Factors Influencing the Formation of Sulfonamide Urinary Concretions1

FACTORS INFLUENCING THE FORMATION OF SULFONAMIDE URINARY CONCRETIONS 1 ROGER W. BARNES

AND

GEORGE K. KAWAICHI

From the Department of Surgery (Urology) College of Medical Evangelists, Los Angeles

Many cases of urinary concretions from sulfonamides have been reported during the past two years. There are several factors which influence the deposition of these concretions, most important of which are: (1) concentration of the drug in the urine; (2) degree of acetylation of the sulfonamide; (3) urinary stasis; (4) pH of the urine; and (5) temperature of the urine. Concentration of the sulfonamide in the urine is influenced by the amount of the drug in the blood stream, the volume of fluid passing through the kidneys and by renal function. Formation of crystals and deposition of concretions may, however, fail to occur in urines containing a high concentration of the drug if the reaction, temperature and other factors are unfavorable. The degree of acetylation of the sulfonamides is an important factor in the formation of urinary concretions, for most of the crystals found in the urine of patients who are taking the drug are the acetyl form. 2 The degree varies in individuals and under different conditions, and at the present time there is no known method whereby it may be altered. Urinary stasis, even without definite obstruction, favors the formation of sulfonamide crystals. These will multiply in urine which stands for several hours, even though the original temperature is sustained. It is probable that this is one reason for the occurrence of more abundant crystals in the bladders of patients who are undergoing sulfonamide therapy. To overcome stasis, free drainage is established and maintained by an indwelling ureteral catheter and by other accepted procedures. There is some disagreement as to whether the pH of the urine has any relation to the solubility of sulfonamides; but a review of the literature reveals that the majority of cases of urinary concretions occurred in patients with neutral or acid urine, although there were a few exceptions. 3 In our series of 10 cases previously reported,4 the urine was acid in every case. Sadusk, Waters and Wilson 5 were of the opinion that the alkalinization of urine was of little value in the prevention of calculi formation in sulfapyridine therapy. Schwartz, Flippin, Reinhold and Domm6 have shown that in patients under sulfathiazole therapy there was 1 Read at annual meeting, American Urological Association, New York, N. Y., June 2, 1942. 2 Prien, E. L., Crabtree, E. G., and Frondel, C.: The mechanism of urinary tract obstruction in sulfathiazole therapy. J. Urol., 46: 1020-1032, 1941. 3 Tsao, Y. F., McCracken, M. E., Chen, Ji, Kuo, P. T., and Dale, C. L.: Renal complication in sulfapyridine therapy. J. A. M.A., 113: 1316-1319, 1939. 4 Kawaichi, George K., and Barnes, Roger W.: Urinary calculi from sulfonamides. Urol. and Cutan. Rev., 65: 477-481, 1941. 5 Sadusk, J. F., Jr., Waters, L. L., and Wilson, D.: Anuria due to sulfapyridine calculi. J. A. M.A., 115: 1968-1973, 1940. 6 Schwartz, L., Flippin, H.F., Reinhold, J. G., and Domm, A. H.: The effect of alkali on crystalluria from sulfathiazole and sulfadiazine. J. A. M.A., 117: 514-515, 1941. 324

325

SULFONAMIDE URINARY CONCRETIONS

less crystal formation in those whos~ urine was alkaline. Recently Climenko and Barlow7 worked with 2 groups of monkeys. One group received sulfathiazole alone, in large doses, and another group was given the same dosage in combination with sodium bicarbonate. In the first group, 4 out of 5 animals died on the twenty-eight day. Autopsy showed urinary calculi formation with severe inflammation of the urinary tract involving the renal medulla, cortex and pelvis, as well as the ureters and bladder. In the second series, no untoward effects were observed and all of the animals survived. Animals sacrificed for autopsy showed only minimal microscopic involvement of the urinary tract. The authors attributed the vast difference to an increased solubility of the drug in the slightly alkaline urine.

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Prien and Frondel 8 noted that as the urine of patients who were taking sulfonamides cooled, a deposition of crystals occurred in the bottom of the test tubes containing it. In the authors' reported cases2, it was observed that in the majority anuria followed a definite drop in temperature (fig. 1). Our observations have led us to believe that sulfonamide concretions occur much more frequently in the Oriental than in the white race. In the Japanese Hospital in Los Angeles, from April 1, 1940 to April 1, 1941 forty patients received sulfapyridine, and of these six (15 per cent) had anuriafrom sulfapyridine 1 Climenko, D. R., and Barlow, 0. W.: Renal lesions resulting from sulfathiazole. Lancet., 1: 770-771, 1941.. . _ . _. 8 Prien, E. L., and Frondel, C.: Crystallography of the urmary sediments with chmcal a,nd pathological observations in sulfonamide drug therapy. J. Urol., 46: 748-758, 1941.

326

ROGER W, BARNES AND GEORGE K. KAWAICHI

concretions. During the same period, 38 patients received sulfathiazole, and three (7.9 per cent) had anuria. The next year, April 1, 1941 to April 1, 1942, the incidence was somewhat lower, probably due to reduction in dosage or more careful observation for red blood cells in the urine during chemotherapy. Throughout this period, 16 cases received sulfapyridine and two (8 per cent) had anuria, 87 received sulfathiazole and two (2.3 per cent) had anuria, and 4 received sulfadiazine, one (25 per cent) of which had anuria. The occurrence of sulfonamide crystals in sufficient quantities to cause anuria in patients who are taking these drugs is much less frequent in other hospitals. The reason for TABLE

1.-Concentration of sulfathiazole in milligrams per 100 cc at different pH values and temperatures TEMPERATURE

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pH

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98

99

100

101

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103

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91.4 93.7 96.1 98.6 104.2 110.2 117.2

96.1 98.6 104.2 110.2 113.6 117.2 120.9

98.6 101.3 104.2 110.2 117.2 117.2 120.9

104.2 107.1 110.2 113.6 117.2 120.9 125.0

107.1 110.2 113.6 117.2 120.9 129.3 129.3

120.9 125.0 129.3 133.9 138.8 150.0 156.2

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105

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(°F.)

pH 100 78.8 98 99 --- --- --- ---

5.0 5.5 6.0 6.5 7.0 7.5 8.0

69.6 72.l 73.5 75.0 76.5 78.1 78.1

89.2 93.7 98.6 101.3 104.1 107.1 113.6

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101

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103

104

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110.2 113.6 117.1 120.9 125.0 129.3 133.9

105

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the greater incidence of this complication in Orientals is not known. The degree of acetylation might be a factor. One of us (G. K.) is of the opinion that stasis, such as that caused by ureteral stricture or angulation, is more common in Orientals than in whites. However, further investigative work must be done before a definite conclusion can be reached. A series of experiments was undertaken by us in an effort to determine the influence of the pH and of the temperature of the urine on the saturation point of sulfathiazole and of sulfadiazine. No attempt at differentiation of the acetylated form of these drugs in the urine was made.

SULFONAMIDE URINARY CONCRETIONS

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MATERIALS AND METHODS

Urine specimens were obtained from patients known to be ingesting large doses of sulfathiazole or sulfadiazine. Only urine saturated with the drug was used, this being determined by the presence of crystals. Specimens of urine containing a large number of crystals were poured into a series of test tubes. The pH of each specimen was then adjusted by adding dilute hydrochloric acid or dilute ammonium hydroxide. The urine in the first tube of the series was adjusted to a pH of 5.0, the second to a pH of 5.5, and the alkalinity increased 0.5 in each ,w

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subsequent tube up to a pH of 8.0. In order to determine the concentration of the drug at different temperatures, 9 of these series were prepared for each drug. One series of different pH values was then put into an incubator at 78.8°F., a second at 98.0°F., a third at 99.0°F., and the temperature was raised 1 degree for each subsequent series up to 105.0°F. After they had stood in the incubator for 24 hours, a definite amount of urine was decanted off from each tube of stated pH value, and the concentration of the drug was determined while still at its specific temperature. Each entire group was run in triplicate, and the average of the three was used as the final concentration of the drug in

328

ROGER W. BARNES AND GEORGE K. KAWAICHI

each instance. Table 1 gives the results obtained for sulfathiazole, and table 2 that for sulfadiazine. These results are plotted on the accompanying graphs (figs. 2 and 3). ..

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Figure 1 shows that the onset of anuria followed a definite drop in temperature and that in most cases the onset was somewhat deferred. That is to say, the anuria was noted at the beginning of a secondary rise in temperature. This was probably due to the fact that crystallization of the sulfonamide does not cause a sudden complete obstruction, but that the formation of crystals gradually impedes the flow of urine, thus producing a delayed effect. That this process takes place can be verified by referring to figure 2. It is noted that the concentration of the drug varies directly with the temperature and with the pH of the urine Inasmuch as the urine is undoubtedly the same as the patient's body temperature, an increase in the latter will cause a greater proportion of the sulfonamide to remain in solution and the likelihood of crystal deposition will be reduced. The same principle is true of the pH value of the urine, although at lower temperatures such as room temperature an increase in pH does not affect the solubility of the sulfonamide to any great extent. But as the temperature is raised,

SULFONAMIDE URINARY CONCRETIONS

329

a corresponding increase in solubility takes place, more marked with sulfathiazole than with sulfadiazine. A knowledge of these facts is important to an understanding of the process which evolves in sulfonamide urinary calculi formation. Thus, when a patient has a high fever, as in pneumonia, he can tolerate a high concentration of sulfonamide, especially if the urinary pH is elevated. As soon as the temperature begins to drop, however, the sulfonamide in the urine has a tendency to crystallize out. PRACTICAL APPLICATION

To control the formation of sulfonamide urinary concretions, the concentration of the drug in the urine and the urinary pH are determined at regular intervals. When the sulfonamide concentration approaches the saturation point for a given pH and temperature, as noted in tables l and 2, the urine must be rendered more alkaline, or the concentration of the drug must be lowered by reducing the ingested dose or by increasing the fluid intake. In this way it is possible to prevent the formation of urinary concretions and at the same time maintain a maximum safe concentration of the drug (safe zone, figure 2). If the concentration is not reduced, nor the pH increased at a given temperature, the urine becomes supersaturated and concretions will be deposited (danger zone, figure 2). The internal body temperature is slightly higher than the rectal temperature, so that the latter provides good indication in determining the safe zone of drug concentration. Elevation of temperature helps, both to prevent the formation of sulfonamide concretions and to dissolve them after their formation. A local rise may be obtained by application of heat, preferably short wave diathermy, to the kidney areas and by kidney pelvic lavage with warm water or sodium bicarbonate solution through ureteral catheters. If sulfonamide crystals have formed in the renal tubules in sufficient quantities to cause anuria, it is probable that raising the body temperature by means of a hyperpyrexia cabinet would greatly aid in relieving the situation. To illustrate the method of determining whether a patient is in danger of developing sulfonamide urinary concretions, 2 cases are presented. CASE REPORTS

Case 1. K. Y., a male, 47 years of age, was given 28 gm. of sulfadiazine in 7 days for pneumonia. On the seventh day, hematuria developed. Determination of the urine concentration of sulfadiazine was found to be 108 mg per 100 cc. The pH of the urine was 6.0 and the body temperature 99.0°F. By referring to figure 3, it is seen that this point is just inside the danger zone. The drug was immediately discontinued, fluids were forced orally and the urinary difficulty ceased. Case 2. T. F .. , a male, 35 years of age, was admitted to the hospital with a diagnosis of pneumonia. He had received 16 gm. sulfathiazole in 4 days. The urine concentration of sulfathiazole was HO mg per 100 cc, and the pH was 7.0. The body temperature was 101.0°F. Figure 2 shows this point to be just inside the safe zone. The urine concentration of sulfathiazole was repeatedly checked

330

ROGER W. BARNES AND GEORGE K. KAWAICHI

and the dose of the drug decreased accordingly, thus preventing sulfonamide urinary concretion formation. SUMMARY

The most important factors influencing the formation of sulfonamide urinary concretions are: (1) Concentration of the drug in the urine, which may be reduced by decreasing the dose of the drug and increasing the fluid intake; (2) degree of acetylation of the sulfonamide, which cannot be influenced by extrinsic means; (3) urinary stasis, which is overcome by establishing and maintaining free drainage; (4) pH of the urine, which may be adjusted; (5) temperature, which may be elevated. Our experimental work shows that as the pH of the urine is increased and the temperature of the urine elevated, the solubility of sulfathiazole and sulfadiazine is heightened. This range is from a sulfathiazole concentration of 78.1 mg. per 100 cc at a pH of 5.0 and temperature of 78.8°F to a concentration of 250.0 mg. per cc at a pH of 8.0 and temperature of 105.0°F. The range for sulfadiazine is from 69.6 mg. per 100 cc to 170.4 mg. per cc. The danger from sulfonamide concretions can be reduced by rendering the urine more alkaline and by elevating the temperature. Anuria from sulfonamide concretions occurs much more frequently in the Oriental than in the white race. The reason for this is not known.

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