WORLD KIDNEY FORUM

Looking at the Urine: The Renaissance of an Unbroken

Tradition

Garabed Eknoyan, MD

The science of looking at the urine for diagnostic purposes, uroscopy, is as

ancient as disease. Throughout history, urine, the first bodily fluid to be
examined, has continuously and persistently provided medicine with an increas-
World Kidney Forum ing body of knowledge about the workings of the inner body. For most of its
Advisory Board history, uroscopy was a visual science; this focus peaked in the Middle Ages,
when the vessel used to examine urine, the matula, became a symbol of the
medical profession. Over time, the practice of uroscopy spread into the hands of
Rashad S. Barsoum quacks and apothecaries, who prescribed and sold their potions by merely
Cairo, Egypt looking at the urine. The consequent reformation measures of the 16th and 17th
centuries coincided with the first attempts at analyzing the contents of urine. As
Christopher R. Blagg
a result, many of the chemical components now reported in metabolic profiles
Mercer Island, Washington
were first analyzed and identified in urine during the first half of the 18th century.
John Boletis In the process, what started as a science that bordered on divination laid the
Athens, Greece foundations of chemical analysis and spawned the disciplines of urology,
endocrinology, and, after the use of urine in clearance studies, nephrology. The
Garabed Eknoyan analytical methods and remarkable achievements of each of these disciplines
Houston, Texas have increased the value of examining urine. A renaissance of this oldest
John T. Harrington diagnostic tool of medicine is now under way in the proteomic profiling and
Boston, Massachusetts detection of biomarkers in the urine, an approach which promises to further
extend the merits of the unbroken tradition of looking at the urine.
Am J Kidney Dis 49:865-872. © 2007 by the National Kidney Foundation, Inc.

T hroughout most of history,

and well into the 18th cen-
tury, the diagnosis of an illness
was based on its presenting
symptoms and examination of
the afflicted individual—most
notably via the pulse and the
urine—for external signs of dis-
ease (Fig 1). Whereas these
remain essential components
of patient evaluation, they are
now supplemented, if not sup-
planted, by the technical devel-
opments that began in the 18th
century, proliferated in the 19th
century, and have grown expo-
nentially since the Second
World War. That is, however,
the end of the story rather than
its beginning.
The science of looking at the
urine for diagnostic purposes,
uroscopy, is as ancient as dis-
ease. The origins of using urine
for diagnosis and prognostica-
tion are buried in the mystical
beginnings of primitive medi-
cine. These prehistoric observa-
tions, memorized and codified
over time, were integrated
gradually into medical care as
it evolved from priestly medi-
cine into that of the ancient
world’s early professional phy-
sicians, now available in the
extant texts of antiquity. Ever
since then, looking at the urine,
in one way or another, has
played a continuous and in-
creasingly important part in the
progress of medicine.1-4 In the
process, what started as uros-
copy has laid the foundations
of chemical analysis and
spawned the disciplines of urol-
ogy, endocrinology, and, after
the use of urine in clearance
studies, nephrology.
BEGINNINGS
Babylonian, Egyptian, and
Far Eastern medical texts make
reference to the diagnostic im-
plications of urine.2,3 By the
time Greek rational medicine
emerged, the basic rudiments
of uroscopy were in place and
From the Renal Section, Depart-
ment of Medicine, Baylor College of
Medicine, Houston, TX.
Received February 12, 2007; ac-
cepted in revised form March 8, 2007.
Support: None. Potential conflicts
of interest: None.
Address correspondence to Garabed
Eknoyan, MD, Department of Medicine
(523-D), Baylor College of Medicine,
One Baylor Plaza, Houston, TX 77030-
3498. E-mail: geknoyan@bcm.edu.
© 2007 by the National Kidney
Foundation, Inc.
0272-6386/07/4906-0020$32.00/0
doi:10.1053/j.ajkd.2007.04.003

American Journal of Kidney Diseases, Vol 49, No 6 (June), 2007: pp 865-872 865
866
Figure 1. The Sick Lady, an engraving by W. French (1815-1861), based on
The Sick Lady and her Doctor, a painting by Caspar Netscher (1639-1684).
(Figure courtesy of Dr Garabed Eknoyan).
inspection of the urine for diag-
nostic purposes was widely
practiced. Hippocrates (460-
377 BCE) highlights these prac-
tices in his aphorisms, com-
ments on the changes in urine
in various states throughout his
corpus, and succinctly summa-
rizes them in a paragraph in his
Prognostics.5 This text was the
original source of Western uro-
scopy, which later authors were
to copy, expand, and elaborate
upon, and so it is worth noting
the fundamentals of uroscopy
that were emphasized in Prog-
nostics: color (white, red,
black), consistency (thin, thick,
watery, clear, cloudy), sedi-
ment (smooth, leafy, farina-
ceous, absent), odor (fetid), and
volume (deficient). Galen (129-
200 CE), who accepted and ex-
panded on these features, more
importantly provided a ratio-
nale for uroscopy. Essentially,
good health consisted of the
harmonious balance of the con-
stitutive elements of bodily flu-
ids, the four humors (blood,
phlegm, yellow and black bile);
disease was their imbalance,
brought about by a failure of
the vital body forces (heat) to
blend (concoct) food into ap-
propriate humors. The kidneys,
Garabed Eknoyan
as excretory organs, separated
excess and poorly concocted
bodily humors, and their secre-
tion (urine) provided a diagnos-
tic mirror of internal imbal-
ances that could be used for
diagnosis and a basis of
therapy. Whereas Galen was
the first to demonstrate the kid-
neys as the source of urine, he
erred in his concept of circula-
tion, in which blood ebbed back
and forth between the liver, the
concocting organ, and the kid-
neys, the filter that separated
and secreted the faulty humors
(unconcocted food) in the
urine, thereby providing in-
sight into the milieu interieur
(internal balance) of the body.6
Given the pervasive influence
of Galen on the medicine that
followed, these notions guided
and increased interest in uros-
copy for centuries to come.
They are succinctly summa-
rized by Avicenna (980-1037)
in his introductory remarks on
uroscopy: “While urine wit-
nesses the quantity of ingested
food and drink, it is a sign of
bad digestion, phlegm, cold,
restlessness or of hepatic ob-
struction.”7
The great compilers of Byz-
antium codified, elaborated,
and expanded uroscopy, add-
ing to it all an intricate, com-
plex, and Byzantine twist. No-
table amongst their uroscopists
are Theophilos (7th century),
who wrote a detailed treatise
on the subject, and Johannes
Actuarius (13th century) who
elaborated on the stratification
of the urinary sediment in the
vessel used to examine the
urine.2,8 Avicenna, in his
Canon, aphorisms, and Poem
on Medicine, best recorded uro-
scopy in Arabic medicine,
Looking at the Urine
which translated and combined
Greek and Far Eastern medical
knowledge and enriched it with
novel observations of its own.
These works show a return to
the simpler style of Hippocrates
and avoid the complexity and
rigidity of the Byzantine au-
thors. In the Poem on Medi-
cine, Avicenna prefaces his
comments by stating that the
“urine is a faithful guide for
the knowledge of the illness”
and goes on to comment suc-
cinctly about color, density, ap-
pearance of the sediment (in-
cluding its location and
consistency), and odor of the
urine.9 This is literally a fac-
simile of the Hippocratic ap-
proach to uroscopy. Two other
physicians of this period, one
an Egyptian Jew who wrote in
Arabic, Isaac Judaeus (10th
century), and the other an Ira-
nian who wrote in Farsi, Ismail
al-Jurjani (11th century), elabo-
rated on the subject and pro-
vided further detail on the con-
ditions to be observed in the
collection and examination of
urine.10
THE MATULA
Throughout these early times
and well into the 18th century,
uroscopy remained principally
a visual science. Urine was ex-
amined in the vessel, the
matula, into which it was
passed. Transparent vessels
made of glass replaced early
opaque earthen containers, and
their shape altered over time
(Fig 2). Initial cylindrical con-
tainers (Fig 2A) were modified
to a bulbous body, to simulate
the shape of the bladder and
increase the surface area of ex-
amination, with a wide-lipped
mouth to allow easy collection
of urine (Fig 2B to H). As
stratification of the cloudiness
and sediment formation were
considered diagnostic, grada-
tions were added to the body
of the matula (Fig 2D to F).
The matula was first divided
into 4 levels, whereby the up-
permost denoted an illness of
the head, and the remainder
indicated afflictions of the heart
and lungs, the abdomen, and
the bladder and urinary tract,
respectively. These divisions
were then expanded into 11
and 24 boxes to denote the
organs involved in each of the
body cavities. They reached a
climax in the 15th century
when the vapors of distilled
urine were collected in a hu-
man body-shaped receptacle
scaled into 24 levels.10
The neck of the matula was
gradually made longer to al-
low for a better grip while the
flask was held to the light (Fig
2G), and its bottom made coni-
cal to allow for better sedimen-
tation (Fig 2H). The changes in
shape (bulbous or conical) ne-
cessitated the use of wicker
baskets to provide stability dur-
ing transportation and prob-
ably a modicum of modesty in
the process. By the time uros-
copy was popularized through-
out Europe in the Middle Ages,
the matula became the symbol
of doctors, captured in the
woodcuts of the 14th and 15th
centuries and the paintings of
Netherlandish artists in the 16th
and 17th centuries (Fig 1).
Containers used nowadays
to collect urine samples are
made of plastic rather than
glass, but remain transparent
and represent a return to the
original, cylindrical vessels
(Fig 2A). Also, the glass con-
867
tainers used to collect and mea-
sure urine volume in the 19th
and early 20th centuries (Fig
2J and K) continued to be made
in the shape of early matulas.
The inverted bulbous matula
(Fig 2B and C) also bears simi-
larity to the modern wine glass.
The old mouth part of the
matula, now sealed, becomes
the base on which the glass
stands, with the bottom of its
bulbous, bladder-shaped body
left open to allow for pouring
and drinking wine. Taken to-
gether with the characteristics
of urine examined (color, con-
sistency, sediment, odor) and
terminology used to describe
them by uroscopists, it is im-
possible to avoid noting their
similarity to the techniques and
language of modern oenolo-
gists. A principal difference is
that, unlike the taste of wine,
there is a dearth of mention of
the flavor of urine. Neverthe-
less, tasting the urine was part
of the uroscopy. Relevant in
this regard are two diseases of
especial interest to nephrolo-
gists, diabetes mellitus and dia-
betes insipidus, whose very
names are based on the taste of
the urine: “sweet as honey”
and “without taste or percep-
tible flavor,” respectively.
THE MIDDLE AGES
It was the translation of the
Byzantine texts on uroscopy
into Latin by Constantinus Af-
ricanus (1015-1082) that
launched the next phase of uro-
scopy in Europe from the 13th
century onwards. The rigid and
didactic, but practical, tone of
these early texts ingrained uro-
scopy in the scholastic psyche
of the Middle Ages. Two indi-
viduals who studied in Salerno
868
Figure 2. The vessels used to examine the urine, the matula, by urosco-
pists. Drawing based on figures reproduced in various manuscripts and pub-
lished woodcuts from the 13th century (A) through 1895 (J, K).
and wrote texts on uroscopy,
Bernard de Gordon (1285-
1318) of Montpellier and Gilles
de Corbeil (1165-1213) of
Paris, were instrumental in the
dissemination of the Byzantine
skills of uroscopy.10-12 As Gor-
don states in the introduction
of his book, “The science of
judging the urine is so easy
that all can learn what they
wish to learn.” And indeed they
did. By the 14th century, the
practice of uroscopy had drifted
largely into the hands of
quacks, who abounded in ev-
ery land. They traveled the
countryside and preyed on the
credulity and ignorance of lay
people, diagnosing, prognosti-
cating, and selling their own
allegedly curative potions after
looking at urines. Their trade
was made all the easier by the
advent of the printing press,
which enabled the publication
of increasingly elaborate charts
by which to compare the color
of the urine, which more than
any other feature of uroscopy
had come to dominate the diag-
nostic aspects of uroscopy.
Garabed Eknoyan
As confidence in the merits
of uroscopy grew, seeing the
patient came to be considered
not even necessary, since im-
portant diagnoses were re-
flected in the urine, if only one
knew what to look for.1,10 As a
consequence, the ability of uro-
scopists began to be questioned
and tested by the delivery of
fake urines, leading to the ap-
pearance of medical texts on
the art of posing the right ques-
tions before examining the
urine in order to avoid the loss
of one’s reputation.10 At the
same time, uroscopists were
advised on how to report their
findings: “take care to inform
the friends of the patient that
his illness is a serious one so
that, should the patient get well
the merit may be due to him
(the physician), or, should the
result of his illness be fatal, the
friends of the deceased there to
witness that he (the physician)
had noted the serious nature of
the disease from the first
visit.”10
A number of texts describ-
ing the proper use of uroscopy
and its limitations were pub-
lished in the 16th century, such
as The Judycyal of Uryns in
1512, based on a 1379 Latin
manuscript by Henry Daniel
(circa 1320-1385), an herbalist
and monk, and the Urinal of
Physick by Robert Recorde
(circa 1510-1558) in 1548.10,13
Still, uromancy continued to
flourish and critical pamphlets
began to appear in the 17th
century, notably The Pisse
Prophet by Thomas Bryant in
1637 and A Pisspot Prophet by
John Collop (circa 1625-1676)
in 1657. It was this general
public concern that led to the
initiation of reformation mea-
Looking at the Urine
sures and the publication of
medical books on the fallacies
deriving from examination of
the urine, such as On Vulgar
Errors in Medicine published
in 1639 by James Primrose
(1598-1659).14,15 In the mean-
time, in one of his first acts as
founding president of the Col-
lege of Physicians, Thomas
Linacre (1460-1524), physi-
cian to Henry VIII, had formu-
lated a statute to restrain apoth-
ecaries from prescribing by
examination of the urine.10,15
The College also began to com-
mission texts on the qualitative
analysis of urine and its limita-
tions, amongst which one by
Thomas Willis (1621-1675) is
probably the best and most eru-
dite, written before his charac-
terization of diabetic urine as
quasi melle (as if imbued with
honey).16,17 A principal contri-
bution of Willis to uroscopy is
his emphasis that the changes
observed in the urine reflect
those in the blood as it per-
fuses the entire body, a rebel-
lion against the humoral and
liver centered concepts of Ga-
len that was strengthened by
the discovery of the circulation
in 1628 by William Harvey
(1578-1657).
SCIENTIFIC FOUNDATIONS
About the time reformation
of uroscopy was getting under-
way, looking into the urine was
extended beyond its mere sen-
sory examination. Medieval al-
chemists never found their
“philosopher’s stone,” but it
was in their bizarre laborato-
ries filled with glassware, fire,
and smoke that analysis of
urine began by what may be
termed proto-chemists.18,19
Probably the first test to be
applied to urine was compari-
son of its weight to that of
rainwater by Nicolaus Cusa-
nus (1401-1464).19 This pro-
cess was refined by Herman
Boerhaave (1668-1738), who
weighed the residue of dis-
tilled urine in order to calcu-
late its density, a complicated
and time consuming proce-
dure. This was greatly simpli-
fied by the later introduction of
gradually refined urinometers
to measure specific gravity, cul-
minating in the thermometer-
shaped mercury-based floating
urinometer introduced in 1849
by Johann Florian (1813-
1871).10,19,20
The new era of analyzing
the contents of urine was intro-
duced by Paracelsus (1493-
1541), who rejected the Ga-
lenic notions of humoral
pathology, replacing them with
external “infections” by “star
born” poisons causing chemi-
cal derangements of the body
which were excreted by the
kidneys, for which the chemis-
try of the urine had to be ana-
lyzed to identify the cause of
disease.18,21 Paracelsus empha-
sized liquidity, metallicity, and
solidity of substances in gen-
eral, and of urine in particular,
describing these qualities in his
mystical language as mercury,
sulphur, and salt, respectively.
He may also have described
proteinuria. But it was 2 of his
followers, dubbed the last al-
chemists and first chemists,
Joan Baptista van Helmont
(1579-1644) and Herman Boer-
haave, who advanced chemi-
cal analysis of bodily flu-
ids.19,20,22 As large volumes
were necessary for much of the
analytical work done at the
time, it was easier to work with
869
the readily accessible and sub-
stantial quantities of urine
rather than blood. In fact, many
of the chemical elements now
reported in blood metabolic
profiles by clinical laboratories
were first identified, isolated,
and analyzed in urine. As such,
urine, which had been the first
bodily fluid to be looked at,
became the first to be analyzed
scientifically.1-4 Analysis of
blood followed, and at the urg-
ing of Robert Boyle (1627-
1697), analysis of urine was
coupled with that of blood in
order to detect their similari-
ties and differences.19-22 This
approach was taken up by
Browne Langrish (?-1759),
who did analyses of blood and
urine during various febrile ill-
nesses and reported them in his
Modern Theory and Practice
of Physic, published in 1684,
which he prefaces by stating,
“the study of the proportions
of several principles of blood
and urine, both in sound and
disease state, will be highly
useful in investigating the
causes and the phenomenon of
disease.”23
Technically, it was the use
of milder and less destructive
solvents (water, alcohol, ether)
rather than the furnace of the
alchemists that allowed for the
progress that followed.18
Of the various components
of urine that came to be identi-
fied over the ensuing decades,
it is probably the analysis of
urea that has contributed most
to the emergence of nephrol-
ogy. Boerhaave had described
the crystalline residue of
evaporated urine as being com-
posed of “sea salt” that had
been taken with food and a
volatile “native salt of the
870
urine,” probably urea. In 1773,
Hilaire Martin Rouelle (1718-
1779) prepared an impure form
of urea from the alcohol ex-
tract of evaporated urine resi-
due, which he termed matière
savonneuse (soapy matter). In
1779, William Cruickshank
(1745-1800) added nitric acid
to the evaporated residue of
urine and isolated crystalline
urea nitrate. In 1799, Francois
Fourcroy (1755-1809) and
Nicholas Vaquelin (1763-1829)
prepared pure urea salt, which
they called urée. In 1817, pure
urea was isolated, its density
calculated, and its properties,
appearance, and chemical reac-
tions described by William
Prout (1785-1850), who also
alluded to its presence in
blood.24,25 Shortly thereafter,
in 1828, Friedrich Wöhler
(1800-1882) synthesized urea
from two inorganic molecules,
ammonium and cyanic acid. 26
This was a turning point that
put the notions of vitalism that
had dominated medical theory
theretofore to rest, validated the
chemical approach to biology,
launched organic chemistry,
and after its application to
physiology, inaugurated the era
of biochemistry.22 Wöhler’s
discovery coincided with the
description in 1827 by Richard
Bright (1789-1858) of the dis-
ease named after him. Within a
year, Robert Christison (1797-
1882) reported increased urea
levels in the serum of patients
with Bright’s disease.27 Since
then, urea has held center stage
in the study of the normal and
abnormal kidney, and with the
introduction in 1847 of the term
“uremia” by Pierre Piorry
(1794-1879), it entered the
clinical parlance of medicine.28
It is important to emphasize
also that it was during the
course of studying colloidal
materials that Thomas Graham
(1805-1869) observed the free
diffusion of urea and intro-
duced the concept of dialysis,
thereby paving the way for the
artificial kidney.29 Moreover,
it is the clearance of urea from
the body that prompted studies
of kidney function, and its
clearance during hemodialysis
that introduced the concept of
Kt/Vurea, which was adopted
as a surrogate of the adequacy
of dialysis.
IMPACT ON MEDICINE
A major stimulus for the
analysis of urine was urolithia-
sis, a disease that plagued the
rich and famous and was funda-
mental to the emergence of
urology.30,31 That story, as well
as that of albumin and glucose
in the urine, has been told else-
where and will not be re-
counted here, except to men-
tion that it was the study of
glycosuria that was instrumen-
tal in launching endocrinol-
ogy.16,30-33 Also relevant in this
regard is the urine test for preg-
nancy introduced in the 20th
century, a practice that dates
back to Pharaonic Egypt. The
Egyptians poured urine over
mixed cereals to test for preg-
nancy, which was confirmed if
germination occurred. In addi-
tion, the gender of the fetus
could be predicted by the type
of seed that sprouted.34 Clearly,
the validity of this early test is
questionable, but it did have a
50% chance of being correct!
Analytical advances not-
withstanding, visual inspec-
tion of the urine remains a use-
ful technique that was refined
Garabed Eknoyan
by the introduction of the mi-
croscope. Robert Hooke (1635-
1703), in his Micrographia,
which was published in 1664,
was the first to use his monofo-
cal microscope to examine
urine and report the rhomboid
crystals he saw. But it was af-
ter bifocal microscopes were
introduced that urine micros-
copy flourished and climaxed
in the clinical studies of Pierre
Rayer (1793-1867).35 This
story has also been told else-
where and will not be covered
here.36,37 Suffice it to say that
today, any self-respecting (but
likely older) nephrologist
would reprimand trainees for
rendering a diagnosis of kid-
ney disease without examining
the urine sediment, a leftover
of the so-called Jerusalem Code
of 1090, which included a pro-
vision for the public beating of
physicians who diagnosed dis-
ease without looking at the
urine.3
CONCLUSION
Chemical analysis of urine
and the microscopic examina-
tion of its sediment flourished
in the first half of the 19th
century, and assumed suffi-
cient importance during the
second half of the century that
several of the dominant figures
and medical authorities of the
period felt compelled to write
monographs on analysis of the
urine. The first definitive text
on the subject, Quantitative
Clinical Chemistry, was writ-
ten by John P. Peters (1887-
1955) and Donald D. Van Slyke
(1883-1971) and published in
1931. This reference was in-
strumental in the studies of
metabolic balance and kidney
function that followed, thereby
Looking at the Urine
accruing the body of knowl-
edge that was to lead to the
emergence of nephrology in
1961.38,39
Looking at the urine has
come a long way from mere
visual inspection in antiquity
to the current detailed chemi-
cal analysis and microscopic
examination reported by clini-
cal laboratories. A renais-
sance of this oldest diagnos-
tic tool of medicine is now
underway due to recent tech-
nological advances in micro-
analysis and molecular biol-
ogy. Proteomic profiling for
low molecular weight pro-
teins and the identification of
biomarkers of disease in
urine, approaches that are now
in their infancy, promise to
provide new insights into dis-
ease and further expand the
diagnostic successes of the
unbroken tradition of looking
at the urine.40-41
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