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The Relationship of Urinary infections to Recurrent Calculi1
THE RELATIONSHIP OF URINARY INFECTIONS TO RECURRENT CALCULI1 LINWOOD D . KEYSER
Roanoke, Virginia
The problem of the etiology of urinary stone is of intriguing interest. In spite of numerous hypotheses, mostly speculative and without basis of fact, urologists as a whole feel constrained to declare that the causative factors are veiled in obscurity. Scientific investigation of the problem has concerned itself chiefly with two factors, viz., metabolic perversions and specific infection. Closely related to these factors and modifying their action, are recognized urostasis, the reaction of the urine, and its concentration. EVIDENCE FOR METABOLIC DISTURBANCE AS A CAUSE OF CALCULUS
As evidence for a metabolic perversion as a cause of stone we may cite these facts . Vitamine A deficient diet fed to rats produces calcium phosphate stones (Osborne, Mendel and Ferry, Fujimaki, McCarrison, Van Leersum and Higgins) . Animals with Eckfistulae develop uratic calculi. Intensely excessive excretion of normal urinary cystalloids produces stone formation . Clinically this occurs with excessive uric acid and urate excretion; likewise to a variable degree in profuse oxalurias and phosphaturias. Experimentally it has been shown by myself and others that artificially produced excessive oxaluria will produce stone under aseptic conditions. Crystalloids normally foreign to the urinary tract excreted therein by metabolic perversion are often found clinically as calculi. Cystin, xanthin, indigo and urostealith are examples. Experimentally 1 Read before the thirtieth annual meeting of American Urological Associ~tion, Chicago, Illinois, June 21, 1933. 219
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I have shown that feeding oxamide (diamido oxalic acid), a crystalloid foreign to the urinary tract, produces aseptic calculosis of this type. Colloids normally absent in the urine when they do find entrance may give rise to stone formation. I refer to fibrin calculi consisting of calcium phosphate and fibrin in alternating layers. EVIDENCE OF SPECIFIC INFECTION AS A CAUSE OF STONE
Clinically, stones formed in alkaline urines are almost constantly found associated with urea-splitting bacteria. Various strains of staphylococci, streptococci, B. coli, and proteus ammoniae are most frequent in incidence. The endemic calculosis of bilharzia infestation is significant. With chronic suppurative wounds, osteomyelitis, spinal fractures, arthritis deformans (see case 13), stone is not uncommon. Likewise, congenital anomalies which interfere with urinary drainage, ureteral obstruction, bladder diverticula, vesical neck obstructions and renal neoplasms predispose to a higher incidence of calculus formation. Infection with urostasis appears at fault. Experimentally, I showed in 1921, that bits of muscle tissue placed surgically into the rabbits kidney pelvis become encrusted in the presence of colon bacillus infection. With no infection the tissue disintegrated and passed away. Rosenow and Meisser produced calculi in dogs by implanting into their devitalized teeth, streptococci from the infected teeth of patients with recurrent lithiasis. Hager and Magath developed alkali encrusted cystitis and vesical calculi in the bladders of rabbits and guinea pigs with B. proteus ammoniae isolated from urines of stoneforming patients. FURTHER EXPERIMENTAL PRODUCTION OF CALCULI WITH STONEFORMING STREPTOCOCCI
In 1931 I isolated a Gram-positive non-hemolytic streptococcus from the urine of a patient with rapidly recurring concrements (case 14). Following the technique of Hager and Magath, I introduced 5 cc. of an eighteen-hour dextrose brain broth culture of this organism into the bladders of 6 rabbits which had been chem-
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ically irritated by an instillation five days previously of 0.5 cc. of a 1: 1000 alcoholic salicylic acid solution. Two of these ani-
FIG. 1.
INTENSE CALCULOSIS FROM INFECTION WITH STREPTOCOCCI FROM URINE OF CASE 16
Note encrusted cystitis, dilated ureters, and pyonephrosis. Multiple concrements in bladder and both kidneys. Rabbit. Experiment X. Five weeks after infection
mals killed three and five weeks later developed calcareous encrustations of the bladder and minute calculi. During 1932-33 a most intensive recurrent stone former has been under observation (case 16). Again Gram-positive strep~
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tococci urme.
Fm. 2.
been isolated repeatedly in pure culture from the few months ago intravesical instillations of d-brain
ENCRUS'J'ED CYSTITIS AND VESICAL CALCULI PRODUCED BY STREPTOCOCCI FROM URINE OF PATIENT WITH STONE-FORMING KIDNEYS
Four weeks after infection.
Experiment XIV
broth cultures were given to 10 rabbits after the previous lishment of chemical cystitis. two to six weeks the animals
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were killed. Four showed definite evidence of encrusted cystitis. In 2 rabbits definite calculi were obtained (figs. 1 and 2). The intensely purulent urine from which the streptococci were recovered, the encrusted cystitis, dilated ureters and pelves, all the site of abundant calcareous material clogging the urinary passages are shown in figure 1. At present I am studying the features of this type of stone formation in more .detaiL Therefore, this experimental evidence for specific infection as a cause stone is presented as a preliminary report. THE MECHANISM OF STONE FORMATION
Years ago Rainey and Ord and Shattock demonstrated that urate and calcium oxalate crystals when precipitated from colloidal solutions assumed widely different forms, some tending to remain isolated and others, chiefly spherical in morphology tending to agglutinate and fuse together. Ord found that uratic and oxalatic calculi were made up of these spherular fusing crystals. Lichtwitz and Schade determined urine to be supersaturated with water insoluble crystalloids held in a state of dispersion absorption to irreversible protective colloids. In concentrated stagnant urines the colloidal particles coalesce to form a "gel," thus losing their surface energy, their adsorptive power and thereby allowing the water insoluble crystalloids to be precipitated and become enmeshed in the organic framework of the forming "geL" Schade produced a calculous mass by simultaneously precipitating fibrin and calcium phosphate from the same solution. In experimental oxamide and oxalate calculosis I demonstrated that the stones were made up of urinary pigment plus fusing coalescent spherular types of crystal. Beer found uric acid showers and stones accompanied by urinary sediments which showed atypical coalescent crystals of uric acid. Likewise, in four patients passing showers of calculi, I have been able to demonstrate by a microscopic study of urinary sediments or of soft stones crushed on a slide that these also consisted of the fusing spheroidal of crystal (fig. 3). The work of Hellstroem,
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FIG. 3. SEDIMENTS FROM URINES SHOWING FUSING SPHERICAL CRYSTALS A. Rabbit with oxamide lithiasis. B. Rabbit with experimental oxalate calculosis. C. Patient passing calcium oxalate calculi. D. Patient passing amorphous phosphate calculi. E. Patient passing triple phosphate and carbonate stones. F. Patient passing alkaline earth phosphate calculi.
Meyer, Newcomb and Eisenstadt, chiefly from dialysis experiments, discredits this evidence that stones are formed by precipitation of the protective colloids simultaneously with that of spheroidal crystals. They hold that calculus deposition is re-
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lated entirely to changes in the hydrogen ion concentration, as influenced chiefly by alkaline infection. These investigators fail to realize however that changes in H-ion concentration alone produce neither stone nor crystals of coalescent stone forming type either in ~"'''""~'- experimentation or in vitro. The urinary reaction does determine the chemical composition of precipitated but it neither affects their morphology nor their ability to fuse to form concrements. Simultaneous gelling the urinary colloids seems necessary for this process. The colloidal chemical mechanism of infectious calculosis and of vitamine deficiency stone is as yet not demonstrated. Eisenstadt finds bacteria as the nuclei of stones. He feels therefore that infectious calculosis takes place by the encrustation of urinary salts on bacterial clumps. Vitamine A deficiency calculus is variously explained by encrustation on effete keratinized urinary tract epithelium, by infection as the result of lowered resistance, or merely by the intense alkalinity of the urine. \V-hether or not these processes take place by coalescence atypical crystals precipitated in colloidal gels is a fertile field for investigation. The problem of infectious calculosis becomes involved with calcification of necrotic tissues, as in encrusted cystitis and is thereby even more complex. CORRELATION OF DATA RELATIVE TO CAUSE OF CALCULOSIS
Albarran divided calculi into primary stones and those secondary to infection. Primary stones include uric acid, sodium urate and calcium oxalate, deposited in urines tending toward an acid range as well as crystalline calcium carbonate and calcium phosphate, precipitated in urines faintly acid or neutral. In addition cystin and xanthin stones belong to this group. Primary stones were held to be aseptic but this is not consistently true in clinical experience. However, they do include those calculi associated with known metabolic error and are probably aseptic at the beginning. Secondary calculi composed of ammonium magnesium phosphate and amorphorus calcium phosphate and carbonate are precipitated in urines which are alkaline. They are found asso-
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ciated with urea-splitting organisms which in addition to lowering the H-ion concentration act in some biologically specific manner to precipitate stone forming crystals. Calculus may start as an aseptic process and secondary infection may occur to produce deposition of phosphates upon the primary stone as a nucleus. Lamination may be explained by such a process. Urostasis per se does not cause stone as is attested by all experimental and clinical investigation. However, in maintaining urinary infection and thereby favoring recurrence it is a factor of greatest importance. Consequently its removal becomes an immediate objective in therapeutic attack. We can do little to prevent the initial formation of calculus. Clinicaly the problem will be to remove the stone and to prevent its recurrence. Recurrence is estimated as from 4 to 25 per cent varying with the series of cases reported. Judd and Scholl and Braasch and Foulds estimated 10.3 per cent recurrence in 1413 cases of renal calculus; 11.8 per cent recurred following pyelolithotomy, 24.3 per cent following nephropelviolithotomy. Small stones are more likely to be associated with recurrence than larger calculi. Branched stones seem more prone to recurrence than smoother varieties. Certain individuals seem especially liable to recurrent lithiasis. This may be at the same site or at different parts of the urinary tract, first one side being involved and then the other. Removal of calculi is only the starting point for a renewal of the stone-forming process. We may speak of such patients as being afflicted with "stone-forming kidney." The most rapid stone formers are those with recurrent ureteral calculi, these probably arising in the kidney above. Another perhaps smaller group tend to confine calculosis to the kidneys and suffer repeated surgical removal of calculi at intervals of months to years. Recurrent vesical calculus is less frequent in evidence. Stones most frequently associated with recurrence are phosphates and carbonates. Recurrent uratic and oxalate stones however are not infrequently noted. As a rule recurrent con-
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crements are chemically distinct and not mixed varieties and are of the same composition as their predecessors. CLINICAL FEATURES OF RECURRENT CALCULI
While working as a fellow in the Mayo Foundation on experimental lithiasis twelve years ago under the direction of Dr. W. F. Braasch, I was given opportunity to study twelve cases of intensive recurrent lithiasis in the Section on Urology. I briefly outline some features presented by this group of patients. The 12 patients were males from twenty-seven to fifty-eight years of age. Six suffered from recurrent ureteral calculi alone while 6 had recurrent renal and ureteral stones. The recurrences occurred at intervals of one month to twenty years. The duration of the active stone forming period was from two to twenty years. The chemistry of the stone passed or removed showed: 2 Uric acid and urates (both infected). 1 Calcium carbonate. 2 Calcium oxalate (1 negative culture and no pus in urine). 1 Calcium oxalate-calcium phosphate. 2 Ammonium magnesium phosphate. 1 Ammonium magnesium phosphate and calcium carbonate. 1 Calcium phosphate and calcium carbonate. 2 Not determined. Cultures of the urine showed: 2 Gram-positive staphylococci. 1 Gram-positive streptococci. 1 Gram-positive streptococci and staphylococci. 2 Gram-positive streptococci and Gram-negative bacilli. 1 No growth on several efforts (calcium oxalate). 5 Not cultured. Pyuria: Some degree was present on admission in 11 cases. Blood cells were noted in 3 cases. One patient was pus-free and the urine bacteria-free (calcium oxalate stone). Two patients with uric acid calculi showed only an occasional pus cell but cultures of the urine showed Gram-positive streptococci in one case and Gram-positive staphylococci with Gram-negative bacilli in the second.
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Foci of infection: The patients uniformly presented possible foci of infection as follows: 10 Infected tonsils and teeth. 1 Infected teeth and chronic parasinusitis (flare of sinusitis associated with exacerbation of calculosis). l Infected teeth and tonsils. Pyorrhea. Prostatic and infection. RESULTS
Following the removal of foci of infection which was routinely carried out as far as possible, following cystoscopic or removal of calculi present and in some instances post-operative renal lavage the results were as follows: Four patients regarded themselves as cured or greatly improved without recurrence after two or more years. They had a minimal or absent pyuria. Four patients were benefited but had residual urinary infection with pyuria. There had been no recurrence of stone. Three patients had had recurrence of calculi and pyuna or dysuria after two or more years. Animal experimentation: Green producing streptococci recovered from the tonsils or teeth of nine of the patients of this group produced experimental calculosis in dogs when implanted in devitalized teeth by Drs. Rosenow and Meisser. Crystallography of urinary sediments or crushed soft stones: Several of these patients passed sandy masses or soft stones which could be easily crushed on a slide to make a suitable preparation for study. In four instances it was possible to demonstrate that the fundamental component units of the forming stone consisted of atypical spherular coalescing or fusing crystals, highly suggestive of the influence of urinary colloids on the process.
During ten years of private practice I have had 16 patients with recurrent lithiasis who were observed over a period long enough to allow a detailed study with an effort to determine etiologic factors at fault. A summary of the clinical derived from this study is of interest. Of the 16 cases 10 were males, aged twenty-six to forty-nine
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years, and 6 females, aged twenty-five to fifty-three years. Ten suffered from recurrent ureteral calculi alone while 6 had recurrent renal and ureteral stones. The 6 patients with recurrent renal stone all gave a history of having passed calculi at some time. The interval of recurrence varied from two weeks to seven years. The duration of the stone-forming period was from one month to thirty-seven years (case 3). The chemistry of stones passed or removed showed: 1 Urates (negative culture-no pyuria). 6 Calcium carbonate. 1 Calcium phosphate and calcium carbonate. 2 Ammonium magnesium phosphate. 6 Not determined. Cultures of the urine on admission showed: 5 Gram-negative bacilli. 1 B. coli and B. proteus. 1 Gram-positive streptococci. 6 Not made. 1 Culture not obtained after several efforts (aseptic) (urates). Pyuria: Varied from grade I to grade IV on admission in 15 cases. Only one, the uratic calculus former, was pus-free. Blood cells were noted occasionally. Urinary reaction: The urines of all patients but one were alkaline to litmus. When the pH was determined (8 cases) it was found above pH 7 in all cases but one. The patient passing uratic calculi had a urinary pH of 5. 6 Foci of infection: Possible foci of infection were present as follows: 4 Infected teeth and tonsils. 1 patient also had chronic prostatitis and chronic appendicitis. 1 Chronic endocervicitis. 4 Infected tonsils-I questionable dental infection. 1 Infected teeth. Tonsils previously removed. Questionable appendicitis. l Infected teeth and tonsils previously removed. Chronic endocervicitis, on admission. 3 Infected tonsils previously removed. l had chronic endocervicitis and 1 chronic arthritis deformans on admission. Treatment: Removal of stones by catheter manipulation or operation in all cases but one. Periodic cystoscopic lavage with frequent use
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of indwelling catheters and of ureteral dilatation with bulbs. Removal of foci of infection (incomplete in 9 cases because of improvement in health or lack of cooperation). Regulation of diet with regard to chemistry of stone and high vitamine A content. Change of pH of urine to high acidity by inorganic acids, acid ash diet, ammonium nitrate, and recently ketogenic diet. Results: All patients who had their calculi removed are stone-free at present. One has a small stone which has changed very slightly in size in six years. Ten pass urine pus- and bacteria-free after one to eight years. Four pass urine with occasional pus cell to grade I. Only two at present have pus which at intervals is graded above I. These are still under treatment. CASE REPORTS
Case 1. R. H. No. 228. 1923. Male, aged thirty. Recurrent bilateral ureteral calculi over ten years since 1918. Ammonium magnesium phosphate. Pus I-IV. Cultures of urine: B. coli and B. proteus. Alkaline urine. Foci: Tonsils and teeth removed 1923. Recurrent passage stones until May, 1928. Acidification of urine. Oral urinary antiseptics. Began renal lavage and dilatation of ureters January, 1927. Repeated every three months for two years. Gradual subsidence of infection. X-ray negative. Urine occasional pus cell 1933. Stone free since 1928. Case 2. R. H. No. 30. 1925. Male, aged thirty. Recurrent bilateral ureteral calculi two years. Calcium carbonate. Urine: Pus I-II, B. coli, pH 7.8. Removal of tonsils and teeth. Ureteral dilatation and renal lavage. Urine pus-free and no recurrence after six years. Case 3. R. H. No. 2532. 1926. Male, aged forty-nine. Recurrent calcium carbonate ureteral calculi-intervals one to two years for thirty-seven years. Alkaline pyuria grade I. Repeated renal lavage with ureteral dilatation several months. Pyuria I-1932. No recurrence in seven years. Caie 4. R.H. No. 6337. 1928. Male, aged forty-one. Repeated right ureteral calculi six months. Calcium carbonate. Pyuria II, alkaline. Repeated cystoscopic lavage and ureteral dilatation. No recurrence after one year. Urine pus- and bacteria-free.
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Case 5. R. H. No. 6951. 1929. Female, aged fifty~three. Repeated right ureteral calculi over two years. Admitted with septic right kidney. Stone impacted lower right ureter. Pyuria IV; B. coli and Gram-positive staphylococci; alkaline. Stone removed by cystoscopy from ureter. Stricture at ureteropelvic juncture associated with fulminating pyonephrosis necessitated right nephrectomy. Recovery. Urine pus- and bacteria-free in 1933. No recurrence of stone. Case 6. R. H. No. 7078. 1929. Female, aged thirty-eight. Repeated right ureteral colic for five years. Several stones passed. Pyuria B. coli; pH 7; chronic endocervicitis. Bilateral hydronephrosis grade I with ureters dilated. Cystoscopic lavage and ureteral dilatation. Occasional ureteral colic but urine pus-free and no recurrence of stone since 1929. Case 7. R. H. No. 9516. 1930. Female, aged thirty-four. Recurrent ureteral calculi one year.. Toxic goitre, seven years. Pyuria IV; B. coli (bilateral); alkaline. Stones manipulated from both ureters, Thyroidectomy with recovery, Cystoscopy with ureteral dilatation over two months. No recurrence of calculus. No pyuria after one year. Case 8. R.H. No. 9755. 1930. Male, aged thirty-three. Passage gravel right ureter for one year. Admitted: Stone impacted right ureter; urosepsis. Pyuria IV; R.B.C. III; B. coli. Alkaline. Cystoscopic removal calcium carbonate stone. Renal lavage with ureteral dilatation, urinary antiseptics and acidification of urine. No recurrence. Urine-pus and bacteria-free, 1932. Case 9. R. H. No. 12279. 1931. Male, aged thirty-five. Recurrent left ureteral calculi over six months. Passed stone after administration of narcotic. Pyuria II, R.B.C. IV from left kidney. Alkaline. Cystoscopic dilatation of ureters. No recurrence. Urine-pus and bacteria-free, 1933. Case 10. R.H. No. 12279. 1931. Male, aged 39. Bilateral recurrent ureteral calculi over seven years. Pyuria IV; B. coli; pH 7.2. Chronic prostatitis. Stone manipulated from left lower ureter. Prostatic massage. Urethral and bilateral ureteral dilatation. Acidification of urine. No recurrence. Urine occasional pus cell.
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Case 11. R. H. No. 2594. 1926. Female, aged twenty-five. Stone removed right kidney 1920. Recurrence and second right pelviolithotomy 1921. Recurrence right pyonephrosis-right nephrectomy 1923. Passage stone left ureter 1924. Recurrent very small shadow in 1926 proved by urogram. Frequent attacks of pyelonephritis since. Admitted 1926: Pyuria I-IV; B. coli; pH 7.3. Chronic endocervicitis. Repeated renal lavage and ureteral dilatation. Indwelling catheters. Urine pus-free and cultures negative at times. In 1932 after an interval of eighteen months since cystoscopy had intense pyelonephritis. Relief by cystoscopy. The calculus in this patient heretofore an intensely rapid stone former has increased very
Fm. 4.
RECURRENT CALCULUS IN LEFT UPPER CALYX WHICH HAS INCREASED VERY SLIGHTLY IN S1zE OVER Six YEARS
Previous rapid recurrence and growth of stones had required right nephrectomy. Case 11.
slightly in size over a seven year period (fig. 4). Phosphoric acid lavage attempted but patient intolerant. Removal of calculus by surgery advised when larger. Periodic pelvic lavage advised. Case 12. R. H. No. 3081. 1926. Male, aged twenty-six. Recurrent passage stone left ureter for eleven years since attack typhoid. Long intervals. Admitted with pain left kidney area. Pyuria I; alkaline. Infected tonsils. X-ray shadow 2 by 1 cm. left renal pelvis proved by urography. Left pelviolithotomy. Cystoscopic dilatation of left ureter. No recurrence. Urine pus- and bacteria-free after six years (1932). Case 13. R. H. No. 3074. 1926. Male, aged thirty-one. Seven years previous to admission passed several stones from bladder.
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Recurrent pain left kidney area. Intense arthritis and spondylitis deformans. Alkaline: pyuria L X-ray: large stone right pelvis. Peviolithotomy. Calcium carbonate and phosphate, Ureteral dilatation, acidification of urine. Urinary antiseptics. No recurrence. Urine pus- and bacteria-free 1932 (six years). Case 14. R. H. No. 10108. 1930. Male, aged thirty-eight Seven-year history pain in back. Passage gravel at times. Recent attack right side. Urine: Bladder, pus IV, R.B.C. IV. Gram-positive streptococci, both kidneys (produced experimental calculosis in ani-mals). Urine alkaline. Tonsils previously removed. X-ray Novem-
FIG. 5, CASE 14
A. November, 1930. Impacted stone right lower ureter. Small calculusleft calyx, Ureteral stone removed. B. March, 1931 (interval four months). Enor-mous growth of left renal calculus. Required nephrectomy.
her 17, 1930: calculus right lower ureter. Small stone 0.5 cm. left kidney. Impacted stone manipulated from right ureter (multiple catheter method under spinal anesthesia). Left pelviolithotomy refused. 1931, readmitted, septic condition. X-ray: right kidney and ureter clear. Left kidney, stone seen in November (0.5 cm previously) has increased in size filling pelvis and calyces (fig. 5). toscopy: calculous left pyonephrosis with functionless left kidney and urosepsis. Left nephrectomy. Stone-ammonium magnesium phosphate. Interval dilatation of right ureter and lavage since. Acidification of urine. Urine pus-free and culture negative March, 1933. No recurrence in two years.
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Case 15. R. H. No. 11021. 1931. Female, aged thirty-five. Passage of small stones and sand both sides one year. Urates. Urine: No pus or blood cells. Culture negative; pH 5.6. X-ray: small shadow left kidney area included in urogram. Tonsils and teeth infected. Removal refused. Blood uric acid 5 mgm. Low purin diet. Cystoscopic renal lavage and ureteral dilatation. No recurrence after one year (1932) . Case 16. R. H. No. 12536. 1931. Female, aged forty-five. Passage stones from right kidney two years-once from left. Stones passed and those subsequently removed were pure calcium carbonate. Pyuria I-IV. Culture: Gram-positive, pleomorphic streptococci (these organisms produced experimental calculosis in rabbits) . React ion pH 7.2. Foci: Infected teeth, chronic cervicitis. X -ray : October, 1931, large stone right kidney area-left clear. Cystoscopy calculous destruction of right kidney. Pus III from right ureter. Left compensatory hypertrophy. Right urine pH 7.2; Gram-positive streptococci; left urine pH 7; culture negative. March 20, 1932, X -ray: stone on right markedly increased in size- left clear. R ight nephrectomy. Large stag horn stone with many small calculi in calyces. Convalescence uneventful while in hospital. April 22, 1932 (thirty-one days after operation), left-sided colic and oliguria with fever. Relief by catheter drainage. K.U.B. showed multiple calculi in left kidney. Urine (left): pus IV; pH 7.2; culture Gram-positive streptococci. Treatment: High vitamine diet, acidification of urine using dilute aqua regia, hydrochloric acid, chloride and nitrate of ammonia alternately. pH shifted to 4.5 to 5, where it has been maintained almost constantly, since. Dilatation of ureter to 18-F at intervals. Indwelling catheters. Pyuria diminished and size of calculi in left kidney diminished during next month. Two small calculi (fig. 6) persisted and could not be made to pass. Urogram May 1932: progressive hydronephrosis. Continuous irrigation of renal pelvis with 1 per cent phosphoric acid with multiple indwelling catheters over several days attempted but patient intolerant to this after one or two hours. Stone wandered into the ureter to be pushed back into the pelvis by the ureteral catheter as shown by x-rays (fig. 6) over several months until September, 1932. The patient began to have frequent chills and fever and required catheter for relief. K.U.B.: September 16, 1932 showed both stones in the kidney area. These removed by pelviolithotomy. Convalescence normal. Repeated cystoscopic irrigation at intervals of two to four
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weeks since. Maintenance of high urinary acidity with drugs and ketogenic diet keep the pyuria to grade I. Cessation of acid therapy results in alkalinity to pH 7 and increase in pyuria. Neoarsphenamine
Fm. 6. CASE 16 Rapid growth of right calculus, November, 1931, to March. 1932. Right nephrectomy, March, 1932. Recurrence multiple stones left kidney April, 1932 (thirty days after nephrectomy). May, 1932, K.U.B. shows diminution of calculus with urinary acidification. Hydronephrosis. Operation removed two stones from pelvis September, 1932. June, 1933, K.U.B. and intravenous urogram. No recurrence.
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and various oral antiseptics have been tried. At present (June, 1933), the two-hour phthalein is 60 per cent. Intravenous urogram (fig. 6) shows a fairly good pelvis without hydronephrosis. Patient in good general health. Urine while acid and taking urotropin or caprokol contains little pus. Streptococci still obtained in culture. IMPRESSIONS FROM ANALYSIS OF CASES
Recurrent calculi of the secondary type of Albarran (amorphous calcium carbonate and phosphate and triple phosphate) are produced by specific urea-splitting organisms, the colon, proteus, staphylococcic and streptococcic groups being most frequent in incideii'.ce. Urostasis by keeping up infection is of great importance in recurrence and a chief point of attack in therapy. The role of focal infection is probably important but not altogether clear. Just why teeth infected with streptococci should produce a stone-forming infection where proteus, colon bacilli or staphylococci are found in the urine is difficult. to ;explain unless one believes these latter organisms are secondary irlvaders. Metabolic disturbances, dietary irregularities and vitamin deficiency except in the case of uratic, and possibly of calcium oxalate stones, from these 28 case studies have not been elucidated. With the evidence at hand: it may not be presumptuous to outline a tentative therapeutic program for the prevention of recurrence of stone. This should include: \ · 1. Removal of existing· calculi as f~ras p,racticable,by surgery or cystoscopy. Use •Of the :fluoroscope at operatio;n, avoiding exposure of suture' material to the ilrinary strea'.m, and the insurance of adeq_u:ite urinary drainage should b~ practised. 2. Shift the hydrogen ion concentration to the opposite of what it was when the stone was formed. This will usually mean acidification of the urine. The ketogenic diet is of great value here and will enjoy wider usage as the result of the work which Dr. Clark has presented today. I have used dilute aqua regia, and the nitrate and chloride of ammonia altetnately or together with good result. 3. A qualitative chemical examination of the stone obtained should
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4.
5. 6.
7.
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9.
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be routinely practised. In uratic and oxalate stones a dietary affording a low intake in these chemicals should be prescribed. With regard to phosphatic and carbonate calculi, no very definite evidence of dietary control has been presented. Vitamine A increase in the dietary is worthy of trial but its place as a factor in urolithiasis is still very uncertain and rests entirely on isolated and indefinite experimentation on rats. Foci of infection should be removed. Repeated x-ray immediately and at periods six months to one year after operation, should be practised. Every patient with urinary calculus has a 4 to 20 per cent chance for recurrence. In treatment this should be borne in mind. Removal of stasis points in the urinary tract by surgery or cystoscopy should be attempted for in urostasis lies our chief obstacle to the eradication of infection. I have practised renal lavage and dilatation of the ureters with bulbs and indwelling catheters in 16 cases. Their freedom from calculus and from gross infection has endured long enough to make me feel that the procedure is of definite value. Urinary antiseptic drugs may be used as adjuvants, especially urotropin if care is taken to keep the pH below 5.6. With this exception, I believe they offer us little in the way of clearing up infection. Irrigation of the renal pelvis with phosphoric acid as advocated by Randall seems of value. The possibility of dissolving alkaline earth calculi in situ by intense urinary acidification inevitably comes up. Unquestionably in my case 16, I reduced the size of the stone by urinary acidification with drugs by mouth. Dilute phosphoric and other acids by catheter irrigation however failed to reduce the two troublesome fragment which remained. CONCLUSION
Aseptic urinary concrements may be formed in consequence of metabolic errors. Pure uratic, cystin and xanthin stones are known examples. While not definitely pr~ven, calcium oxalate and crystalline carbonate and phosphate calculi may at times have such an origin. Stones composed chiefly of triple phosphate and the amorphous carbonate and phosphate of calcium are formed in alkaline urine
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probably the result of specific urea-splitting organisms. These are the varieties of calculi most frequent to recur and those which are seen most often in patients with stone-forming kidneys. Therapy directed toward the relief of urostasis and clearing up of infection is rational and attended with good result. The mechanism of the formation of urinary concrements as determined by physical chemists and by animal experimentation seems to consist of the coalescence of atypical crystals in the gels of urinary colloids.
Medical Arts Building, Roanoke, Va. REFERENCES (1) KEYSER, L. D., AND BRAASCH, W. F .: The etiology of urinary Iithiasis. International Abstract of Surg., January, 1922, 1-10. (Complete bibliography to date.) (2) KEYSER, L. D.: The mechanism of the formation of urinary calculi. Ann. Surg., February, 1923, 210-222. KEYSER, L. D.: The etiology of urinary lithiasis: An experimental study. Arch. Surg., 1923, vi, 525-553. KEYSER, L. D.: Urinary lithiasis: Its cause and prevention. An evaluation of contributions to our knowledge during the past decade. South. Med. Jour., 1932, xxv, no. 10, 1031-1040. (Complete bibliography to date.) (3) BRAASCH, W. F.: Recurring renal lithiasis. Proc. Staff Meet. Mayo Clinic, March, 1932, vii, 169. (4) SCHULTEIS, G.: Histologische Untersuchungen an Steinnieren. Zts. f. Urol. Chir., March, 1931, xxxi, 196. (5) EISENSTADT, J . E.: Certain tangible factors in the etiology of urinary calculus. Trans. Chicago Urol. Soc., 1931, i, 65-72. EISENSTADT, J . E.: Surg., Gynecol. and Obstet., liii, 730. (6) RANDALL, A. : Recurrent calculi in the urinary tract. Ann. Surg., 1932, 133- 139. RANDALL, A.: Prevention of the recurrence of urinary calculi. Amer. Jour. Surg., 1932, N. S., xviii, no. 3, 482-485. (7) HIGGINS, C . C.: The experimental production of urinary calculi. Jour. Urol., 1933, xxix, no. 2, 157-171. (8) RAVICH, A.: Critical study of ureteral calculi. Jour. Urol., 1933, xxix, no. 2, 171-197. (9) CooK, E . N., AND CLARK, A. L.: Oxaluria. Proc. Staff Meet. Mayo Clinic, 1933, viii, no. 15, 222-226. (10) LIVERMORE, G. R.: Ureteral calculi. Amer. Jour. Surg., 1933, xx, N. S., no. 2, 214-222. (11) PEDERSEN, V. C.: Calculous prostatitis (anatomical cure), colon bacilluria. General treatment (physiological cure) . Med. Times, 1932, Ix, no. 11, 337.
Roanoke, Virginia
The problem of the etiology of urinary stone is of intriguing interest. In spite of numerous hypotheses, mostly speculative and without basis of fact, urologists as a whole feel constrained to declare that the causative factors are veiled in obscurity. Scientific investigation of the problem has concerned itself chiefly with two factors, viz., metabolic perversions and specific infection. Closely related to these factors and modifying their action, are recognized urostasis, the reaction of the urine, and its concentration. EVIDENCE FOR METABOLIC DISTURBANCE AS A CAUSE OF CALCULUS
As evidence for a metabolic perversion as a cause of stone we may cite these facts . Vitamine A deficient diet fed to rats produces calcium phosphate stones (Osborne, Mendel and Ferry, Fujimaki, McCarrison, Van Leersum and Higgins) . Animals with Eckfistulae develop uratic calculi. Intensely excessive excretion of normal urinary cystalloids produces stone formation . Clinically this occurs with excessive uric acid and urate excretion; likewise to a variable degree in profuse oxalurias and phosphaturias. Experimentally it has been shown by myself and others that artificially produced excessive oxaluria will produce stone under aseptic conditions. Crystalloids normally foreign to the urinary tract excreted therein by metabolic perversion are often found clinically as calculi. Cystin, xanthin, indigo and urostealith are examples. Experimentally 1 Read before the thirtieth annual meeting of American Urological Associ~tion, Chicago, Illinois, June 21, 1933. 219
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I have shown that feeding oxamide (diamido oxalic acid), a crystalloid foreign to the urinary tract, produces aseptic calculosis of this type. Colloids normally absent in the urine when they do find entrance may give rise to stone formation. I refer to fibrin calculi consisting of calcium phosphate and fibrin in alternating layers. EVIDENCE OF SPECIFIC INFECTION AS A CAUSE OF STONE
Clinically, stones formed in alkaline urines are almost constantly found associated with urea-splitting bacteria. Various strains of staphylococci, streptococci, B. coli, and proteus ammoniae are most frequent in incidence. The endemic calculosis of bilharzia infestation is significant. With chronic suppurative wounds, osteomyelitis, spinal fractures, arthritis deformans (see case 13), stone is not uncommon. Likewise, congenital anomalies which interfere with urinary drainage, ureteral obstruction, bladder diverticula, vesical neck obstructions and renal neoplasms predispose to a higher incidence of calculus formation. Infection with urostasis appears at fault. Experimentally, I showed in 1921, that bits of muscle tissue placed surgically into the rabbits kidney pelvis become encrusted in the presence of colon bacillus infection. With no infection the tissue disintegrated and passed away. Rosenow and Meisser produced calculi in dogs by implanting into their devitalized teeth, streptococci from the infected teeth of patients with recurrent lithiasis. Hager and Magath developed alkali encrusted cystitis and vesical calculi in the bladders of rabbits and guinea pigs with B. proteus ammoniae isolated from urines of stoneforming patients. FURTHER EXPERIMENTAL PRODUCTION OF CALCULI WITH STONEFORMING STREPTOCOCCI
In 1931 I isolated a Gram-positive non-hemolytic streptococcus from the urine of a patient with rapidly recurring concrements (case 14). Following the technique of Hager and Magath, I introduced 5 cc. of an eighteen-hour dextrose brain broth culture of this organism into the bladders of 6 rabbits which had been chem-
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ically irritated by an instillation five days previously of 0.5 cc. of a 1: 1000 alcoholic salicylic acid solution. Two of these ani-
FIG. 1.
INTENSE CALCULOSIS FROM INFECTION WITH STREPTOCOCCI FROM URINE OF CASE 16
Note encrusted cystitis, dilated ureters, and pyonephrosis. Multiple concrements in bladder and both kidneys. Rabbit. Experiment X. Five weeks after infection
mals killed three and five weeks later developed calcareous encrustations of the bladder and minute calculi. During 1932-33 a most intensive recurrent stone former has been under observation (case 16). Again Gram-positive strep~
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tococci urme.
Fm. 2.
been isolated repeatedly in pure culture from the few months ago intravesical instillations of d-brain
ENCRUS'J'ED CYSTITIS AND VESICAL CALCULI PRODUCED BY STREPTOCOCCI FROM URINE OF PATIENT WITH STONE-FORMING KIDNEYS
Four weeks after infection.
Experiment XIV
broth cultures were given to 10 rabbits after the previous lishment of chemical cystitis. two to six weeks the animals
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were killed. Four showed definite evidence of encrusted cystitis. In 2 rabbits definite calculi were obtained (figs. 1 and 2). The intensely purulent urine from which the streptococci were recovered, the encrusted cystitis, dilated ureters and pelves, all the site of abundant calcareous material clogging the urinary passages are shown in figure 1. At present I am studying the features of this type of stone formation in more .detaiL Therefore, this experimental evidence for specific infection as a cause stone is presented as a preliminary report. THE MECHANISM OF STONE FORMATION
Years ago Rainey and Ord and Shattock demonstrated that urate and calcium oxalate crystals when precipitated from colloidal solutions assumed widely different forms, some tending to remain isolated and others, chiefly spherical in morphology tending to agglutinate and fuse together. Ord found that uratic and oxalatic calculi were made up of these spherular fusing crystals. Lichtwitz and Schade determined urine to be supersaturated with water insoluble crystalloids held in a state of dispersion absorption to irreversible protective colloids. In concentrated stagnant urines the colloidal particles coalesce to form a "gel," thus losing their surface energy, their adsorptive power and thereby allowing the water insoluble crystalloids to be precipitated and become enmeshed in the organic framework of the forming "geL" Schade produced a calculous mass by simultaneously precipitating fibrin and calcium phosphate from the same solution. In experimental oxamide and oxalate calculosis I demonstrated that the stones were made up of urinary pigment plus fusing coalescent spherular types of crystal. Beer found uric acid showers and stones accompanied by urinary sediments which showed atypical coalescent crystals of uric acid. Likewise, in four patients passing showers of calculi, I have been able to demonstrate by a microscopic study of urinary sediments or of soft stones crushed on a slide that these also consisted of the fusing spheroidal of crystal (fig. 3). The work of Hellstroem,
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FIG. 3. SEDIMENTS FROM URINES SHOWING FUSING SPHERICAL CRYSTALS A. Rabbit with oxamide lithiasis. B. Rabbit with experimental oxalate calculosis. C. Patient passing calcium oxalate calculi. D. Patient passing amorphous phosphate calculi. E. Patient passing triple phosphate and carbonate stones. F. Patient passing alkaline earth phosphate calculi.
Meyer, Newcomb and Eisenstadt, chiefly from dialysis experiments, discredits this evidence that stones are formed by precipitation of the protective colloids simultaneously with that of spheroidal crystals. They hold that calculus deposition is re-
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lated entirely to changes in the hydrogen ion concentration, as influenced chiefly by alkaline infection. These investigators fail to realize however that changes in H-ion concentration alone produce neither stone nor crystals of coalescent stone forming type either in ~"'''""~'- experimentation or in vitro. The urinary reaction does determine the chemical composition of precipitated but it neither affects their morphology nor their ability to fuse to form concrements. Simultaneous gelling the urinary colloids seems necessary for this process. The colloidal chemical mechanism of infectious calculosis and of vitamine deficiency stone is as yet not demonstrated. Eisenstadt finds bacteria as the nuclei of stones. He feels therefore that infectious calculosis takes place by the encrustation of urinary salts on bacterial clumps. Vitamine A deficiency calculus is variously explained by encrustation on effete keratinized urinary tract epithelium, by infection as the result of lowered resistance, or merely by the intense alkalinity of the urine. \V-hether or not these processes take place by coalescence atypical crystals precipitated in colloidal gels is a fertile field for investigation. The problem of infectious calculosis becomes involved with calcification of necrotic tissues, as in encrusted cystitis and is thereby even more complex. CORRELATION OF DATA RELATIVE TO CAUSE OF CALCULOSIS
Albarran divided calculi into primary stones and those secondary to infection. Primary stones include uric acid, sodium urate and calcium oxalate, deposited in urines tending toward an acid range as well as crystalline calcium carbonate and calcium phosphate, precipitated in urines faintly acid or neutral. In addition cystin and xanthin stones belong to this group. Primary stones were held to be aseptic but this is not consistently true in clinical experience. However, they do include those calculi associated with known metabolic error and are probably aseptic at the beginning. Secondary calculi composed of ammonium magnesium phosphate and amorphorus calcium phosphate and carbonate are precipitated in urines which are alkaline. They are found asso-
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ciated with urea-splitting organisms which in addition to lowering the H-ion concentration act in some biologically specific manner to precipitate stone forming crystals. Calculus may start as an aseptic process and secondary infection may occur to produce deposition of phosphates upon the primary stone as a nucleus. Lamination may be explained by such a process. Urostasis per se does not cause stone as is attested by all experimental and clinical investigation. However, in maintaining urinary infection and thereby favoring recurrence it is a factor of greatest importance. Consequently its removal becomes an immediate objective in therapeutic attack. We can do little to prevent the initial formation of calculus. Clinicaly the problem will be to remove the stone and to prevent its recurrence. Recurrence is estimated as from 4 to 25 per cent varying with the series of cases reported. Judd and Scholl and Braasch and Foulds estimated 10.3 per cent recurrence in 1413 cases of renal calculus; 11.8 per cent recurred following pyelolithotomy, 24.3 per cent following nephropelviolithotomy. Small stones are more likely to be associated with recurrence than larger calculi. Branched stones seem more prone to recurrence than smoother varieties. Certain individuals seem especially liable to recurrent lithiasis. This may be at the same site or at different parts of the urinary tract, first one side being involved and then the other. Removal of calculi is only the starting point for a renewal of the stone-forming process. We may speak of such patients as being afflicted with "stone-forming kidney." The most rapid stone formers are those with recurrent ureteral calculi, these probably arising in the kidney above. Another perhaps smaller group tend to confine calculosis to the kidneys and suffer repeated surgical removal of calculi at intervals of months to years. Recurrent vesical calculus is less frequent in evidence. Stones most frequently associated with recurrence are phosphates and carbonates. Recurrent uratic and oxalate stones however are not infrequently noted. As a rule recurrent con-
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crements are chemically distinct and not mixed varieties and are of the same composition as their predecessors. CLINICAL FEATURES OF RECURRENT CALCULI
While working as a fellow in the Mayo Foundation on experimental lithiasis twelve years ago under the direction of Dr. W. F. Braasch, I was given opportunity to study twelve cases of intensive recurrent lithiasis in the Section on Urology. I briefly outline some features presented by this group of patients. The 12 patients were males from twenty-seven to fifty-eight years of age. Six suffered from recurrent ureteral calculi alone while 6 had recurrent renal and ureteral stones. The recurrences occurred at intervals of one month to twenty years. The duration of the active stone forming period was from two to twenty years. The chemistry of the stone passed or removed showed: 2 Uric acid and urates (both infected). 1 Calcium carbonate. 2 Calcium oxalate (1 negative culture and no pus in urine). 1 Calcium oxalate-calcium phosphate. 2 Ammonium magnesium phosphate. 1 Ammonium magnesium phosphate and calcium carbonate. 1 Calcium phosphate and calcium carbonate. 2 Not determined. Cultures of the urine showed: 2 Gram-positive staphylococci. 1 Gram-positive streptococci. 1 Gram-positive streptococci and staphylococci. 2 Gram-positive streptococci and Gram-negative bacilli. 1 No growth on several efforts (calcium oxalate). 5 Not cultured. Pyuria: Some degree was present on admission in 11 cases. Blood cells were noted in 3 cases. One patient was pus-free and the urine bacteria-free (calcium oxalate stone). Two patients with uric acid calculi showed only an occasional pus cell but cultures of the urine showed Gram-positive streptococci in one case and Gram-positive staphylococci with Gram-negative bacilli in the second.
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Foci of infection: The patients uniformly presented possible foci of infection as follows: 10 Infected tonsils and teeth. 1 Infected teeth and chronic parasinusitis (flare of sinusitis associated with exacerbation of calculosis). l Infected teeth and tonsils. Pyorrhea. Prostatic and infection. RESULTS
Following the removal of foci of infection which was routinely carried out as far as possible, following cystoscopic or removal of calculi present and in some instances post-operative renal lavage the results were as follows: Four patients regarded themselves as cured or greatly improved without recurrence after two or more years. They had a minimal or absent pyuria. Four patients were benefited but had residual urinary infection with pyuria. There had been no recurrence of stone. Three patients had had recurrence of calculi and pyuna or dysuria after two or more years. Animal experimentation: Green producing streptococci recovered from the tonsils or teeth of nine of the patients of this group produced experimental calculosis in dogs when implanted in devitalized teeth by Drs. Rosenow and Meisser. Crystallography of urinary sediments or crushed soft stones: Several of these patients passed sandy masses or soft stones which could be easily crushed on a slide to make a suitable preparation for study. In four instances it was possible to demonstrate that the fundamental component units of the forming stone consisted of atypical spherular coalescing or fusing crystals, highly suggestive of the influence of urinary colloids on the process.
During ten years of private practice I have had 16 patients with recurrent lithiasis who were observed over a period long enough to allow a detailed study with an effort to determine etiologic factors at fault. A summary of the clinical derived from this study is of interest. Of the 16 cases 10 were males, aged twenty-six to forty-nine
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years, and 6 females, aged twenty-five to fifty-three years. Ten suffered from recurrent ureteral calculi alone while 6 had recurrent renal and ureteral stones. The 6 patients with recurrent renal stone all gave a history of having passed calculi at some time. The interval of recurrence varied from two weeks to seven years. The duration of the stone-forming period was from one month to thirty-seven years (case 3). The chemistry of stones passed or removed showed: 1 Urates (negative culture-no pyuria). 6 Calcium carbonate. 1 Calcium phosphate and calcium carbonate. 2 Ammonium magnesium phosphate. 6 Not determined. Cultures of the urine on admission showed: 5 Gram-negative bacilli. 1 B. coli and B. proteus. 1 Gram-positive streptococci. 6 Not made. 1 Culture not obtained after several efforts (aseptic) (urates). Pyuria: Varied from grade I to grade IV on admission in 15 cases. Only one, the uratic calculus former, was pus-free. Blood cells were noted occasionally. Urinary reaction: The urines of all patients but one were alkaline to litmus. When the pH was determined (8 cases) it was found above pH 7 in all cases but one. The patient passing uratic calculi had a urinary pH of 5. 6 Foci of infection: Possible foci of infection were present as follows: 4 Infected teeth and tonsils. 1 patient also had chronic prostatitis and chronic appendicitis. 1 Chronic endocervicitis. 4 Infected tonsils-I questionable dental infection. 1 Infected teeth. Tonsils previously removed. Questionable appendicitis. l Infected teeth and tonsils previously removed. Chronic endocervicitis, on admission. 3 Infected tonsils previously removed. l had chronic endocervicitis and 1 chronic arthritis deformans on admission. Treatment: Removal of stones by catheter manipulation or operation in all cases but one. Periodic cystoscopic lavage with frequent use
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of indwelling catheters and of ureteral dilatation with bulbs. Removal of foci of infection (incomplete in 9 cases because of improvement in health or lack of cooperation). Regulation of diet with regard to chemistry of stone and high vitamine A content. Change of pH of urine to high acidity by inorganic acids, acid ash diet, ammonium nitrate, and recently ketogenic diet. Results: All patients who had their calculi removed are stone-free at present. One has a small stone which has changed very slightly in size in six years. Ten pass urine pus- and bacteria-free after one to eight years. Four pass urine with occasional pus cell to grade I. Only two at present have pus which at intervals is graded above I. These are still under treatment. CASE REPORTS
Case 1. R. H. No. 228. 1923. Male, aged thirty. Recurrent bilateral ureteral calculi over ten years since 1918. Ammonium magnesium phosphate. Pus I-IV. Cultures of urine: B. coli and B. proteus. Alkaline urine. Foci: Tonsils and teeth removed 1923. Recurrent passage stones until May, 1928. Acidification of urine. Oral urinary antiseptics. Began renal lavage and dilatation of ureters January, 1927. Repeated every three months for two years. Gradual subsidence of infection. X-ray negative. Urine occasional pus cell 1933. Stone free since 1928. Case 2. R. H. No. 30. 1925. Male, aged thirty. Recurrent bilateral ureteral calculi two years. Calcium carbonate. Urine: Pus I-II, B. coli, pH 7.8. Removal of tonsils and teeth. Ureteral dilatation and renal lavage. Urine pus-free and no recurrence after six years. Case 3. R. H. No. 2532. 1926. Male, aged forty-nine. Recurrent calcium carbonate ureteral calculi-intervals one to two years for thirty-seven years. Alkaline pyuria grade I. Repeated renal lavage with ureteral dilatation several months. Pyuria I-1932. No recurrence in seven years. Caie 4. R.H. No. 6337. 1928. Male, aged forty-one. Repeated right ureteral calculi six months. Calcium carbonate. Pyuria II, alkaline. Repeated cystoscopic lavage and ureteral dilatation. No recurrence after one year. Urine pus- and bacteria-free.
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Case 5. R. H. No. 6951. 1929. Female, aged fifty~three. Repeated right ureteral calculi over two years. Admitted with septic right kidney. Stone impacted lower right ureter. Pyuria IV; B. coli and Gram-positive staphylococci; alkaline. Stone removed by cystoscopy from ureter. Stricture at ureteropelvic juncture associated with fulminating pyonephrosis necessitated right nephrectomy. Recovery. Urine pus- and bacteria-free in 1933. No recurrence of stone. Case 6. R. H. No. 7078. 1929. Female, aged thirty-eight. Repeated right ureteral colic for five years. Several stones passed. Pyuria B. coli; pH 7; chronic endocervicitis. Bilateral hydronephrosis grade I with ureters dilated. Cystoscopic lavage and ureteral dilatation. Occasional ureteral colic but urine pus-free and no recurrence of stone since 1929. Case 7. R. H. No. 9516. 1930. Female, aged thirty-four. Recurrent ureteral calculi one year.. Toxic goitre, seven years. Pyuria IV; B. coli (bilateral); alkaline. Stones manipulated from both ureters, Thyroidectomy with recovery, Cystoscopy with ureteral dilatation over two months. No recurrence of calculus. No pyuria after one year. Case 8. R.H. No. 9755. 1930. Male, aged thirty-three. Passage gravel right ureter for one year. Admitted: Stone impacted right ureter; urosepsis. Pyuria IV; R.B.C. III; B. coli. Alkaline. Cystoscopic removal calcium carbonate stone. Renal lavage with ureteral dilatation, urinary antiseptics and acidification of urine. No recurrence. Urine-pus and bacteria-free, 1932. Case 9. R. H. No. 12279. 1931. Male, aged thirty-five. Recurrent left ureteral calculi over six months. Passed stone after administration of narcotic. Pyuria II, R.B.C. IV from left kidney. Alkaline. Cystoscopic dilatation of ureters. No recurrence. Urine-pus and bacteria-free, 1933. Case 10. R.H. No. 12279. 1931. Male, aged 39. Bilateral recurrent ureteral calculi over seven years. Pyuria IV; B. coli; pH 7.2. Chronic prostatitis. Stone manipulated from left lower ureter. Prostatic massage. Urethral and bilateral ureteral dilatation. Acidification of urine. No recurrence. Urine occasional pus cell.
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Case 11. R. H. No. 2594. 1926. Female, aged twenty-five. Stone removed right kidney 1920. Recurrence and second right pelviolithotomy 1921. Recurrence right pyonephrosis-right nephrectomy 1923. Passage stone left ureter 1924. Recurrent very small shadow in 1926 proved by urogram. Frequent attacks of pyelonephritis since. Admitted 1926: Pyuria I-IV; B. coli; pH 7.3. Chronic endocervicitis. Repeated renal lavage and ureteral dilatation. Indwelling catheters. Urine pus-free and cultures negative at times. In 1932 after an interval of eighteen months since cystoscopy had intense pyelonephritis. Relief by cystoscopy. The calculus in this patient heretofore an intensely rapid stone former has increased very
Fm. 4.
RECURRENT CALCULUS IN LEFT UPPER CALYX WHICH HAS INCREASED VERY SLIGHTLY IN S1zE OVER Six YEARS
Previous rapid recurrence and growth of stones had required right nephrectomy. Case 11.
slightly in size over a seven year period (fig. 4). Phosphoric acid lavage attempted but patient intolerant. Removal of calculus by surgery advised when larger. Periodic pelvic lavage advised. Case 12. R. H. No. 3081. 1926. Male, aged twenty-six. Recurrent passage stone left ureter for eleven years since attack typhoid. Long intervals. Admitted with pain left kidney area. Pyuria I; alkaline. Infected tonsils. X-ray shadow 2 by 1 cm. left renal pelvis proved by urography. Left pelviolithotomy. Cystoscopic dilatation of left ureter. No recurrence. Urine pus- and bacteria-free after six years (1932). Case 13. R. H. No. 3074. 1926. Male, aged thirty-one. Seven years previous to admission passed several stones from bladder.
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Recurrent pain left kidney area. Intense arthritis and spondylitis deformans. Alkaline: pyuria L X-ray: large stone right pelvis. Peviolithotomy. Calcium carbonate and phosphate, Ureteral dilatation, acidification of urine. Urinary antiseptics. No recurrence. Urine pus- and bacteria-free 1932 (six years). Case 14. R. H. No. 10108. 1930. Male, aged thirty-eight Seven-year history pain in back. Passage gravel at times. Recent attack right side. Urine: Bladder, pus IV, R.B.C. IV. Gram-positive streptococci, both kidneys (produced experimental calculosis in ani-mals). Urine alkaline. Tonsils previously removed. X-ray Novem-
FIG. 5, CASE 14
A. November, 1930. Impacted stone right lower ureter. Small calculusleft calyx, Ureteral stone removed. B. March, 1931 (interval four months). Enor-mous growth of left renal calculus. Required nephrectomy.
her 17, 1930: calculus right lower ureter. Small stone 0.5 cm. left kidney. Impacted stone manipulated from right ureter (multiple catheter method under spinal anesthesia). Left pelviolithotomy refused. 1931, readmitted, septic condition. X-ray: right kidney and ureter clear. Left kidney, stone seen in November (0.5 cm previously) has increased in size filling pelvis and calyces (fig. 5). toscopy: calculous left pyonephrosis with functionless left kidney and urosepsis. Left nephrectomy. Stone-ammonium magnesium phosphate. Interval dilatation of right ureter and lavage since. Acidification of urine. Urine pus-free and culture negative March, 1933. No recurrence in two years.
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Case 15. R. H. No. 11021. 1931. Female, aged thirty-five. Passage of small stones and sand both sides one year. Urates. Urine: No pus or blood cells. Culture negative; pH 5.6. X-ray: small shadow left kidney area included in urogram. Tonsils and teeth infected. Removal refused. Blood uric acid 5 mgm. Low purin diet. Cystoscopic renal lavage and ureteral dilatation. No recurrence after one year (1932) . Case 16. R. H. No. 12536. 1931. Female, aged forty-five. Passage stones from right kidney two years-once from left. Stones passed and those subsequently removed were pure calcium carbonate. Pyuria I-IV. Culture: Gram-positive, pleomorphic streptococci (these organisms produced experimental calculosis in rabbits) . React ion pH 7.2. Foci: Infected teeth, chronic cervicitis. X -ray : October, 1931, large stone right kidney area-left clear. Cystoscopy calculous destruction of right kidney. Pus III from right ureter. Left compensatory hypertrophy. Right urine pH 7.2; Gram-positive streptococci; left urine pH 7; culture negative. March 20, 1932, X -ray: stone on right markedly increased in size- left clear. R ight nephrectomy. Large stag horn stone with many small calculi in calyces. Convalescence uneventful while in hospital. April 22, 1932 (thirty-one days after operation), left-sided colic and oliguria with fever. Relief by catheter drainage. K.U.B. showed multiple calculi in left kidney. Urine (left): pus IV; pH 7.2; culture Gram-positive streptococci. Treatment: High vitamine diet, acidification of urine using dilute aqua regia, hydrochloric acid, chloride and nitrate of ammonia alternately. pH shifted to 4.5 to 5, where it has been maintained almost constantly, since. Dilatation of ureter to 18-F at intervals. Indwelling catheters. Pyuria diminished and size of calculi in left kidney diminished during next month. Two small calculi (fig. 6) persisted and could not be made to pass. Urogram May 1932: progressive hydronephrosis. Continuous irrigation of renal pelvis with 1 per cent phosphoric acid with multiple indwelling catheters over several days attempted but patient intolerant to this after one or two hours. Stone wandered into the ureter to be pushed back into the pelvis by the ureteral catheter as shown by x-rays (fig. 6) over several months until September, 1932. The patient began to have frequent chills and fever and required catheter for relief. K.U.B.: September 16, 1932 showed both stones in the kidney area. These removed by pelviolithotomy. Convalescence normal. Repeated cystoscopic irrigation at intervals of two to four
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weeks since. Maintenance of high urinary acidity with drugs and ketogenic diet keep the pyuria to grade I. Cessation of acid therapy results in alkalinity to pH 7 and increase in pyuria. Neoarsphenamine
Fm. 6. CASE 16 Rapid growth of right calculus, November, 1931, to March. 1932. Right nephrectomy, March, 1932. Recurrence multiple stones left kidney April, 1932 (thirty days after nephrectomy). May, 1932, K.U.B. shows diminution of calculus with urinary acidification. Hydronephrosis. Operation removed two stones from pelvis September, 1932. June, 1933, K.U.B. and intravenous urogram. No recurrence.
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and various oral antiseptics have been tried. At present (June, 1933), the two-hour phthalein is 60 per cent. Intravenous urogram (fig. 6) shows a fairly good pelvis without hydronephrosis. Patient in good general health. Urine while acid and taking urotropin or caprokol contains little pus. Streptococci still obtained in culture. IMPRESSIONS FROM ANALYSIS OF CASES
Recurrent calculi of the secondary type of Albarran (amorphous calcium carbonate and phosphate and triple phosphate) are produced by specific urea-splitting organisms, the colon, proteus, staphylococcic and streptococcic groups being most frequent in incideii'.ce. Urostasis by keeping up infection is of great importance in recurrence and a chief point of attack in therapy. The role of focal infection is probably important but not altogether clear. Just why teeth infected with streptococci should produce a stone-forming infection where proteus, colon bacilli or staphylococci are found in the urine is difficult. to ;explain unless one believes these latter organisms are secondary irlvaders. Metabolic disturbances, dietary irregularities and vitamin deficiency except in the case of uratic, and possibly of calcium oxalate stones, from these 28 case studies have not been elucidated. With the evidence at hand: it may not be presumptuous to outline a tentative therapeutic program for the prevention of recurrence of stone. This should include: \ · 1. Removal of existing· calculi as f~ras p,racticable,by surgery or cystoscopy. Use •Of the :fluoroscope at operatio;n, avoiding exposure of suture' material to the ilrinary strea'.m, and the insurance of adeq_u:ite urinary drainage should b~ practised. 2. Shift the hydrogen ion concentration to the opposite of what it was when the stone was formed. This will usually mean acidification of the urine. The ketogenic diet is of great value here and will enjoy wider usage as the result of the work which Dr. Clark has presented today. I have used dilute aqua regia, and the nitrate and chloride of ammonia altetnately or together with good result. 3. A qualitative chemical examination of the stone obtained should
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5. 6.
7.
8.
9.
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be routinely practised. In uratic and oxalate stones a dietary affording a low intake in these chemicals should be prescribed. With regard to phosphatic and carbonate calculi, no very definite evidence of dietary control has been presented. Vitamine A increase in the dietary is worthy of trial but its place as a factor in urolithiasis is still very uncertain and rests entirely on isolated and indefinite experimentation on rats. Foci of infection should be removed. Repeated x-ray immediately and at periods six months to one year after operation, should be practised. Every patient with urinary calculus has a 4 to 20 per cent chance for recurrence. In treatment this should be borne in mind. Removal of stasis points in the urinary tract by surgery or cystoscopy should be attempted for in urostasis lies our chief obstacle to the eradication of infection. I have practised renal lavage and dilatation of the ureters with bulbs and indwelling catheters in 16 cases. Their freedom from calculus and from gross infection has endured long enough to make me feel that the procedure is of definite value. Urinary antiseptic drugs may be used as adjuvants, especially urotropin if care is taken to keep the pH below 5.6. With this exception, I believe they offer us little in the way of clearing up infection. Irrigation of the renal pelvis with phosphoric acid as advocated by Randall seems of value. The possibility of dissolving alkaline earth calculi in situ by intense urinary acidification inevitably comes up. Unquestionably in my case 16, I reduced the size of the stone by urinary acidification with drugs by mouth. Dilute phosphoric and other acids by catheter irrigation however failed to reduce the two troublesome fragment which remained. CONCLUSION
Aseptic urinary concrements may be formed in consequence of metabolic errors. Pure uratic, cystin and xanthin stones are known examples. While not definitely pr~ven, calcium oxalate and crystalline carbonate and phosphate calculi may at times have such an origin. Stones composed chiefly of triple phosphate and the amorphous carbonate and phosphate of calcium are formed in alkaline urine
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probably the result of specific urea-splitting organisms. These are the varieties of calculi most frequent to recur and those which are seen most often in patients with stone-forming kidneys. Therapy directed toward the relief of urostasis and clearing up of infection is rational and attended with good result. The mechanism of the formation of urinary concrements as determined by physical chemists and by animal experimentation seems to consist of the coalescence of atypical crystals in the gels of urinary colloids.
Medical Arts Building, Roanoke, Va. REFERENCES (1) KEYSER, L. D., AND BRAASCH, W. F .: The etiology of urinary Iithiasis. International Abstract of Surg., January, 1922, 1-10. (Complete bibliography to date.) (2) KEYSER, L. D.: The mechanism of the formation of urinary calculi. Ann. Surg., February, 1923, 210-222. KEYSER, L. D.: The etiology of urinary lithiasis: An experimental study. Arch. Surg., 1923, vi, 525-553. KEYSER, L. D.: Urinary lithiasis: Its cause and prevention. An evaluation of contributions to our knowledge during the past decade. South. Med. Jour., 1932, xxv, no. 10, 1031-1040. (Complete bibliography to date.) (3) BRAASCH, W. F.: Recurring renal lithiasis. Proc. Staff Meet. Mayo Clinic, March, 1932, vii, 169. (4) SCHULTEIS, G.: Histologische Untersuchungen an Steinnieren. Zts. f. Urol. Chir., March, 1931, xxxi, 196. (5) EISENSTADT, J . E.: Certain tangible factors in the etiology of urinary calculus. Trans. Chicago Urol. Soc., 1931, i, 65-72. EISENSTADT, J . E.: Surg., Gynecol. and Obstet., liii, 730. (6) RANDALL, A. : Recurrent calculi in the urinary tract. Ann. Surg., 1932, 133- 139. RANDALL, A.: Prevention of the recurrence of urinary calculi. Amer. Jour. Surg., 1932, N. S., xviii, no. 3, 482-485. (7) HIGGINS, C . C.: The experimental production of urinary calculi. Jour. Urol., 1933, xxix, no. 2, 157-171. (8) RAVICH, A.: Critical study of ureteral calculi. Jour. Urol., 1933, xxix, no. 2, 171-197. (9) CooK, E . N., AND CLARK, A. L.: Oxaluria. Proc. Staff Meet. Mayo Clinic, 1933, viii, no. 15, 222-226. (10) LIVERMORE, G. R.: Ureteral calculi. Amer. Jour. Surg., 1933, xx, N. S., no. 2, 214-222. (11) PEDERSEN, V. C.: Calculous prostatitis (anatomical cure), colon bacilluria. General treatment (physiological cure) . Med. Times, 1932, Ix, no. 11, 337.