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Experimental Urolithiasis. II. The Influence of Urine Volume Upon Calculi Experimentally Produced Upon Foreign Bodies
THE JOURNAL OF UROLOGY
Vol. 64, No. 4, October 1950 Printed in U.S.A.
EXPERIMENTAL UROLITHIASIS. IL THE INFLUENCE OF URINE VOLUME UPON CALCULI EXPERIMENTALLY PRODUCED UPON FOREIGN BODIES WILLIAM J. GROVE, M.D., C. W. VERMEULEN, M.D., R. GOETZ AND H. D. RAGINS From The Department of Surgery, University of Illinois, College of Medicine, Chicago
Patients afflicted with urinary calculi are commonly advised to increase their fluid intake to aid in preventing growth or recurrence of stone. This advice would appear to be logical; urinary dilution reduces the concentration of the crystalloids in the urine and thereby decreases precipitation. Conversely, ol.iguria has long been considered to favor stone formation. Recent experiences with troops in tropical climates tend to strengthen the belief that excessive concentration of the urine is conducive to the production of calculi. So far as we have been able to determine, the relationship of urine volume to the production of stone has not been subjected to controlled experimental investigation. Previous work indicated that a foreign body in the urinary system is a powerful stimulus to stone formation in rats. The purpose of the present study was to determine if chronic diuresis could prevent stone development in the presence of such a strong stimulus. If diuresis prevented stone formation a study was to be made of the effect of diuresis in dissolving stones already formed upon a foreign body. METHODS
Plan of experiments. Adult male white rats of a single strain and weighing 200-250 gm. each were used throughout this study. The method used to induce calculus was the same as that described in the preceding paper, using a standard foreign body composed of a piece of zinc implanted by cystotomy in the bladder of the rat. Two types of experiments were designed to test the effect of diuresis: Experiment 1 (prophylactic) : Immediately following the introduction of the foreign body a chronic diuresis was produced. After 4 weeks the bladder was reopened and the amount of calculus formed was determined by weighing. Experiment 2 (curative): Here a stone was first allowed to form upon the foreign body. After 4 to 8 weeks the amount of stone present was ascertained by removal and immediate weighing. The weighed stone was replaced in the bladder of the same rat at the same operation. ("Daughter" calculi were removed and discarded.) Chronic diuresis was now begun and continued for 4 weeks. The calculus was then removed and the weight compared with its previous weight before diuresis was begun. 1 Read at annual meeting, North Central Section, American Urological Association, Grand Rapids, Mich,, October 6, 1949. 1 In the second experiment it was necessary to modify the method of weighing the calculus. At the first weighing, time did not allow for drying of the stone. Therefore the calculi were weighed wet on an analytical balance as rapidly as possible after rolling the stone on :a clean filter paper for 30 seconds. For comparison the final weighing was done in an identical fashion. 549
550
GROVE, VERMEULEN, GOETZ AND RAGINS
Production of diuresis. In preliminary experiments it was found that rats apparently enjoy drinking a water solution of ordinary glucose. If a 10 per cent solution of glucose is substituted for their usual tap water drinking fluid, they will drink surprising amounts with a great increase in urine volume (but without glycosuria). Diuresis by this means can be maintained for weeks without change. It was therefore decided to use the method to produce a chronic increase in urine volume for our experiments. There is one disadvantage in producing diuresis by this means. The animals drink such quantities of glucose solution as to diminish their intake of the regular diet, since the glucose partially · satisfies their caloric requirement. In consequence the intake of noncarbohydrate food is lessened. To dispose of this difficulty it became necessary to have an additional control series of animals also receiving an excessive amount of carbohydrate. Here it was supplied, not as a solution of glucose, but as glucose powder mixed in the diet. Diets and fluids given. To make this new control diet, further preliminary experiments were made. They showed that animals given water to drink and a diet consisting of equal parts of dry stock diet and dry glucose actually have the same food intake as those getting glucose in their drinking fluid and a diet consisting of stock alone. The only difference in the total intake is in the amount of water. When glucose is given dry in the diet the animals have a fluid intake distinctly less than normal, while with glucose solution the water intake is very large. The calculus experiments were all run with three groups of rats, each one differing in food and water intake. The first group (water control) received only stock diet to eat and water to drink. The second group (diuresis) received stock diet to eat and 10 per cent glucose solution to drink. The third group (dry glucose control) received a mixture of equal parts stock diet and dry glucose to eat and water to drink. So far as we were able to observe, the nutritional status of the rats on the three regimens remained normal. Body weight gain of the rats on the different diets was the same in all groups. Collection of urine and urine chemistry. Urine from individual rats was collected for volume measurement or chemical analysis by placing the rats in a special metabolism cage. All samples were quantitatively collected for periods of 24 hours, collections being made for 3 days from each rat. The results of each rat were then averaged. Some urines were analysed for the content of calcium, magnesium, and phosphorus. The chemical methods were the same as those reported in the previous paper for the analysis of calculi. Analysis of each urine was done in triplicate for each of the three days of collection. Besides computing the average concentration of the substances in the urine of each rat, the per diem excretion was also calculated. 2 2 Since the calculi formed by the method used are chiefly composed of MgNHJ'04·6H20 and contain very little calcium, the results of the determinations of urinary calcium will not be discussed in this paper.
551
EXPERIMENTAL UROLITHIASIS II RESULTS
Urine volume and chemical findings. The results shown in table 1 indicate that a distinct and marked difference in the average daily urine volume was found in the three groups of rats upon different types of treatment. The experimental animals given drinking water containing glucose excreted nearly 5 times the normal volume of urine. The control series given glucose dry mixed in the diet were found to have a urine volume only a little over half that of the stockwater controls. As expected, the concentrations of magnesium and phosphorus were inversely related to the urine volume. The concentrations of both phosphorus and magnesium in the diuresis group were found to be only one fifth that seen in either of the other two groups without diuresis. It is worth mentioning, on the other hand, that the total excretion of magnesium and phosphorus per day is slightly 1. Average urine volume and concentration of phosphorus and magnesium (Number of rats on whom determinations are available given in parentheses)
TABLE
DRY DIET AND DRINKING FLUID
Ul!IN'.EVOLUME CC PER DIEM
PHOSPHORUS
Mg. per 100 cc
Per Diem
MAGNESIUM
Mg. per 100 cc.
Per Diem
Stock diet Water
13.8 ± 0.4* 148.5 ± 13.. 9 18.1 ± 0.14 34.2 ± 5.7 3.1 ± 0.8 (103) (16) (25)
Stock diet Glucose soln.
66.0 ± 4.0 30.2 ± 2.7 18.8 ± 0.26 6.5 ± 1.1 3.6 ± 0.5 (9) (43) (25)
Stock-Gluc. diet Water
7.0 ± 0.6 207.0 ± 12.2 13.5 ± 0.08 45.4 ± 8.1 2.6 ± 0.5 (11) (24) (12)
* Standard error.
increased by diuresis but because of the extreme urinary dilution the concentration remains low. Prevention of stone formation. The results of experiment 1 (prophylactic) are given in table 2. After 4 weeks with a foreign body in the bladder, no stone (defined as 10 or more mg. of calculus deposit) had formed in the 12 animals of the diuresis group. In the other 2 groups, consisting of control animals, a stone was found in more than half. Under the conditions of the experiment, glucose drinking fluid was found to be a very effective stone preventive. With glucose dry in the diet stones were not prevented. Thus it is clear that prevention is not due to glucose per se, but is dependent upon the amount of fluid ingested. If glucose is given as a solution, rats drink very large quantities and diuresis develops. The dilute urine prevents stone formation. If rats are given the same amount of glucose in a dry form mixed in the diet the urine volume is not increased and stones are not prevented. Dissolution of calculi. Results are available in this experiment on 99 rats distributed in the three dietary groups previously mentioned. Figure 1 shows
552
GROVE, VERMEULEN, GOETZ AND RAGINS
I.No pH obtained
f•PH 6.1 -7.5 f,pH ABOVE 7.5
lor i ~COMPLETE DISSOLUTION OF CALCULUS Mgm. WEIGHT CHANGE
500
z400
STOCK DIET- WATER
l
STOCK•GLUCOSE DIET-WATER
ci
1!1
~ '300
STOCK DIET-GLUCOSE SOL 'N
....
:=
200
100
0
No weight change
No weight change
II cases
I case No weight change 10 cases
Fm. 1. (experiment 2, curative). Graphs show change in weight of preformed calculi during 4 weeks of treatment. Stone weight gain or loss is indicated for each rat by a vertical line above or below zero base line. If pH of urine was obtained, it is indicated by an open or solid triangle. Animals undergoing diuresis are shown in center graph while other 2 graphs show results of 2 control groups. TABLE
2. Calculus production upon zinc foreign body in four weeks. Experiment 1 (prophylactic).
D:RY DIET AND DRINKING FLUID
NO. OF RATS
AVERAGE WEIGHT OF CAI.CULOUS DEPOSIT IN MG.
NO. OF RATS WITH MORE THAN 10 MG. OF CALCULOUS DEPOSIT
Stock diet Water
41
37.0 ±
6.8*
26
(63%)
Stock diet Glucose soln.
12
1.4 ±
0.76
0
( 0%)
Stock-Gluc. diet Water
23
18
(78%)
40.6 ± 10.1
* Standard error.
the pertinent data on the rats of all 3 groups and indicates the increase or decrease in weight of each calculus during the period of investigation, along with our results on the urinary pH. Study of the graphs and explanatory legend in figure 1 will reveal that almost all of the calculi in the two control groups continued to grow. However the diuresis group receiving glucose solution to drink showed a loss of stone weight
553
EXPERIMENTAL UROLITIDASIS II
in more than half of the animals. In 15 cases the stones originally present completely dissolved leaving the zinc bare in the bladder. The data available on urinary pH help to explain the unexpected rapid growth of some calculi despite diuresis. Unfortunately, because of small urine volume at the time of final operation, it was not possible to obtain pH determinations in every animal. In every instance where the pH was obtained and found higher than 7.5, growth of stone occurred whether or not the urine volume was increased by diuresis. In all such cases infection with a urea splitting organism was found (a bacillus of the Pasteurella group or, in a few instances, a staphylococcus). Where infection with such a urea splitting organism exists, the intensely alkaline urine would lead us to expect rapid stone growth because of the insolubility of magnesium ammonium phosphate in an alkaline medium. The results suggest that indeed this is the cause of the contradictory rapid growth of some calculi in the diuresis group. It is of interest that the incidence of infection with the Pasteurella organism was far higher in the animals reTABLE
3. Growth or dissolution of preformed calculi during 4 weeks. Experiment 2 (curative). (Includes only rats with urinary pH known to be below 7 .5)
DRY DIET AND D11.INKING FLUID
NUMBEII. OF :RATS
:RATS GROUPED BY STONE CHANGE
AVERAGE WEIGHT CRANGE
Growth
Weight Loss
No Change
OF CALCULUS
Mgm.
Stock diet Water
22
12
2
8
+50
Stock diet Glucose soln
16
2
12
2
-44
6
5
0
1
+94
Stock-Gluc. diet Water
ceiving glucose, either in a dry form or in solution. We do not know whether an abnormally high carbohydrate intake or an accidental contamination of the groups is responsible for the infection. Table 3 gives the average results of the animals in which the urinary pH was found to be 7.5 or below. In these rats diuresis resulted in a loss of stone weight averaging 44 mg. during the 4 week period. In the 2 control groups the stones continued to grow. DISCUSSION
The work presented here illustrates the fundamental importance of the concentration in the urine of the poorly soluble crystalloids. It appears that by diuresis alone the concentration can sometimes be reduced to the extent that dissolution of foreign body stones actually occurs. It is not suggested that simple diuresis would be an adequate therapy clinically for it is difficult or impossible to produce a urine volume in humans equivalent to that obtained in our rats and maintain it for long periods. Calculating by body weight, a
554
GROVE, VERMEULEN, GOETZ AND RAGINS
normal adult human being weighing 70 kilograms would produce somewhat over 3 liters of urine per day if the volume were to be equivalent to that ia our normal rats. If man were to match the diuresis rats, he would be required to produce a volume of over 15 liters a day. Obviously this would be too much to ask of a patient, and possibly too much to be safe. The experiments do suggest that a considerable increase in urine volume would indeed be a worthwhile deterrent and possibly a determining factor in preventing a recurrence of stone. Whereas in the preceding paper only a hint of the role of pH in stone formation was obtained, in this experiment the extreme importance of pH is demonstrated. It was found that in spite of dilution of the urine to 5 times normal, where infection with a urea splitting organism was present the concentration of the poorly soluble crystalloids was still high enough to produce calculi because of the extreme alkalinity of the urine. The complete failure of diuresis in such cases suggests that medical dissolution of calculi in infected clinical cases will have to await more effective means of preventing growth of the organism or a means of preventing its urease activity. We are not prepared to say that a high carbohydrate diet increases stone formation. The observations in the dry glucose control group suggest such a relation. In our rats a high glucose diet (dry) resulted in a lowering of urine volume and an increased incidence of urea splitting infection. We do not know whether high carbohydrate diets in general result in a lowered urine volume or increased urinary infection. However the possibility is worth consideration. SUMMARY
The influence of urine volume upon calculus formation was tested in rats in two types of experiments. The stimulus to stone formation was a foreign body operatively implanted into the bladder. Chronic diuresis was produced by substituting glucose solution for the ordinary tap water drinking fluid. This results in a 5 fold increase in urine volume. In the first experiment the effect of diuresis was studied as a prophylactic agent against stone formation. It was found to completely prevent calculus formation. In the second experiment the effect of diuresis upon preformed calculi was observed. By the production of a chronic large urine volume calculi were completely dissolved in 15 of 46 rats. In this experiment the effect of secondary infection was very pronounced. In spite of diuresis, where an infection with a urea splitting organism was present, the stones grew to large size. Each of the two experiments were accompanied by two suitable control groups of rats. REFERENCES MILBERT, A.H. AND GERSH, J.: Urolithiasis in the soldier. J. Urol., PIERCE, L. W. AND BLOOM, B.: Observations on urolithiasis among
63: 440, 1945. American troops in a
desert area. J. Urol., 54: 466, 1945. C. W. ET AL.: Development of calculi upon foreign bodies surgically introduced into bladders of rats. J. Urol., 64: 541, 1950.
VERMEULEN,
Vol. 64, No. 4, October 1950 Printed in U.S.A.
EXPERIMENTAL UROLITHIASIS. IL THE INFLUENCE OF URINE VOLUME UPON CALCULI EXPERIMENTALLY PRODUCED UPON FOREIGN BODIES WILLIAM J. GROVE, M.D., C. W. VERMEULEN, M.D., R. GOETZ AND H. D. RAGINS From The Department of Surgery, University of Illinois, College of Medicine, Chicago
Patients afflicted with urinary calculi are commonly advised to increase their fluid intake to aid in preventing growth or recurrence of stone. This advice would appear to be logical; urinary dilution reduces the concentration of the crystalloids in the urine and thereby decreases precipitation. Conversely, ol.iguria has long been considered to favor stone formation. Recent experiences with troops in tropical climates tend to strengthen the belief that excessive concentration of the urine is conducive to the production of calculi. So far as we have been able to determine, the relationship of urine volume to the production of stone has not been subjected to controlled experimental investigation. Previous work indicated that a foreign body in the urinary system is a powerful stimulus to stone formation in rats. The purpose of the present study was to determine if chronic diuresis could prevent stone development in the presence of such a strong stimulus. If diuresis prevented stone formation a study was to be made of the effect of diuresis in dissolving stones already formed upon a foreign body. METHODS
Plan of experiments. Adult male white rats of a single strain and weighing 200-250 gm. each were used throughout this study. The method used to induce calculus was the same as that described in the preceding paper, using a standard foreign body composed of a piece of zinc implanted by cystotomy in the bladder of the rat. Two types of experiments were designed to test the effect of diuresis: Experiment 1 (prophylactic) : Immediately following the introduction of the foreign body a chronic diuresis was produced. After 4 weeks the bladder was reopened and the amount of calculus formed was determined by weighing. Experiment 2 (curative): Here a stone was first allowed to form upon the foreign body. After 4 to 8 weeks the amount of stone present was ascertained by removal and immediate weighing. The weighed stone was replaced in the bladder of the same rat at the same operation. ("Daughter" calculi were removed and discarded.) Chronic diuresis was now begun and continued for 4 weeks. The calculus was then removed and the weight compared with its previous weight before diuresis was begun. 1 Read at annual meeting, North Central Section, American Urological Association, Grand Rapids, Mich,, October 6, 1949. 1 In the second experiment it was necessary to modify the method of weighing the calculus. At the first weighing, time did not allow for drying of the stone. Therefore the calculi were weighed wet on an analytical balance as rapidly as possible after rolling the stone on :a clean filter paper for 30 seconds. For comparison the final weighing was done in an identical fashion. 549
550
GROVE, VERMEULEN, GOETZ AND RAGINS
Production of diuresis. In preliminary experiments it was found that rats apparently enjoy drinking a water solution of ordinary glucose. If a 10 per cent solution of glucose is substituted for their usual tap water drinking fluid, they will drink surprising amounts with a great increase in urine volume (but without glycosuria). Diuresis by this means can be maintained for weeks without change. It was therefore decided to use the method to produce a chronic increase in urine volume for our experiments. There is one disadvantage in producing diuresis by this means. The animals drink such quantities of glucose solution as to diminish their intake of the regular diet, since the glucose partially · satisfies their caloric requirement. In consequence the intake of noncarbohydrate food is lessened. To dispose of this difficulty it became necessary to have an additional control series of animals also receiving an excessive amount of carbohydrate. Here it was supplied, not as a solution of glucose, but as glucose powder mixed in the diet. Diets and fluids given. To make this new control diet, further preliminary experiments were made. They showed that animals given water to drink and a diet consisting of equal parts of dry stock diet and dry glucose actually have the same food intake as those getting glucose in their drinking fluid and a diet consisting of stock alone. The only difference in the total intake is in the amount of water. When glucose is given dry in the diet the animals have a fluid intake distinctly less than normal, while with glucose solution the water intake is very large. The calculus experiments were all run with three groups of rats, each one differing in food and water intake. The first group (water control) received only stock diet to eat and water to drink. The second group (diuresis) received stock diet to eat and 10 per cent glucose solution to drink. The third group (dry glucose control) received a mixture of equal parts stock diet and dry glucose to eat and water to drink. So far as we were able to observe, the nutritional status of the rats on the three regimens remained normal. Body weight gain of the rats on the different diets was the same in all groups. Collection of urine and urine chemistry. Urine from individual rats was collected for volume measurement or chemical analysis by placing the rats in a special metabolism cage. All samples were quantitatively collected for periods of 24 hours, collections being made for 3 days from each rat. The results of each rat were then averaged. Some urines were analysed for the content of calcium, magnesium, and phosphorus. The chemical methods were the same as those reported in the previous paper for the analysis of calculi. Analysis of each urine was done in triplicate for each of the three days of collection. Besides computing the average concentration of the substances in the urine of each rat, the per diem excretion was also calculated. 2 2 Since the calculi formed by the method used are chiefly composed of MgNHJ'04·6H20 and contain very little calcium, the results of the determinations of urinary calcium will not be discussed in this paper.
551
EXPERIMENTAL UROLITHIASIS II RESULTS
Urine volume and chemical findings. The results shown in table 1 indicate that a distinct and marked difference in the average daily urine volume was found in the three groups of rats upon different types of treatment. The experimental animals given drinking water containing glucose excreted nearly 5 times the normal volume of urine. The control series given glucose dry mixed in the diet were found to have a urine volume only a little over half that of the stockwater controls. As expected, the concentrations of magnesium and phosphorus were inversely related to the urine volume. The concentrations of both phosphorus and magnesium in the diuresis group were found to be only one fifth that seen in either of the other two groups without diuresis. It is worth mentioning, on the other hand, that the total excretion of magnesium and phosphorus per day is slightly 1. Average urine volume and concentration of phosphorus and magnesium (Number of rats on whom determinations are available given in parentheses)
TABLE
DRY DIET AND DRINKING FLUID
Ul!IN'.EVOLUME CC PER DIEM
PHOSPHORUS
Mg. per 100 cc
Per Diem
MAGNESIUM
Mg. per 100 cc.
Per Diem
Stock diet Water
13.8 ± 0.4* 148.5 ± 13.. 9 18.1 ± 0.14 34.2 ± 5.7 3.1 ± 0.8 (103) (16) (25)
Stock diet Glucose soln.
66.0 ± 4.0 30.2 ± 2.7 18.8 ± 0.26 6.5 ± 1.1 3.6 ± 0.5 (9) (43) (25)
Stock-Gluc. diet Water
7.0 ± 0.6 207.0 ± 12.2 13.5 ± 0.08 45.4 ± 8.1 2.6 ± 0.5 (11) (24) (12)
* Standard error.
increased by diuresis but because of the extreme urinary dilution the concentration remains low. Prevention of stone formation. The results of experiment 1 (prophylactic) are given in table 2. After 4 weeks with a foreign body in the bladder, no stone (defined as 10 or more mg. of calculus deposit) had formed in the 12 animals of the diuresis group. In the other 2 groups, consisting of control animals, a stone was found in more than half. Under the conditions of the experiment, glucose drinking fluid was found to be a very effective stone preventive. With glucose dry in the diet stones were not prevented. Thus it is clear that prevention is not due to glucose per se, but is dependent upon the amount of fluid ingested. If glucose is given as a solution, rats drink very large quantities and diuresis develops. The dilute urine prevents stone formation. If rats are given the same amount of glucose in a dry form mixed in the diet the urine volume is not increased and stones are not prevented. Dissolution of calculi. Results are available in this experiment on 99 rats distributed in the three dietary groups previously mentioned. Figure 1 shows
552
GROVE, VERMEULEN, GOETZ AND RAGINS
I.No pH obtained
f•PH 6.1 -7.5 f,pH ABOVE 7.5
lor i ~COMPLETE DISSOLUTION OF CALCULUS Mgm. WEIGHT CHANGE
500
z400
STOCK DIET- WATER
l
STOCK•GLUCOSE DIET-WATER
ci
1!1
~ '300
STOCK DIET-GLUCOSE SOL 'N
....
:=
200
100
0
No weight change
No weight change
II cases
I case No weight change 10 cases
Fm. 1. (experiment 2, curative). Graphs show change in weight of preformed calculi during 4 weeks of treatment. Stone weight gain or loss is indicated for each rat by a vertical line above or below zero base line. If pH of urine was obtained, it is indicated by an open or solid triangle. Animals undergoing diuresis are shown in center graph while other 2 graphs show results of 2 control groups. TABLE
2. Calculus production upon zinc foreign body in four weeks. Experiment 1 (prophylactic).
D:RY DIET AND DRINKING FLUID
NO. OF RATS
AVERAGE WEIGHT OF CAI.CULOUS DEPOSIT IN MG.
NO. OF RATS WITH MORE THAN 10 MG. OF CALCULOUS DEPOSIT
Stock diet Water
41
37.0 ±
6.8*
26
(63%)
Stock diet Glucose soln.
12
1.4 ±
0.76
0
( 0%)
Stock-Gluc. diet Water
23
18
(78%)
40.6 ± 10.1
* Standard error.
the pertinent data on the rats of all 3 groups and indicates the increase or decrease in weight of each calculus during the period of investigation, along with our results on the urinary pH. Study of the graphs and explanatory legend in figure 1 will reveal that almost all of the calculi in the two control groups continued to grow. However the diuresis group receiving glucose solution to drink showed a loss of stone weight
553
EXPERIMENTAL UROLITIDASIS II
in more than half of the animals. In 15 cases the stones originally present completely dissolved leaving the zinc bare in the bladder. The data available on urinary pH help to explain the unexpected rapid growth of some calculi despite diuresis. Unfortunately, because of small urine volume at the time of final operation, it was not possible to obtain pH determinations in every animal. In every instance where the pH was obtained and found higher than 7.5, growth of stone occurred whether or not the urine volume was increased by diuresis. In all such cases infection with a urea splitting organism was found (a bacillus of the Pasteurella group or, in a few instances, a staphylococcus). Where infection with such a urea splitting organism exists, the intensely alkaline urine would lead us to expect rapid stone growth because of the insolubility of magnesium ammonium phosphate in an alkaline medium. The results suggest that indeed this is the cause of the contradictory rapid growth of some calculi in the diuresis group. It is of interest that the incidence of infection with the Pasteurella organism was far higher in the animals reTABLE
3. Growth or dissolution of preformed calculi during 4 weeks. Experiment 2 (curative). (Includes only rats with urinary pH known to be below 7 .5)
DRY DIET AND D11.INKING FLUID
NUMBEII. OF :RATS
:RATS GROUPED BY STONE CHANGE
AVERAGE WEIGHT CRANGE
Growth
Weight Loss
No Change
OF CALCULUS
Mgm.
Stock diet Water
22
12
2
8
+50
Stock diet Glucose soln
16
2
12
2
-44
6
5
0
1
+94
Stock-Gluc. diet Water
ceiving glucose, either in a dry form or in solution. We do not know whether an abnormally high carbohydrate intake or an accidental contamination of the groups is responsible for the infection. Table 3 gives the average results of the animals in which the urinary pH was found to be 7.5 or below. In these rats diuresis resulted in a loss of stone weight averaging 44 mg. during the 4 week period. In the 2 control groups the stones continued to grow. DISCUSSION
The work presented here illustrates the fundamental importance of the concentration in the urine of the poorly soluble crystalloids. It appears that by diuresis alone the concentration can sometimes be reduced to the extent that dissolution of foreign body stones actually occurs. It is not suggested that simple diuresis would be an adequate therapy clinically for it is difficult or impossible to produce a urine volume in humans equivalent to that obtained in our rats and maintain it for long periods. Calculating by body weight, a
554
GROVE, VERMEULEN, GOETZ AND RAGINS
normal adult human being weighing 70 kilograms would produce somewhat over 3 liters of urine per day if the volume were to be equivalent to that ia our normal rats. If man were to match the diuresis rats, he would be required to produce a volume of over 15 liters a day. Obviously this would be too much to ask of a patient, and possibly too much to be safe. The experiments do suggest that a considerable increase in urine volume would indeed be a worthwhile deterrent and possibly a determining factor in preventing a recurrence of stone. Whereas in the preceding paper only a hint of the role of pH in stone formation was obtained, in this experiment the extreme importance of pH is demonstrated. It was found that in spite of dilution of the urine to 5 times normal, where infection with a urea splitting organism was present the concentration of the poorly soluble crystalloids was still high enough to produce calculi because of the extreme alkalinity of the urine. The complete failure of diuresis in such cases suggests that medical dissolution of calculi in infected clinical cases will have to await more effective means of preventing growth of the organism or a means of preventing its urease activity. We are not prepared to say that a high carbohydrate diet increases stone formation. The observations in the dry glucose control group suggest such a relation. In our rats a high glucose diet (dry) resulted in a lowering of urine volume and an increased incidence of urea splitting infection. We do not know whether high carbohydrate diets in general result in a lowered urine volume or increased urinary infection. However the possibility is worth consideration. SUMMARY
The influence of urine volume upon calculus formation was tested in rats in two types of experiments. The stimulus to stone formation was a foreign body operatively implanted into the bladder. Chronic diuresis was produced by substituting glucose solution for the ordinary tap water drinking fluid. This results in a 5 fold increase in urine volume. In the first experiment the effect of diuresis was studied as a prophylactic agent against stone formation. It was found to completely prevent calculus formation. In the second experiment the effect of diuresis upon preformed calculi was observed. By the production of a chronic large urine volume calculi were completely dissolved in 15 of 46 rats. In this experiment the effect of secondary infection was very pronounced. In spite of diuresis, where an infection with a urea splitting organism was present, the stones grew to large size. Each of the two experiments were accompanied by two suitable control groups of rats. REFERENCES MILBERT, A.H. AND GERSH, J.: Urolithiasis in the soldier. J. Urol., PIERCE, L. W. AND BLOOM, B.: Observations on urolithiasis among
63: 440, 1945. American troops in a
desert area. J. Urol., 54: 466, 1945. C. W. ET AL.: Development of calculi upon foreign bodies surgically introduced into bladders of rats. J. Urol., 64: 541, 1950.
VERMEULEN,