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The chemistry of urinary stones around 1800: A first in clinical chemistry
Kidney International, Vol. 48 (1995), pp. 876—886
HISTORICAL ARCHIVE EDITED BY CARL GOTFSCHALK
The chemistry of urinary stones around 1800: A first in clinical chemistry GABRIEL RICHET de l'Académie Nationale de Médecine, Paris, France
The chemistry of urinary stones around 1800: A first in clinical chemistry. At the end of the 18th century, as soon as modern chemistry
was created, dedicated physicians tried to apply it to medicine. A rewarding field was that of urinary lithiasis. Stones offered a sufficient amount of a relatively pure chemical present in the body. Indeed, urine and the solidified matter was within the analytical grasp of the existing techniques. The first step was made by Scheele in Sweden who identified uric acid in calculi and normal human urine. During the following thirty years, Fourcroy and Vauquelin in Paris and Wollaston, Pearson, Marcet and Prout in London identified the various salts, uric acid, urate, various phosphates, oxalate, calcium, ammonium and magnesium forming current calculi. The conditions of their solubility in vitro were described. Even rare components such as cystine and xanthine were unraveled in London. The impetus given by these studies offered a good start to clinical chemistry in general and to the understanding of urinary lithiasis in particular. This led to the discovery of the corresponding solutes in the urine of such patients. Unfortunately, during the following decades nothing was added to these chemical investigations, and most of what had been acquired was forgotten. Research was concentrated on clinical pathology. The implementation of chemistry to medicine had to wait.
applications to medicine were soon explored. The demonstration by Priestley and Lavoisier that living organisms take up oxygen and reject carbonic acid is famous. Chemical analysis at the time required large amounts of material, but urine and urinary stones
fitted the technical requirements. The composition of urinary stones were successfully defined, and within four decades the possible clinical and therapeutical implications scientifically unraveled. The pioneers saw clearly the value of understanding the humoral complexity underliying these diseases. They strove to push the underlying direction of medicine towards the wider use of chemistry in solving clinical problems. Hence urinary calculi were the principal foundation stones of clinical chemistry.
Manifold attempts were made to characterize them, first in Sweden and then in England and France, all countries in which animal chemistry was blossoming out. Results chaotically heaped
up during these years and could not be checked in foreign
laboratories since borders were sealed during the French Revolution. Therefore, the results are grouped according to the places Modern chemistry emerged at the end of the eighteenth in which they were obtained. The leading thread of thought is thus century when solid matters were identified, which was soon better understood than if a chronological order had been adopted followed by the identification of gases. The invention by Stephen which would have disrupted the chain of the intellectual developHales (1677—1761) and Henri Cavendish (1731—1810) of tech- ments. The topic is presented as follows: the discovery of a stone niques to collect gases under water and mercury, respectively, made of uric acid; from Scheele to Pearson and Fourcroy; paved the way for major discoveries. Several pure gases, including Fourcroy and Vauquelin; the English School, Wollaston, Marcet, oxygen (Priestley, Scheele, Lavoisier), carbonic acid (Black), Prout; and the rise and early fall of clinical chemistry. hydrogen (Cavendish), and nitrogen (Priestley, Lavoisier) were identified. In addition the analysis and synthesis of water were Uric acid stone, the linchpin of urinary calculi successfully done. It was also shown that gases could be present in solid components from which they were cleared by heat, acids or In 1776 Karl Wilheim Scheele (1742—86) revealed that the main bases. More important perhaps were the concepts and the methods of Antoine Laurent Lavoisier (1743—94), the lawgiver in component of a bladder stone he had studied was a substance chemistry as he is known, who, applying techniques used in which was barely soluble in cold water, but sufficiently so to turn physics, pioneered quantitative chemistry. He discovered oxidiza- litmus paper red. The matter melted in alkali and formed a tion and thus disproved the phlogistic system of Georg Ernst Stahl precipitate in acid solution which dissolved in a hot nitric acid
leaving a residue which, after evaporation, turned a pinkish
(1660—1734).
Many, if not most, chemists were physicians or pharmacists and
crimson. Upon heating, and depending on the temperature, there arose a smell of prussic acid, ammonia or even something like smouldering horn. These were the properties that, according to
Fourcroy 1] and Pearson [2], Scheele had described at the Received for publication January 6, 1995 and in revised form April 10, 1995 Accepted for publication April 10, 1995
Academy of Sciences in Stockholm. Scheele named the substance lithic acid, subsequently it was named uric acid. This discovery was
© 1995 by the International Society of Nephrology
distinction.
confirmed by T.B. Bergman (1734—1794), a chemist of some
876
877
Richet: Early chemistiy of urinary calculi
KARL WILHELM SCHEELE 1742—1788 Fig. 1. Karl Wilhelm Scheele (Courtesy of the Faculté de Pharmacie, 75006, Paris).
Scheele's work contained an observation of outstanding importance and one substantial weakness. His very important contribu-
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tion was to establish that uric acid is a normal constituent of Fig. 2. Stephen Hales (Courtesy of the Welcome Institute Libray, London). human urine, and that when it is cold it gives rise to a brick red sediment. Thus uric acid became the first metabolite to be identified in human urine, twenty years before Antoine F. inspired [5]. On his travels abroad the King so often heard Fourcroy (1755—1809) and Nicolas L. Vauquelin (1763—1829) isolated urea in 1799 [3, 4]. Scheele's weakness stemmed from his
Scheele's name mentioned that he indicated that Sheele should be
present in urine.
unrecognized in his country; Joseph Priestley (1733—1804), com-
awarded the title of Chevalier. Unfortunately another Scheele conclusion that because most stones contained uric acid they received the award as the chemist was unknown to the relevant contained only uric acid. He thus missed the contribution of officials. According to Dumas the three founders of modern calcium and phosphorus which he himself had confirmed was chemistry all suffered a sad fate: Scheele remained poor and Scheele's harsh life
Scheele (Fig. 1) was born in Swedish Pomerania. His parents were not well off, so that at the age of 13 he became an apprentice
pharmacist where he taught himself chemistry. One of his first
promised by his revolutionary sympathies (the Convention had made him a French citizen), became an exile in the United States; and A.L. Lavoisier had his head cut off by the same Convention. Scheele 's predecessors
Before Scheele, work on urinary stones was more alchemy than discoveries, fluosilicilic acid, was ignored by the Academy. Scheele then left Stockholm for Uppsala where Bergman was working. science. Fourcroy [6] noted three exceptions. The oldest had been One of Bergman's experiments was unsuccessful which he blamed made by the Reverend Stephen Hales (Fig. 2) whose main claims on the saltpeter which had been supplied by Scheele's pharmacy. to fame were that he had measured the arterial pressure of two
Unconvinced by this accusation Scheele worked out that Bergman's results were based on an experimental error. This won Bergman's respect and his continuing support thereafter. Scheele's place in the history of chemistry is engraved by his identification of fifteen novel substances and the properties of many others. Scheele was the ideal experimental chemist. J.B.
Dumas (1800—84) remarked that, in spite of being poorly equipped, and holding some simplistic theories, his work was
dogs and a couple of horses early in the century and the respiration of plants. When attempting to dissolve bladder calculi
he first wanted to know their chemical nature. He therefore measured the volume of gas which was released when they were exposed to heat or various acids. He concluded from the amount of gas released and the "earth-like" residue that they contained "chalk" [7]. Then, with faultless logic, he injected weak acids into
the bladder of animals into which he had previously placed a
878
Richet: Early chemistry of urinaty calculi
human calculus. B. de Sauvages from Montpellier, who was one of his translators, wrote of Hales, "The human spirit without experimental evidence, relying on theory alone, is unable to discover a single phenomenon" [8]. The second of Scheele's predecessors to be mentioned by Fourcroy was Lorenz Bellini (1643—1704) in Pisa, who studied the role of water in the formation of stones. He had
found that urinary residues obtained by evaporation could be redissolved in water. He therefore suggested that urinary stones could be dispersed by increasing the flow of urine. A pharmacistphysician-chemist, A.S. Marggraf (1709—82) was the third prede-
cessor already known for his method of extracting phosphorus from urine, which was much simpler than that of Brand, a 17th century alchemist. At the Berlin Academy in 1775 he described a stone that consisted of calcium salts, principally those of phosphorus. Pearson [2] said it was confirmed in 1788 by Link from Gottingen. From Scheele to Pearson and Fourcroy At the time, Scheele's discovery of lithic acid made little impact, though urinary stones were very common. Subsequently further work was either nosological or anatomical. Felix Vicq D'Azyr (1748—94) in 1780 discussed all the animal concretions he had come across without discussing their possible chemical composition [9, 10]. He suspected that uric acid urinary stones were due to hyperconcentration of the urine, as in man urine always contains
uric acid regardless of the presence of calculi. In a somewhat analogous but reciprocal manner, Lavoisier, on his return in 1767
from a geological expedition with his teacher J.E. Guettard (1715—86), had pointed out that the composition of geological
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stratas could be discerned by analyzing the water which had - 4 traversed through them: what better guide can there be for a mineralogist than to study the water [11]? At that time the chemical explanation of geology had begun, and Rouelle at the Fig. 3. George Pearson (Courtesy of the Bibliotheque de l'Académie de Jardin du Roi in Paris (Jardin des Plantes or Museum) taught Médecine, 75006, Paris; Cliché Charmet). both disciplines. A little later Fourcroy studied the relationship of bone disease to urinary stones, in particular the frequency of "earthy" stones
range of concentrations from 1 part per 200 to 199 parts per 200,
(calcium salts) in ricketts. He suspected that there was an the majority containing 80 to 140 parts per 200, The other underlying abnormality of phosphoric acid metabolism. In order to stimulate research he put this idea forward as the subject of an open competition at the Société Royale de Médecine in 1786 [12]. The winner was a surgeon who mentioned the age of 1463 patients with vesical calculi on whom he had operated. Nine hundred and
constituents were salts of calcium or ammonia, particularly phosphates, and in addition there was some animal matter, for upon
being heated to a high temperature ammonia was released,
demonstrating the presence of nitrogen. That all living substances contain nitrogen had recently been shown by Berthollet in 1781 fifty were less than 10 years old and they were nearly all boys. Two (animals) and Fourcroy in 1789 (plants) [141. Pearson rounded off other competitors subscribed to the generaly held opinion that the his paper with the results of a chemical analysis of calculi whether composition of urinary stones and bones were almost the same, if or not they were urinary, from different animals, stating that not identical, but they did not appear to have worked on the except in man they never contained uric acid. Finally he claimed subject themselves. So far clinical chemistry had not emerged that articular deposits of sodium urate do not occur outside the On the 14th December 1795 George Pearson (1751—I 828) (Fig. human species [2 (p. 39)]. 3), who was both doctor and chemist, gave a paper to the Royal In England Pearson's work was ignored, for six months earlier Society in London [2] on 300 urinary stones obtained from a Mr. William H. Wollaston (1766—1826), a physician and wide ranging Heaviside's collection of 800 such specimens. Pearson had come chemist, had spoken on the same subject at the same place. to two conclusions. One was chemical. Lithic acid does not exist, Except for his erroneous deduction about uric acid, most of it is an oxide. The next year Fourcroy, stung by this denial, Pearson's findings merely confirmed and extended those of Wolrepeated each of Pearson's experiments and demonstrated that laston. his assertion was untenable and that on the contrary Scheele was Pearson greatly admired Lavoisier, "the immortal and ever to right [13]. Pearson had also suggested that the term lithic should be deplored Lavoisier" [15], and in 1787 had published a Transbe changed to uric. Pearson's second conclusion was a valuable lation of the Table of Chemical Nomenclature in order to popularclinical chemical correlation. He had found that almost all calculi ize modern chemistry in England. Pearson also studied the contained some uric acid (194 out of 200 stones), but over a wide dissociation of water and a technique whereby carbon could be
Richet: Early chemistty of urina,y calculi
obtained from chalk. In medicine he studied the role of the carbon deposits found in "the black spots of the lungs." His enthusiasm
879
The accumulation of a vast database
In order to have a sufficient amount of useful pathological
for vaccination led him to set up a special center, but its material Fourcroy organized colleagues to send him urinary imperfections brought the procedure into such disrepute that he crossed swords with E. Jenner (1749—1823) [17].
Fourcroy's and Vauquelin's views on urinary stones The early years: The introduction of chemistiy into medicine
Fourcroy was a chemist and physician who now would be accused of being a workaholic. Because of his extensive knowl-
edge of medicine he had a clear understanding of the various clinical implications which might stem from an experimental finding. In 1801 he published an eleven volume text on Système des
Connaissances Chimiques [1], which included a 190 page index. The two volumes on the organic composition of vegetables and animals bear witness to a mind attuned to physiology and patho-
stones together with some relevant environmental and clinical information, such as what was the geological configuration of the region where the stone originated, and whether the patient's urine
was usually acid or alkaline [23]. He received more than 700 calculi of which 600 were bladder stones. A unique collection, its abundance matched the wealth of notes that accompanied each stone. Before, most chemicaly analyzed specimens had come from museums and those who had analyzed them had been foolhardy enough to use them without knowning whether they came from men or animals, or from the urinary or intestinal tract. Fourcroy's inquiry was probably the first efficiently carried out multi-center investigation in medicine. The chemical composition of bladder stones
In 1802 Fourcroy published an overview of the results he and physiology. The chapters on urine (110 pages) and calculi (67 Vauquelin had obtained, though surprisingly, Vauquelin's name is pages) give a precise account both of old and new findings and of his own work, together with his views on biology which were often prophetic. Fourcroy had the necessary medical background for this type of research. In 1789 he had published his results on the chemistry of biliary stones [18] and in 1793 a contribution to the Concrétions des Dijférentes EspècesAnimales et Végétales [19, 20], reporting the
results of observations on bladder calculi begun in 1787. The
not included as an author [24]. They had identified twelve constituents. The seven found in human urinary calculi were separated into three groups in the hope that each might be
dissolved by a specific solvent. Uric acid and its sodium and ammonium salts made up the first
trio which revealed nothing new except that ammonium urate emerged as an important constituent of urinary stones. Fourcroy and Vauquelin confirmed Pearson's observation that sodium
method he used was derived from Lavoisier and included solubil- urate was the substance deposited into the joints of gouty patients. Three mineral salts. (1.) Calcium phosphate was also present in ity measurements in water at various temperatures, in alcohol, in various acids and caustic soda, combustion and distillation prop- concretions outside the urinary tract. (2.) Magnesium ammonium erties when exposed to a naked flame or in the presence of phosphate, often associated with calcium phosphate, already had carbon, precipitation with various compounds followed by mea- been observed by Wollaston [25]. Vauquelin and Fourcroy had suring the weight of the residues. The recent introduction of the recently reported [26] that in fresh normal urine only magnesium balance in analytical procedures had allowed great strides to be phosphate was present and that magnesium ammonium phosmade. Thus he established the basic composition of uric acid, that phate appeared later when the urine became ammoniacal and it was rich in carbon and nitrogen but poor in oxygen and fetid from the formation of ammonia from urea. Fourcroy conhydrogen. Moreover, he concluded that besides uric acid which is sidered that this observation was related to the formation of almost always present, urinary stones contain other substances, bladder stones in chronic urinary retention, "urine that remains either alone or linked to one another in various proportions such too long in the bladder becomes fetid and ammoniacal" [27]. as calcium phosphate and magnesium ammonium phosphate, and Fourcroy and Vauquelin were struck by the fact that in both that in man the composition of renal and bladder stones were groups phosphorus was only present as phosphate which was at variance with what they observed in living tissues, bone [28], similar [21]. His curiosity extended beyond these simple chemical descrip- pollen [29] and the soft roe of fish [30]. It was perhaps the first tions to a new approach which was to lead a new discipline. He indication that phosphorus in another chemical form had other had the novel idea to explore the connections between chemistry, physiological functions. (3.) Calcium oxalate was often the main physiology and medicine [22]. He posed the following questions: constituent of a stone. They failed to find calcium oxalate in
(1.) Is uric acid confined to humans? (2.) Does uric acid exist normal urine until they found that it precipitated out upon the outside the urine? (3.) How is uric acid formed? (4.) Is there more addition of a minimal amount of oxalic acid, an example of of it in the urine of a patient with urinary stones? (5.) What is its supersaturation which later would be studied by Gay Lussac [31]. relation to hippuric acid (then thought to be benzoic acid) in the Fourcroy and Vauquelin proposed that oxalic acid was normally urine of infants, particularly those who are prone to have urinary made somewhere within the wall of the urinary tract, and that stones? (6.) What are uric acid's relation to phosphoric acid, when it came into contact with urine it caused the formation of microscopic crystals of calcium oxalate. They also proposed as calcium phosphate and ammonium phosphate? In this way Fourcroy demonstrated that clinical medicine is these were so small most were excreted unless they became the more than a case history and some physical signs, and that nucleus of a calculus upon which other urinary salts were then sometimes a precise diagnosis can be revealed by chemical deposited. And so it turned out, a small deposit of calcium oxalate investigation. In this way the chemistry of urinary stones opened is now known to be often the center of a calculus. up a new era in medicine controlled by scientific principles. Animal matter which was sometimes referred to as gelatin was the only constituent of the third group. It could be destroyed by Fourcroy became its leading exponent.
880
Richet: Early chemisoy of urina,y calculi
came from the large amounts contained in cereals [42]. This led gen. Fourcroy thought that this substance could be either the them to comment that their interest into the chemistry of urine nucleus of a stone or the cement which held it together. was due to its being the natural source of the stones it contains heat, it contained nitrogen as well as carbon, oxygen and hydro-
Fourcroy's extensive chemical inventory permitted him to state that roughly 25% of the stones he had analyzed were made of uric acid, that another 25% were made of calcium oxalate, either pure
or almost so, while the rest were mixed stones, uric acid and
[43].
Fourcroy and Vauquelin
Fourcroy (Fig. 5) was the son of a modest pharmacist who had established a business in the heart of the Latin Quarter in Paris. During his medical studies, which were beset by financial probThe chemical composition of a stone determines its shape lems, Fourcroy became so intensely interested in chemistry that Pearson and Fourcroy each remarked that the appearance of he joined Lavoisier's laboratory. Fourcroy's lucid exposition of the external and cut surface of a stone are linked to its chemical contemporary chemical theories singled him out. He became composition, and that the visual variations of a mixed stone are involved in all the ways that chemistry might illuminate medicine. each due to a corresponding chemical which can often be identi- In 1776, under the aegis of F. Vicq d'Azyr, he created the fied by the naked eye (Fig. 4). They pointed out that the central chemical section of the Société Royale de Médecine which was nucleus of a stone may contain either animal matter, a crystal of given the task, among others, to determine the chemical compouric or oxalic acid or a foreign body upon the periphery of which sition of all new medicines. His main research interest was the deposits are laid. Stones, the cut surface of which has a concentric chemistry of animal substances, particularly urine and its stones. pattern, an onion-like appearance, have Iamellae either closely or Fourcroy had a talent for spotting the connection between his loosely held together. It was the differences between the chemicals experimental results and their physiological and pathological forming the successive layers which frustrated therapeutic at- relevance, and also of their application to hospital management tempts to dissolve these stones by the administration of oral or and basic teaching. He became involved in the various means intravesical substances which alter the acidity of the urine [33, 34], whereby chemistry could illuminate medicine.This orientation is The only stones which respond to such a treatment are those well expressed by the title of his review, Médecine Eclairée par les calcium oxalate or phosphate with or without magnesium ammonium phosphate [32].
entirely made of uric acid. Other deposits might occupy part of the
Sciences Physiques [44], which with Philosophie Chimique [45] and
stone leaving the surface smooth or rough depending on the Système des Connaissances Chimiques [46] demonstrate his wish to
introduce chemistry into medicine. In Dc Urina Homer W. Smith speaks highly of Fourcroy's introduction of chemistry into physiSpecies, diet and organ specificity of stones ology [47]. Complete accounts of his life and work are by Kersaint Species specificity. Pearson had noted that man is the only [48] and Smeaton [49, 50]. Fourcroy was also a politician and an executive. During the mammal to form uric acid stones and to excrete this metabolite. Vauquelin [35] confirmed that even the urine of large carnivores Convention, the Directory, the Consulate and the Empire he such as lions and tigers do not contain uric acid. On the other organized a new national teaching network, from primary school hand he found that it is present in large amounts in the urine of to higher education. As a deputy at the Convention at the end of birds [36], even the ostrich which is reputed to be a strict 1794 he re-established the legal necessity to hold a diploma in herbivore [37]. He was thus able to state that a sample of guano order to practice medicine and created three "Ecoles de Sante". collected by A.v.Humbolt in South America was of avian origin This law merged the teaching of physicians and surgeons and surface deposit.
[38].
imposed a basic culture of science, theory and experiment. It
cat, pig and rat, however, he found that the stones are made of calcium and magnesium phosphates and sometimes of oxalates,
was born in Normandy where he became an assistant in a
Diet influenced the type of stone which appear in the bladder of underlined the need for anatomical dissection and for an active animals. Thus Fourcroy showed that in the horse, cow and rabbit participation in hospital care and outpatient clinics which also led they were made of carbonates which is in plentiful supply in their to an increase of intellectual activity, etc. . . . There is only one urine, in contrast to the small amount of phosphate. In the dog, shadow: did Fourcroy do all he could to save Lavoisier's life?
salts which are present in large amounts in their urine. In comparing herbivores to carnivores, Fourcroy had shown that an exogenous factor, the usual diet, could influence the pathological chemistry
Organ specificity clearly appears in biliary concretions giving
further evidence that stones are related to the liquid which surrounds them. Fourcroy noted that these calculi contained
Vauquelin (Fig. 6) also came from a modest background. He pharmacy and developed a passion for chemistry. When he came to Paris he joined a pharmacist who organized his entry, at the age of 21, into his cousin Fourcroy's laboratory. The collaboration of these two gifted chemists lasted until Fourcroy's death in 1809. Vauquelin's attention was focused exclusively on his laboratory bench. He was never deflected from his experiments by extraneous intellectual fireworks. His mastery of chemistry, however, was
"adipocer" with crystalization and solubility characteristics of superior to his ability as a teacher. Apart from his studies on cholesterol which is also present in the bile and the liver [41]. He also observed that in the center of the "bezoars," which are found in the intestinal tracts of certain animals, there is a foreign body covered with calcium or magnesium phosphate and almost always
urine, urea and stones, he isolated chromium and berilium sulphate, he was renowned for the purity of the reagents he
prepared and he was head of the Faculté de Pharmacie de Paris until he died. From 1809 his research efforts were mostly oriented magnesium ammonium phosphate, all of which are present in on animal and vegetable substances, a choice which explains the large amounts in the digestive tract. Struck by the importance of role he and his pupils played in the chemical elucidation of the magnesium, Fourcroy and Vauquelin searched and found that it alkaloids and other plant drugs such as nicotine, asparagine and
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a-, Fig. 4. Macroscopic aspect of the surfaces and cross sections of various types of urinaty calculi. Engraved plate from Fourcroy [241. 1 a, b, c. Uric acid. 2
a, b. Ammonium urate. 3. Sodium urate. 4 a, b. Calcium phosphate (neutral). 5. Calcium Phosphate (acid). 6 a, b. Ammonium magnesium phosphate. 7 a, b, c. Calcium oxalate. 8. Calcium carbonate. 9 a, b. Adipocer (ancient word for cholesterol).
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Fig. 5. Antoine Francois Fourcroy (Courtesy of the Bibliotheque de l'Académie de Médecine, 75006, Paris).
Fig. 6. Nicolas Louis Vauquelin (Courtesy of Bibliotheque de l'Académie de Médecine, 75006, Paris).
quinine [51]. In 1822, he and ten of his colleagues were fired from ammonia to fresh urine or to a solution of phosphoric acid and magnesium [541. He had found that, in contrast to magnesium the medical school for political reasons.
ammonium phosphate, the isolated two salts, ammonium phosphate and magnesium phosphate, could not be melted down. He demonstrated that mulberry calculi are composed of an organic William Hyde Wollaston acid, oxalic which is destroyed by combustion leaving a small Wollaston (1766—1826), a contemporary of Fourcroy and Vau- calcium deposit. Wollaston suspected [55] that oxalic acid came quelin, was one of those who helped to disentangle the origin of from the vegetable content of the diet. Stones that consisted of urinary stones 1521. In June 1797, at the Royal Society, he pure, or almost pure, calcium phosphate which appeared to be the described the chemical composition of most forms of urinary same as in bone, he named bone earth calculi. He identified the calculi. Until then in England Scheele's lithic acid had made little same substance to be present in sites of tissue calcification such as impression, and calculi were considered to be a sort of "chalk." To is found in arteries [56]. To these five chemical groups Wollaston in 1812 added a cystine illuminate the etiological origin of urinary stones Wollaston also used precise chemical techniques. He isolated five constituents: oxide stone [57]. He had observed that this was a nitrogenScheele's lithic acid to which he added, after much detailed containing organic substance that was macro- and microscopically analysis, the presence of sodium lithate, gouly matter is lithiated and chemically different from uric acid. It was the first amino acid soda [53]; afssible calculus which melted in the heat of a blow pipe to be identified. The familial occurrence of cystine stones was releasing a volatile alkali (ammonia). He did not consider that it observed soon after by Alexandre Marcet (1770—1822) [58]. Wollaston's family had been members of the Royal Society for was lithic acid, for after combustion an important white crystaline deposit remained. Wollaston, who was an expert crystalographer, 100 years occupying various official positions [59]. Wollaston's identified the crystals in the deposit to be of magnesium and father was a clergyman and an enthusiastic astronomer, one uncle ammonium phosphate, for he could reproduce them by adding was physician to the royal family and another was Heberden The English School: Wollaston, Marcet and Prout
883
Richet: Early chemist,y of urinaty calculi
instruments which were widely used in research projects in the
early part of the 19th century [61]. Were Fourcroy and Vauquelin aware of Wollaston's work?
This question was posed in 1817 by their contemporary A. Marcet [58]. If the original texts are compared there are some substantial discrepancies. The approaches were different, the existence of ammonium urate which was championed in Paris was denied in London, and the discrepancies to be observed between
stones from various passages and different animals were not studied with the same ardor on both sides of the channel. It has to be noted that Fourcroy had published the techniques he had used to study the chemistry of concretions in the bile canulae in 1789 [62] and of various stones of the bladder in 1793 [63]. In addition one must not forget that between 1795 and 1801 the two countries were at war, which had greatly reduced the normal exchange of ideas. It is quite possible, however, that this was not complete and
that Fourcroy had heard rumors of Wollaston's publication in 1797. The latter in return must have had some idea of what was going on in Paris before and at the beginning of the Revolution. Though some seepage of information may have occurred, there is
no evidence of plagiarism. On the other hand neither Fourcroy nor Wollaston clearly cited each other. It is to be hoped that this
was due more to a lack of awareness than to an inelegant antagonism which in science would have been out of place. Alexander Marcet Marcet, who was a friend of Wollaston, was a physician chemist
at Guy's Hospital interested in urinary stones. He organized a collection of stones from both England and the continent. His most important work is An Essay on the Chemical Histoty and Medical Treatment of Calculous Disorders published in 1817 [58]. Fig. 7. William Hyde Wollaston (Courtesy of Welcome Institute Libraty, London).
(1710—1801). Wollaston (Fig. 7) qualified as a doctor and chemist and went into practice for awhile before focusing his attention on theoretical and applied chemistry. In collaboration with Smithson
Tennant (1761—1815), they prepared platinum discovering osmium, iridium, palladium and rhodium on the way. One of the first to accept Dalton's atomic theory, Wollaston verified its truth by studying the structure of carbonates, suiphates and oxalates. He was devoted to crystalography and by using a goniometer (an angle measuring device) of his own design he was able to correct
Most of his calculi came from Norwich Hospital which had a
national reputation for "cutting for" the stone and for the excellence of its records. Marcet's original aim, to obtain a regional register of urinary stones, came to nothing. His account of the chemistry of stones, however, was thorough and he also gave an account of the effect of diet on the composition of the urine. This led him to try and dissolve urinary stones in vivo by
changing the acidity of the urine by dietary means. In his monograph which is clear and factual he juxtaposes the clinical
and chemical aspects of urinary calculi. His work deserves a
special place in the early history of applied medical chemistry. Marcet's clinical curiosity led him to discover the first xanthine stone. A compact, hard lamellar stone with a smooth red surface Hauy's theory, thus enabling Mitscherlich to launch his new had been sent to him. On analysis almost all of it disappeared at concept on the formation of crystals. He used total refraction to high temperature, and it was soluble in mineral acids as well as in measure the index of refraction. It is not surprising, therefore, that potash and ammonical solutions. Evaporation left a yellow residue he improved the optical system of the microscope and a camera which made him called it Xanthine. In the presence of caustic lucida. He was no longer practising medicine when he made a potash it turned red. Marcet did not recognize the metabolic serious error in suggesting that, because he could not detect sugar congenital and hereditary condition now known as Xanthinuria. Marcet (Fig. 8) was born in Geneva and traveled to England in in the blood, "diabetic glycosuria was due to the existence of some chemical conveyance from the stomach to the bladder without 1794. There are divergent views on why he did so. One was that he was expelled by the French revolutionary forces which occupied passing through the general system of blood vessels" [60]. Wollaston's life cannot be separated from that of Tennant who Geneva at that time. Another was that he left of his own free will also came from an ecclesiastical family. He was professor of to get away from a political climate he did not favor. His choice of chemistry at Cambridge University and a founding member of the Great Britain was a natural one in that there were strong Geological Society. In addition to their joint discovery of plati- intellectual bonds between Geneva and the Universities of Britnum, Wollaston and Tennant used it to design various scientific ain. The journal Bibliothèque Britannique published in 1795 by the
884
Richet: Early chemistiy of urinary calculi
proteins and was one of the first to adopt Dalton's atomic theory [67, 68].
The rise and the early fall of clinical chemistry The remarkable success of the early workers was dependent in large part on the fortunate capacity of the body to prepare such pure deposits of certain substances and in such amounts, in the form of calculi, that they were within the analytical grasp of the existing techniques. And the chemical identification of each of
these compounds enabled several diseases to be disentangled from a variety of interwoven clinical syndromes.
Most of the detailed chemistry of urinary stones was known
around 1810 to 1820. In Great Britain Marcet and Prout's handbooks had described how calculi could be analyzed. It was therefore theoretically possible for any medical practitioner to obtain some information which would help him treat urinary sand, gravel and stones. These publications, which were translated into French, were in line with P.H. Nysten's (1771—1818) Recherches de Physiologie et de Chimie Pathologiques published in 1811 169]. In
his preface Nysten declared that medical chemistry should be developed and recalled that Fourcroy himself had recommended that un hôpital clinico chimique should be built in Paris. "This is the way that medicine will advance," he announced, "particularly how we shall learn how to dissolve urinary calculi" (pp. X-XIII). He devoted forty pages to the chemistry of urine. He noted the
association of proteinuria and edema (pp. 259—265) and remarked that he had twice found urea in the profuse vomit of
patients just before death, but he made no mention of the
_1 Fig. 8. Alexander John Gaspard Marcet (Courtesy of Welcome Institute Library, London).
post-mortem result! It is a pity that for the next 100 years the literature on urinary
stones was more concerned with various clinical and surgical anecdotes than the study of their chemistry. Handbooks and treatises merely repeated the findings of Fourcroy, Wollaston, Marcet and Prout without commenting on their possible therapeutic implications. No attention was paid to the study of crystals in the urine which was being pionered by Rayer [70]. The general
apathy is apparent in Ferrus's article in the Dictionnaire de Pictet brothers in Geneva bears witness to this closeness. Marcet retired to Geneva and died in London when on a visit [64, 65]. William Prout In 1821 W. Prout (1785—1850) published An Enquiry into the
Médecine in 1823 [71] and in Chevallier's [72] and Ségalas's [73] books which were published in 1837 and 1839, respectively. In addition there were eight editions of the Elements de Chimie by Orfila which ran from 1817 to 1851 [74]. The only addition to the
first edition are the basic formula of cystine and xanthine. The Nature and Treatment of Grave4 Calculus and Other Diseases French translation from the English of Beagle's book which Connected with a Deranged Operation of the Urinary Organs [66, appeared in 1865 [75] was no better. The prejudice of clinicians 67]. His book resembles that of Marcet with whom he had worked. against chemistry, which they scorned in favor of structure, both Prout concentrated on the examination of the urinary sediment macro- and microscopical, was triumphant presumably because and proposed that the presence of sand, gravel and calculi were chemistry was new and initially difficult to grasp. variations of the same disease. He carefully documented the effect of a change in the acidity of the urine on the color of its sediment. And he applied Gay Lussac's observations on supersaturation to
Around 1820 a few individuals did try and change the status quo
on urinary stones by publishing therapeutic results and observations based on the chemical nature of the stones. J.J. Berzélius the formation of urinary calculi [31]. He made one surprising (1779—1848) published an article in 1822 [76] which stated that error of some magnitude when he united under one umbrella from a practical point of view the application of intense heat with urinary stones, proteinuria, diabetes and a raised excretion of a blow-pipe to a stone was usually sufficient to identify it's nature. urea, which he considered to occur quite frequently and to be a J.L. Prevost (1790—1850) and J.B. Dumas, who had revealed that bilateral nephrectomy was followed by a rise in blood urea, renal disturbance. Prout, who was a physician and chemist on the staff of Guy's claimed that in order to avoid a surgical operation it might be Hospital, became famous for an analysis of the elements con- possible to dissolve bladder calculi by electrolysis [77]. And there tained in urea, which was more precise than that worked out by was F. Magendie (1783—i 855) who, after analyzing the conditions Fourcroy and Vauquelin [41. He isolated hydrochloric acid from which were associated with the appearance of gravel, put forward gastric juice, divided foodstuffs into carbohydrates, fats and chemical arguments on how the urine should be alkalanized or
Richet: Early chemistry of urinary calculi
885
acidified, depending on the stone. He also underlined that the 18. FOURCROY AF: Examen chimique de Ia substance feuilletée et cristalline contenue dans les calculs biliaires et de ha nature des intake of protein should be reduced in order to lower the content of urinary solutes [781. In this respect it is interesting that between
concrétions cystiques cristahlisées. Ann Chimie 3:242—252, 1789 19. FOURCROY AF: Nouvelles experiences sur les matières animales faites dans le laboratoire du Lycée. Ann Chimie 7:146—193, 1790 20. FOURCROY AF: Analyse comparée des différentes espèces de concrétions animales et vegetales. Ann Chimie 16:63—108 and 113—167, 1793 21. Ibid. pp 93—94 22. Ibid. pp 165—166 23. FOURCROY AF: Avis aux médecins, aux chirurgiens et aux naturalistes
1940 and 1946 during World War II, urinary calculi practically disappeared from Paris hospitals. Despite the reputation of these scientists almost no one listened to them. An appreciative review of Magendie's book ended with the following disillusioned comment: "This work, which discusses the mode of action of some medicines according to their chemical de Ia Republique francaise et des pays étrangers. Ann Chimie 1798, properties, must displease men who appear to fear, above all else, 27:291—293 (at the end of ref. 13) the steady advance into medicine of the results of experiment" 24. FOURCROY AF: Mémoire sur Ic nombre, Ia nature et les caractères distinctifs des différents matériaux qui forment les calculs, les bézo[79]. This despondent note was not signed but the two editors of ards et les diverses concrétions des animawc. Ann Museum 1:93—113, the Annales de Chimie were F. Arago (1780-4853) and L.J. Gay 1802 Lussac (1778—1850), world renowned scientists. Sadly they were 25. Ref. 15, p 390 26. Ref. 3, p 59 27. Ref. 4, p 156
right.
Acknowledgments The author is deeply indepted to Professor Hugh de Wardener for his invaluable help in discussing and translating the manuscript and to his Secretary; to the Bibliothèque de l'Académie Nationale de Médecine
(75006, Paris) and the Bibliotheque Interuniversitaire de Médecine (75006, Paris) and their staffs, especially Mrs. Casseyre, Lenoir, Chapuis, Molitor and Mr. Rivet. Reprint requests to Gabriel Richet, 76 Rue d'Assas, 75006, Paris, France.
References 1. FOURCROY AF: Système des Connaissances Chimiques, Paris, 1800, X, p 206 (Translated into English by WILLIAM NICHOLSON under the title of General system of chemical knowledge, 11 Vol. London 1804)
2. PEARSON G: Experiments and observations, tending to show the composition and properties of urinary concretions. Phil Trans 1798, pp 15—46
3. FOURCROY AF, VAUQUELIN NL: Premier mémoire pour servir a l'histoire naturelle, chimique et médicale, de l'urine humaine. Ann Chimie 31:48—71, 1799
4. FOURCROY AF, VAUQUELIN NL: Second mémoire pour servir a
l'histoire naturelle, chimique et naturelle de l'urine humaine dans lequel on s'occupe spécialement des propriétés de Ia matière particuhere qui Ia caractérise. Ann Chimie 32:80—162, 1799 5. DUMAS JB: Lecons de Philosophic Chimique. Quoted by ROBERT MASSAIN, Chimie et Chimistes, edited by MAGNARD, Paris, 1982, pp 289—297
6. FOURCROY AF: Ref. 1, p 204 —205 7. HALES S: Haemastique. 1 Vol, translated into French by DE SAUVAGES,
Geneva, 1744, 160 et seq 8. Ibid. Foreword 9. VICQ D'AZYR F: Recherches et observations sur divers objets de médecine, de chirurgie et d'anatomie. Histoire de Ia Société Royale de Médecine 3:204—234, 1779 10. VICQ D'AZYR F: Suite des observations sur les concrétions animales. Histoire de Ia Société Royale de Médecine 4:279—286, 1780
11. Lvoisi AL: Oeuvres completes Tome III, p 146, quoted by POIRIER JP, in Lavoisier 1 vol, Paris, 1993, p 21 12. SOCIETE ROYALE DE MEDECINE: Paris Séance du 7 Mars 1786. Dossier
134 DR 28 Academic Nale Médecine Paris 13. FOURCROY AF: Examen des experiences et des observations nouvelles de Mr G. Pearson Ann Chimie 1798, vol 27, pp 225—293 14. FOURCROY AF: Recherches pour servir a l'histoire du gaz azote ou de
ha mofette, comme principe des matières animahes. Ann ('himie 1:40—46, 1789
15. WOLLASTON WH: On gouty and urinary concretions. Phil Trans ii:386—400, 1797
16. Ref. 2, p 17
17. GILLISPIE CCG: Pearson, edited by EL Scorr, in Dictionary of Scientific Biography, vol 10 pp 445— 447
28. FOURCROY, VAUQUELIN: Mémoire sur Ia presence d'un nouveau sd
phosphorique terreux dans les os des animaux et sur l'analyse de ces organes en general. Ann Chimie 47:244—261, 1803 29. FOURCROY AF: Recherches chimiques sur he Pollen ou Ia poussière fécondante du dattier d'Egypte. Phoenix Dactylifera Ann Museum 1:417—438, 1802 30. FOURCROY AF, VAUQUELIN N: Experiences chimiques pour servir a l'histoire de Ia laite (sic) des poissons Ann Museum 10:169—178, 1807 31. GAY-LUSSAC U: Dissohubilité des sels dans l'eau. Ann Chimie Physique 11:296—315, 1819
32. Ref. 1, p 235 & 245 33. Ref. 1, p 252
34. FOURCROY AF, VAUQUELIN N: Note et correspondance sur des envois de calculs aux citoyens Fourcroy et Vauquehin. Ann Chimie 30:54—65, 1799
35. VAUQUELIN N: Analyse de l'urine du lion et du tigre. Ann Museum 18:82—87, 1811
36. VAUQUELIN N: Experiences sur les excrements des poules, compares a Ia nourriture qu'elles prennent et réflexions sur ha formation de ha coquille d'oeuf. Ann Chimie 28:3—25, 1799 37. FOURCROY AF, VAUQUELIN N: Analyse de l'urine de l'autruche et experiences sur les urines de quelques autres familIes d' oiseaux. Ann Museum 17:310—319, 1811
38. FOURCROY AF, VAUQUELIN NL: Mémoire sur Ic guano ou sur l'engrais naturel des ilots de ha mer du sud, près des côtes du Pérou. Ann Chimie 56:258—268, 1805 39. FOURCROY AF: Observations sur hes calculs des animaux, compares a ceux de l'homme. Ann Museum 2:201—209, 1803 40. FOURCROY AF, VAUQUELIN NL: Mémoire sur ha nature chimique et ha classification des calculs ou concrétions qui naissent chez les animaux et que l'on connait sous he nom de Bézoards.Ann Museum 4:329—339, 1804
41. Ref. 18, p 245 et seq 42. Ref. 39, p 207 43. Ref. 3, p 63 44. LA MEDECINE ECLAIREE PAR LES SCIENCES PHYSIQUE: Paris, 1791,
entirely edited by Fourcroy himself. (It was the first post-graduate educational medical journal in existence. It survived only one year!) 45. FOURCROY AF: Philosophic Chimique. 1 vol. 3rd Edition 1806, Paris, (The introduction is a strong plea in favor of clinical chemistry)
46. Ref. 1 47. SMITH HW: Dc Urina. Kayser Foundation Medical Bulletin 6:1, 1958 48. KERSAINT G: Antoine Fran cois de Fourcroy, sa vie et son oeuvre. 1 vol, Paris, 1966, Museum Ed 49. GILLISPIE CC, FOURCROY A: in Dictionary of Scientific Biography, edited by WA SMEATON, vol. 5, pp 89—93 50. SMEATON WA: Fourcroy, Chemist and Revolutionary, I Vol., London, 1962 51. GILLISPIE CC, VAUQUELIN NL: Dictionary of Scientific Biography, edited by WA SMEATON, vol 14, pp 596—598
52. Ref. 15 53. Ibid., p 389 54. Ibid., p 390 55. Ibid., p 399
886
Richet: Early chemist,y of urinaty calculi
56. Ibid., p 398 57. WOLLASTON WH: On cystic Oxide, a new species of urinaly Calculus. Phil Trans ii:223—230, 1810 58. MARCET A: An essay on the chemical histoiy and medical treatment of calculous disorders. (1 Vol. 2nd ed) London, 1819 (French translation;
page 63 for the case opposing Wollaston and Fourcroy and their respective priorities) 59. GILLISPIE CC, WH WOLLASTON: in Dictionaty of Scientific Biography, edited by DC GOODMAN, vol 14, pp 486—494
60. WOLLASTON WH: On the non existence of Sugar in the blood of
67. GILLISPIE CC, PROUT W: in Dictionaiy of Scientific Biography, edited by WH BROCK, vol. 11, pp 172—174
68. BROCK WH: The life and work of William Prout. Medical Histo,y IX: 101—126, 1965
69. NYSTEN P H: Recherches de Physiologie et de Chimie Pathologiques. 1 vol, Paris, 1811 70. RAYER P: Traité des Maladies des Reins. Paris, 1839, Vol 1, pp 191—213 71. Dictionnaire de Medecine, Lithiase. Edited by FERRUS, Paris, 1823, pp 354 —364
61. GILLISPIE CC, TENNANT S: in Dictionaiy of Scientific Biography, edited by DC GOODMAN, vol 13, pp 280—281
72. CHEVALIER A: Essai Sur Ia Dissolution de la Gravelle et des Calculs de Ia Vessie. 1 vol, Paris, 1837 73. SEGALAS PS: Essai Sur Ia Gravelle et la Pierre. 1 vol, Paris, 1839 74. ORFILA P: Elements de Chimie. vol II, 8 editions from 1817 to 1851 75. BEAGLE LS: De l'Urine, des Depots Urinaires et des Calculs. French
62. Ref. 18 63. Ref. 20 64. HOEFER A: Marcet, in Nouvelle biographie génerale (vol)XXXIII,
translation, 1 Vo!, Paris, 1865, 540 pp 76. BERZELIUS JJ: Phénomènes développés par le traitement des calculs urinaires par le chalumeau. J Phar,nacie Paris 7:419—422, 1822
edited by F DIDOT, Paris, 1840, pp 464—465 65. COLEY NG: Alexander Marcet (17770—1822), physician and animal chemist. Medical Histoty XII:394—402, 1968 66. PROUT W: An Inqui,y into the Nature and Treatment of Gravel Calculus and Other Diseases Connected with a Deranged Operation of the Urinaiy Otgans. 1 vol, London, 1821, 227 pp
77. PREVOST JL, DUMAS JB: Note sur l'emploi de Ia pile dans le
persons labouring under diabetes mellitus, Phil Trans 101:96—109 (see p 102), 1811
traitement des calculs de Ia vessie. Ann Chimie Physique 23:202—208, 1823 78. MAGENDIE F: Recherches Physiologiques et Médicales sur les Causes, les Symptomes et le Traitement de Ia Gravelle. 1 vol, Paris, 1818, 91 pp 79. Editorial Note. Ann Chimie Physique 7:430—436, 1817
HISTORICAL ARCHIVE EDITED BY CARL GOTFSCHALK
The chemistry of urinary stones around 1800: A first in clinical chemistry GABRIEL RICHET de l'Académie Nationale de Médecine, Paris, France
The chemistry of urinary stones around 1800: A first in clinical chemistry. At the end of the 18th century, as soon as modern chemistry
was created, dedicated physicians tried to apply it to medicine. A rewarding field was that of urinary lithiasis. Stones offered a sufficient amount of a relatively pure chemical present in the body. Indeed, urine and the solidified matter was within the analytical grasp of the existing techniques. The first step was made by Scheele in Sweden who identified uric acid in calculi and normal human urine. During the following thirty years, Fourcroy and Vauquelin in Paris and Wollaston, Pearson, Marcet and Prout in London identified the various salts, uric acid, urate, various phosphates, oxalate, calcium, ammonium and magnesium forming current calculi. The conditions of their solubility in vitro were described. Even rare components such as cystine and xanthine were unraveled in London. The impetus given by these studies offered a good start to clinical chemistry in general and to the understanding of urinary lithiasis in particular. This led to the discovery of the corresponding solutes in the urine of such patients. Unfortunately, during the following decades nothing was added to these chemical investigations, and most of what had been acquired was forgotten. Research was concentrated on clinical pathology. The implementation of chemistry to medicine had to wait.
applications to medicine were soon explored. The demonstration by Priestley and Lavoisier that living organisms take up oxygen and reject carbonic acid is famous. Chemical analysis at the time required large amounts of material, but urine and urinary stones
fitted the technical requirements. The composition of urinary stones were successfully defined, and within four decades the possible clinical and therapeutical implications scientifically unraveled. The pioneers saw clearly the value of understanding the humoral complexity underliying these diseases. They strove to push the underlying direction of medicine towards the wider use of chemistry in solving clinical problems. Hence urinary calculi were the principal foundation stones of clinical chemistry.
Manifold attempts were made to characterize them, first in Sweden and then in England and France, all countries in which animal chemistry was blossoming out. Results chaotically heaped
up during these years and could not be checked in foreign
laboratories since borders were sealed during the French Revolution. Therefore, the results are grouped according to the places Modern chemistry emerged at the end of the eighteenth in which they were obtained. The leading thread of thought is thus century when solid matters were identified, which was soon better understood than if a chronological order had been adopted followed by the identification of gases. The invention by Stephen which would have disrupted the chain of the intellectual developHales (1677—1761) and Henri Cavendish (1731—1810) of tech- ments. The topic is presented as follows: the discovery of a stone niques to collect gases under water and mercury, respectively, made of uric acid; from Scheele to Pearson and Fourcroy; paved the way for major discoveries. Several pure gases, including Fourcroy and Vauquelin; the English School, Wollaston, Marcet, oxygen (Priestley, Scheele, Lavoisier), carbonic acid (Black), Prout; and the rise and early fall of clinical chemistry. hydrogen (Cavendish), and nitrogen (Priestley, Lavoisier) were identified. In addition the analysis and synthesis of water were Uric acid stone, the linchpin of urinary calculi successfully done. It was also shown that gases could be present in solid components from which they were cleared by heat, acids or In 1776 Karl Wilheim Scheele (1742—86) revealed that the main bases. More important perhaps were the concepts and the methods of Antoine Laurent Lavoisier (1743—94), the lawgiver in component of a bladder stone he had studied was a substance chemistry as he is known, who, applying techniques used in which was barely soluble in cold water, but sufficiently so to turn physics, pioneered quantitative chemistry. He discovered oxidiza- litmus paper red. The matter melted in alkali and formed a tion and thus disproved the phlogistic system of Georg Ernst Stahl precipitate in acid solution which dissolved in a hot nitric acid
leaving a residue which, after evaporation, turned a pinkish
(1660—1734).
Many, if not most, chemists were physicians or pharmacists and
crimson. Upon heating, and depending on the temperature, there arose a smell of prussic acid, ammonia or even something like smouldering horn. These were the properties that, according to
Fourcroy 1] and Pearson [2], Scheele had described at the Received for publication January 6, 1995 and in revised form April 10, 1995 Accepted for publication April 10, 1995
Academy of Sciences in Stockholm. Scheele named the substance lithic acid, subsequently it was named uric acid. This discovery was
© 1995 by the International Society of Nephrology
distinction.
confirmed by T.B. Bergman (1734—1794), a chemist of some
876
877
Richet: Early chemistiy of urinary calculi
KARL WILHELM SCHEELE 1742—1788 Fig. 1. Karl Wilhelm Scheele (Courtesy of the Faculté de Pharmacie, 75006, Paris).
Scheele's work contained an observation of outstanding importance and one substantial weakness. His very important contribu-
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tion was to establish that uric acid is a normal constituent of Fig. 2. Stephen Hales (Courtesy of the Welcome Institute Libray, London). human urine, and that when it is cold it gives rise to a brick red sediment. Thus uric acid became the first metabolite to be identified in human urine, twenty years before Antoine F. inspired [5]. On his travels abroad the King so often heard Fourcroy (1755—1809) and Nicolas L. Vauquelin (1763—1829) isolated urea in 1799 [3, 4]. Scheele's weakness stemmed from his
Scheele's name mentioned that he indicated that Sheele should be
present in urine.
unrecognized in his country; Joseph Priestley (1733—1804), com-
awarded the title of Chevalier. Unfortunately another Scheele conclusion that because most stones contained uric acid they received the award as the chemist was unknown to the relevant contained only uric acid. He thus missed the contribution of officials. According to Dumas the three founders of modern calcium and phosphorus which he himself had confirmed was chemistry all suffered a sad fate: Scheele remained poor and Scheele's harsh life
Scheele (Fig. 1) was born in Swedish Pomerania. His parents were not well off, so that at the age of 13 he became an apprentice
pharmacist where he taught himself chemistry. One of his first
promised by his revolutionary sympathies (the Convention had made him a French citizen), became an exile in the United States; and A.L. Lavoisier had his head cut off by the same Convention. Scheele 's predecessors
Before Scheele, work on urinary stones was more alchemy than discoveries, fluosilicilic acid, was ignored by the Academy. Scheele then left Stockholm for Uppsala where Bergman was working. science. Fourcroy [6] noted three exceptions. The oldest had been One of Bergman's experiments was unsuccessful which he blamed made by the Reverend Stephen Hales (Fig. 2) whose main claims on the saltpeter which had been supplied by Scheele's pharmacy. to fame were that he had measured the arterial pressure of two
Unconvinced by this accusation Scheele worked out that Bergman's results were based on an experimental error. This won Bergman's respect and his continuing support thereafter. Scheele's place in the history of chemistry is engraved by his identification of fifteen novel substances and the properties of many others. Scheele was the ideal experimental chemist. J.B.
Dumas (1800—84) remarked that, in spite of being poorly equipped, and holding some simplistic theories, his work was
dogs and a couple of horses early in the century and the respiration of plants. When attempting to dissolve bladder calculi
he first wanted to know their chemical nature. He therefore measured the volume of gas which was released when they were exposed to heat or various acids. He concluded from the amount of gas released and the "earth-like" residue that they contained "chalk" [7]. Then, with faultless logic, he injected weak acids into
the bladder of animals into which he had previously placed a
878
Richet: Early chemistry of urinaty calculi
human calculus. B. de Sauvages from Montpellier, who was one of his translators, wrote of Hales, "The human spirit without experimental evidence, relying on theory alone, is unable to discover a single phenomenon" [8]. The second of Scheele's predecessors to be mentioned by Fourcroy was Lorenz Bellini (1643—1704) in Pisa, who studied the role of water in the formation of stones. He had
found that urinary residues obtained by evaporation could be redissolved in water. He therefore suggested that urinary stones could be dispersed by increasing the flow of urine. A pharmacistphysician-chemist, A.S. Marggraf (1709—82) was the third prede-
cessor already known for his method of extracting phosphorus from urine, which was much simpler than that of Brand, a 17th century alchemist. At the Berlin Academy in 1775 he described a stone that consisted of calcium salts, principally those of phosphorus. Pearson [2] said it was confirmed in 1788 by Link from Gottingen. From Scheele to Pearson and Fourcroy At the time, Scheele's discovery of lithic acid made little impact, though urinary stones were very common. Subsequently further work was either nosological or anatomical. Felix Vicq D'Azyr (1748—94) in 1780 discussed all the animal concretions he had come across without discussing their possible chemical composition [9, 10]. He suspected that uric acid urinary stones were due to hyperconcentration of the urine, as in man urine always contains
uric acid regardless of the presence of calculi. In a somewhat analogous but reciprocal manner, Lavoisier, on his return in 1767
from a geological expedition with his teacher J.E. Guettard (1715—86), had pointed out that the composition of geological
13! GEORGE
PEARSCN.
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stratas could be discerned by analyzing the water which had - 4 traversed through them: what better guide can there be for a mineralogist than to study the water [11]? At that time the chemical explanation of geology had begun, and Rouelle at the Fig. 3. George Pearson (Courtesy of the Bibliotheque de l'Académie de Jardin du Roi in Paris (Jardin des Plantes or Museum) taught Médecine, 75006, Paris; Cliché Charmet). both disciplines. A little later Fourcroy studied the relationship of bone disease to urinary stones, in particular the frequency of "earthy" stones
range of concentrations from 1 part per 200 to 199 parts per 200,
(calcium salts) in ricketts. He suspected that there was an the majority containing 80 to 140 parts per 200, The other underlying abnormality of phosphoric acid metabolism. In order to stimulate research he put this idea forward as the subject of an open competition at the Société Royale de Médecine in 1786 [12]. The winner was a surgeon who mentioned the age of 1463 patients with vesical calculi on whom he had operated. Nine hundred and
constituents were salts of calcium or ammonia, particularly phosphates, and in addition there was some animal matter, for upon
being heated to a high temperature ammonia was released,
demonstrating the presence of nitrogen. That all living substances contain nitrogen had recently been shown by Berthollet in 1781 fifty were less than 10 years old and they were nearly all boys. Two (animals) and Fourcroy in 1789 (plants) [141. Pearson rounded off other competitors subscribed to the generaly held opinion that the his paper with the results of a chemical analysis of calculi whether composition of urinary stones and bones were almost the same, if or not they were urinary, from different animals, stating that not identical, but they did not appear to have worked on the except in man they never contained uric acid. Finally he claimed subject themselves. So far clinical chemistry had not emerged that articular deposits of sodium urate do not occur outside the On the 14th December 1795 George Pearson (1751—I 828) (Fig. human species [2 (p. 39)]. 3), who was both doctor and chemist, gave a paper to the Royal In England Pearson's work was ignored, for six months earlier Society in London [2] on 300 urinary stones obtained from a Mr. William H. Wollaston (1766—1826), a physician and wide ranging Heaviside's collection of 800 such specimens. Pearson had come chemist, had spoken on the same subject at the same place. to two conclusions. One was chemical. Lithic acid does not exist, Except for his erroneous deduction about uric acid, most of it is an oxide. The next year Fourcroy, stung by this denial, Pearson's findings merely confirmed and extended those of Wolrepeated each of Pearson's experiments and demonstrated that laston. his assertion was untenable and that on the contrary Scheele was Pearson greatly admired Lavoisier, "the immortal and ever to right [13]. Pearson had also suggested that the term lithic should be deplored Lavoisier" [15], and in 1787 had published a Transbe changed to uric. Pearson's second conclusion was a valuable lation of the Table of Chemical Nomenclature in order to popularclinical chemical correlation. He had found that almost all calculi ize modern chemistry in England. Pearson also studied the contained some uric acid (194 out of 200 stones), but over a wide dissociation of water and a technique whereby carbon could be
Richet: Early chemistty of urina,y calculi
obtained from chalk. In medicine he studied the role of the carbon deposits found in "the black spots of the lungs." His enthusiasm
879
The accumulation of a vast database
In order to have a sufficient amount of useful pathological
for vaccination led him to set up a special center, but its material Fourcroy organized colleagues to send him urinary imperfections brought the procedure into such disrepute that he crossed swords with E. Jenner (1749—1823) [17].
Fourcroy's and Vauquelin's views on urinary stones The early years: The introduction of chemistiy into medicine
Fourcroy was a chemist and physician who now would be accused of being a workaholic. Because of his extensive knowl-
edge of medicine he had a clear understanding of the various clinical implications which might stem from an experimental finding. In 1801 he published an eleven volume text on Système des
Connaissances Chimiques [1], which included a 190 page index. The two volumes on the organic composition of vegetables and animals bear witness to a mind attuned to physiology and patho-
stones together with some relevant environmental and clinical information, such as what was the geological configuration of the region where the stone originated, and whether the patient's urine
was usually acid or alkaline [23]. He received more than 700 calculi of which 600 were bladder stones. A unique collection, its abundance matched the wealth of notes that accompanied each stone. Before, most chemicaly analyzed specimens had come from museums and those who had analyzed them had been foolhardy enough to use them without knowning whether they came from men or animals, or from the urinary or intestinal tract. Fourcroy's inquiry was probably the first efficiently carried out multi-center investigation in medicine. The chemical composition of bladder stones
In 1802 Fourcroy published an overview of the results he and physiology. The chapters on urine (110 pages) and calculi (67 Vauquelin had obtained, though surprisingly, Vauquelin's name is pages) give a precise account both of old and new findings and of his own work, together with his views on biology which were often prophetic. Fourcroy had the necessary medical background for this type of research. In 1789 he had published his results on the chemistry of biliary stones [18] and in 1793 a contribution to the Concrétions des Dijférentes EspècesAnimales et Végétales [19, 20], reporting the
results of observations on bladder calculi begun in 1787. The
not included as an author [24]. They had identified twelve constituents. The seven found in human urinary calculi were separated into three groups in the hope that each might be
dissolved by a specific solvent. Uric acid and its sodium and ammonium salts made up the first
trio which revealed nothing new except that ammonium urate emerged as an important constituent of urinary stones. Fourcroy and Vauquelin confirmed Pearson's observation that sodium
method he used was derived from Lavoisier and included solubil- urate was the substance deposited into the joints of gouty patients. Three mineral salts. (1.) Calcium phosphate was also present in ity measurements in water at various temperatures, in alcohol, in various acids and caustic soda, combustion and distillation prop- concretions outside the urinary tract. (2.) Magnesium ammonium erties when exposed to a naked flame or in the presence of phosphate, often associated with calcium phosphate, already had carbon, precipitation with various compounds followed by mea- been observed by Wollaston [25]. Vauquelin and Fourcroy had suring the weight of the residues. The recent introduction of the recently reported [26] that in fresh normal urine only magnesium balance in analytical procedures had allowed great strides to be phosphate was present and that magnesium ammonium phosmade. Thus he established the basic composition of uric acid, that phate appeared later when the urine became ammoniacal and it was rich in carbon and nitrogen but poor in oxygen and fetid from the formation of ammonia from urea. Fourcroy conhydrogen. Moreover, he concluded that besides uric acid which is sidered that this observation was related to the formation of almost always present, urinary stones contain other substances, bladder stones in chronic urinary retention, "urine that remains either alone or linked to one another in various proportions such too long in the bladder becomes fetid and ammoniacal" [27]. as calcium phosphate and magnesium ammonium phosphate, and Fourcroy and Vauquelin were struck by the fact that in both that in man the composition of renal and bladder stones were groups phosphorus was only present as phosphate which was at variance with what they observed in living tissues, bone [28], similar [21]. His curiosity extended beyond these simple chemical descrip- pollen [29] and the soft roe of fish [30]. It was perhaps the first tions to a new approach which was to lead a new discipline. He indication that phosphorus in another chemical form had other had the novel idea to explore the connections between chemistry, physiological functions. (3.) Calcium oxalate was often the main physiology and medicine [22]. He posed the following questions: constituent of a stone. They failed to find calcium oxalate in
(1.) Is uric acid confined to humans? (2.) Does uric acid exist normal urine until they found that it precipitated out upon the outside the urine? (3.) How is uric acid formed? (4.) Is there more addition of a minimal amount of oxalic acid, an example of of it in the urine of a patient with urinary stones? (5.) What is its supersaturation which later would be studied by Gay Lussac [31]. relation to hippuric acid (then thought to be benzoic acid) in the Fourcroy and Vauquelin proposed that oxalic acid was normally urine of infants, particularly those who are prone to have urinary made somewhere within the wall of the urinary tract, and that stones? (6.) What are uric acid's relation to phosphoric acid, when it came into contact with urine it caused the formation of microscopic crystals of calcium oxalate. They also proposed as calcium phosphate and ammonium phosphate? In this way Fourcroy demonstrated that clinical medicine is these were so small most were excreted unless they became the more than a case history and some physical signs, and that nucleus of a calculus upon which other urinary salts were then sometimes a precise diagnosis can be revealed by chemical deposited. And so it turned out, a small deposit of calcium oxalate investigation. In this way the chemistry of urinary stones opened is now known to be often the center of a calculus. up a new era in medicine controlled by scientific principles. Animal matter which was sometimes referred to as gelatin was the only constituent of the third group. It could be destroyed by Fourcroy became its leading exponent.
880
Richet: Early chemisoy of urina,y calculi
came from the large amounts contained in cereals [42]. This led gen. Fourcroy thought that this substance could be either the them to comment that their interest into the chemistry of urine nucleus of a stone or the cement which held it together. was due to its being the natural source of the stones it contains heat, it contained nitrogen as well as carbon, oxygen and hydro-
Fourcroy's extensive chemical inventory permitted him to state that roughly 25% of the stones he had analyzed were made of uric acid, that another 25% were made of calcium oxalate, either pure
or almost so, while the rest were mixed stones, uric acid and
[43].
Fourcroy and Vauquelin
Fourcroy (Fig. 5) was the son of a modest pharmacist who had established a business in the heart of the Latin Quarter in Paris. During his medical studies, which were beset by financial probThe chemical composition of a stone determines its shape lems, Fourcroy became so intensely interested in chemistry that Pearson and Fourcroy each remarked that the appearance of he joined Lavoisier's laboratory. Fourcroy's lucid exposition of the external and cut surface of a stone are linked to its chemical contemporary chemical theories singled him out. He became composition, and that the visual variations of a mixed stone are involved in all the ways that chemistry might illuminate medicine. each due to a corresponding chemical which can often be identi- In 1776, under the aegis of F. Vicq d'Azyr, he created the fied by the naked eye (Fig. 4). They pointed out that the central chemical section of the Société Royale de Médecine which was nucleus of a stone may contain either animal matter, a crystal of given the task, among others, to determine the chemical compouric or oxalic acid or a foreign body upon the periphery of which sition of all new medicines. His main research interest was the deposits are laid. Stones, the cut surface of which has a concentric chemistry of animal substances, particularly urine and its stones. pattern, an onion-like appearance, have Iamellae either closely or Fourcroy had a talent for spotting the connection between his loosely held together. It was the differences between the chemicals experimental results and their physiological and pathological forming the successive layers which frustrated therapeutic at- relevance, and also of their application to hospital management tempts to dissolve these stones by the administration of oral or and basic teaching. He became involved in the various means intravesical substances which alter the acidity of the urine [33, 34], whereby chemistry could illuminate medicine.This orientation is The only stones which respond to such a treatment are those well expressed by the title of his review, Médecine Eclairée par les calcium oxalate or phosphate with or without magnesium ammonium phosphate [32].
entirely made of uric acid. Other deposits might occupy part of the
Sciences Physiques [44], which with Philosophie Chimique [45] and
stone leaving the surface smooth or rough depending on the Système des Connaissances Chimiques [46] demonstrate his wish to
introduce chemistry into medicine. In Dc Urina Homer W. Smith speaks highly of Fourcroy's introduction of chemistry into physiSpecies, diet and organ specificity of stones ology [47]. Complete accounts of his life and work are by Kersaint Species specificity. Pearson had noted that man is the only [48] and Smeaton [49, 50]. Fourcroy was also a politician and an executive. During the mammal to form uric acid stones and to excrete this metabolite. Vauquelin [35] confirmed that even the urine of large carnivores Convention, the Directory, the Consulate and the Empire he such as lions and tigers do not contain uric acid. On the other organized a new national teaching network, from primary school hand he found that it is present in large amounts in the urine of to higher education. As a deputy at the Convention at the end of birds [36], even the ostrich which is reputed to be a strict 1794 he re-established the legal necessity to hold a diploma in herbivore [37]. He was thus able to state that a sample of guano order to practice medicine and created three "Ecoles de Sante". collected by A.v.Humbolt in South America was of avian origin This law merged the teaching of physicians and surgeons and surface deposit.
[38].
imposed a basic culture of science, theory and experiment. It
cat, pig and rat, however, he found that the stones are made of calcium and magnesium phosphates and sometimes of oxalates,
was born in Normandy where he became an assistant in a
Diet influenced the type of stone which appear in the bladder of underlined the need for anatomical dissection and for an active animals. Thus Fourcroy showed that in the horse, cow and rabbit participation in hospital care and outpatient clinics which also led they were made of carbonates which is in plentiful supply in their to an increase of intellectual activity, etc. . . . There is only one urine, in contrast to the small amount of phosphate. In the dog, shadow: did Fourcroy do all he could to save Lavoisier's life?
salts which are present in large amounts in their urine. In comparing herbivores to carnivores, Fourcroy had shown that an exogenous factor, the usual diet, could influence the pathological chemistry
Organ specificity clearly appears in biliary concretions giving
further evidence that stones are related to the liquid which surrounds them. Fourcroy noted that these calculi contained
Vauquelin (Fig. 6) also came from a modest background. He pharmacy and developed a passion for chemistry. When he came to Paris he joined a pharmacist who organized his entry, at the age of 21, into his cousin Fourcroy's laboratory. The collaboration of these two gifted chemists lasted until Fourcroy's death in 1809. Vauquelin's attention was focused exclusively on his laboratory bench. He was never deflected from his experiments by extraneous intellectual fireworks. His mastery of chemistry, however, was
"adipocer" with crystalization and solubility characteristics of superior to his ability as a teacher. Apart from his studies on cholesterol which is also present in the bile and the liver [41]. He also observed that in the center of the "bezoars," which are found in the intestinal tracts of certain animals, there is a foreign body covered with calcium or magnesium phosphate and almost always
urine, urea and stones, he isolated chromium and berilium sulphate, he was renowned for the purity of the reagents he
prepared and he was head of the Faculté de Pharmacie de Paris until he died. From 1809 his research efforts were mostly oriented magnesium ammonium phosphate, all of which are present in on animal and vegetable substances, a choice which explains the large amounts in the digestive tract. Struck by the importance of role he and his pupils played in the chemical elucidation of the magnesium, Fourcroy and Vauquelin searched and found that it alkaloids and other plant drugs such as nicotine, asparagine and
881
Richet: Early chemistiy of urinary calculi .4
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a-, Fig. 4. Macroscopic aspect of the surfaces and cross sections of various types of urinaty calculi. Engraved plate from Fourcroy [241. 1 a, b, c. Uric acid. 2
a, b. Ammonium urate. 3. Sodium urate. 4 a, b. Calcium phosphate (neutral). 5. Calcium Phosphate (acid). 6 a, b. Ammonium magnesium phosphate. 7 a, b, c. Calcium oxalate. 8. Calcium carbonate. 9 a, b. Adipocer (ancient word for cholesterol).
882
Richet: Early chemistry of urinary calculi
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Fig. 5. Antoine Francois Fourcroy (Courtesy of the Bibliotheque de l'Académie de Médecine, 75006, Paris).
Fig. 6. Nicolas Louis Vauquelin (Courtesy of Bibliotheque de l'Académie de Médecine, 75006, Paris).
quinine [51]. In 1822, he and ten of his colleagues were fired from ammonia to fresh urine or to a solution of phosphoric acid and magnesium [541. He had found that, in contrast to magnesium the medical school for political reasons.
ammonium phosphate, the isolated two salts, ammonium phosphate and magnesium phosphate, could not be melted down. He demonstrated that mulberry calculi are composed of an organic William Hyde Wollaston acid, oxalic which is destroyed by combustion leaving a small Wollaston (1766—1826), a contemporary of Fourcroy and Vau- calcium deposit. Wollaston suspected [55] that oxalic acid came quelin, was one of those who helped to disentangle the origin of from the vegetable content of the diet. Stones that consisted of urinary stones 1521. In June 1797, at the Royal Society, he pure, or almost pure, calcium phosphate which appeared to be the described the chemical composition of most forms of urinary same as in bone, he named bone earth calculi. He identified the calculi. Until then in England Scheele's lithic acid had made little same substance to be present in sites of tissue calcification such as impression, and calculi were considered to be a sort of "chalk." To is found in arteries [56]. To these five chemical groups Wollaston in 1812 added a cystine illuminate the etiological origin of urinary stones Wollaston also used precise chemical techniques. He isolated five constituents: oxide stone [57]. He had observed that this was a nitrogenScheele's lithic acid to which he added, after much detailed containing organic substance that was macro- and microscopically analysis, the presence of sodium lithate, gouly matter is lithiated and chemically different from uric acid. It was the first amino acid soda [53]; afssible calculus which melted in the heat of a blow pipe to be identified. The familial occurrence of cystine stones was releasing a volatile alkali (ammonia). He did not consider that it observed soon after by Alexandre Marcet (1770—1822) [58]. Wollaston's family had been members of the Royal Society for was lithic acid, for after combustion an important white crystaline deposit remained. Wollaston, who was an expert crystalographer, 100 years occupying various official positions [59]. Wollaston's identified the crystals in the deposit to be of magnesium and father was a clergyman and an enthusiastic astronomer, one uncle ammonium phosphate, for he could reproduce them by adding was physician to the royal family and another was Heberden The English School: Wollaston, Marcet and Prout
883
Richet: Early chemist,y of urinaty calculi
instruments which were widely used in research projects in the
early part of the 19th century [61]. Were Fourcroy and Vauquelin aware of Wollaston's work?
This question was posed in 1817 by their contemporary A. Marcet [58]. If the original texts are compared there are some substantial discrepancies. The approaches were different, the existence of ammonium urate which was championed in Paris was denied in London, and the discrepancies to be observed between
stones from various passages and different animals were not studied with the same ardor on both sides of the channel. It has to be noted that Fourcroy had published the techniques he had used to study the chemistry of concretions in the bile canulae in 1789 [62] and of various stones of the bladder in 1793 [63]. In addition one must not forget that between 1795 and 1801 the two countries were at war, which had greatly reduced the normal exchange of ideas. It is quite possible, however, that this was not complete and
that Fourcroy had heard rumors of Wollaston's publication in 1797. The latter in return must have had some idea of what was going on in Paris before and at the beginning of the Revolution. Though some seepage of information may have occurred, there is
no evidence of plagiarism. On the other hand neither Fourcroy nor Wollaston clearly cited each other. It is to be hoped that this
was due more to a lack of awareness than to an inelegant antagonism which in science would have been out of place. Alexander Marcet Marcet, who was a friend of Wollaston, was a physician chemist
at Guy's Hospital interested in urinary stones. He organized a collection of stones from both England and the continent. His most important work is An Essay on the Chemical Histoty and Medical Treatment of Calculous Disorders published in 1817 [58]. Fig. 7. William Hyde Wollaston (Courtesy of Welcome Institute Libraty, London).
(1710—1801). Wollaston (Fig. 7) qualified as a doctor and chemist and went into practice for awhile before focusing his attention on theoretical and applied chemistry. In collaboration with Smithson
Tennant (1761—1815), they prepared platinum discovering osmium, iridium, palladium and rhodium on the way. One of the first to accept Dalton's atomic theory, Wollaston verified its truth by studying the structure of carbonates, suiphates and oxalates. He was devoted to crystalography and by using a goniometer (an angle measuring device) of his own design he was able to correct
Most of his calculi came from Norwich Hospital which had a
national reputation for "cutting for" the stone and for the excellence of its records. Marcet's original aim, to obtain a regional register of urinary stones, came to nothing. His account of the chemistry of stones, however, was thorough and he also gave an account of the effect of diet on the composition of the urine. This led him to try and dissolve urinary stones in vivo by
changing the acidity of the urine by dietary means. In his monograph which is clear and factual he juxtaposes the clinical
and chemical aspects of urinary calculi. His work deserves a
special place in the early history of applied medical chemistry. Marcet's clinical curiosity led him to discover the first xanthine stone. A compact, hard lamellar stone with a smooth red surface Hauy's theory, thus enabling Mitscherlich to launch his new had been sent to him. On analysis almost all of it disappeared at concept on the formation of crystals. He used total refraction to high temperature, and it was soluble in mineral acids as well as in measure the index of refraction. It is not surprising, therefore, that potash and ammonical solutions. Evaporation left a yellow residue he improved the optical system of the microscope and a camera which made him called it Xanthine. In the presence of caustic lucida. He was no longer practising medicine when he made a potash it turned red. Marcet did not recognize the metabolic serious error in suggesting that, because he could not detect sugar congenital and hereditary condition now known as Xanthinuria. Marcet (Fig. 8) was born in Geneva and traveled to England in in the blood, "diabetic glycosuria was due to the existence of some chemical conveyance from the stomach to the bladder without 1794. There are divergent views on why he did so. One was that he was expelled by the French revolutionary forces which occupied passing through the general system of blood vessels" [60]. Wollaston's life cannot be separated from that of Tennant who Geneva at that time. Another was that he left of his own free will also came from an ecclesiastical family. He was professor of to get away from a political climate he did not favor. His choice of chemistry at Cambridge University and a founding member of the Great Britain was a natural one in that there were strong Geological Society. In addition to their joint discovery of plati- intellectual bonds between Geneva and the Universities of Britnum, Wollaston and Tennant used it to design various scientific ain. The journal Bibliothèque Britannique published in 1795 by the
884
Richet: Early chemistiy of urinary calculi
proteins and was one of the first to adopt Dalton's atomic theory [67, 68].
The rise and the early fall of clinical chemistry The remarkable success of the early workers was dependent in large part on the fortunate capacity of the body to prepare such pure deposits of certain substances and in such amounts, in the form of calculi, that they were within the analytical grasp of the existing techniques. And the chemical identification of each of
these compounds enabled several diseases to be disentangled from a variety of interwoven clinical syndromes.
Most of the detailed chemistry of urinary stones was known
around 1810 to 1820. In Great Britain Marcet and Prout's handbooks had described how calculi could be analyzed. It was therefore theoretically possible for any medical practitioner to obtain some information which would help him treat urinary sand, gravel and stones. These publications, which were translated into French, were in line with P.H. Nysten's (1771—1818) Recherches de Physiologie et de Chimie Pathologiques published in 1811 169]. In
his preface Nysten declared that medical chemistry should be developed and recalled that Fourcroy himself had recommended that un hôpital clinico chimique should be built in Paris. "This is the way that medicine will advance," he announced, "particularly how we shall learn how to dissolve urinary calculi" (pp. X-XIII). He devoted forty pages to the chemistry of urine. He noted the
association of proteinuria and edema (pp. 259—265) and remarked that he had twice found urea in the profuse vomit of
patients just before death, but he made no mention of the
_1 Fig. 8. Alexander John Gaspard Marcet (Courtesy of Welcome Institute Library, London).
post-mortem result! It is a pity that for the next 100 years the literature on urinary
stones was more concerned with various clinical and surgical anecdotes than the study of their chemistry. Handbooks and treatises merely repeated the findings of Fourcroy, Wollaston, Marcet and Prout without commenting on their possible therapeutic implications. No attention was paid to the study of crystals in the urine which was being pionered by Rayer [70]. The general
apathy is apparent in Ferrus's article in the Dictionnaire de Pictet brothers in Geneva bears witness to this closeness. Marcet retired to Geneva and died in London when on a visit [64, 65]. William Prout In 1821 W. Prout (1785—1850) published An Enquiry into the
Médecine in 1823 [71] and in Chevallier's [72] and Ségalas's [73] books which were published in 1837 and 1839, respectively. In addition there were eight editions of the Elements de Chimie by Orfila which ran from 1817 to 1851 [74]. The only addition to the
first edition are the basic formula of cystine and xanthine. The Nature and Treatment of Grave4 Calculus and Other Diseases French translation from the English of Beagle's book which Connected with a Deranged Operation of the Urinary Organs [66, appeared in 1865 [75] was no better. The prejudice of clinicians 67]. His book resembles that of Marcet with whom he had worked. against chemistry, which they scorned in favor of structure, both Prout concentrated on the examination of the urinary sediment macro- and microscopical, was triumphant presumably because and proposed that the presence of sand, gravel and calculi were chemistry was new and initially difficult to grasp. variations of the same disease. He carefully documented the effect of a change in the acidity of the urine on the color of its sediment. And he applied Gay Lussac's observations on supersaturation to
Around 1820 a few individuals did try and change the status quo
on urinary stones by publishing therapeutic results and observations based on the chemical nature of the stones. J.J. Berzélius the formation of urinary calculi [31]. He made one surprising (1779—1848) published an article in 1822 [76] which stated that error of some magnitude when he united under one umbrella from a practical point of view the application of intense heat with urinary stones, proteinuria, diabetes and a raised excretion of a blow-pipe to a stone was usually sufficient to identify it's nature. urea, which he considered to occur quite frequently and to be a J.L. Prevost (1790—1850) and J.B. Dumas, who had revealed that bilateral nephrectomy was followed by a rise in blood urea, renal disturbance. Prout, who was a physician and chemist on the staff of Guy's claimed that in order to avoid a surgical operation it might be Hospital, became famous for an analysis of the elements con- possible to dissolve bladder calculi by electrolysis [77]. And there tained in urea, which was more precise than that worked out by was F. Magendie (1783—i 855) who, after analyzing the conditions Fourcroy and Vauquelin [41. He isolated hydrochloric acid from which were associated with the appearance of gravel, put forward gastric juice, divided foodstuffs into carbohydrates, fats and chemical arguments on how the urine should be alkalanized or
Richet: Early chemistry of urinary calculi
885
acidified, depending on the stone. He also underlined that the 18. FOURCROY AF: Examen chimique de Ia substance feuilletée et cristalline contenue dans les calculs biliaires et de ha nature des intake of protein should be reduced in order to lower the content of urinary solutes [781. In this respect it is interesting that between
concrétions cystiques cristahlisées. Ann Chimie 3:242—252, 1789 19. FOURCROY AF: Nouvelles experiences sur les matières animales faites dans le laboratoire du Lycée. Ann Chimie 7:146—193, 1790 20. FOURCROY AF: Analyse comparée des différentes espèces de concrétions animales et vegetales. Ann Chimie 16:63—108 and 113—167, 1793 21. Ibid. pp 93—94 22. Ibid. pp 165—166 23. FOURCROY AF: Avis aux médecins, aux chirurgiens et aux naturalistes
1940 and 1946 during World War II, urinary calculi practically disappeared from Paris hospitals. Despite the reputation of these scientists almost no one listened to them. An appreciative review of Magendie's book ended with the following disillusioned comment: "This work, which discusses the mode of action of some medicines according to their chemical de Ia Republique francaise et des pays étrangers. Ann Chimie 1798, properties, must displease men who appear to fear, above all else, 27:291—293 (at the end of ref. 13) the steady advance into medicine of the results of experiment" 24. FOURCROY AF: Mémoire sur Ic nombre, Ia nature et les caractères distinctifs des différents matériaux qui forment les calculs, les bézo[79]. This despondent note was not signed but the two editors of ards et les diverses concrétions des animawc. Ann Museum 1:93—113, the Annales de Chimie were F. Arago (1780-4853) and L.J. Gay 1802 Lussac (1778—1850), world renowned scientists. Sadly they were 25. Ref. 15, p 390 26. Ref. 3, p 59 27. Ref. 4, p 156
right.
Acknowledgments The author is deeply indepted to Professor Hugh de Wardener for his invaluable help in discussing and translating the manuscript and to his Secretary; to the Bibliothèque de l'Académie Nationale de Médecine
(75006, Paris) and the Bibliotheque Interuniversitaire de Médecine (75006, Paris) and their staffs, especially Mrs. Casseyre, Lenoir, Chapuis, Molitor and Mr. Rivet. Reprint requests to Gabriel Richet, 76 Rue d'Assas, 75006, Paris, France.
References 1. FOURCROY AF: Système des Connaissances Chimiques, Paris, 1800, X, p 206 (Translated into English by WILLIAM NICHOLSON under the title of General system of chemical knowledge, 11 Vol. London 1804)
2. PEARSON G: Experiments and observations, tending to show the composition and properties of urinary concretions. Phil Trans 1798, pp 15—46
3. FOURCROY AF, VAUQUELIN NL: Premier mémoire pour servir a l'histoire naturelle, chimique et médicale, de l'urine humaine. Ann Chimie 31:48—71, 1799
4. FOURCROY AF, VAUQUELIN NL: Second mémoire pour servir a
l'histoire naturelle, chimique et naturelle de l'urine humaine dans lequel on s'occupe spécialement des propriétés de Ia matière particuhere qui Ia caractérise. Ann Chimie 32:80—162, 1799 5. DUMAS JB: Lecons de Philosophic Chimique. Quoted by ROBERT MASSAIN, Chimie et Chimistes, edited by MAGNARD, Paris, 1982, pp 289—297
6. FOURCROY AF: Ref. 1, p 204 —205 7. HALES S: Haemastique. 1 Vol, translated into French by DE SAUVAGES,
Geneva, 1744, 160 et seq 8. Ibid. Foreword 9. VICQ D'AZYR F: Recherches et observations sur divers objets de médecine, de chirurgie et d'anatomie. Histoire de Ia Société Royale de Médecine 3:204—234, 1779 10. VICQ D'AZYR F: Suite des observations sur les concrétions animales. Histoire de Ia Société Royale de Médecine 4:279—286, 1780
11. Lvoisi AL: Oeuvres completes Tome III, p 146, quoted by POIRIER JP, in Lavoisier 1 vol, Paris, 1993, p 21 12. SOCIETE ROYALE DE MEDECINE: Paris Séance du 7 Mars 1786. Dossier
134 DR 28 Academic Nale Médecine Paris 13. FOURCROY AF: Examen des experiences et des observations nouvelles de Mr G. Pearson Ann Chimie 1798, vol 27, pp 225—293 14. FOURCROY AF: Recherches pour servir a l'histoire du gaz azote ou de
ha mofette, comme principe des matières animahes. Ann ('himie 1:40—46, 1789
15. WOLLASTON WH: On gouty and urinary concretions. Phil Trans ii:386—400, 1797
16. Ref. 2, p 17
17. GILLISPIE CCG: Pearson, edited by EL Scorr, in Dictionary of Scientific Biography, vol 10 pp 445— 447
28. FOURCROY, VAUQUELIN: Mémoire sur Ia presence d'un nouveau sd
phosphorique terreux dans les os des animaux et sur l'analyse de ces organes en general. Ann Chimie 47:244—261, 1803 29. FOURCROY AF: Recherches chimiques sur he Pollen ou Ia poussière fécondante du dattier d'Egypte. Phoenix Dactylifera Ann Museum 1:417—438, 1802 30. FOURCROY AF, VAUQUELIN N: Experiences chimiques pour servir a l'histoire de Ia laite (sic) des poissons Ann Museum 10:169—178, 1807 31. GAY-LUSSAC U: Dissohubilité des sels dans l'eau. Ann Chimie Physique 11:296—315, 1819
32. Ref. 1, p 235 & 245 33. Ref. 1, p 252
34. FOURCROY AF, VAUQUELIN N: Note et correspondance sur des envois de calculs aux citoyens Fourcroy et Vauquehin. Ann Chimie 30:54—65, 1799
35. VAUQUELIN N: Analyse de l'urine du lion et du tigre. Ann Museum 18:82—87, 1811
36. VAUQUELIN N: Experiences sur les excrements des poules, compares a Ia nourriture qu'elles prennent et réflexions sur ha formation de ha coquille d'oeuf. Ann Chimie 28:3—25, 1799 37. FOURCROY AF, VAUQUELIN N: Analyse de l'urine de l'autruche et experiences sur les urines de quelques autres familIes d' oiseaux. Ann Museum 17:310—319, 1811
38. FOURCROY AF, VAUQUELIN NL: Mémoire sur Ic guano ou sur l'engrais naturel des ilots de ha mer du sud, près des côtes du Pérou. Ann Chimie 56:258—268, 1805 39. FOURCROY AF: Observations sur hes calculs des animaux, compares a ceux de l'homme. Ann Museum 2:201—209, 1803 40. FOURCROY AF, VAUQUELIN NL: Mémoire sur ha nature chimique et ha classification des calculs ou concrétions qui naissent chez les animaux et que l'on connait sous he nom de Bézoards.Ann Museum 4:329—339, 1804
41. Ref. 18, p 245 et seq 42. Ref. 39, p 207 43. Ref. 3, p 63 44. LA MEDECINE ECLAIREE PAR LES SCIENCES PHYSIQUE: Paris, 1791,
entirely edited by Fourcroy himself. (It was the first post-graduate educational medical journal in existence. It survived only one year!) 45. FOURCROY AF: Philosophic Chimique. 1 vol. 3rd Edition 1806, Paris, (The introduction is a strong plea in favor of clinical chemistry)
46. Ref. 1 47. SMITH HW: Dc Urina. Kayser Foundation Medical Bulletin 6:1, 1958 48. KERSAINT G: Antoine Fran cois de Fourcroy, sa vie et son oeuvre. 1 vol, Paris, 1966, Museum Ed 49. GILLISPIE CC, FOURCROY A: in Dictionary of Scientific Biography, edited by WA SMEATON, vol. 5, pp 89—93 50. SMEATON WA: Fourcroy, Chemist and Revolutionary, I Vol., London, 1962 51. GILLISPIE CC, VAUQUELIN NL: Dictionary of Scientific Biography, edited by WA SMEATON, vol 14, pp 596—598
52. Ref. 15 53. Ibid., p 389 54. Ibid., p 390 55. Ibid., p 399
886
Richet: Early chemist,y of urinaty calculi
56. Ibid., p 398 57. WOLLASTON WH: On cystic Oxide, a new species of urinaly Calculus. Phil Trans ii:223—230, 1810 58. MARCET A: An essay on the chemical histoiy and medical treatment of calculous disorders. (1 Vol. 2nd ed) London, 1819 (French translation;
page 63 for the case opposing Wollaston and Fourcroy and their respective priorities) 59. GILLISPIE CC, WH WOLLASTON: in Dictionaty of Scientific Biography, edited by DC GOODMAN, vol 14, pp 486—494
60. WOLLASTON WH: On the non existence of Sugar in the blood of
67. GILLISPIE CC, PROUT W: in Dictionaiy of Scientific Biography, edited by WH BROCK, vol. 11, pp 172—174
68. BROCK WH: The life and work of William Prout. Medical Histo,y IX: 101—126, 1965
69. NYSTEN P H: Recherches de Physiologie et de Chimie Pathologiques. 1 vol, Paris, 1811 70. RAYER P: Traité des Maladies des Reins. Paris, 1839, Vol 1, pp 191—213 71. Dictionnaire de Medecine, Lithiase. Edited by FERRUS, Paris, 1823, pp 354 —364
61. GILLISPIE CC, TENNANT S: in Dictionaiy of Scientific Biography, edited by DC GOODMAN, vol 13, pp 280—281
72. CHEVALIER A: Essai Sur Ia Dissolution de la Gravelle et des Calculs de Ia Vessie. 1 vol, Paris, 1837 73. SEGALAS PS: Essai Sur Ia Gravelle et la Pierre. 1 vol, Paris, 1839 74. ORFILA P: Elements de Chimie. vol II, 8 editions from 1817 to 1851 75. BEAGLE LS: De l'Urine, des Depots Urinaires et des Calculs. French
62. Ref. 18 63. Ref. 20 64. HOEFER A: Marcet, in Nouvelle biographie génerale (vol)XXXIII,
translation, 1 Vo!, Paris, 1865, 540 pp 76. BERZELIUS JJ: Phénomènes développés par le traitement des calculs urinaires par le chalumeau. J Phar,nacie Paris 7:419—422, 1822
edited by F DIDOT, Paris, 1840, pp 464—465 65. COLEY NG: Alexander Marcet (17770—1822), physician and animal chemist. Medical Histoty XII:394—402, 1968 66. PROUT W: An Inqui,y into the Nature and Treatment of Gravel Calculus and Other Diseases Connected with a Deranged Operation of the Urinaiy Otgans. 1 vol, London, 1821, 227 pp
77. PREVOST JL, DUMAS JB: Note sur l'emploi de Ia pile dans le
persons labouring under diabetes mellitus, Phil Trans 101:96—109 (see p 102), 1811
traitement des calculs de Ia vessie. Ann Chimie Physique 23:202—208, 1823 78. MAGENDIE F: Recherches Physiologiques et Médicales sur les Causes, les Symptomes et le Traitement de Ia Gravelle. 1 vol, Paris, 1818, 91 pp 79. Editorial Note. Ann Chimie Physique 7:430—436, 1817