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The Formation of Urinary Calculi1, 2
THE FORMATION OF URINARY CALCULP• 2 H. KRIEGER LASSEN From The Bispebjerg Hospital, Copenhagen, Denmark
It is realized that this subject is very extensive, and that even if everything in connection with historical aspects were omitted, it still would b~ impossible within reasonable limits of space to give even a tolerably satisfactory review of present knowledge in this field. Such being the case, I shall confine myself to what I consider essential material, and I shall only slightly approach the litera. ture in general. Many facts of more or less significance in the origin and development of renal calculi are known and will be reviewed herein, and certain salient individual facts will be discussed briefly. Such knowledge may be divided into two main groups: (I) general factors, and (2) individual factors.. GENERAL FACTORS IN THE FORMATION OF RENAL CALCULI
Frequency of occurrence and geographic distribution. Among general factors, mention should be made of the connection between the frequency of occurrence of renal stones and the special geographic distribution of renal lithiasis; that is, the predilection of the condition for certain places, the so-called stone districts. The most important of these are the valley of the Volga River, Mesopotamia and Persia, Afghanistan arid Turkestan, Northwestern India, Eastern India and the Dutch East Indi~s, South China, in the vicinity of Canton, and Japan. In Africa, urinary stones in particular are frequent among the population of the northern and eastern coasts. The cause of this special geographic distribution has been the subject of much deliberation and has prompted many explanations. It has been suggested that· soil, drinking water, climate, diet and several other factors might be responsible. The Soil: Conditions of the soil give no common explanation, since soils in the various "stone areas" are of different origin and consist of such different materials as limestone, basalt, granite and the like, arising in various prehistoric periods. Drinking Water: In respect to water, it has been thought that in places in which there is a considerable amount of calcium in the drinking water, the conditions requisite for the formation of urinary stones among the population should be present. This theory cannot be substantiated in all places because, for instance, in Canton the water is soft, and the Chinese drink much tea made from boiled water. Conversely, stones are found very seldom among the people of Switzerland, where the water is very hard. Holland, where the frequency of renal lithiasis as compared with that of the other European countries is considerable, has very soft drinking water. Evidence such as has been given would 1 Presented before the Society for Theoretical and Applied Therapy, February, 1940, and in abridged form before the Danish Surgical Society, December, 1940. 2 Undertaken with subvention from the P. Carl Petersen Fund. 110
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seem rather to indicate that lack of calcium in drinking water predisposes to formation of stones. Climate: The possibility that the climate may, as mentioned, be of significance in the occurrence of renal lithiasis is one that cannot be precluded absolutely, a number of the "stone districts" being found to be situated precisely in countries with dry heat, where a considerable loss of liquid takes place by means of perspiration and 1evaporation, so that the urine of persons residing in such countries is more concentrated than is the urine of persons in other countries. On the other hand, the climate alone cannot explain the formation of stones, since in such a case lithiasis should most often appear in tropical countries, which it by no means does. It is very seldom that stones are found, for example, among the population in the Sudan. Diet: Diet seems to play a considerable part in the development of stones among a population. The universal rule applies that in districts in which the population lives chiefly by the growing of corn, and in which corn products form the major part of the diet, the frequency of stones is great; conversely, the frequency is low among peoples who raise cattle and live mainly on milk and milk products, or on a mixed diet. In this latter instance, the theory has been principally that the greater or smaller content of vitamin A in the diet is of definite significance in the frequency of the condition. This particular factor will be discussed later. Race: It should also be mentioned that there seems to be a considerable difference in the frequency of stones among different races. It is especially remarkable, for example, how seldom stones appear among Negroes. Heredity: In various quarters, as well as in Denmark, the view has been advocated that inheritance might play a certain part in the appearance of renal calculi. However, this part seems. to .be very inconsiderable, and only of actual significance among persons who have cystinuria or cystine calculi, but in such cases, it should be said, the lesions are decidedly familial in nature. Age: In the matter of the frequency of renal calculi in various age groups, great differences occur in "stone districts" and in other places. Whereas the appearance of calculi among children frequently occurs in "stone districts," it is relatively rare outside such districts. Members of middle age groups are preferential sufferers from renal calculi outside the "stone areas." For instance, analysis of data concerning calculous material collected partly in England and partly in Denmark, shows that 54 per cent and 47 per cent, respectively, of all patients suffering from renal calculi were in the age group 30 to 50 years, and that 87 per cent and 89 per cent, respectively, of the patients wer{) between the ages of 20 and 60 years. However, figures from the 2 aforementioned countries vary somewhat when the distribution of renal calculi among men and women is considered. In an English study 1202 male and 898 female patients had renal calculi. In Danish statistics collected by Rydgaard, 582 male and 301 female patients had renal calculi. Thus, the frequency of renal calculi in the English study, in ratio form, would ?e 4 males to every 3 females, whereas in Denmark the predisposition of
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this lesion for men seems to be twice what it is for women. But the distribution of calculi between right and left sides seems to be the same. The occurrence of bilateral stones is always far less frequent than the occurrence of unilateral stones. In Rydgaard's Danish study bilateral lithiasis occurred in only about 3 per cent of the cases. The role of war in lithiasis. It is a curious and to a certain extent inexplicable fact that war has an effect on the formation and frequency of occurrence of urinary calculi. After World War I it was thought in various European countries that the existence of a veritable "stone wave" could be substantiated; that is, that the condition had become much more frequent than previously. This phenomenon was in fact recognized long before that time, every great war in Europe having been followed by a period characterized by a considerably increased incidence of calculi among the population. Such a situation seems now to apply in particular to those occupied c_ountries in Europe in which the blockade has caused a perceptible limitation of the ordinary constituents of food. Such a situation during World War I, however, was not demonstrable while the restrictions themselves were in force; it did not become manifest until about 1923 or 1924. Some investigators have explained such lithiasis on the basis of its being one factor in an otherwise latent state of vitamin A deficiency which was tardy in becoming fully manifested; others have sought to explain it as a type of vitamin A deficiency which was not revealed until there had been a copious intake of food rich in vitamin A; others again have said that no importance should be attached to vitamin A in this particular respect, and have explained the "stone wave" by the more or less rushed work of many people, more intense efforts in the field of sports, and possibly, by the increased intake of foodstuffs contain:ing oxalic acid. Although Hellstrom considered it possible to demonstrate a definite "stone wave" in Sweden which commenced during the years 1919 to 1922, a study made in that country by Rydgaard did not demonstrate an actual "stone wave," but merely a gradual increase in cases of calculi during the ten years prior to Rydgaard's study. The increase was hardly much more than could have been expected, in view of the refined and improved facilities for detection of calculi now available in clinical medi~ine. INDIVIDUAL FACTORS IN THE FORMATION OF RENAL CALCULI
Mention should be made first, of various diseases of significance, partly within and partly outside the urinary system. Conditions confined to the urinary system. In the urinary system itself any condition which causes urinary stasis or infection predisposes to the formation of calculi, as for instance, various kinds of congenital anomaly, such as horseshoe kidney, aberrant vessels, valvular formations in the pelvis of the kidney or ureter, strictures and the like, or acquired lesions, such as infection of the urinary system by various bacteria, ren mobilis, stricture, and others. Stasis: Stasis in the urinary system, with stagnating urine, has the effect that various urinary salts, which often are found in considerable concentrations, have
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more time in which to precipitate than would be the case if there were free discharge of urine. Also, any small particles or gravel present when stasis obtains are retained, and may form stone centers. Infection: Infection seems to have the effect of changing the reaction of the urine and particularly the effect of increasing the pH; as a consequence, the condition of saturation in the urine often will undergo considerable change, so that the chance of precipitation, especially of phosphates and carbonates, becomes greater. This is seen in particular in cases of infection by urea-splitting organisms, members of the genus Proteus and others. It is possible that in the case of infection there is also an increase in colloids, or that colloid metabolism is changed. Furthermore, bacteria and inflammatory products themselves may form nuclei for stones, which may become incrusted and continue to grow. Rovsing, Hellstrom and other authors have suggested such a possibility. Conditions outside the urinary system. Morbid conditions may be seen to increase the tendency toward formation of stones, especially when such conditions obtain outside the urinary system. This applies, for example, to various disturbances of metabolism of unknown nature, which cause either cystinuria or xanthinuria, which in turn predisposes to the formation of cystine and xanthic calculi, respectively. Lesions of Bone: Furthermore, it is not a rare occurrence for renal calculi to arise among patients suffering from certain osseous lesions; for instance, chronic osteomyelitis, fracture (particularly columnar fracture), spondylitis, and the like, all of which lesions require that the patient affected stay in bed for a time. Considerable necrosis of bone and osseous resorption, with simultaneous and consequent heavy excretion of calcium phosphate in the urine, combined with poor discharge from the kidneys because of the patient's stay in bed, may constitute the explanation. Hyperthyroidism: Renal calculi often develop in the presence of hyperthyroidism, particularly if one adenoma or more has developed in the glands. Renal calculi may form in such circumstances with or without simultaneous involvement of the bones. But this type of lesion presumably is responsible for only about 0.5 per cent of all renal calculi, and consequently is of relatively slight practical significance. Theoretically, on the other hand, it is exceedingly interesting. Such stones consist of calcium phosphate, and are similar to those appearing in the presence of lesions of bone. The increase in excretion of calcium salts caused by hyperfunction of the parathyroid glands, and the consequent increased concentration of calcium in the urine explain the formation of .calculi. Peptic Ulcer: For the sake of completeness, it may be pointed out that peptic ulcer is often encountered among patients who have renal calculi. Peptic ulcer in this instance is considered to be the primary lesion. Hyperchlorhydria as well as eventual treatment with alkali presumably contributes toward changes in the reaction of the urine; furthermore, food given in the actual dietetic treatment presumably is often insufficient in vitamins. Diet: Among other individual factors, in addition to the diseases mentioned,
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diet seems to be of great significance in the formation of stones. It has been mentioned previously that the food of the population undoubtedly plays the greatest role in the appearance of "stone districts." Results of various inquiries into the food of the populations in "stone districts" are at hand. McCarrison's report from India, in which it was demonstrated that the population there, where urinary stones are very frequent, subsists almost exclusively on corn products, as previously stated, is worthy of mention. The rare appearance of renal lithiasis among Negroes is difficult to explain. Cary has said that urolithiasis is 3½ to 5 times as frequent among white people as it is among Negores, and results of his study do not suggest that economic factors exert effects on the 2 races which would explain the great difference in the ratio. Cary's report concerned 126,543 white patients with 990 stones and 48,032 colored patients with 95 ~tones. This discrepancy in comparative incidence might be a consequence of the fact that the food of Negroes has a low calcium content, high vitamin A content, and produces an acid urine. It is of especial interest in this respect to note the very low content of calcium in the diet of the Negroes. However, in general, it may be said, particularly with regard to the population in "stone districts," that persons living on poor, monotonous, ill-proportioned diets have a far greater susceptibility to the formation of stones than do persons who eat richer and more diversified foods. Thus, in spite of the fact that the diet of wealthy people contains far more stone-forming substances than does that of the poor, the former nevertheless seem to have calculi far more seldom than do the latter. The people of India live chiefly on food poor in oxalates and purines; nevertheless, the urinary calculi of Indian people contain uric acid and urates as well as calcium oxalate in 80 to 90 per cent of cases. The conclusion is that urinary calculi are not usually formed because of an excess of stone-forming substances in the diet, and that calculi may even consist of constituents which hardly appear at all in the food. The theory has been advanced from various quarters, and various experiments to be mentioned subsequently seem to confirm it, that the vitamin content of the diet, and in particular the vitamin A content, plays a certain part in the genesis of urinary calculi. Many investigators think that the vitaminAcontent of the food is of definite significance in this respect. Special attention should be paid, in this respect, to the work of McCarrison and Higgins. The latter, and also a number of other authors, has shown, in studies involving large series of patients, by means of Jeans' light threshold test, which is thought to reveal latent A-avitaminosis, that the number of positive reactions to the test among patients who had calculi was striking, that the number of positive reactions was far lower among persons who did not have stones, and that poor patients exhibit far more positive reactions to the test than do wealthy patients. Ezickson recently has shown in a s:tudy of 39 patients that 90 per cent of the patients had a lowered hepatic function as manifested by results of the bromsulfalein test; the lowered function was to be referable to lack of storage of
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vitamin A in the liver, as indicated by the fact that among 34 patients who had or had had renal or ureteral calculi, 32 or 94 per cent had vitamin A deficiency revealed by Feldman's test for adaptation to darkness. 3 On the other hand, several investigators have not been able to confirm the significance of vitamin A in this respect. In the taking of the history of the diet among persons who have calculi, it'has not been possible to show that they have lived on food particularly poor in vitamins. In Denmark in 1937, Martin Olesen and myself, working with 44 patien,ts who had renal calculi and 44 control patients (without calculi), were not able to demonstrate any differences between members of these two groups in respect to determinations of hemeralopia carried out according to the method of Frandsen. I recently repeated Ezickson's experiment, with the result that although I did find retention of bromsulfalein sufficient to indicate a pathologic condition among about a fourth of patients who had calculi, retention in some cases was so vaguely defined, and in all cases was present so much less than it was in Ezickson's series, that it did not appear that vitamin A deficiency and a consequent lowering of hepatic function could have any definite relationship to the genesis of urinary calculi among the Danish people. Nevertheless, it is a fact that in the two countries of Europe in which renal calculi are most rare, for example, Switzerland and Finland, the people live on a diet very rich in vitamin A and drink much milk and eat many milk products. It is possible, however, that the low frequency of occurrence of calculi in the population of these countries is due to other properties of the milk than the content of vitamin A. The content of various salts probably plays a role, also, in this respect. Among other dietary factors of significance in the formation of calculi, mention should be made of the content of calcium, phosphorus, purines, oxalates, and the quantity of substances which form acids and bases. As far as purines a,nd oxalates are concerned, it is probable that the intake of large quantities of these substances considerably increases the excretion of them in the urine. It is thought that the quantity of phosphorus and calcium in the diet should have a fairly constant mutual proportion, so as to render the conditions of resorption and deposition optimal. Results of certain experiments seem to indicate that deficiency of calcium in the diet increases the possibility of formation of calculi because of the increased excretion of calcium salts in the urine. The fact that stones are rare in districts in which water is hard points in the same direction. Another fact, however, points to the opposite conclusion: the Negroes in South Africa, with an excessively low content of calcium in their diets, only seldom have stones. Negroes possibly may possess some intrinsic protection against renal calculi. In the matter of the exertion of any influence on the formation of stones by virtue of the diet's developing acid or alkaline urine, nothing is known. On the other hand, several authors, particularly Higgins, seem to have proved that the frequency of recidivation after operation may be considerably reduced, for 3
The Feldman adaptometer.
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instance, among patients with stones precipitated in alkaline urine, by the insuring of acidification of the urine after operation. Acidification usually may be maintained merely by the patients' ingestion of a diet rich in proteins and poor in carbohydrates and vegetable substances. So far as I am aware, no account exists of the relative frequency of occurrence of calculi among vegetarians and eaters of flesh. Sports: As previously mentioned, several authors have written on the significance of sports as a causative factor in the genesis of urinary calculi. Energetic and continuous activity in sports causes a considerable loss of fluid, with simultaneous cellular necrosis, and as a consequence, excretion of a strongly concentrated urine. It is a fact that many clinicians have found among their patients suffering from urinary calculi a strikingly large number of young people who are active in sports. SOME CHEMICAL ASPECTS OF THE PROBLEM
With the object of casting more light, if possible, on some of the chemical aspects involved in the formation of renal calculi, and in collaboration with a chemist, Dr. Branner, M.A., and aided by Dr. Prrest, I made a long series of chemical examinations in the chemical laboratory of the Royal Danish Veterinary and Agricultural College at Copenhagen, the head of which is Professor Bjerrum. These examinations, which have been carried out by means of subvention from the P. Carl Petersen Fund, will be mentioned briefly, because they show the importance which knowledge of the chemistry of the urine may have in an understanding of the formation and growth of calculi. We began with the working hypothesis that beginning formation of calculi is most often, perhaps always, a consequence of abnormalities in the composition of the urine which are responsible for the tendency toward formation of urinary sediment. It is somewhat difficult to explain Randall's papillary lesion on the basis of this hypothesis if it is not presumed that these deposits in the renal tissue also are caused by an abnormal composition of the urine, a presumption which does not, however, seem to be entertained by Randall. In a number of cases, however, it can be said that the cause of formation of stone is clear; that is to say, there is no doubt that in cases of experimental hypervitaminosis D, hyperparathyroidism, and experimental hypovitaminosis A, the deposition of calcium in the renal ducts and eventual formation of stone is due to the hyperexcretion of calcium, with consequent precipitation of the supersaturated salt in question, which is difficult to dissolve. On the basis of the various results of analyses obtained and reported by Greta Hammarsten in connection with experiments with rats, it is possible to compute (which Hammarsten did not do) the degree to which the urine is saturated by calcium oxalate. Such computation indicates that the specimens of urine (rat) with which Hammarsten worked were greatly supersaturated with calcium oxalate. Thus, results of these experiments seem to support the aforementioned hypothesis. Other known and previously reported observations concerning the genesis of renal calculi do not militate against such a hypothesis, at any rate.
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In the population of the "stone districts," as a result of osseous disease of long duration, or as a result of stones produced experimentally in different ways (infection and the like), there may appear either an increase in the excretion of stoneforming salts, especially in concentrated urine, or changes associated with saturation of the urine brought about by alteration in the hydrogen ion concentration of the urine. Normal urine, which, it is true, is moderately supersaturated with various salts which dissolve with difficulty, yields no stone-forming substances, provided that the urinary tract is undamaged, and that there are no centers of crystallization. One period or se;eral transient periods of considerable supersaturation arising from several causes will produce deposition of salts in the kidney, particularly in the tissues and the urinary tubules ~ear the renal papillae, or possibly in the mucous membrane of a calyx. As is always the case when a crystalloid is excreted, colloid material is carried along with it, and this colloid material may serve to bind the salts together. A nucleus for a stone is thereby formed, a,nd even though the abnormally strong supersaturation of the urine abates, the conditions requisite to growth of such a nucleus will thereafter be present, if the nucleus continues to be retained. Particularly strong supersaturation of the urine, presumably taking place most often at the ends of convoluted tubules of the s.econd order as the reabsorption of water phase is about to end, probably causes the momentary formation of sediment and consequently, the state of supersaturation of the urine immediately disappears, so that nuclei for stones are no longer likely to form in that urine which is excreted through the renal papillae. This hypothesis is supported by the fact that formation of calculi in cases of experimental hypervitaminosis D is encountered only when the state of intoxication is less pronounced, whereas pronounced intoxication causes formation of sediment where the cortex and the medulla meet. We considered it to be of interest to learn whether the urine of patients who have calculi is of abnormal composition. The possibility that the cause of the formation of nuclei for stones might still reveal itself by abnormalities in .the chemical composition of the urine is not improbable, although it i.s hardly to be expected that this cause could be demonstrated among patients on a hospital diet if such abnormalities are caused by nutritional disturbances. A series of quantitative analyses were made of the factors thought to determine the solubility of calcium oxalate and calcium phosphate; namely, calcium, magnesium, phosphate, and oxalate. Measurements of pH and determinations of conductivity also were undertaken. It was proved that urine from patients who had calculi exhibited no great deviation from that of normal patients. Values for calcium, magnesium and phosphate were similar to those considered generally to be normal; on the other hand, the oxalate content of urine from patients who had calculi as well as urine from normal patients was somewhat higher than that considered to be normal. Total ion concentration of the urine (measurable approximately by electrolytic conductivity), diuresis and hydrogen ion concentration were determined
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in a series of day and night specimens of urine and also urine portions. Analysis of these measurements produce the interesting conclusion that oscillations in conductivity are relatively slight, and are wholly independent of diuresis. Diuresis of between 330 and 3250 c.c. has been recorded, whereas almost all the figures for conductivity lie between 1 X 10 + 2 and 2 X 10 + 2, which is a relatively small variation. In clinical medicine there never has been much interest in estimation of the degree of saturation of the urine. The reason no doubt is partly that such analysis is difficult to do and requires much time, and partly that the results are difficult to judge because of the many factors involved which concern saturation of the urinary salts. Therefore, in the Royal Veterinary and Agricultural College, we undertook a series of examinations concerning the solubility and degree of saturation of calcium oxalate in the urine. It was recognized that the solubility of calcium oxalate in the urine would be determined essentially by the total content of salts in the urine, which determines the total ion concentration and the concentrations of calcium, magnesium and oxalic acid, and increases as the content of magnesium increases. We sought to determine whether a solubility computation made on the basis herein mentioned might be used to assay actual solubility. In the procedure we used, urine from normal persons was centrifuged at 37° (98.6°F.) with calcium oxalate until saturation occurred. The content of oxalate in the urine was determined before and after centrifuging; as was also the content of calcium and magnesium, and conductivity as an approximate gauge of the total ion concentration (the total salt concentration) was established. By this procedure it was possible to compute the amount of oxalate in the urine just saturated, and to compare this value with the value as determined. The values found directly and those computed proved to conform fairly well, which indicates that it is actually possible to compute the degree of saturation of the urine with calcium oxalate, attention having been paid to all the substances and factors which affect the solubility of this salt. In these experiments we found, further, that the specimens of urines we used, from patients who had sound kidneys and were subsisting on an ordinary hospital diet, were always supersaturated with calcium oxalate (2½ to 3½ times; pH of about 5.5). In some cases deviations in the concentration of oxalate in the course of 24 hours were studied in conjunction with variations in pH and diuresis. After an intake of spinach, it was found, a greater excretion of oxalate occurred. The factors regulating the excretion and concentration of calcium in the urine, which it is very necessary to know, are as yet to a great extent uninvestigated. Results of purely chemical experiments which we undertook show that calcium oxalate actually is able to form considerably supersaturated solutions at a temperature of 37°C. (98.6°F.). Since the literature contains reports of successful attempts made to dissolve renal calculi, both clinically and in experimentation with animals, it is plain
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that the urine of such persons or of the animals employed must have been unsaturated, in so far as stone-forming substances are concerned. We also, therefore, interested ourselves in the possibility of obtaining desired variations in the composition of the urine. Our efforts toward such an objective consisted in administering to patients a saline solution containing certain amounts of calcium, magnesium and phosphate (Hammarsten's mixture) and a solution of sodium chloride and magnesium chloride. Considerable diuresis was promoted thereby, the concentration of oxalate was decreased and the concentration of magnesium and calcium was increased. Consequently, the urine became less saturated with calcium oxalate, and in a single case the urine even became unsaturated. Moreover, results of these experiments indicated that the composition of the urine of patients who have renal calculi but also have good renal function might be varied, exactly as composition of the urine of normal persons is varied. COMMENT
It is hoped that an idea has been conveyed of the importance of knowledge of the condition of saturation of the urine by so-called urinary salts. Much investigation is still lacking and until extensive investigation is undertaken, I do not believe that much progress can be made in the scientific prevention of the formation of urinary calculi, or that similar progress can be made in conservative treatment to the point of successful dissolution of calculi that have already formed. CONCLUSIONS
It is concluded that there are two main groups of causes in the genesis of urinary calculi. One group, which undoubtedly is the more rare of the two, is that in which disease processes within or outside the urinary tract operate to supply the conditions requisite for the formation of calculi. The other group of causes, which is the more important group by far, consists largely in dietary insufficiency. Both these two groups of causes, which, as has been demonstrated, consist of a large number of various factors, can bring about changes in the saturation of the urine, and as a consequence, nuclei for the formation of calculi arise. These retained nuclei may, even though the original pathologic condition which caused them does not remain active, continue to grow despite the fact that the urine is absolutely normal. REFERENCES M. K.: The racial incidence of urolithi~sis. J. Ur_ol., 37: 651:-654, 193~. . . EzrcKSON, W. J.: Liver dysfunction as a possible causative factor m renal lrthrasis. J. Lab. & Clin. Med., 24: 836-840, 1939. FELDMAN, J.B.: An instrument for qualitative study of dark adaptation. Arch. Ophth. n.s., 18: 821-826, 1937. . . . .. . HAMMARSTEN, GRETA: Dietetic therapy m format10n of calcrnm oxalate calculi m urmary passages. Skandinav. Arch. f. Physiol., 80: 165-175, 1938. HAMMARSTEN, GRETA: Urinary calculi and their analysis. Nord. med. (Hygiea), 7: 13291332, 1940. CARY,
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HELLSTROM, J.: Increasing frequency of urinary calculi in Sweden. Hygiea, 94: 337-353, 1932. HELLSTROM, JoHN: Uber Rezidive nach Operationen wegen Nieren- und Uretersteinen. Ztschr. f. urol. Chir. u. Gynak., 37: 83-98, 1933. HIGGINS, C. C.: Experimental production of urinary calculi. J. Urol., 29: 157-170, 1933. HIGGINS, C. C.: Production and solution of urinary calculi; experimental and clinical studies. J. A. M. A., 104: 1296-1298, 1935. - - - - : The dietary regimen in the treatment of renal calculi. Journal-Lancet, 68: 9-12, 1938. - - - : Factors in recurrence of renal calculi. J. A. M.A., 113: 1460-1465, 1939. JEANS, P. C., AND ZENTMIRE, ZELMA: The prevalence of vitamin A deficiency among Iowa children. J. A. M.A., 106: 996-997, 1936. LASSEN, H.K., AND OLESEN, M.: Significance of A avitaminosis and hyperparathyroidism in formation of urinary calculi. Hospitalstid, 80: 435-443, 1937. McCARRISON, ROBERT: A lecture on the causation of stone in India. Brit. M. J., 1: 10091015, 1931. McCARRISON, ROBERT: Deficiency disease. Acta Convent. tertii de trop. ataque malar. morbis., 1: 93-102, 1938. RANDALL, ALEXANDER: The etiology of primary renal calculus. Internat. Soc. Urol. Rep. (pt. 1), 7: 186-249, 1939. RovsrNG, C. M.: Discussion of Brongersma, H.: Les resultats eloignes des operations contre la lithiase renales. Tr. Secondo Congresso del Societa Internationale di Urologia, 1924, vol. 2, p. 269. RYDGAARD, FRODE: Aetiology and preventive treatment of primary urinary calculus. Internat. Soc. Urol., Rep. (pt. 1), 7: 146-179, 1939.
It is realized that this subject is very extensive, and that even if everything in connection with historical aspects were omitted, it still would b~ impossible within reasonable limits of space to give even a tolerably satisfactory review of present knowledge in this field. Such being the case, I shall confine myself to what I consider essential material, and I shall only slightly approach the litera. ture in general. Many facts of more or less significance in the origin and development of renal calculi are known and will be reviewed herein, and certain salient individual facts will be discussed briefly. Such knowledge may be divided into two main groups: (I) general factors, and (2) individual factors.. GENERAL FACTORS IN THE FORMATION OF RENAL CALCULI
Frequency of occurrence and geographic distribution. Among general factors, mention should be made of the connection between the frequency of occurrence of renal stones and the special geographic distribution of renal lithiasis; that is, the predilection of the condition for certain places, the so-called stone districts. The most important of these are the valley of the Volga River, Mesopotamia and Persia, Afghanistan arid Turkestan, Northwestern India, Eastern India and the Dutch East Indi~s, South China, in the vicinity of Canton, and Japan. In Africa, urinary stones in particular are frequent among the population of the northern and eastern coasts. The cause of this special geographic distribution has been the subject of much deliberation and has prompted many explanations. It has been suggested that· soil, drinking water, climate, diet and several other factors might be responsible. The Soil: Conditions of the soil give no common explanation, since soils in the various "stone areas" are of different origin and consist of such different materials as limestone, basalt, granite and the like, arising in various prehistoric periods. Drinking Water: In respect to water, it has been thought that in places in which there is a considerable amount of calcium in the drinking water, the conditions requisite for the formation of urinary stones among the population should be present. This theory cannot be substantiated in all places because, for instance, in Canton the water is soft, and the Chinese drink much tea made from boiled water. Conversely, stones are found very seldom among the people of Switzerland, where the water is very hard. Holland, where the frequency of renal lithiasis as compared with that of the other European countries is considerable, has very soft drinking water. Evidence such as has been given would 1 Presented before the Society for Theoretical and Applied Therapy, February, 1940, and in abridged form before the Danish Surgical Society, December, 1940. 2 Undertaken with subvention from the P. Carl Petersen Fund. 110
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seem rather to indicate that lack of calcium in drinking water predisposes to formation of stones. Climate: The possibility that the climate may, as mentioned, be of significance in the occurrence of renal lithiasis is one that cannot be precluded absolutely, a number of the "stone districts" being found to be situated precisely in countries with dry heat, where a considerable loss of liquid takes place by means of perspiration and 1evaporation, so that the urine of persons residing in such countries is more concentrated than is the urine of persons in other countries. On the other hand, the climate alone cannot explain the formation of stones, since in such a case lithiasis should most often appear in tropical countries, which it by no means does. It is very seldom that stones are found, for example, among the population in the Sudan. Diet: Diet seems to play a considerable part in the development of stones among a population. The universal rule applies that in districts in which the population lives chiefly by the growing of corn, and in which corn products form the major part of the diet, the frequency of stones is great; conversely, the frequency is low among peoples who raise cattle and live mainly on milk and milk products, or on a mixed diet. In this latter instance, the theory has been principally that the greater or smaller content of vitamin A in the diet is of definite significance in the frequency of the condition. This particular factor will be discussed later. Race: It should also be mentioned that there seems to be a considerable difference in the frequency of stones among different races. It is especially remarkable, for example, how seldom stones appear among Negroes. Heredity: In various quarters, as well as in Denmark, the view has been advocated that inheritance might play a certain part in the appearance of renal calculi. However, this part seems. to .be very inconsiderable, and only of actual significance among persons who have cystinuria or cystine calculi, but in such cases, it should be said, the lesions are decidedly familial in nature. Age: In the matter of the frequency of renal calculi in various age groups, great differences occur in "stone districts" and in other places. Whereas the appearance of calculi among children frequently occurs in "stone districts," it is relatively rare outside such districts. Members of middle age groups are preferential sufferers from renal calculi outside the "stone areas." For instance, analysis of data concerning calculous material collected partly in England and partly in Denmark, shows that 54 per cent and 47 per cent, respectively, of all patients suffering from renal calculi were in the age group 30 to 50 years, and that 87 per cent and 89 per cent, respectively, of the patients wer{) between the ages of 20 and 60 years. However, figures from the 2 aforementioned countries vary somewhat when the distribution of renal calculi among men and women is considered. In an English study 1202 male and 898 female patients had renal calculi. In Danish statistics collected by Rydgaard, 582 male and 301 female patients had renal calculi. Thus, the frequency of renal calculi in the English study, in ratio form, would ?e 4 males to every 3 females, whereas in Denmark the predisposition of
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this lesion for men seems to be twice what it is for women. But the distribution of calculi between right and left sides seems to be the same. The occurrence of bilateral stones is always far less frequent than the occurrence of unilateral stones. In Rydgaard's Danish study bilateral lithiasis occurred in only about 3 per cent of the cases. The role of war in lithiasis. It is a curious and to a certain extent inexplicable fact that war has an effect on the formation and frequency of occurrence of urinary calculi. After World War I it was thought in various European countries that the existence of a veritable "stone wave" could be substantiated; that is, that the condition had become much more frequent than previously. This phenomenon was in fact recognized long before that time, every great war in Europe having been followed by a period characterized by a considerably increased incidence of calculi among the population. Such a situation seems now to apply in particular to those occupied c_ountries in Europe in which the blockade has caused a perceptible limitation of the ordinary constituents of food. Such a situation during World War I, however, was not demonstrable while the restrictions themselves were in force; it did not become manifest until about 1923 or 1924. Some investigators have explained such lithiasis on the basis of its being one factor in an otherwise latent state of vitamin A deficiency which was tardy in becoming fully manifested; others have sought to explain it as a type of vitamin A deficiency which was not revealed until there had been a copious intake of food rich in vitamin A; others again have said that no importance should be attached to vitamin A in this particular respect, and have explained the "stone wave" by the more or less rushed work of many people, more intense efforts in the field of sports, and possibly, by the increased intake of foodstuffs contain:ing oxalic acid. Although Hellstrom considered it possible to demonstrate a definite "stone wave" in Sweden which commenced during the years 1919 to 1922, a study made in that country by Rydgaard did not demonstrate an actual "stone wave," but merely a gradual increase in cases of calculi during the ten years prior to Rydgaard's study. The increase was hardly much more than could have been expected, in view of the refined and improved facilities for detection of calculi now available in clinical medi~ine. INDIVIDUAL FACTORS IN THE FORMATION OF RENAL CALCULI
Mention should be made first, of various diseases of significance, partly within and partly outside the urinary system. Conditions confined to the urinary system. In the urinary system itself any condition which causes urinary stasis or infection predisposes to the formation of calculi, as for instance, various kinds of congenital anomaly, such as horseshoe kidney, aberrant vessels, valvular formations in the pelvis of the kidney or ureter, strictures and the like, or acquired lesions, such as infection of the urinary system by various bacteria, ren mobilis, stricture, and others. Stasis: Stasis in the urinary system, with stagnating urine, has the effect that various urinary salts, which often are found in considerable concentrations, have
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more time in which to precipitate than would be the case if there were free discharge of urine. Also, any small particles or gravel present when stasis obtains are retained, and may form stone centers. Infection: Infection seems to have the effect of changing the reaction of the urine and particularly the effect of increasing the pH; as a consequence, the condition of saturation in the urine often will undergo considerable change, so that the chance of precipitation, especially of phosphates and carbonates, becomes greater. This is seen in particular in cases of infection by urea-splitting organisms, members of the genus Proteus and others. It is possible that in the case of infection there is also an increase in colloids, or that colloid metabolism is changed. Furthermore, bacteria and inflammatory products themselves may form nuclei for stones, which may become incrusted and continue to grow. Rovsing, Hellstrom and other authors have suggested such a possibility. Conditions outside the urinary system. Morbid conditions may be seen to increase the tendency toward formation of stones, especially when such conditions obtain outside the urinary system. This applies, for example, to various disturbances of metabolism of unknown nature, which cause either cystinuria or xanthinuria, which in turn predisposes to the formation of cystine and xanthic calculi, respectively. Lesions of Bone: Furthermore, it is not a rare occurrence for renal calculi to arise among patients suffering from certain osseous lesions; for instance, chronic osteomyelitis, fracture (particularly columnar fracture), spondylitis, and the like, all of which lesions require that the patient affected stay in bed for a time. Considerable necrosis of bone and osseous resorption, with simultaneous and consequent heavy excretion of calcium phosphate in the urine, combined with poor discharge from the kidneys because of the patient's stay in bed, may constitute the explanation. Hyperthyroidism: Renal calculi often develop in the presence of hyperthyroidism, particularly if one adenoma or more has developed in the glands. Renal calculi may form in such circumstances with or without simultaneous involvement of the bones. But this type of lesion presumably is responsible for only about 0.5 per cent of all renal calculi, and consequently is of relatively slight practical significance. Theoretically, on the other hand, it is exceedingly interesting. Such stones consist of calcium phosphate, and are similar to those appearing in the presence of lesions of bone. The increase in excretion of calcium salts caused by hyperfunction of the parathyroid glands, and the consequent increased concentration of calcium in the urine explain the formation of .calculi. Peptic Ulcer: For the sake of completeness, it may be pointed out that peptic ulcer is often encountered among patients who have renal calculi. Peptic ulcer in this instance is considered to be the primary lesion. Hyperchlorhydria as well as eventual treatment with alkali presumably contributes toward changes in the reaction of the urine; furthermore, food given in the actual dietetic treatment presumably is often insufficient in vitamins. Diet: Among other individual factors, in addition to the diseases mentioned,
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diet seems to be of great significance in the formation of stones. It has been mentioned previously that the food of the population undoubtedly plays the greatest role in the appearance of "stone districts." Results of various inquiries into the food of the populations in "stone districts" are at hand. McCarrison's report from India, in which it was demonstrated that the population there, where urinary stones are very frequent, subsists almost exclusively on corn products, as previously stated, is worthy of mention. The rare appearance of renal lithiasis among Negroes is difficult to explain. Cary has said that urolithiasis is 3½ to 5 times as frequent among white people as it is among Negores, and results of his study do not suggest that economic factors exert effects on the 2 races which would explain the great difference in the ratio. Cary's report concerned 126,543 white patients with 990 stones and 48,032 colored patients with 95 ~tones. This discrepancy in comparative incidence might be a consequence of the fact that the food of Negroes has a low calcium content, high vitamin A content, and produces an acid urine. It is of especial interest in this respect to note the very low content of calcium in the diet of the Negroes. However, in general, it may be said, particularly with regard to the population in "stone districts," that persons living on poor, monotonous, ill-proportioned diets have a far greater susceptibility to the formation of stones than do persons who eat richer and more diversified foods. Thus, in spite of the fact that the diet of wealthy people contains far more stone-forming substances than does that of the poor, the former nevertheless seem to have calculi far more seldom than do the latter. The people of India live chiefly on food poor in oxalates and purines; nevertheless, the urinary calculi of Indian people contain uric acid and urates as well as calcium oxalate in 80 to 90 per cent of cases. The conclusion is that urinary calculi are not usually formed because of an excess of stone-forming substances in the diet, and that calculi may even consist of constituents which hardly appear at all in the food. The theory has been advanced from various quarters, and various experiments to be mentioned subsequently seem to confirm it, that the vitamin content of the diet, and in particular the vitamin A content, plays a certain part in the genesis of urinary calculi. Many investigators think that the vitaminAcontent of the food is of definite significance in this respect. Special attention should be paid, in this respect, to the work of McCarrison and Higgins. The latter, and also a number of other authors, has shown, in studies involving large series of patients, by means of Jeans' light threshold test, which is thought to reveal latent A-avitaminosis, that the number of positive reactions to the test among patients who had calculi was striking, that the number of positive reactions was far lower among persons who did not have stones, and that poor patients exhibit far more positive reactions to the test than do wealthy patients. Ezickson recently has shown in a s:tudy of 39 patients that 90 per cent of the patients had a lowered hepatic function as manifested by results of the bromsulfalein test; the lowered function was to be referable to lack of storage of
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vitamin A in the liver, as indicated by the fact that among 34 patients who had or had had renal or ureteral calculi, 32 or 94 per cent had vitamin A deficiency revealed by Feldman's test for adaptation to darkness. 3 On the other hand, several investigators have not been able to confirm the significance of vitamin A in this respect. In the taking of the history of the diet among persons who have calculi, it'has not been possible to show that they have lived on food particularly poor in vitamins. In Denmark in 1937, Martin Olesen and myself, working with 44 patien,ts who had renal calculi and 44 control patients (without calculi), were not able to demonstrate any differences between members of these two groups in respect to determinations of hemeralopia carried out according to the method of Frandsen. I recently repeated Ezickson's experiment, with the result that although I did find retention of bromsulfalein sufficient to indicate a pathologic condition among about a fourth of patients who had calculi, retention in some cases was so vaguely defined, and in all cases was present so much less than it was in Ezickson's series, that it did not appear that vitamin A deficiency and a consequent lowering of hepatic function could have any definite relationship to the genesis of urinary calculi among the Danish people. Nevertheless, it is a fact that in the two countries of Europe in which renal calculi are most rare, for example, Switzerland and Finland, the people live on a diet very rich in vitamin A and drink much milk and eat many milk products. It is possible, however, that the low frequency of occurrence of calculi in the population of these countries is due to other properties of the milk than the content of vitamin A. The content of various salts probably plays a role, also, in this respect. Among other dietary factors of significance in the formation of calculi, mention should be made of the content of calcium, phosphorus, purines, oxalates, and the quantity of substances which form acids and bases. As far as purines a,nd oxalates are concerned, it is probable that the intake of large quantities of these substances considerably increases the excretion of them in the urine. It is thought that the quantity of phosphorus and calcium in the diet should have a fairly constant mutual proportion, so as to render the conditions of resorption and deposition optimal. Results of certain experiments seem to indicate that deficiency of calcium in the diet increases the possibility of formation of calculi because of the increased excretion of calcium salts in the urine. The fact that stones are rare in districts in which water is hard points in the same direction. Another fact, however, points to the opposite conclusion: the Negroes in South Africa, with an excessively low content of calcium in their diets, only seldom have stones. Negroes possibly may possess some intrinsic protection against renal calculi. In the matter of the exertion of any influence on the formation of stones by virtue of the diet's developing acid or alkaline urine, nothing is known. On the other hand, several authors, particularly Higgins, seem to have proved that the frequency of recidivation after operation may be considerably reduced, for 3
The Feldman adaptometer.
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instance, among patients with stones precipitated in alkaline urine, by the insuring of acidification of the urine after operation. Acidification usually may be maintained merely by the patients' ingestion of a diet rich in proteins and poor in carbohydrates and vegetable substances. So far as I am aware, no account exists of the relative frequency of occurrence of calculi among vegetarians and eaters of flesh. Sports: As previously mentioned, several authors have written on the significance of sports as a causative factor in the genesis of urinary calculi. Energetic and continuous activity in sports causes a considerable loss of fluid, with simultaneous cellular necrosis, and as a consequence, excretion of a strongly concentrated urine. It is a fact that many clinicians have found among their patients suffering from urinary calculi a strikingly large number of young people who are active in sports. SOME CHEMICAL ASPECTS OF THE PROBLEM
With the object of casting more light, if possible, on some of the chemical aspects involved in the formation of renal calculi, and in collaboration with a chemist, Dr. Branner, M.A., and aided by Dr. Prrest, I made a long series of chemical examinations in the chemical laboratory of the Royal Danish Veterinary and Agricultural College at Copenhagen, the head of which is Professor Bjerrum. These examinations, which have been carried out by means of subvention from the P. Carl Petersen Fund, will be mentioned briefly, because they show the importance which knowledge of the chemistry of the urine may have in an understanding of the formation and growth of calculi. We began with the working hypothesis that beginning formation of calculi is most often, perhaps always, a consequence of abnormalities in the composition of the urine which are responsible for the tendency toward formation of urinary sediment. It is somewhat difficult to explain Randall's papillary lesion on the basis of this hypothesis if it is not presumed that these deposits in the renal tissue also are caused by an abnormal composition of the urine, a presumption which does not, however, seem to be entertained by Randall. In a number of cases, however, it can be said that the cause of formation of stone is clear; that is to say, there is no doubt that in cases of experimental hypervitaminosis D, hyperparathyroidism, and experimental hypovitaminosis A, the deposition of calcium in the renal ducts and eventual formation of stone is due to the hyperexcretion of calcium, with consequent precipitation of the supersaturated salt in question, which is difficult to dissolve. On the basis of the various results of analyses obtained and reported by Greta Hammarsten in connection with experiments with rats, it is possible to compute (which Hammarsten did not do) the degree to which the urine is saturated by calcium oxalate. Such computation indicates that the specimens of urine (rat) with which Hammarsten worked were greatly supersaturated with calcium oxalate. Thus, results of these experiments seem to support the aforementioned hypothesis. Other known and previously reported observations concerning the genesis of renal calculi do not militate against such a hypothesis, at any rate.
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In the population of the "stone districts," as a result of osseous disease of long duration, or as a result of stones produced experimentally in different ways (infection and the like), there may appear either an increase in the excretion of stoneforming salts, especially in concentrated urine, or changes associated with saturation of the urine brought about by alteration in the hydrogen ion concentration of the urine. Normal urine, which, it is true, is moderately supersaturated with various salts which dissolve with difficulty, yields no stone-forming substances, provided that the urinary tract is undamaged, and that there are no centers of crystallization. One period or se;eral transient periods of considerable supersaturation arising from several causes will produce deposition of salts in the kidney, particularly in the tissues and the urinary tubules ~ear the renal papillae, or possibly in the mucous membrane of a calyx. As is always the case when a crystalloid is excreted, colloid material is carried along with it, and this colloid material may serve to bind the salts together. A nucleus for a stone is thereby formed, a,nd even though the abnormally strong supersaturation of the urine abates, the conditions requisite to growth of such a nucleus will thereafter be present, if the nucleus continues to be retained. Particularly strong supersaturation of the urine, presumably taking place most often at the ends of convoluted tubules of the s.econd order as the reabsorption of water phase is about to end, probably causes the momentary formation of sediment and consequently, the state of supersaturation of the urine immediately disappears, so that nuclei for stones are no longer likely to form in that urine which is excreted through the renal papillae. This hypothesis is supported by the fact that formation of calculi in cases of experimental hypervitaminosis D is encountered only when the state of intoxication is less pronounced, whereas pronounced intoxication causes formation of sediment where the cortex and the medulla meet. We considered it to be of interest to learn whether the urine of patients who have calculi is of abnormal composition. The possibility that the cause of the formation of nuclei for stones might still reveal itself by abnormalities in .the chemical composition of the urine is not improbable, although it i.s hardly to be expected that this cause could be demonstrated among patients on a hospital diet if such abnormalities are caused by nutritional disturbances. A series of quantitative analyses were made of the factors thought to determine the solubility of calcium oxalate and calcium phosphate; namely, calcium, magnesium, phosphate, and oxalate. Measurements of pH and determinations of conductivity also were undertaken. It was proved that urine from patients who had calculi exhibited no great deviation from that of normal patients. Values for calcium, magnesium and phosphate were similar to those considered generally to be normal; on the other hand, the oxalate content of urine from patients who had calculi as well as urine from normal patients was somewhat higher than that considered to be normal. Total ion concentration of the urine (measurable approximately by electrolytic conductivity), diuresis and hydrogen ion concentration were determined
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in a series of day and night specimens of urine and also urine portions. Analysis of these measurements produce the interesting conclusion that oscillations in conductivity are relatively slight, and are wholly independent of diuresis. Diuresis of between 330 and 3250 c.c. has been recorded, whereas almost all the figures for conductivity lie between 1 X 10 + 2 and 2 X 10 + 2, which is a relatively small variation. In clinical medicine there never has been much interest in estimation of the degree of saturation of the urine. The reason no doubt is partly that such analysis is difficult to do and requires much time, and partly that the results are difficult to judge because of the many factors involved which concern saturation of the urinary salts. Therefore, in the Royal Veterinary and Agricultural College, we undertook a series of examinations concerning the solubility and degree of saturation of calcium oxalate in the urine. It was recognized that the solubility of calcium oxalate in the urine would be determined essentially by the total content of salts in the urine, which determines the total ion concentration and the concentrations of calcium, magnesium and oxalic acid, and increases as the content of magnesium increases. We sought to determine whether a solubility computation made on the basis herein mentioned might be used to assay actual solubility. In the procedure we used, urine from normal persons was centrifuged at 37° (98.6°F.) with calcium oxalate until saturation occurred. The content of oxalate in the urine was determined before and after centrifuging; as was also the content of calcium and magnesium, and conductivity as an approximate gauge of the total ion concentration (the total salt concentration) was established. By this procedure it was possible to compute the amount of oxalate in the urine just saturated, and to compare this value with the value as determined. The values found directly and those computed proved to conform fairly well, which indicates that it is actually possible to compute the degree of saturation of the urine with calcium oxalate, attention having been paid to all the substances and factors which affect the solubility of this salt. In these experiments we found, further, that the specimens of urines we used, from patients who had sound kidneys and were subsisting on an ordinary hospital diet, were always supersaturated with calcium oxalate (2½ to 3½ times; pH of about 5.5). In some cases deviations in the concentration of oxalate in the course of 24 hours were studied in conjunction with variations in pH and diuresis. After an intake of spinach, it was found, a greater excretion of oxalate occurred. The factors regulating the excretion and concentration of calcium in the urine, which it is very necessary to know, are as yet to a great extent uninvestigated. Results of purely chemical experiments which we undertook show that calcium oxalate actually is able to form considerably supersaturated solutions at a temperature of 37°C. (98.6°F.). Since the literature contains reports of successful attempts made to dissolve renal calculi, both clinically and in experimentation with animals, it is plain
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that the urine of such persons or of the animals employed must have been unsaturated, in so far as stone-forming substances are concerned. We also, therefore, interested ourselves in the possibility of obtaining desired variations in the composition of the urine. Our efforts toward such an objective consisted in administering to patients a saline solution containing certain amounts of calcium, magnesium and phosphate (Hammarsten's mixture) and a solution of sodium chloride and magnesium chloride. Considerable diuresis was promoted thereby, the concentration of oxalate was decreased and the concentration of magnesium and calcium was increased. Consequently, the urine became less saturated with calcium oxalate, and in a single case the urine even became unsaturated. Moreover, results of these experiments indicated that the composition of the urine of patients who have renal calculi but also have good renal function might be varied, exactly as composition of the urine of normal persons is varied. COMMENT
It is hoped that an idea has been conveyed of the importance of knowledge of the condition of saturation of the urine by so-called urinary salts. Much investigation is still lacking and until extensive investigation is undertaken, I do not believe that much progress can be made in the scientific prevention of the formation of urinary calculi, or that similar progress can be made in conservative treatment to the point of successful dissolution of calculi that have already formed. CONCLUSIONS
It is concluded that there are two main groups of causes in the genesis of urinary calculi. One group, which undoubtedly is the more rare of the two, is that in which disease processes within or outside the urinary tract operate to supply the conditions requisite for the formation of calculi. The other group of causes, which is the more important group by far, consists largely in dietary insufficiency. Both these two groups of causes, which, as has been demonstrated, consist of a large number of various factors, can bring about changes in the saturation of the urine, and as a consequence, nuclei for the formation of calculi arise. These retained nuclei may, even though the original pathologic condition which caused them does not remain active, continue to grow despite the fact that the urine is absolutely normal. REFERENCES M. K.: The racial incidence of urolithi~sis. J. Ur_ol., 37: 651:-654, 193~. . . EzrcKSON, W. J.: Liver dysfunction as a possible causative factor m renal lrthrasis. J. Lab. & Clin. Med., 24: 836-840, 1939. FELDMAN, J.B.: An instrument for qualitative study of dark adaptation. Arch. Ophth. n.s., 18: 821-826, 1937. . . . .. . HAMMARSTEN, GRETA: Dietetic therapy m format10n of calcrnm oxalate calculi m urmary passages. Skandinav. Arch. f. Physiol., 80: 165-175, 1938. HAMMARSTEN, GRETA: Urinary calculi and their analysis. Nord. med. (Hygiea), 7: 13291332, 1940. CARY,
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HELLSTROM, J.: Increasing frequency of urinary calculi in Sweden. Hygiea, 94: 337-353, 1932. HELLSTROM, JoHN: Uber Rezidive nach Operationen wegen Nieren- und Uretersteinen. Ztschr. f. urol. Chir. u. Gynak., 37: 83-98, 1933. HIGGINS, C. C.: Experimental production of urinary calculi. J. Urol., 29: 157-170, 1933. HIGGINS, C. C.: Production and solution of urinary calculi; experimental and clinical studies. J. A. M. A., 104: 1296-1298, 1935. - - - - : The dietary regimen in the treatment of renal calculi. Journal-Lancet, 68: 9-12, 1938. - - - : Factors in recurrence of renal calculi. J. A. M.A., 113: 1460-1465, 1939. JEANS, P. C., AND ZENTMIRE, ZELMA: The prevalence of vitamin A deficiency among Iowa children. J. A. M.A., 106: 996-997, 1936. LASSEN, H.K., AND OLESEN, M.: Significance of A avitaminosis and hyperparathyroidism in formation of urinary calculi. Hospitalstid, 80: 435-443, 1937. McCARRISON, ROBERT: A lecture on the causation of stone in India. Brit. M. J., 1: 10091015, 1931. McCARRISON, ROBERT: Deficiency disease. Acta Convent. tertii de trop. ataque malar. morbis., 1: 93-102, 1938. RANDALL, ALEXANDER: The etiology of primary renal calculus. Internat. Soc. Urol. Rep. (pt. 1), 7: 186-249, 1939. RovsrNG, C. M.: Discussion of Brongersma, H.: Les resultats eloignes des operations contre la lithiase renales. Tr. Secondo Congresso del Societa Internationale di Urologia, 1924, vol. 2, p. 269. RYDGAARD, FRODE: Aetiology and preventive treatment of primary urinary calculus. Internat. Soc. Urol., Rep. (pt. 1), 7: 146-179, 1939.