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Prevalence and Importance of Urea-Splitting Bacterial Infections of the Urinary Tract in the Formation of Calculi1
PREVALENCE AND IMPORTANCE OF UREA-SPLITTING BACTERIAL INFECTIONS OF THE URINARY TRACT IN THE FORMATION OF CALCULP RICHARD CHUTE
AND
HOW ARD L SUBY
From the Stone Clinic, l,1 assachusetts General JI ospital, Boston
Several years ago a so-called "stone clinic" was organized at the Massachusetts General Hospital for the purpose of studying the causes of urinary calculi. Various aspects of each case: pH of the urine, of infection (if any), composition of the stone, dietary abnormalities and metabolic disorders (hyperparathyoidism, gout or cystinuria) and any other factors apparently pertinent, are investigated in an attempt to correlate them and learn more about calculus formation. In everv case we have tried to determine what was the cause of stone formation. As we have gone over these cases in detail we have become impressed with the prevalence and potency of urea-splitting bacterial infections as a major etiological factor in the formation of urinary stones, many of which are multiple or recurrent. The urea-splitting bacteria constitute the most common single cause of stone formation in our cases, accounting for 54 per cent, or more than half of all cases. When the urinary tract is infected by urea-splitting organisms, the urea which is being excreted in the urine is "split" by the bacteria with the formation of ammonia which renders the urine alkaline. In this alkaline urine there tend to be precipitated crystals of calcium and magnesium phosphate (amorphous phosphates), of ammonium mag nesium phosphate (triple phosphates) and of calcium carbonate. Such crystals are often seen in the urine of a normal person during the alkaline tide, and in such cases are without pathological significance. However, urine which is infected with urea-splitting bacteria is perpetually alkaline and contains these crystals in abundance. With this continued presence of an abundance of crystalloids, there is a strong tendency to the forma tion of calcium phosphate-calcium carbonate calculi. This tendency is probably aided and abetted by the partial destruction of the urea, which is one of the so-called hydrotropic substances in the urine which increases the solubility of calcium salts and helps keep the urinary crystalloids from precipitating out of solution. Hellstrom of Stockholm has demon1
Read at the American Urological Association, Buffalo, N. Y., June 25, 1940. 590
BACTERIAL INFECTIONS AND URINARY CALCULI
591
strated that staphylococci themselves formed an integral part of the organic substance in the stones which he studied, and it may be that masses of urea-splitting bacteria act as a substance upon which the crystals may be precipitated and which helps hold them together. A number of writers in this country (Albright, Dienes and Sulkowitch, Burns, Hager, Higgins, Keyser, Scholl and Twinem), and also abroad (Lett, Rovsing) have reported on the definite relationship between ureasplitting bacteria and the formation of urinary calculi (figs. 1 and 2). From this point of view we studied 90 cases in our stone clinic during the 2 years 1938 and 1939. Sixty-six (about 75 per cent) were infected.
FIG. 2 FrG. 1 FIG. 1. A case of infection with urea-splitting Staph. albus. Note stone in mid-ureter
on left side. It was removed surgically, but the infection was not eradicated. FIG. 2. An x-ray taken 1 year later shows large new stone in left kidney.
Cultures to determine the presence or absence of urea-splitting organisms were not done on every case. However, Dr. Louis G. Johnson of the Massachusetts General Hospital, kindly did more than 50 special ureasplitting cultures for us, using the technique described by Thompson and Schulte. In general, Dr. Johnson's results confirmed the observations of previous workers. We were somewhat surprised to find how many of the pure colon bacillus infections split urea, and also were impressed by the very great urea-splitting ability of the mixed infections. On the basis of the experiences of the authors already quoted and of our series of urea-splitting cultures confirming those findings, we considered
592
RICHARD CHUTE AND HOWARD I. SUBY
as urea-splitters all cases of B. proteus, B. pyocyaneus and B. influenzae infection, also those cases of staphylococcus, colon bacillus and nonhemolytic streptococcus with alkaline urines, and also all cases of mixed infections with these organisms (table 1). The largest single group among the 66 infected cases, comprising onethird of them (23 cases, 35 per cent) was that of the mixed infections with 2 or occasionally 3 of the following 4 organisms: colon bacillus, staphylococcus (usually albus), non-hemolytic streptococcus and B. proteus. These occurred in almost every possible combination with one another, but either the colon bacillus or the staphylococcus (and sometimes both) were always among those present in every single case. All of these cases of mixed infection were pronounced urea-splitters, and showed a marked tendency to stone recurrence which took place in three quarters of the cases (17 of the 23 cases or 74 per cent). Furthermore, since the majority of these cases have been followed only 2 or 3 years, TABLE
1.-Forty-nine cases of i;rea-splitting injection with calcitlits formation cases
Mixed infections. Pure Staphylococcus albus . Pure B. coli .... Pure B. proteus. Pure B. influenzae .
23 10 9
5 2
it seems not improbable that with the passage of more time recurrences of the stone may appear in a larger percentage of cases. The analysis of these recurrent stones showed that calcium phosphate was always the predominating constituent. When it came to the pure cultures, the colon bacillus was the commonest, comprising just over one quarter (27 per cent of the grand total of infected cases). We considered half of the B. coli cases to be ureasplitters. Of these 9, there were recurrences in 6 cases. In 4 of the 6 cases, the stones were predominantly calcium phosphate, and in the other 2 there was no analysis. Of the 9 cases where B. coli were not splitting urea, there were recurrences in only 3 cases, and in each of these 3 it seemed as if an underlying metabolic or dietary abnormality played the principal part in the stone formation rather than the infection. In 1 case the patient had hyperparathyroidism; in the second, the patient had gout, and the stones were composed of uric acid; and in the third case the patient had been taking large quantities of alkalies (figs. 3, 4, 5).
BACTERIAL INFECTIONS AND URINARY CALCULI
593
The next most common group in the pure infections was the staphylococcus, which comprised just under one-quarter (16 cases, 24 per cent) of all infected cases. Of these 16 cases, 10 at a conservative estimate were considered to be urea splitters. Recurrences occurred in 6 of these 10 cases, but in none of the 6 non-urea splitting cases. The stones in 4 of these recurrences were predominantly phosphate, but were lost or were still in the kidney in the other cases. The B. proteus came next with 5 cases (7 ½per cent). All cases of Proteus were urea-splitters, all had recurrent stones, all of which were
Frc. 3
Frc. 4
Frc. 5
Frc. 3. Recurrent stone in a case of infection with a urea-splitting colon bacillus. Left kidney essentially free of stones after nephrolithotomy. Infection not eradicatedFIG. 4. An x-ray taken 6 months later shows a large stone that fills lower calyx. FIG. 5. An x-ray taken 13 months later that shows kidney completely filled with a large staghorn calculus.
composed predominantly of calcium phosphate. We feel that practically all Proteus infections are contaminations which are introduced during instrumentation or through rubber tubing that has been in place for some time; e.g., cystostomy and nephostomy tubes. Finally there were 2 cases of B. influenzae infection, both urea-splitters, with extensive bilateral multiple and recurrent renal calculi, and 1 case each of non-hemolytic streptococcus and of diphtheroids. The diphtheroid infection was in a case of cystinuria and may well have been a contaminant. Thus, in general, we see that the urine in cases of urea-splitting infec-
594
RICHARD CHUTE AND HOWARD I. SUBY
tion is usually alkaline, the stones are predominantly calcium phosphate and have a marked tendency to recur (table 2). Twenty-four (twenty-seven per cent) of the 90 cases had urine which was sterile at the time the patients were first found to have calculi; and therefore, these cases do not come especially into the scope of this paper. However, among these cases of so-called aseptic stone, many of which were due to metabolic changes, it was interesting to note that more than half had a urinary pH of 5.5 or less, and were thus on the acid side. Only 3 were alkaline enough to have pH of 7.0 or higher, and one of these was undoubtedly due to diet. Furthermore, if one excludes those cases in which there was no analysis of the stone, either because it was lost or because it was still in the kidney, the majority of the calculi were preTABLE
2.-Ninety cases of calculus per cent
54
Urine infected with urea-splitting bacteria .... Urine infected with non-urea-splitting bacteria .. Urine sterile ...
TABLE
19
27
3.-Average pH, stone composition, and percentage of recitrrences in cases with sterile urine and with urea-splitting infections STERILE URINE
Average pH ................. Stone composition .. Per cent of recurrence ... ...
5.5 Oxalate, uric acid
29
URINE INFECTED WITH UREASPLITTING BACTERIA
7.0 Phosphate, carbonate 73
dominantly oxalate or uric acid; there were only 3 cases in which the stone was composed chiefly of phosphate or carbonate, one of which was a case of hyperparathyroidism. There were 7 recurrences out of the 24 cases (29 per cent). Thus it appears that in general, in contrast to the case in urea-splitting infections, sterile urines are apt to be on the acid side, and that stones in such cases are apt to be composed of oxalate or of uric acid (table 3). When one analyzes these figures, the number of cases in which ureasplitting bacteria were the apparent cause of the stone formation was impressive. They comprised slightly more than half (54 per cent) of the total cases of stone, and nearly three quarters (74 per cent) of all infected cases. As for recurrences, the average for recurrences in the 49 urea-splitting cases was 73 per cent or nearly three quarters. This 73
BACTERIAL INFECTIONS AND URINARY CALCULI
595
per cent is in marked and horrible contrast to the 23 per cent of recurrences in non-urea-splitting infections, and the 29 per cent of recurrences in the cases with sterile urines. Taking the evidence as a whole, there can be no doubt that the ureasplitting infections are associated with the most frequent, the most active, and the most stubborn stone formation known. The discussion of therapy is not the purpose of this paper, but the inference is clear that it is of the very greatest importance to eradicate urea-splitting infections of the urinary tract by medical and surgical means, especially after the removal of stones to prevent continued stone formation. 352 Marlborough St., Boston, Mass. REFERENCES ALBRIGHT, DIENES AND SULKOWITCH: J. A. M. A., :110: 357, 1936. BURNS, E.: Surgery, 4; 673, 1938. HAGER, B. H.: J. Urol., 15: 133, 1926. HELLSTROM, J.: Brit. J. Urol., 10: 348, 1938. HIGGINS, C. C.: J. Urol., 40: 184, 1938. KEYSER, L. D.: Bull. New York Acad. Med., 14: 76, 1938; J. Urol. 31: 219, 1934. LETT, H.: Brit. J. Urol., 8: 205, 1936. RovsmG, C.: Cited by FOWLER, H. A.: Urol. & Cutan. Rev., 38: 594, 1934. SCHOLL, A. J.: Cabot's Modern Urology, vol. 2, Philadelphia, Lea & Febiger, p. 604, 1936. THOMPSON AND ScHULTE: Proc. Staff Meet. Mayo Clin., 14: 361, 1939. TWINEM, F. P.: J. UroL, 37: 259, 1937.
AND
HOW ARD L SUBY
From the Stone Clinic, l,1 assachusetts General JI ospital, Boston
Several years ago a so-called "stone clinic" was organized at the Massachusetts General Hospital for the purpose of studying the causes of urinary calculi. Various aspects of each case: pH of the urine, of infection (if any), composition of the stone, dietary abnormalities and metabolic disorders (hyperparathyoidism, gout or cystinuria) and any other factors apparently pertinent, are investigated in an attempt to correlate them and learn more about calculus formation. In everv case we have tried to determine what was the cause of stone formation. As we have gone over these cases in detail we have become impressed with the prevalence and potency of urea-splitting bacterial infections as a major etiological factor in the formation of urinary stones, many of which are multiple or recurrent. The urea-splitting bacteria constitute the most common single cause of stone formation in our cases, accounting for 54 per cent, or more than half of all cases. When the urinary tract is infected by urea-splitting organisms, the urea which is being excreted in the urine is "split" by the bacteria with the formation of ammonia which renders the urine alkaline. In this alkaline urine there tend to be precipitated crystals of calcium and magnesium phosphate (amorphous phosphates), of ammonium mag nesium phosphate (triple phosphates) and of calcium carbonate. Such crystals are often seen in the urine of a normal person during the alkaline tide, and in such cases are without pathological significance. However, urine which is infected with urea-splitting bacteria is perpetually alkaline and contains these crystals in abundance. With this continued presence of an abundance of crystalloids, there is a strong tendency to the forma tion of calcium phosphate-calcium carbonate calculi. This tendency is probably aided and abetted by the partial destruction of the urea, which is one of the so-called hydrotropic substances in the urine which increases the solubility of calcium salts and helps keep the urinary crystalloids from precipitating out of solution. Hellstrom of Stockholm has demon1
Read at the American Urological Association, Buffalo, N. Y., June 25, 1940. 590
BACTERIAL INFECTIONS AND URINARY CALCULI
591
strated that staphylococci themselves formed an integral part of the organic substance in the stones which he studied, and it may be that masses of urea-splitting bacteria act as a substance upon which the crystals may be precipitated and which helps hold them together. A number of writers in this country (Albright, Dienes and Sulkowitch, Burns, Hager, Higgins, Keyser, Scholl and Twinem), and also abroad (Lett, Rovsing) have reported on the definite relationship between ureasplitting bacteria and the formation of urinary calculi (figs. 1 and 2). From this point of view we studied 90 cases in our stone clinic during the 2 years 1938 and 1939. Sixty-six (about 75 per cent) were infected.
FIG. 2 FrG. 1 FIG. 1. A case of infection with urea-splitting Staph. albus. Note stone in mid-ureter
on left side. It was removed surgically, but the infection was not eradicated. FIG. 2. An x-ray taken 1 year later shows large new stone in left kidney.
Cultures to determine the presence or absence of urea-splitting organisms were not done on every case. However, Dr. Louis G. Johnson of the Massachusetts General Hospital, kindly did more than 50 special ureasplitting cultures for us, using the technique described by Thompson and Schulte. In general, Dr. Johnson's results confirmed the observations of previous workers. We were somewhat surprised to find how many of the pure colon bacillus infections split urea, and also were impressed by the very great urea-splitting ability of the mixed infections. On the basis of the experiences of the authors already quoted and of our series of urea-splitting cultures confirming those findings, we considered
592
RICHARD CHUTE AND HOWARD I. SUBY
as urea-splitters all cases of B. proteus, B. pyocyaneus and B. influenzae infection, also those cases of staphylococcus, colon bacillus and nonhemolytic streptococcus with alkaline urines, and also all cases of mixed infections with these organisms (table 1). The largest single group among the 66 infected cases, comprising onethird of them (23 cases, 35 per cent) was that of the mixed infections with 2 or occasionally 3 of the following 4 organisms: colon bacillus, staphylococcus (usually albus), non-hemolytic streptococcus and B. proteus. These occurred in almost every possible combination with one another, but either the colon bacillus or the staphylococcus (and sometimes both) were always among those present in every single case. All of these cases of mixed infection were pronounced urea-splitters, and showed a marked tendency to stone recurrence which took place in three quarters of the cases (17 of the 23 cases or 74 per cent). Furthermore, since the majority of these cases have been followed only 2 or 3 years, TABLE
1.-Forty-nine cases of i;rea-splitting injection with calcitlits formation cases
Mixed infections. Pure Staphylococcus albus . Pure B. coli .... Pure B. proteus. Pure B. influenzae .
23 10 9
5 2
it seems not improbable that with the passage of more time recurrences of the stone may appear in a larger percentage of cases. The analysis of these recurrent stones showed that calcium phosphate was always the predominating constituent. When it came to the pure cultures, the colon bacillus was the commonest, comprising just over one quarter (27 per cent of the grand total of infected cases). We considered half of the B. coli cases to be ureasplitters. Of these 9, there were recurrences in 6 cases. In 4 of the 6 cases, the stones were predominantly calcium phosphate, and in the other 2 there was no analysis. Of the 9 cases where B. coli were not splitting urea, there were recurrences in only 3 cases, and in each of these 3 it seemed as if an underlying metabolic or dietary abnormality played the principal part in the stone formation rather than the infection. In 1 case the patient had hyperparathyroidism; in the second, the patient had gout, and the stones were composed of uric acid; and in the third case the patient had been taking large quantities of alkalies (figs. 3, 4, 5).
BACTERIAL INFECTIONS AND URINARY CALCULI
593
The next most common group in the pure infections was the staphylococcus, which comprised just under one-quarter (16 cases, 24 per cent) of all infected cases. Of these 16 cases, 10 at a conservative estimate were considered to be urea splitters. Recurrences occurred in 6 of these 10 cases, but in none of the 6 non-urea splitting cases. The stones in 4 of these recurrences were predominantly phosphate, but were lost or were still in the kidney in the other cases. The B. proteus came next with 5 cases (7 ½per cent). All cases of Proteus were urea-splitters, all had recurrent stones, all of which were
Frc. 3
Frc. 4
Frc. 5
Frc. 3. Recurrent stone in a case of infection with a urea-splitting colon bacillus. Left kidney essentially free of stones after nephrolithotomy. Infection not eradicatedFIG. 4. An x-ray taken 6 months later shows a large stone that fills lower calyx. FIG. 5. An x-ray taken 13 months later that shows kidney completely filled with a large staghorn calculus.
composed predominantly of calcium phosphate. We feel that practically all Proteus infections are contaminations which are introduced during instrumentation or through rubber tubing that has been in place for some time; e.g., cystostomy and nephostomy tubes. Finally there were 2 cases of B. influenzae infection, both urea-splitters, with extensive bilateral multiple and recurrent renal calculi, and 1 case each of non-hemolytic streptococcus and of diphtheroids. The diphtheroid infection was in a case of cystinuria and may well have been a contaminant. Thus, in general, we see that the urine in cases of urea-splitting infec-
594
RICHARD CHUTE AND HOWARD I. SUBY
tion is usually alkaline, the stones are predominantly calcium phosphate and have a marked tendency to recur (table 2). Twenty-four (twenty-seven per cent) of the 90 cases had urine which was sterile at the time the patients were first found to have calculi; and therefore, these cases do not come especially into the scope of this paper. However, among these cases of so-called aseptic stone, many of which were due to metabolic changes, it was interesting to note that more than half had a urinary pH of 5.5 or less, and were thus on the acid side. Only 3 were alkaline enough to have pH of 7.0 or higher, and one of these was undoubtedly due to diet. Furthermore, if one excludes those cases in which there was no analysis of the stone, either because it was lost or because it was still in the kidney, the majority of the calculi were preTABLE
2.-Ninety cases of calculus per cent
54
Urine infected with urea-splitting bacteria .... Urine infected with non-urea-splitting bacteria .. Urine sterile ...
TABLE
19
27
3.-Average pH, stone composition, and percentage of recitrrences in cases with sterile urine and with urea-splitting infections STERILE URINE
Average pH ................. Stone composition .. Per cent of recurrence ... ...
5.5 Oxalate, uric acid
29
URINE INFECTED WITH UREASPLITTING BACTERIA
7.0 Phosphate, carbonate 73
dominantly oxalate or uric acid; there were only 3 cases in which the stone was composed chiefly of phosphate or carbonate, one of which was a case of hyperparathyroidism. There were 7 recurrences out of the 24 cases (29 per cent). Thus it appears that in general, in contrast to the case in urea-splitting infections, sterile urines are apt to be on the acid side, and that stones in such cases are apt to be composed of oxalate or of uric acid (table 3). When one analyzes these figures, the number of cases in which ureasplitting bacteria were the apparent cause of the stone formation was impressive. They comprised slightly more than half (54 per cent) of the total cases of stone, and nearly three quarters (74 per cent) of all infected cases. As for recurrences, the average for recurrences in the 49 urea-splitting cases was 73 per cent or nearly three quarters. This 73
BACTERIAL INFECTIONS AND URINARY CALCULI
595
per cent is in marked and horrible contrast to the 23 per cent of recurrences in non-urea-splitting infections, and the 29 per cent of recurrences in the cases with sterile urines. Taking the evidence as a whole, there can be no doubt that the ureasplitting infections are associated with the most frequent, the most active, and the most stubborn stone formation known. The discussion of therapy is not the purpose of this paper, but the inference is clear that it is of the very greatest importance to eradicate urea-splitting infections of the urinary tract by medical and surgical means, especially after the removal of stones to prevent continued stone formation. 352 Marlborough St., Boston, Mass. REFERENCES ALBRIGHT, DIENES AND SULKOWITCH: J. A. M. A., :110: 357, 1936. BURNS, E.: Surgery, 4; 673, 1938. HAGER, B. H.: J. Urol., 15: 133, 1926. HELLSTROM, J.: Brit. J. Urol., 10: 348, 1938. HIGGINS, C. C.: J. Urol., 40: 184, 1938. KEYSER, L. D.: Bull. New York Acad. Med., 14: 76, 1938; J. Urol. 31: 219, 1934. LETT, H.: Brit. J. Urol., 8: 205, 1936. RovsmG, C.: Cited by FOWLER, H. A.: Urol. & Cutan. Rev., 38: 594, 1934. SCHOLL, A. J.: Cabot's Modern Urology, vol. 2, Philadelphia, Lea & Febiger, p. 604, 1936. THOMPSON AND ScHULTE: Proc. Staff Meet. Mayo Clin., 14: 361, 1939. TWINEM, F. P.: J. UroL, 37: 259, 1937.