii) make
continuous observations over time, (iii) perturb the sys-
tem to expose hidden properties, (iv) seek additional ex-
amples in biology, and (v) design an experiment which
could yield a contrary result. This approach is as rel-
evant today as it was at the time of Harvey.

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Contribution 3: the understanding that
there is a fine struCture to the kidneys
and that this provides an insight into
how it may funCtion
Marcello Malpighi (1628-1694),
De Viscerum Structura, 1666
The landmark anatomical treatise of Andreas Vesalius (1514-
1574) paid little attention to the kidneys (2). Eustachius, in
1564, in his Opuscula Anatomica, illustrated the multipapil-
lated human kidney with a pelvicaliceal system (he was the
first to observe the adrenal glands). In describing the sub-
stance of the kidney, he said: “For my part, I think that there
are certain furrows and small canals in the substance of the
kidney which are caused only for flowing liquids and fluids. It
is through these that urine is filtered into the renal cavity” (2).
Lorenzo Bellini (1643-1704), an Italian anatomist, also in-
troduced the concept that the kidneys are made of a hard,
fleshy substance, and also spoke of “fibers that are continu-
ous from the outermost surface to the bellow of the pelvis”
(2). When these filaments (tubules) were compressed, Bellini
observed water welling up everywhere. With the bravado of
the true investigator, he showed that “if you are not afraid to
present this to your tongue you will discover a certain salti-
ness and, in some, the taste of urine.” He observed that the
same “juice” arises from a kidney that had been sectioned.
With the use of a magnifying lens, he observed that when
tubules are compressed, “the urine is very clearly seen well-
ing out as if pushing forth from so many little water pipes….
From these things one can confidently infer that the sub-
stance of the kidney … is nothing else than … a mass of
canalicular and capillary spaces through which urine flows
into the pelvis.”
Only 4 years after Bellini’s description of the kidney, Mar-
cello Malpighi (1628-1694) published his classic description
of human anatomy in De Viscerum Structura in 1666 (5), in
which there was a section titled “De Renibus” (On the kid-
neys) (Fig. 1).
One of the most important contributions made by Malpi-
ghi was to demonstrate the existence of capillaries, using a
frog’s lung preparation. This was the missing link in Harvey’s
description of the circulation.
Malpighi devoted a whole section of his anatomy to the
kidneys. This work was a landmark in understanding re-
nal function because of its great detail and clarity, and was
unsurpassed for nearly 2 centuries afterward. So precisely
were the kidneys described by Malpighi, that he apparently
did not feel the need to use illustrations. This is indeed sur-
prising in light of the magnificent plates that accompany his
embryological and botanical works.
Malpighi first described the lobular appearance of the exter-
nal surface of the kidney and correctly concluded that this
is the vestige of the lobular structure of the fetal kidney. The
interior of the kidney is also clearly divided into many-sided
pyramids, each with a discrete blood supply. He then dra-
matically described the “very small round bodies, like a coil
of small worms” on the surface of the kidney. These were
seen to be attached to the tortuous vessels (i.e., tubules)
that, “after short, sharp convolutions close to the outer
surface, run in a straight course toward the pelvis” (5). In
examining the substance of the renal cortex, Malpighi noted
Fig. 1 - Title page to Marcello Malpighi’s De Viscerum Structu-
ra (1666), on human anatomy, in which a section on the kidney
(“De Renibus”) appeared.

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excretory vessels. He was able to trace these urinary ves-
sels to the outermost surface of the kidney.
Malpighi described the “glands” of the kidney (i.e., the
glomeruli) as “attached like apples to the blood vessels, the
latter swollen with the black liquid and stretched out into the
form of a beautiful tree” (5). He was frustrated at not being
able to perceive the precise structure of these glands. He
considered them to be surrounded by the terminal buds of
the blood vessels, thus being stained the same color as the
vessels when a dye was perfused into the renal artery. Dye
injected into the veins similarly arrived at the glands, albeit
less predictably.
Having concluded that both arteries and veins are in direct
connection with the glomeruli, Malpighi addressed the more
difficult question of whether the urinary vessels (i.e., tubules)
were similarly connected. He acknowledged that he had
never been able to observe liquids perfused through the re-
nal arteries penetrating into the tubules. He even attempted
to highlight the connection (the existence of which, he was
convinced, must be present) by ligating the ureter and renal
veins of a live dog to produce a kidney swollen by the blood
driven into it. Despite the fact that a connection between
glands and urinary vessels was suggested, it was “not such
as satisfied the senses in all particulars.”
The final chapter of “De Renibus” is devoted to a consid-
eration of the function of the kidney. Malpighi assumed
that the glands were responsible for separating urine from
blood; however, the precise mechanism by which this was
achieved eluded him. He clearly stated that the excreting
bodies probably have little pores through which small par-
ticles (salty or sulfurous) can pass but not those of large
size or different shape. All particles of use to the organism
are retained, whereas those of no use are eliminated. He
supported this contention by observing that when blood is
thinned, urine may become bloody; when it grows thicker
bleeding subsides.
Contribution 4: the realization that
there are different forms of kidney
disease, whiCh Can lead to disorders
of multiple organ systems
Richard Bright (1789-1858), Reports of Medical
Cases: Selected With a View of Illustrating the
Symptoms and Cure of Diseases by a Reference
to Morbid Anatomy, 1827
Richard Bright worked as a physician in Guy’s Hospital,
London. His contribution was seminal in that he organized
and elaborated information and presented it in a way that
persuaded the medical community that expertise in diseases
of the kidney was necessary and that clinical observations
linked to pathological correlations exposed different pat-
terns of disease. If the disease were better understood, the
appropriate treatment would be more likely to be selected.
Bright employed detailed clinical histories and physical ex-
aminations of his patients coupled to an analysis of the urine
for the presence of albumen (6). He confirmed in a large se-
ries of patients that the existence of albumen in the urine is
a sign of kidney disease. His publications described indi-
vidual patients in terms of the onset and progression of their
symptoms and, since death was a common outcome, the
autopsy findings, which revealed multisystem disease.
The following description of a patient typifies Bright’s style
of observation:
CASE VII
Elizabeth Stewart, aged about 40. This woman, who ap-
peared to have been exposed to the difficulties and
temptations of the lower classes, had for eight years
been subject to slight attacks of dropsy; during which
time she had twice been in the London Hospital labor-
ing under this disease, and had received relief. She
ascribed her present attack to great exposure about
a year ago, having walked in the rain from Deal to Gra-
vesend without afterwards putting off her wet clothes.
She was admitted Guy’s in October 1826, greatly swol-
len with anasarca, the serum running from her legs: she
passed but little urine, and her breathing was greatly
oppressed. She first particularly attracted my attention
November 25. At the time she had been taking the Pil. Scil-
lae cum Hydrargyro till her mouth was very sore, combined
with other diuretics: all her symptoms were greatly im-
proved; the swelling had nearly subsided. Urine increased
to nearly three pints in the twenty-four hours; pretty clear
and natural in appearance: but from the history she gave of
herself, her pallid cachectic appearance, and the soft un-
natural feel of her flesh, I was led to suspect that this might
be one of those cases in which the urine would coagulate,
and probably the kidneys proved diseased. Accordingly,
on the application of heat to the urine I found that it co-
agulated very considerably: and she stated that for the last
six months she had experienced a good deal of pain and
uneasiness in her loins.
The improvement she had experienced was but temporary.
In about a week the urine again become most exceedingly
scanty; the quality varied much. On the 10th of December
I found it to be scanty and clear, but coagulating by heat,
becoming first milky and then loaded with a great num-

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ber of flakes. She spoke very decidedly as to feeling at
all times a pain, weight, and weakness across her loins.
There was after this time frequent evidence of inflamma-
tory action going on within the chest, and of effusion into
the cavities, which led to several changes in the medicine,
and to the application of blisters. – Jan. 2nd. She did not
pass above an ounce of urine in the night. On the 3rd there
were about four ounces, coagulating freely; and on this
Dr. Bostock was so kind as to make some experiments.
Jan. 18th. She has been growing decidedly worse for the
last three days: before that time she had been so much
better as to be sitting up the greater part of the day. She
is now confined to her bed, can scarcely lie on either side:
her abdomen begins to swell, and her hands are oedema-
tous; she has a frequent dry cough; her face is puffy. Urine
scanty, and she complains of pain all around the lower part
of the body.
27th. Evidently sinking, complaining much of pain pass-
ing through from the chest to the back; sits nearly erect;
coughs, and expectorates a tough mucus slightly tinged
with blood. – She died on the following morning.
SECTIO CADAVERIS
We were not permitted to examine the chest. In the abdo-
men three or four pints of clear serum were effused. The
liver was slightly lobulated in its appearance, and the acute
margin rounded; the peritoneal coat a little thickened. The
substance of the liver rather increased; the acini light-
coloured, not projecting the least; the intervening sub-
stance of a brighter red than natural. Gall-bladder rather
small, but containing well colored bile. Kidneys small, rather
lobulated, of a semi-cartilaginous hardness, completely
granulated; the small whitish or yellow granules project-
ing with red intervening spaces, so as to form a scabrous
surface, both appearing and feeling rough. On making a
longitudinal section, the kidney cut with the resistance of
a schirrous gland; the tubular part was drawn much nearer
to the surface than is natural; the cortical part indistinctly
granulated throughout, of a grayish drab about mixed with
purple (6).
Bright himself conducted the autopsies with an artist pres-
ent to record the appearances of the organs (Fig. 2).
Bright was to conclude that there are more than 1 form of
chronic kidney disease. He thought that there were at least
3. His approach was to be enduring. It has been modified
by new diagnostic technologies including biopsy, chemi-
cal tests and imaging, but the basic approach will remain
fundamental to the practice of nephrology, if it ultimately
survives as an independent discipline.
Contribution 5: the realization that
the glomerular Capillary tuft aCts as
a filter whiCh is part of a disCrete
anatomiCal unit
William Bowman (1816-1892), “On the Structure
and Use of the Malpighian Bodies of the Kidney,
With Observations on the Circulation Through
That Gland,” 1842
Bowman’s description of the nephron (as we now call it) was
the most definitive contribution to the microscopic anatomy
of the kidney and remains accurate in all of its details (7).
Fig. 2 - Richard Bright’s depiction of the kidneys in dropsy,
1827 (6).

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Why was Bowman able to see more than Malpighi did?
First, Bowman’s optical equipment was far superior to
that available to Malpighi; second, a method of vascu-
lar injection allowed small blood vessels to be outlined
with clarity; and finally, the use of thin microscopic slices
allowed the continuity of anatomical structures to be
determined with certainty. Bowman’s investigations in-
cluded a wide variety of species, including parrots and
boa constrictors!
Here is his classic depiction of the human nephron:
The Malpighian bodies I saw to be a rounded mass of
minute vessels invested by a cyst or capsule of pre-
cisely similar appearance to the basement membrane
of the tubes. Seeing these similar tissues in such close
proximity, it was not easy to resist the conviction that
the capsule was the basement membrane of the tubes
expanded over their vessels (7).
However, Bowman was unable to gain an unequivo-
cal view of this continuity. It was here that the method
of vascular injection allowed the critical observation
to be made, for, he says, “the injected material had in
many instances burst through the tuft and, being ex-
travasated into the capsule, had passed off along the
tube” (7). He was now able to construct the anatomy
of the nephron with great clarity, and the single plate
in his paper (7), containing 17 separate figures, il-
lustrates more effectively than many lines of text how
precisely he appreciated the structure of the neph-
ron. The afferent and efferent arterioles, respectively
supplying and emerging from the glomerulus (the “portal
system of the kidney” as Bowman termed it), as well as
the peritubular capillary plexuses are shown with clarity
and precision. His graphic depiction of the human neph-
ron is unsurpassed (Fig. 3).
Did Bowman’s revealing anatomical insights lead him to
an appreciation of the function of the glomerulus? His
own words could not be more explicit:
It would indeed be difficult to conceive a disposition
of parts more calculated to favor the escape of water
from the blood than of the Malpighian body. A large ar-
tery breaks up in a very direct manner into a number of
minute branches each of which suddenly opens into an
assemblage of vessels of far greater aggregate capac-
ity than itself and from which there is but one narrow
exit. Hence must arise a very abrupt retardation in the
velocity of the current of blood. The vessels in which
this delay occurs are uncovered by any structure. They
lie bare in a cell from which there is but one outlet, the
orifice of the tube…. Why is so wondrous an apparatus
placed at the extremity of each uriniferous tube if not
furnish water to aid in the separation and solution of the
urinous products from the epithelium of the tube? The
secretion is brought from the tubules of the gland in a
fluid state and only becomes solid by the reabsorption
of its aqueous portion after it has traversed the tortuous
canals where it was formed (7).
Although Bowman did not articulate the concept of filtra-
tion in physiochemical terms, his clear understanding of
the existence of 2 separate processes now recognized
as glomerular filtration and tubular reabsorption, and his
precise description of the anatomy of the nephron, be-
came the basis for all future studies on the physiology of
the kidney.
Fig. 3 - William Bowman’s depiction of the anatomy of the hu-
man nephron, 1842 (7).

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Contribution 6: the realization that
glomerular filtration Can be explained
on physiCal prinCiples: a biophysiCal
proCess of ultrafiltration
Carl Friedrich Wilhelm Ludwig (1816-1895),
Lehrbuch de Physiologie des Menschen,
1852 and 1856
A new vision of physiology was emerging in the mid-19th
century. In the words of Carl Ludwig (8):
In accordance with this experience, it is concluded that all
the phenomena of the animal body are the consequence of
simple attractions and repulsions (between a limited number
of chemical atoms) such as can be observed when these
elementary components collide. This conclusion will be irre-
futable, when it is proven, with mathematical precision, that
the above mentioned elementary conditions are so ordered,
with respect to direction, time and mass, in the animal body
that all the accomplishments of the living or dead organism
must, of necessity, follow from their interactions.
Ludwig’s experiments had revealed to him that the fluid
component of blood can cross a semipermeable mem-
brane in both directions and that this occurred through min-
ute openings. However, for protein-containing solutions,
this process falls off, because, he presumed, the pores are
becoming clogged up. But the rate of filtration was found
to increase as the pressure increased. Since the laws of
hydraulics were well known, Ludwig was able to predict
the hydrostatic pressures and flows in the glomerular and
peritubular vascular components of the kidney which he
depicted with clarity (Fig. 4).
Since the urine was known to be derived from blood, and
the concentrations of its constituents are not altered dur-
ing filtration, any change in concentration in the final urine
must be due to entry or exit of filtration from the filtrate.
Ludwig’s rigid application of physiochemical principles put
to an end any other “vitalistic” theories which were extant.
He was able to speculate that glomerular filtration might be
regulated by contractions or dilations of the afferent and
efferent arterioles.
Ludwig was also able to propose that reabsorptive and
secretary processes must take place in the renal tubules.
It subsequently became clear that these latter process-
es could not be explained solely according to the laws
of hydrodynamics, as Ludwig postulated at the time. He
gradually changed his view to include the idea that “some
special component of the tubular wall reduces the rate of
diffusion or that sodium chloride is reabsorbed back into
the blood stream by some force analogous to a chemical
force” (8). This was in line with contemporaneous views
that cells could selectively transport solutes across their
membranes. How they achieved that was not clear.
Contribution 7: the realization that
the renal exCretion serves the
funCtion of maintaining the ConstanCy
of body fluid Composition and volume:
introduCtion of quantitative physiology,
pathophysiology and mediCine
Ernest Henry Starling (1866-1927), On the absorp-
tion of fluids from the connective tissue spaces,
1899 and The Fluids of the Body, 1909
Ernest Henry Starling was professor of physiology at Univer-
sity College London and was medically trained, which ex-
plains his ability to cross the border between physiology and
Fig. 4 - Karl Ludwig’s depiction of the forces determining ul-
trafiltration across glomerular capillaries, 1852 (8).

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Fine: 2000-year nephrology history landmarks
medicine. Starling’s quantitative approach opened the door to
a quantitative clinical approach to fluid balance and compart-
mentalization, which blossomed over subsequent decades
(9, 10). He was centrally concerned with understanding how
fluid crosses the capillary wall and whether it was possible to
deduce the forces which governed this process. His filtration
theory was a milestone in quantitative physiology. His prede-
cessors, Ludwig and Heidenhain, had concluded that simple
physiochemical processes could not fully explain the forma-
tion of lymph, and were drawn to invoke an additional “vital”
force. After entering a number of blind alleys, Starling and
his colleague William Bayless were able to provide estimates
of changes in hydrostatic pressure of capillaries based upon
changes in arterial and venous pressures. A change in arte-
rial pressure did not necessarily mean an equivalent change
in capillary pressure. By measuring changes in pressures and
volumes in different compartments of the body, Starling was
able to infer the forces which govern fluid exchange between
such compartments.
Moreover, Starling had realized that the oncotic pressure of
the plasma proteins plays an essential role in transcapillary
fluid dynamics:
Whereas enormous pressures of the salts and crystalloids
in the various fluids of the body are of very little importance
for the function of absorption by the blood vessels, the
comparatively insignificant osmotic pressure of the albumin
is, I believe, of great importance.…
The importance of these measurements lies in the fact that,
although the osmotic pressure of the proteids of the plasma
is so insignificant, it is of an order of magnitude compara-
ble to that of the capillary pressures; and whereas capillary
pressure determines transudation, the osmotic pressure of
the protein of serum determines absorption … so that, at
any given time, there must be a balance between the hy-
drostatic pressure of the blood in the capillaries and the
osmotic attraction of the blood for the surrounding fluids.
With increased capillary pressure there must be increased
transudation, until equilibrium is established at a somewhat
higher point, where there is a more dilute fluid in the tissue-
spaces and therefore a higher absorption forced to balance
increased capillary pressure. With diminished capillary pres-
sure there will be an osmotic absorption of salt solution from
the extravascular fluid, until this becomes richer in proteids;
Here then we have the balance of forces necessary to ex-
plain the accurate and speedy regulation of the quantity of
circulating fluid (9).
In his book The Fluids of the Body (10), Starling encapsu-
lates the function of the kidneys as follows:
The function of the kidney is to keep the composition of the
circulating fluids constant, and we can therefore alter the
urine in any direction according to the nature of the change
which we bring about in the composition of the body.
The kidney therefore presents in the highest degree the
phenomenon of “sensibility,” the power of reacting to vari-
ous stimuli in a direction which is appropriate for the sur-
vival of the organism: a power of adaptation which almost
gives one the idea that its component parts must be en-
dowed with intelligence (10).
It was in the footsteps of Starling that mid-20th century
“giants” in renal physiology later walked. Homer Smith,
James Shannon, James Gamble, Dexter Van Slyke, John P.
Peters and Robert Pitts were to introduce quantitative anal-
ysis into measurement of kidney function and homeostatic
mechanisms and to propose how the nephron is regulated
in health and disease.
Contribution 8: the realization that
kidney funCtion Could be understood
at a Cellular level, leading to the
Creation of therapeutiC agents whiCh
regulate kidney funCtions
Hans H. Ussing (1911-2000): Koefoed-Johnsen
and Ussing, “The Nature of the Frog Skin
Potential,” 1958
It was none other than a marine biologist who opened the
door to understanding how a previously described “vital
force” moved ions, solution and fluids across the walls of
the nephron. Hans Ussing was a scientist studying ion trans-
port, and the introduction of radioactive tracers had made
it possible to study unidirectional ion transport. Ussing’s
seminal observations were made on the isolated frog skin
throughout his career. Together with his colleague Koefoed-
Johnsen, he proposed a model of a polarized cell which
transports ions and water from one side to the other (11).
This model was derived from the ability to distinguish active
from passive transport and the coupling of water movement
to ion transport (Fig. 5).
The model opened the door to the understanding of
nephron function. All that was needed was to find meth-
ods of gaining access to the renal tubular cells which
constitute the nephron. Thus were born the methodolo-
gies of micropuncture, isolated renal tubular perfusion
and isolated membrane studies and ultimately, single
transporter and ion channel analysis. Eventually from

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such approaches, the abilities to confirm mechanisms of
tubular reabsorption and secretion, urine concentration
and dilution and acidification hormone responsiveness
became possible. It became possible to test earlier hy-
potheses such as that of Hargitay, Wirz and Kuhn who
proposed a counter current model of urine concentra-
tion, and ultimately led to the search for genetic defects
which explained tubular transport diseases.
Equally important, this very basic model which Ussing pro-
posed led to the search for agents which could alter tubular
transport and affect excretory rates. Although diuretic sub-
stances had been discovered and used in the treatment of
dropsy, an appreciation of how they worked at the nephron
level led to the more detailed understanding of these agents
and to the development of more potent and more site-
specific agents.
Contribution 9: the realization that
some human renal diseases may have
an immunologiCal basis and that these
Could be modified by pharmaCologiCal
agents
R. Schwarrz, A. Eisner and W. Dameshek
(1900-1969), “The Effect of 6-Mercaptopurine
on Primary and Secondary Immune Responses,”
1959, and R.A. Lerner and F.J. Dixon, “Transfer of
Ovine Experimental Allergic Glomerulonephritis
(EAG) With Serum,” 1966
In 1902, Charles Richet, a Nobel Laureate and the grandfa-
ther of a modern-day leader in nephrology, Gabriel Richet,
described the effects of repeated injections of a biological
extract into animals. Even in very dilute amounts, these
led to death, and the phenomenon was named “anaphy-
laxis.” This was the first revelation that there could be a
dark side to immunity. The mechanisms of anaphylaxis
were not known, but subsequent studies by Donath and
Landsteiner and by Von Pirquet confirmed this.
There was little progress made with any relevance to kid-
ney disease until the seminal paper of Schwartz, Eisner
and Dameshek in 1959 (12), in which they demonstrat-
ed that an immune response to a foreign antigen could
be modified by a chemical agent and that appropriately
timed 6-mercaptopurine administration could induce ac-
quired tolerance to a foreign antigen.
The first convincing application of this principle to kid-
ney disease came from Lerner and Dixon in the United
States (13). They described the fact that serum globulin
derived from sheep made nephritic by immunization with
glomerular basement membrane, contained a specific
kidney-fixing antibody. This antibody was found to be
capable of inducing an immediate, transient glomerulo-
nephritis when injected into unilaterally nephrectomized
lambs. The disease was characterized by proteinuria,
polymorphonuclear neutrophil (PMN) infiltration into the
glomerulus, and localization of globulin in a linear fashion
along the glomerular capillary walls. They could absorb
this out with isolated sheep basement membranes. A sub-
sequent demonstration by them, that human anti–glomer-
ular basement membrane antibodies could be transferred
into monkeys and that these antibodies could be localized
to the site of injury in man and in monkeys, strongly sug-
gested a causal role in glomerular injury.
Since those understandings became widespread, the role
of specific immunoglobulins in causing human kidney dis-
ease, and the ability to detect these and to reduce their ef-
fects using immunosuppressive treatment, have become
central to the modern understanding of “primary” kidney
diseases and their treatments, and novel molecular tar-
gets for therapies are starting to emerge.
Fig. 5 - Koefoed-Johnson and Ussing’s diagram of a polari-
zed cell, illustrating the processes which determine transcel-
lular sodium transport, 1958 (11).

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Fine: 2000-year nephrology history landmarks
referenCes
1. Galen of Pergamum. In: On the natural faculties and the use-
fulness of the parts of the body. A. Talmadge trans. Cambrid-
ge, MA: Harvard University Press; 1916.
2. Fine LG. Renal physiology from earliest times to the Re-
naissance. In: Gottschalk CW, Berliner RW, Giebisch GH,
eds. Renal physiology: people and ideas. Bethesda, MD:
American Physiological Society; 1987:1-30.
3. Fine LG. William Harvey: experimental physician who di-
scovered the circulation of the blood. In: Robinson A, ed.
The scientists: an epic of discovery. New York: Thames and
Hudson; 2012:248-251.
4. Harvey W. G Keynes, trans. An anatomical disquisition on the
motion of the heart and the blood in animals. Birmingham,
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5. Malpighi M. De Viscera Structura. In: Opera Omnia. London:
Scott; 1686.
Contribution 10: the realization that
life Can be extended in patients with
end-stage renal disease
W. Kolff (1911-2009), “Artificial Kidney Use in Hu-
mans,” 1945; B.H. Scribner (1921-2003), “Treatment
of Uremia by Means of Hemodialysis,” 1960; R.
Schwartz and W. Dameshek, “The Effects of
6-Mercaptopurine on Homograft Rejections,” 1960
In the 1940s, William Kolff, of Dutch origin and working
in Groningen, established the fact that hemodialysis is
a treatment modality which could keep patients alive
with acute kidney failure (14). Of greater importance with
regard to patient numbers, was the very modest com-
munication in 1960 to the first International Congress of
Nephrology, a half century ago, by Belding Scribner and
colleagues from Seattle on the “Treatment of Chronic
Uremia by Means of Hemodialysis” (15). Using a Teflon
cannula as a means of vascular access in only 4 patients
with chronic uremia, they showed, over a total of 29 pa-
tient-years, that chronic hemodialysis was a feasible mo-
dality for maintaining human life in the absence of renal
function, over long periods of time.
The era of renal replacement therapy had arrived. A
direct extension of the demonstration of clinical im-
munosuppression was the emergence of the field of
renal transplantation. Once again it was Schwartz and
Dameshek who extended their original observations into
the field of organ rejection and the effects of an immu-
nosuppressive agent on this phenomenon in animals
(16). This work was extended into renal homograft re-
jection in the same year by Roy Calne. (Schwartz and
Dameshek had assessed their findings at a meeting in
London the previous year.) This line of work was con-
tinued in the research laboratory of Joseph Murray
(Nobel Laureate) and Frances Moore and John Merrill at
the Peter Bent Brigham Hospital in Boston and led to the
first human renal transplantation. Similar work was going
on in Paris at the Necker Hospital under Jean Hamburg-
er. Chemical immunosuppression spread from bench to
bedside and became the cornerstone of modern renal
transplantation.
ConClusions
I have attempted to identify the seminal contributions
which have led the field of nephrology to where it stands
today. There is little doubt that some of the choices made
here are open to dispute. What is not in dispute is that all
of the contributions discussed are landmarks in the field.
aCknowledgements
The author wishes to thank Dr. Richard Glassock for his very
helpful and insightful suggestions on seminal contributions to
renal pathology and the treatment of kidney diseases in the
20th century.
Financial support: No grants or funding have been received for
this study.
Conflict of interest: None of the authors has financial interest
related to this study to disclose.
Address for correspondence:
Leon G. Fine, MD
Department of Biomedical Sciences
Cedars-Sinai Medical Center
8700 Beverly Blvd
Los Angeles, CA, 90048 USA
leon.fine@cshs.org

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JN (2013; :Suppl 22) S6-S1726
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lustrating the symptoms and cure of diseases by a reference
to morbid anatomy. London: Longman, Rees, Orme, Brown
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7. Bowman W. On the structure and use of the Malpighian
bodies of the kidney, with observations on the circulation
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8. Ludwig CFW. Lehrbuch der Physiologie des Menschen. Hei-
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9. Starling EH. On the absorption of fluids from the connective
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10. Starling EH. The fluids of the body. Chicago, IL: Keener;
1909.
11. Koefoed-Johnsen V, Ussing HH. The nature of the frog skin
potential. Acta Physiol Scand. 1958;42:298-308.
12. Schwartz R, Eisner A, Dameshek W. The effect of 6-mercap-
topurine on primary and secondary immune responses. J
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13. Lerner RA, Dixon FJ. Transfer of ovine experimental al-
lergic glomerulonephritis (EAG) with serum. J Exp Med.
1966;124(3):431-442.
14. Kolff W. Artificial kidney use in humans. In: Maher JF, ed.
Replacement of renal function by dialysis: a textbook of
dialysis. 3rd ed. Dordrecht: Kluwer Academic; 1989.
15. Scribner BH. Treatment of chronic uremia by means of he-
modialysis. Proceedings of the First International Congress
of Nephrology. Basel: Karger; 1961.
16. Schwartz R, Dameshek W, Donovan J. The effects of
6-mercaptopurine on homograft reactions. J Clin Invest.
1960;39(6):952-958.
Accepted: September 26, 2013