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American Journal of Kidney Diseases

Looking at the Urine: The Renaissance of an Unbroken Tradition

  • Garabed Eknoyan
    Correspondence
    Address correspondence to Garabed Eknoyan, MD, Department of Medicine (523-D), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-3498.
    Affiliations
    Renal Section, Department of Medicine, Baylor College of Medicine, Houston, TX.
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      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 increasing body of knowledge about the workings of the inner body. For most of its 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 quacks and apothecaries, who prescribed and sold their potions by merely 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 a result, many of the chemical components now reported in metabolic profiles were first analyzed and identified in urine during the first half of the 18th century. In the process, what started as a science that bordered on divination laid the foundations of chemical analysis and spawned the disciplines of urology, endocrinology, and, after the use of urine in clearance studies, nephrology. The analytical methods and remarkable achievements of each of these disciplines have increased the value of examining urine. A renaissance of this oldest diagnostic tool of medicine is now under way in the proteomic profiling and detection of biomarkers in the urine, an approach which promises to further extend the merits of the unbroken tradition of looking at the urine.
      Throughout most of history, and well into the 18th century, 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 disease (Fig 1). Whereas these remain essential components of patient evaluation, they are now supplemented, if not supplanted, by the technical developments that began in the 18th century, proliferated in the 19th century, and have grown exponentially since the Second World War. That is, however, the end of the story rather than its beginning.
      Figure thumbnail gr1
      Figure 1The 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).
      The science of looking at the urine for diagnostic purposes, uroscopy, is as ancient as disease. The origins of using urine for diagnosis and prognostication are buried in the mystical beginnings of primitive medicine. These prehistoric observations, memorized and codified over time, were integrated gradually into medical care as it evolved from priestly medicine into that of the ancient world’s early professional physicians, 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 increasingly important part in the progress of medicine.
      • Kiefer J.H.
      Uroscopy: the clinical laboratory of the past.
      IBMS Historical Section Committee
      • Berger D.
      A brief history of medical diagnosis and the birth of the clinical laboratory Part 1. Ancient times through the 19th century.
      • Bolodeoku J.
      • Donaldson D.
      Urinalysis in clinical diagnosis.
      In the process, what started as uroscopy has laid the foundations of chemical analysis and spawned the disciplines of urology, endocrinology, and, after the use of urine in clearance studies, nephrology.

      Beginnings

      Babylonian, Egyptian, and Far Eastern medical texts make reference to the diagnostic implications of urine.
      IBMS Historical Section Committee
      • Berger D.
      A brief history of medical diagnosis and the birth of the clinical laboratory Part 1. Ancient times through the 19th century.
      By the time Greek rational medicine emerged, the basic rudiments of uroscopy were in place and inspection of the urine for diagnostic purposes was widely practiced. Hippocrates (460-377 bce) highlights these practices in his aphorisms, comments on the changes in urine in various states throughout his corpus, and succinctly summarizes them in a paragraph in his Prognostics.
      • Adams F.
      This text was the original source of Western uroscopy, which later authors were to copy, expand, and elaborate upon, and so it is worth noting the fundamentals of uroscopy that were emphasized in Prognostics: color (white, red, black), consistency (thin, thick, watery, clear, cloudy), sediment (smooth, leafy, farinaceous, absent), odor (fetid), and volume (deficient). Galen (129-200 ce), who accepted and expanded on these features, more importantly provided a rationale for uroscopy. Essentially, good health consisted of the harmonious balance of the constitutive elements of bodily fluids, 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 appropriate humors. The kidneys, as excretory organs, separated excess and poorly concocted bodily humors, and their secretion (urine) provided a diagnostic mirror of internal imbalances that could be used for diagnosis and a basis of therapy. Whereas Galen was the first to demonstrate the kidneys as the source of urine, he erred in his concept of circulation, in which blood ebbed back and forth between the liver, the concocting organ, and the kidneys, the filter that separated and secreted the faulty humors (unconcocted food) in the urine, thereby providing insight into the milieu interieur (internal balance) of the body.
      • Eknoyan G.
      The origins of nephrology Galen, the founding father of experimental renal physiology.
      Given the pervasive influence of Galen on the medicine that followed, these notions guided and increased interest in uroscopy for centuries to come. They are succinctly summarized by Avicenna (980-1037) in his introductory remarks on uroscopy: “While urine witnesses the quantity of ingested food and drink, it is a sign of bad digestion, phlegm, cold, restlessness or of hepatic obstruction.”
      • Eknoyan G.
      Arabic medicine and nephrology.
      The great compilers of Byzantium codified, elaborated, and expanded uroscopy, adding to it all an intricate, complex, and Byzantine twist. Notable 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.
      IBMS Historical Section Committee
      • Diamandapoulos A.
      Uroscopy in Byzantium.
      Avicenna, in his Canon, aphorisms, and Poem on Medicine, best recorded uroscopy in Arabic medicine, 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 authors. In the Poem on Medicine, Avicenna prefaces his comments by stating that the “urine is a faithful guide for the knowledge of the illness” and goes on to comment succinctly about color, density, appearance of the sediment (including its location and consistency), and odor of the urine.
      • Krueger H.C.
      This is literally a facsimile of the Hippocratic approach to uroscopy. Two other physicians of this period, one an Egyptian Jew who wrote in Arabic, Isaac Judaeus (10th century), and the other an Iranian who wrote in Farsi, Ismail al-Jurjani (11th century), elaborated on the subject and provided further detail on the conditions to be observed in the collection and examination of urine.
      • Wellcome H.S.

      The Matula

      Throughout these early times and well into the 18th century, uroscopy remained principally a visual science. Urine was examined 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 containers (Fig 2A) were modified to a bulbous body, to simulate the shape of the bladder and increase the surface area of examination, 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, gradations were added to the body of the matula (Fig 2D to F). The matula was first divided into 4 levels, whereby the uppermost 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 human body-shaped receptacle scaled into 24 levels.
      • Wellcome H.S.
      Figure thumbnail gr2
      Figure 2The vessels used to examine the urine, the matula, by uroscopists. Drawing based on figures reproduced in various manuscripts and published woodcuts from the 13th century (A) through 1895 (J, K).
      The neck of the matula was gradually made longer to allow for a better grip while the flask was held to the light (Fig 2G), and its bottom made conical to allow for better sedimentation (Fig 2H). The changes in shape (bulbous or conical) necessitated the use of wicker baskets to provide stability during transportation and probably a modicum of modesty in the process. By the time uroscopy was popularized throughout 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 containers used to collect and measure 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 similarity 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 together with the characteristics of urine examined (color, consistency, sediment, odor) and terminology used to describe them by uroscopists, it is impossible to avoid noting their similarity to the techniques and language of modern oenologists. A principal difference is that, unlike the taste of wine, there is a dearth of mention of the flavor of urine. Nevertheless, tasting the urine was part of the uroscopy. Relevant in this regard are two diseases of especial interest to nephrologists, diabetes mellitus and diabetes insipidus, whose very names are based on the taste of the urine: “sweet as honey” and “without taste or perceptible flavor,” respectively.

      The Middle Ages

      It was the translation of the Byzantine texts on uroscopy into Latin by Constantinus Africanus (1015-1082) that launched the next phase of uroscopy in Europe from the 13th century onwards. The rigid and didactic, but practical, tone of these early texts ingrained uroscopy in the scholastic psyche of the Middle Ages. Two individuals who studied in Salerno 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.
      • Wellcome H.S.
      • Dumaitre L.E.
      • D’Irsay S.
      The life and works of Gilles de Corbeil.
      As Gordon 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 every land. They traveled the countryside and preyed on the credulity and ignorance of lay people, diagnosing, prognosticating, 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 diagnostic aspects of uroscopy.
      As confidence in the merits of uroscopy grew, seeing the patient came to be considered not even necessary, since important diagnoses were reflected in the urine, if only one knew what to look for.
      • Kiefer J.H.
      Uroscopy: the clinical laboratory of the past.
      • Wellcome H.S.
      As a consequence, the ability of uroscopists began to be questioned and tested by the delivery of fake urines, leading to the appearance of medical texts on the art of posing the right questions before examining the urine in order to avoid the loss of one’s reputation.
      • Wellcome H.S.
      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.”
      • Wellcome H.S.
      A number of texts describing the proper use of uroscopy and its limitations were published 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.
      • Wellcome H.S.
      • Kaplan E.
      Robert Recorde and the authorities on uroscopy.
      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 measures 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).
      • DeSanto N.G.
      • Capasso G.
      • Ciacci C.
      • Gallo L.
      • Eknoyan G.
      Origins of nephrology 17th century fallacies deriving from examination of urine according to James Primrose.
      • Pelling M.
      • White F.
      In the meantime, in one of his first acts as founding president of the College of Physicians, Thomas Linacre (1460-1524), physician to Henry VIII, had formulated a statute to restrain apothecaries from prescribing by examination of the urine.
      • Wellcome H.S.
      • Pelling M.
      • White F.
      The College also began to commission texts on the qualitative analysis of urine and its limitations, amongst which one by Thomas Willis (1621-1675) is probably the best and most erudite, written before his characterization of diabetic urine as quasi melle (as if imbued with honey).
      • Eknoyan G.
      • Nagy J.
      A history of diabetes or how a disease of the kidneys evolved into a kidney disease.
      • Willis T.
      A principal contribution of Willis to uroscopy is his emphasis that the changes observed in the urine reflect those in the blood as it perfuses the entire body, a rebellion against the humoral and liver centered concepts of Galen 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 underway, looking into the urine was extended beyond its mere sensory examination. Medieval alchemists never found their “philosopher’s stone,” but it was in their bizarre laboratories filled with glassware, fire, and smoke that analysis of urine began by what may be termed proto-chemists.
      • Holmes F.L.
      Analysis by fire and solvent extractions: The metamorphosis of a tradition.
      • Hoff H.E.
      Nicolas of Cusa, van Helmont, and Boyle The first experiment of the Renaissance in quantitative biology and medicine.
      Probably the first test to be applied to urine was comparison of its weight to that of rainwater by Nicolaus Cusanus (1401-1464).
      • Hoff H.E.
      Nicolas of Cusa, van Helmont, and Boyle The first experiment of the Renaissance in quantitative biology and medicine.
      This process was refined by Herman Boerhaave (1668-1738), who weighed the residue of distilled urine in order to calculate its density, a complicated and time consuming procedure. This was greatly simplified by the later introduction of gradually refined urinometers to measure specific gravity, culminating in the thermometer-shaped mercury-based floating urinometer introduced in 1849 by Johann Florian (1813-1871).
      • Wellcome H.S.
      • Hoff H.E.
      Nicolas of Cusa, van Helmont, and Boyle The first experiment of the Renaissance in quantitative biology and medicine.
      • Winsten S.
      The skeptical chemist.
      The new era of analyzing the contents of urine was introduced by Paracelsus (1493-1541), who rejected the Galenic notions of humoral pathology, replacing them with external “infections” by “star born” poisons causing chemical derangements of the body which were excreted by the kidneys, for which the chemistry of the urine had to be analyzed to identify the cause of disease.
      • Holmes F.L.
      Analysis by fire and solvent extractions: The metamorphosis of a tradition.
      • Eknoyan G.
      On the contributions of Paracelsus to nephrology.
      Paracelsus emphasized liquidity, metallicity, and solidity of substances in general, 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 alchemists and first chemists, Joan Baptista van Helmont (1579-1644) and Herman Boerhaave, who advanced chemical analysis of bodily fluids.
      • Hoff H.E.
      Nicolas of Cusa, van Helmont, and Boyle The first experiment of the Renaissance in quantitative biology and medicine.
      • Winsten S.
      The skeptical chemist.
      • Fruton J.S.
      The emergence of biochemistry.
      As large volumes were necessary for much of the analytical work done at the time, it was easier to work with the readily accessible and substantial 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.
      • Kiefer J.H.
      Uroscopy: the clinical laboratory of the past.
      IBMS Historical Section Committee
      • Berger D.
      A brief history of medical diagnosis and the birth of the clinical laboratory Part 1. Ancient times through the 19th century.
      • Bolodeoku J.
      • Donaldson D.
      Urinalysis in clinical diagnosis.
      Analysis of blood followed, and at the urging of Robert Boyle (1627-1697), analysis of urine was coupled with that of blood in order to detect their similarities and differences.
      • Hoff H.E.
      Nicolas of Cusa, van Helmont, and Boyle The first experiment of the Renaissance in quantitative biology and medicine.
      • Winsten S.
      The skeptical chemist.
      • Eknoyan G.
      On the contributions of Paracelsus to nephrology.
      • Fruton J.S.
      The emergence of biochemistry.
      This approach was taken up by Browne Langrish (?-1759), who did analyses of blood and urine during various febrile illnesses 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.”
      • Foster W.D.
      The early history of clinical pathology in Great Britain.
      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.
      • Holmes F.L.
      Analysis by fire and solvent extractions: The metamorphosis of a tradition.
      Of the various components of urine that came to be identified over the ensuing decades, it is probably the analysis of urea that has contributed most to the emergence of nephrology. Boerhaave had described the crystalline residue of evaporated urine as being composed of “sea salt” that had been taken with food and a volatile “native salt of the urine,” probably urea. In 1773, Hilaire Martin Rouelle (1718-1779) prepared an impure form of urea from the alcohol extract of evaporated urine residue, 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 reactions described by William Prout (1785-1850), who also alluded to its presence in blood.
      • Rosenfeld L.
      William Prout Early 19th century physician-chemist.
      • Prout W.
      Shortly thereafter, in 1828, Friedrich Wöhler (1800-1882) synthesized urea from two inorganic molecules, ammonium and cyanic acid.
      • Kinne-Safran E.
      • Kinne R.K.H.
      Vitalism and synthesis of urea From Frederich Vöhler to Hans A. Krebs.
      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.
      • Fruton J.S.
      The emergence of biochemistry.
      Wöhler’s discovery coincided with the description in 1827 by Richard Bright (1789-1858) of the disease named after him. Within a year, Robert Christison (1797-1882) reported increased urea levels in the serum of patients with Bright’s disease.
      • Cameron J.S.
      • Hicks J.
      Sir Robert Christison (1797-1862): a neglected founder of nephrology.
      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.
      • George C.R.P.
      Development of the idea of chronic renal failure.
      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 introduced the concept of dialysis, thereby paving the way for the artificial kidney.
      • Gottschalk C.W.
      • Fellner S.K.
      History of the science of dialysis.
      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 urolithiasis, a disease that plagued the rich and famous and was fundamental to the emergence of urology.
      • Richet G.
      The chemistry of urinary stones around 1800: a first in clinical chemistry.
      • Eknoyan G.
      History of urolithiasis.
      That story, as well as that of albumin and glucose in the urine, has been told elsewhere and will not be recounted here, except to mention that it was the study of glycosuria that was instrumental in launching endocrinology.
      • Eknoyan G.
      • Nagy J.
      A history of diabetes or how a disease of the kidneys evolved into a kidney disease.
      • Richet G.
      The chemistry of urinary stones around 1800: a first in clinical chemistry.
      • Eknoyan G.
      History of urolithiasis.
      • Cameron J.S.
      Milk or albumin? The history of proteinuria before Richard Bright.
      • Eknoyan G.
      Emergence of the concept of endocrine function and endocrinology.
      Also relevant in this regard is the urine test for pregnancy introduced in the 20th century, a practice that dates back to Pharaonic Egypt. The Egyptians poured urine over mixed cereals to test for pregnancy, which was confirmed if germination occurred. In addition, the gender of the fetus could be predicted by the type of seed that sprouted.
      Clearly, the validity of this early test is questionable, but it did have a 50% chance of being correct!
      Analytical advances notwithstanding, visual inspection of the urine remains a useful technique that was refined by the introduction of the microscope. Robert Hooke (1635-1703), in his Micrographia, which was published in 1664, was the first to use his monofocal microscope to examine urine and report the rhomboid crystals he saw. But it was after bifocal microscopes were introduced that urine microscopy flourished and climaxed in the clinical studies of Pierre Rayer (1793-1867).
      • Rayer P.F.O.
      This story has also been told elsewhere and will not be covered here.
      • Fogazzi G.B.
      • Cameron J.S.
      Urinary microscopy from the seventeenth century to the present day.
      • Calucci G.
      • Floege J.
      • Schena F.P.
      The urinary sediment beyond light microscopy.
      Suffice it to say that today, any self-respecting (but likely older) nephrologist would reprimand trainees for rendering a diagnosis of kidney disease without examining the urine sediment, a leftover of the so-called Jerusalem Code of 1090, which included a provision for the public beating of physicians who diagnosed disease without looking at the urine.
      • Berger D.
      A brief history of medical diagnosis and the birth of the clinical laboratory Part 1. Ancient times through the 19th century.

      Conclusion

      Chemical analysis of urine and the microscopic examination of its sediment flourished in the first half of the 19th century, and assumed sufficient 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 written by John P. Peters (1887-1955) and Donald D. Van Slyke (1883-1971) and published in 1931. This reference was instrumental in the studies of metabolic balance and kidney function that followed, thereby accruing the body of knowledge that was to lead to the emergence of nephrology in 1961.
      • Seldin D.W.
      Scientific achievements of John P. Peters.
      • Robinson R.R.
      • Richet G.
      International Society of Nephrology
      A forty years history.
      Looking at the urine has come a long way from mere visual inspection in antiquity to the current detailed chemical analysis and microscopic examination reported by clinical laboratories. A renaissance of this oldest diagnostic tool of medicine is now underway due to recent technological advances in microanalysis and molecular biology. Proteomic profiling for low molecular weight proteins and the identification of biomarkers of disease in urine, approaches that are now in their infancy, promise to provide new insights into disease and further expand the diagnostic successes of the unbroken tradition of looking at the urine.
      • Pisitkun T.
      • Johnstone R.
      • Knepper M.A.
      Discovery of urinary biomarkers.
      • Janich M.G.
      • Raymond J.R.
      • Arthur J.M.
      Proteomics in renal research.

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