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Oxalate Stone Disease After Intestinal Resection
Vol. 117,May Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
OXALATE STONE DISEASE AFTER INTESTINAL RESECTION JOHN G. GREGORY,*,t Kl Y. PARK
AND
HARRY W. SCHOENBERG
From the Division of Urology and Experimental Surgery, St. Louis University School of Medicine, St. Louis, Missouri
ABSTRACT
There have been 543 jejuno-ileal bypass patients screened for the presence of urinary calculi 1 to 6 years postoperatively. Of these patients 9 per cent have had 1 to 2 calculi during the followup and 3 per cent have had multiple calculi. Ninety-four per cent of the recovered calculi consisted entirely of calcium oxalate. Seven patients had a history of stones before the bypass, 6 of whom have had additional stones postoperatively. To define the conditions associated with stone formation in these patients measurements of serum and urinary oxalate concentration, urinary calcium oxalate saturation, urinary crystal size distribution, and the rates of intestinal oxalate absorption and urinary crystallization have been performed on patients who did and did not have stones postoperatively. On the basis of these studies it appears that the patients in whom stones formed differ from those in whom they did not form only in the rate of urinary crystallization and in the number of large crystal particles present in the urine. Evaluation of current therapeutic modalities in terms of the capability to correct these stone-forming characteristics and to reduce actual calculus formation reveals that the only successful regimen is that which includes an extreme reduction of oxalate ingestion. Urinary calculous formation is an acknowledged complication ofjejuno-ileal bypass procedures performed for alleviation of morbid obesity. The mechanism of calculogenesis, while not completely understood, is thought to be similar to that seen in patients with inflammatory bowel disease and in those patients who have undergone varying degrees of ileal resection. The occurrence of nephrolithiasis in association with inflammatory bowel disease has been recognized for some time. 1 It was at first believed that the resultant calculi were composed of uric acid, with the postulated pathogenesis being dehydration, sodium conservation and a consequent secretion of an acid urine. 2 In a study of 885 cases of inflammatory bowel disease Gelzayd and associates reported an incidence of stone formation of 7 .2 per cent and unexpectedly found that only 12 per cent of the analyzed stones contained uric acid. 3 In 1970 Hofmann and associates observed the combined findings of hyperoxaluria and calcium oxalate nephrolithiasis occurring in patients after ileal resections. 4 They thought that the operation led to altered bile-absorbing capabilities in the terminal ileum and allowed glycine-conjugated bile salts to enter the colon, where bacteria split off and deaminated the glycine moiety to glyoxalate, which in tum was absorbed by the gut and metabolized to oxalate in the liver. On the basis of this mechanism the therapeutic use of taurine was suggested as a means to alter the ratio oftaurine to glycine available for bile salt binding, which in tum reduced the amount of glycine available for exposure to colon bacteria. 5 Admirand and associates found that taurine reduced urinary oxalate in 7 patients who had undergone ileal resection. 6 Smith and associates were unable to confirm the beneficial effects of taurine in similar patients but were able to lower urinary oxalate to normal by the use of cholestyramine, an anion-binding resin. 7 The mechAccepted for publication July 9, 1976. Read at annual meeting of American Urological Association, Las Vegas, Nevada, May 16-20, 1976. Supported in part by the National Institute of Arthritis, Metabolism and Digestive Diseases, Grant AM18599-01, and in part by the American Urologic Research Scholar Fund. * Requests for reprints: Division of Urology, St. Louis University School of Medicine, 1325 South Grand Blvd., St. Louis, Missouri 63104. t American Urologic Research Scholar, 1975-1976.
anism postulated here was that cholestyramine bound the free bile acids, reducing the normally increased production of hepatic glycine necessary for bile salt binding in the ileal resection patients. Glyoxalate is a possible common precursor for glycine and oxalate and it was reasoned that reduction in glycine production also might act to reduce oxalate production. Using 14C-labeled glycine to measure the incorporation of bile acid glycine into oxalate, Hofmann and associates found that it was negligible in patients with ileal disease or resections, thus disproving the very mechanism that they had suggested previously. 8 Chadwick and associates confirmed this finding and, furthermore, showed that ileal resection patients had a markedly increased intestinal absorption of exogenous oxalate. 9 In 4 such hyperoxaluric patients they were able to lower the oxalate excretion to normal levels merely by the use of an oxalate-free diet. Stauffer and associates also showed a moderate increase in oxalate excretion in patients who had undergone ileal resection and were able to correct this hyperoxaluria by the use of cholestyramine, which was shown by in vitro experiments to be an oxalate-binding agent. 10 Earnest and associates performed oxalate-loading studies on patients with ileal resections and found that patients with extensive resections absorbed 30 per cent more oxalic acid and 24 per cent more dietary oxalate than did the normal control subjects. 11 This group also has shown a direct correlation between dietary fat malabsorption and urinary oxalate excretion. In view of the considerable literature relating ileal dysfunction and resection to hyperoxaluria and renal stone formation it was not unexpected that the formation ofrenal calculi would be an important complication after small bowel bypass procedures performed for morbid obesity. Various series have substantiated this expectation and have reported stone incidences ranging from 2 to 32 per cent. 12- 15 Why patients with generally reduced intestinal absorption capabilities should hyperabsorb oxalate has not been explained convincingly. One possible mechanism is that steatorrhea associated with bypasses allows intestinal fat to combine with dietary calcium, resulting in intestinal soap formation. In this manner free intraluminal calcium is reduced, thus limiting the formation of highly insoluble calcium oxalate, and in tum allows free and highly 631
632
GREGORY, PARK AND SCHOENBERG
soluble oxalate to pass across the intestinal lumen. 11 Therapeutic measures suggested for the reduction of hyperoxaluria have included low oxalate diets, 9 low fat diets, 11 calcium ingestion, 11 magnesium oxide ingestion (alone and in combination with folic acid and pyridoxine), 13 cholestyramine 10 and the use of a low caloric diet. 14 Despite recent interest the frequency of calculus formation and therapy for this condition remain uncertain. We believe that a better understanding of the calculogenesis in these patients could prove of therapeutic benefit and, at the same time, a study of this population might open investigative pathways for the study of that equally elusive but more widespread problem of idiopathic calcium oxalate calculogenesis. Since 1968, 543 small bowel bypass procedures have been performed at our university. This patient group has formed the subject pool for the present study, which is a continuation of work first reported in 1974. 15 Our purpose has been 3-fold: 1) to establish in our population the incidence and pattern of stone formation after jejuno-ileal bypass procedures, 2) to try to identify and tabulate those characteristics that differentiate normal persons and bypass patients without stones from those patients with stones and 3) to use the aforementioned criteria to evaluate the efficacy of various therapeutic measures aimed at reducing hyperoxaluria and stone formation. METHODS
Registry. A small bowel bypass registry has been established that maintains patient contact through followup examination, interviews and mail questionnaires for the purpose of supplying postoperative data of stone incidence and identifying subjects for followup studies. Parameters studied. A population of 10 normal control subjects, 10 pre-bypass obese patients, 10 postoperative patients without stones and 10 postoperative patients with stones have been evaluated in terms of the criteria suggested by the recent literature as differentiating stone forming from non-stone forming patients (table 1). Serum and urinary oxalate measurements. A gas chromatographic method for the rapid and accurate determination of plasma and urinary oxalate has been developed. 16 The normal values are in fairly close agreement with those of Zarembski and Hodgkinson (urine less than 23 mg. per 24 hours and plasma 1 to 2 µ,g. per ml.). 17 Oxalate absorption studies. Thirty-two patients (22 without and 10 with stones) were fasted for 12 hours before and after the small bowel bypass operation and then given 200 mg. oxalic acid orally, diluted in 200 cc deionized water. At 1-hour intervals voided urine specimens were collected and the patients were given an additional 100 ml. oral water. Hourly urinary oxalate determinations were made and these values were plotted against time. Calcium oxalate saturation. The rate of disappearance of small amounts of added 14 C-labeled oxalate from test urine has been used to determine the relative levels of urinary supersaturation o:r under-saturation ,vith respect to calcium oxalate. 18 In addition, a kinetic measurement of the rate of crystallization has been possible with this method in patients with supersaturated urine. According to Gill and associates paTABLE
tients in whom stones form have more highly supersaturated urine specimens with more rapid crystallization rates than do patients in whom stones do not form. 18 Urinary crystal sizes. The Coulter counter method of Robertson19 has been used to measure the number and size of crystal complexes present in freshly voided urine specimens. In this study the percentage of crystal complexes 15 mu. or greater has been calculated for normal controls and for small bowel bypass patients with and without calculi. Robertson has found that idiopathic stone formers generally have more large crystal complexes than do non-stone formers. 19 Therapeutic trial. Small bowel bypass patients who have passed renal calculi have been placed into various therapeutic groups. The agents or methods used have been those suggested by the current literature to be of benefit in reducing the incidence of stone formation after intestinal resection. Prior to the institution of the therapeutic modality those base line studies shown to best characterize patients in whom stones will form were performed. These studies included a measurement of urinary oxalate, urinary particle size, percentage saturation and urinary crystallization rates. These studies were repeated after 3 months of therapy. The therapeutic agents used were: 1) 400 mg. magnesium oxide twice a day, 2) 800 mg. calcium carbonate 5 times a day, 3) 500 mg. calcium gluconate 5 times a day, 4) a low (40 gm.) fat diet, 5) 1, 9 gm. packet cholestyramine containing 4 gm. active resin dissolved in water 5 times a day, 6) a low oxalate diet, which consisted of a standard diet with avoidance of those fruits, vegetables and beverages shown to be high in oxalate, 7) a more severe low oxalate diet, which consisted of limiting the patient's dietary intake to meats, fats and carbohydrates, with a total avoidance of fruits and vegetables, and 8) a no oxalate diet, consisting of an elemental diet that supplied complete nutritional requirements but with an oxalate content of less than 15 mg. per day. RESULTS
Patient statistics. Followup studies have been completed within the last 3 months in 70 per cent of the 543 bypass patients. Sixty patients have passed calculi that have been recovered and 6 additional patients who have a history strongly suggestive of stone passage have been included as stone formers. Therefore, the incidence of stone disease is 12 per cent as calculated on the basis of the total population or 17 per cent if based on the group reviewed. We believe the severity of stone symptoms encourages physician contact and, therefore, favors the 12 per cent incidence. Seven patients reported a history of calculi preoperatively and all but 1 of these has had postoperative calculi. Surgical extraction has been necessary in only 7 instances. Thirty-two stones have been analyzed: 30 consisted entirely of calcium oxalate and 2 consisted of ammonium urate. The first indication of stone disease occurred 1 year postoperatively in 57 per cent of the cases, 2 years postoperatively in 18 per cent, 3 years postoperatively in 18 per cent and more than 4 years postoperatively in 7 per cent. A solitary calculus was present in 59 per cent of the cases, while 2 calculi were noted in 16 per cent, 3 calculi in 12 per cent and multiple calculi in 13 per cent.
1. Results of studies done on 10 bypass patients with calculi, 10 patients 4 years after bypass operation without calculi, 10 obese patients
before bypass operation and 10 normal control subjects Pts. With Stones Mean Urine volume (ml./24 hrs.) Plasma oxalate (µg./ml.) Urine oxalate (mg./24 hrs.) Calcium oxalate supersaturation (%) 18 Crystallization rate" % Urine particles > 15 /L· 19 Urine calcium (mg./24 hrs.)
850 3 130 30 75 43 71
(range) (410-997) (2.5-3.5) (80-210) (9-50) (30-90) (10-60) (10-149)
Pts. Without Stones Mean 970 3 124 31 30 21 80
(range) (430-1,041) (2.5-3.5) (60-190) (9-40) (10-50) (0-30) (55-147)
Pre-Bypass Pts. Mean 1,800 1.8 18 24 15 11
170
(range) (870-2,200) (1-2.5) (8-25) (9-37) (0-30) (0-18) (100-260)
Normal Controls Mean 1,670 1.6 16 31 20 10 167
(range) (900-2,010) (1-2) (9-23) (10-50) (0-35) (0-25) (90-250)
633
OXALATE STONE DISEASE AFTER INTESTINAL RESECTION 24--~----~----,---r---r---,
Identification of patients in whom stones will form. Studies designed to characterize patients in whom stones will form are shown in table 1. These data show that there were no differences in the parameters studied between the normal control subjects and the pre-bypass patients. All patients studied showed increased urinary and plasma oxalate levels postoperatively, while urinary calcium excretion was reduced. There was no absolute difference in plasma or urinary oxalate levels, urinary calcium or percentage saturation between patients with and without stones but a difference in the kinetics of crystal formation (crystallization rate) was observed between the 2 groups, which also may be responsible for the observed increased number of large particles present in the urine of the stone formers. Oxalate absorption. Figure 1 shows the response to a 200 mg. oral load of oxalate in a normal person and in a patient 1 year after a small bowel bypass. The control subject absorbed 6 per cent of the oxalate load, while the bypass patient absorbed 38 per cent. This pattern of response is typical of that seen in all patients studied. Preoperatively the non-stone formers absorbed 5 to 12 per cent and the stone formers 7 to 15 per cent. Postoperatively, the non-stone formers absorbed 35 to 55 per cent and the stone formers 34 to 58 per cent. Results of therapy. Table 2 shows the lack of effect of various therapeutic regimens on those aforementioned factors to have some relationship with stone formation. Our period offollowup is too short to show any change in the pattern of stone formation in response to therapeutic measures but 1 patient who passes in excess of 2 recoverable calculi per week has been tried for at least a 2-month period on each of these regimens without change in the stone production rate (fig. 2). This patient is in serious difficulty but will not consider having the bypass reversed. He has been placed on an elemental diet containing no oxalate with immediate cessation of stone formation. Unfortunately, such a diet is not palatable for long periods. At present the patient is eating only meat, fish, carbohydrates and dairy products. The urinary oxalate has decreased from 200 to 100 mg. per 24 hours and the patient has passed 6 calculi in the last 2 months.
22
20 18
16 Bypass Patient
Urinary 14 Excretion
of Oxalic Acid Mg.
12 10
8 6
(1'
4
I
I
I
p.
\
\
\
Normal Control
\ \
/
\
/
/
b,
t
..... "0-
3
2
-
o---o
4
5
6
Hr.
Load
Fm. 1. Urinary excretion of oxalate after 200 mg. oral load of oxalic acid. Both subjects fasted for 12 hours before loading. Bypass patient is 1 year postoperative. TABLE
2. Patients with a decrease in measured parameters after 3
months of therapy No. OxPts. in Urine alate Trial Magnesium oxide Calcium carbonate Calcium gluconate Cholestyramine Low fat diet Low oxalate diet
12 11 9
14 20 30
Particle Size
Calcium Oxalate Supersaturation
Calcium Oxalate Crystallization Rate
2 1 0 0 0 2
3 1 2 1 1 3
1 1 1 1 0 1
0 1 2 3 2 4
I
+ I
Small bowel bypass patients are difficult subjects to work with. Extensive psychologic testing at our institution suggests that this group uses much denial in regard to body image and condition, and that eating is a form of addiction. For these
first stone
bypass
6/73
DISCUSSION
9/73 I
12/73 + I
I
3/74 I
6/74
9/74
12/74
3/75
I
I
I
I
low oxalate diet low fat diet
cholestyromine
mg.oxide
THERAPY
ca. 9luconote
ca. carbonate
no oxalate no fruit or vegetables
URINE OXALATE MG./24HR. 5 0 - - - -.....
100150200-
STONES/WK.
0------------..... 1-
234-
Fm. 2. Effect of various therapeutic measures on urinary oxalate excretion and stone production in 28-year-old man who weighed 410 pounds at time of bypass operation in July 1973. Current weight of patient is 195 pounds.
634
GREGORY, PARK AND SCHOENBERG
reasons patient followup and compliance with therapy are difficult to obtain. Diets are not followed and medications are ignored often. The observed 12 per cent incidence of calculogenesis is not excessive, especially if viewed in light of the fact that the majority of calculi are passed spontaneously and that to date 57 per cent of stone formers pass only 1 calculus. The fact that 6 of 7 patients who had stones preoperatively had additional stones postoperatively does underline the importance of a careful preoperative urologic history on patients undergoing small bowel bypass procedures. It is our opinion at this time that patients with a positive stone history should not have this procedure performed. As could be expected, the intestinal absorption studies show a marked increase in oxalate absorption after an intestinal bypass. It is interesting that these patients who have a mouthto-colon transit time of only 20 minutes as seen on postoperative upper gastrointestinal series have an oxalate absorption curve peak that occurs later and remains elevated for a longer time than is the case in normal patients. We interpret this as an indication that the site of intestinal oxalate absorption is different in the normal individual from that in the patient with intestinal resection. It is most likely that the site of oxalate absorption in the bypass patient is the colon, which after a bypass procedure has undergone adaptive changes to become the principal site of intestinal absorption. The mechanism of hyperabsorption of oxalate is not understood but is under investigation currently. Developments in this area could be of major therapeutic importance. Of all therapeutic measures currently available only reduced ingestion of oxalate has had beneficial results. Inasmuch as detectable oxalate exists in a large percentage of standard food products it does not appear practical to expect a reduction of oxaluria by dietary controls, especially in a population highly resistant to dieting. Even by eliminating all dietary fruits and vegetables we have been unable to reduce oxalate excretion to normal levels. In our hands no suitable agent has been successful in achieving intestinal oxalate chelation in the bypass population, despite the fact that chelation with calcium11 and also with cholestyramine 10 has been reported to be of therapeutic importance for patients who have hyperoxaluria resulting from ulcerative colitis. A possible explanation for this discrepancy is the generally lower level of oxaluria demonstrated by the patients with ulcerative colitis and bowel resections less extensive than those done in a jejuno-ileal bypass. The observed incidence of oxalate stone formation in our bypass patients is far higher than the idiopathic rate for this geographic area but it is of interest that the rate is no higher, with a marked hyperoxaluria and some degree of calcium oxalate supersaturation occurring in essentially all our postoperative patients. Obviously, other factors responsible for stone induction or for calcium inhibition are acting here. Hopefully, these factors can be defined. Toward this end we have demonstrated an increased crystallization rate in the group of bypass stone formers and believe that future investigations involving the kinetics of stone formation will prove fruitful in elaborating the mechanism of this disorder. Until the time that prevention or treatment is available it is fortunate for those patients requiring small bowel bypass and for those surgeons undertaking this procedure that the incidence of stone formation and the rate of recurrence are relatively low and that the incidence of spontaneous stone passage is quite high. REFERENCES
1. Melick, R. A. and Henneman, P. H.: Clinical and laboratory studies of 207 consecutive patients in a kidney-stone clinic. New Engl. J. Med., 259: 307, 1958. 2. Clarke, A. M. and McKenzie, R. G.: Ileostomy and the risk of urinary uric acid stones. Lancet, 2: 395, 1969.
3. Gelzayd, E. A., Breuer, R. I. andKirsner, J.B.: Nephrolithiasis in inflammatory bowel disease. Amer. J. Dig. Dis., 13: 1027, 1968. 4. Hofmann, A. F., Thomas, P. J., Smith, L. H. and McCall, J. T.: Pathogenesis of secondary hyperoxaluria in patients with ileal resection and diarrhea. Gastroenterology, 58: 960, 1970. 5. Dowling, R.H., Rose, G. A. and Sutor, D. J.: Hyperoxaluria and renal calculi in ileal disease. Lancet, 1: 1103, 1971. 6. Admirand, W. H., Earnest, D. L. and Williams, H. E.: Hyperoxaluria and bowel disease. Trans. Ass. Amer. Physicians, 84: 307, 1971. 7. Smith, L. H., Fromm, H. and Hofmann, A. F.: Acquired hyperoxaluria, nephrolithiasis, and intestinal disease. Description of a syndrome. New Engl. J. Med., 286: 1371, 1972. 8. Hofmann, A. F., Tacker, M. M., Fromm, H., Thomas, P. J. and Smith, L. H.: Acquired hyperoxaluria and intestinal disease. Evidence that bile acid glycine is not a precursor of oxalate. Mayo Clin. Proc., 48: 35, 1973. 9. Chadwick, V. S., Modha, J. and Dowling, R.H.: Mechanism for hyperoxaluria in patients with ileal dysfunction. New Engl. J. Med., 289: 172, 1973. 10. Stauffer, J. Q., Humphreys, M. H. and Weir, G. J.: Acquired hyperoxaluria with regional enteritis after ileal resection. Role of dietary oxalate. Ann. Intern. Med., 79: 383, 1973. 11. Earnest, D. L., Johnson, G., Williams, H. E. and Admirand, W. H.: Hyperoxaluria in patients with ileal resection: an abnormality in dietary oxalate absorption. Gastroenterology, 66: 1114, 1974. 12. Woodward, E. R., Payne, J. H., Salmon, P. A. and O'Leary, J. P.: Morbid obesity. Arch. Surg., 110: 1440, 1975. 13. Dickstein, S.S. and Frame, B.: Urinary tract calculi after intestinal shunt operation for the treatment of obesity. Surg., Gynec. & Obst., 136: 257, 1973. 14. O'Leary, J. P., Thomas, W. C. and Woodward, B. R.: Urinary tract stone after small bowel bypass for morbid obesity. Amer. J. Surg., 127: 142, 1974. 15. Gregory, J. G., Starkloff, E. B., Miyai, K. and Schoenberg, H. W.: Urologic complications ofileal bypass operation for morbid obesity. J. Urol., 113: 521, 1975. 16. Gregory, J. G. and Park, K. Y.: Clinical measurement of urine and plasma oxalate. In preparation. 17. Zarembski, P. M. and Hodgkinson, A.: The fluorimetric determination of oxalic acid in blood and other biological materials. Biochem. J., 96: 717, 1965. 18. Gill, W. B., Silvert, M. A. and Roma, M. J.: Supersaturation levels and crystallization rates of calcium oxalate from urines of normal humans and stone formers determined by a 14Coxalate technique. Invest. Urol., 12: 203, 1974. 19. Robertson, W. G.: A method for measuring calcium crystalluria. Clin. Chim. Acta, 26: 105, 1969. COMMENT Unfortunately, the jejuno-ileal bypass procedure has become a predictable means of inducing calcareous renal calculi in a significant number of patients. The authors have emphasized the similarity of the urinary abnormalities of patients with and without calculi, so that we still do not know why stones develop in some patients but not in the majority. The authors' pessimistic views on effective therapy of the induced stone disease are shared by many. Because of the intestinal bypass it is almost impossible for these patients to achieve a copious volume of urine. Larger amounts of calcium than used in this study will reduce urinary oxalate to within the range of normal but patient compliance is difficult to maintain and the potential ill-effects of long-term treatment are not known. If the current popularity of the bypass procedure is to persist some simple but effective means to prevent renal calculi must be devised. W.C .T. REPLY BY AUTHORS The failure of stone prevention limits the role of the urologist in small bowel bypass operations to the area of preoperative patient selection and consultation, and as therapists for those patients in whom stones eventually form. In our institution bypass reversal is recommended to patients who have passed multiple calculi and who appear to be developing a degree of renal impairment secondary to the stone disease. Despite impending renal failure acceptance of this advice frequently is not heeded and, when heeded, a return to prebypass weight invariably is seen.
THE JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
OXALATE STONE DISEASE AFTER INTESTINAL RESECTION JOHN G. GREGORY,*,t Kl Y. PARK
AND
HARRY W. SCHOENBERG
From the Division of Urology and Experimental Surgery, St. Louis University School of Medicine, St. Louis, Missouri
ABSTRACT
There have been 543 jejuno-ileal bypass patients screened for the presence of urinary calculi 1 to 6 years postoperatively. Of these patients 9 per cent have had 1 to 2 calculi during the followup and 3 per cent have had multiple calculi. Ninety-four per cent of the recovered calculi consisted entirely of calcium oxalate. Seven patients had a history of stones before the bypass, 6 of whom have had additional stones postoperatively. To define the conditions associated with stone formation in these patients measurements of serum and urinary oxalate concentration, urinary calcium oxalate saturation, urinary crystal size distribution, and the rates of intestinal oxalate absorption and urinary crystallization have been performed on patients who did and did not have stones postoperatively. On the basis of these studies it appears that the patients in whom stones formed differ from those in whom they did not form only in the rate of urinary crystallization and in the number of large crystal particles present in the urine. Evaluation of current therapeutic modalities in terms of the capability to correct these stone-forming characteristics and to reduce actual calculus formation reveals that the only successful regimen is that which includes an extreme reduction of oxalate ingestion. Urinary calculous formation is an acknowledged complication ofjejuno-ileal bypass procedures performed for alleviation of morbid obesity. The mechanism of calculogenesis, while not completely understood, is thought to be similar to that seen in patients with inflammatory bowel disease and in those patients who have undergone varying degrees of ileal resection. The occurrence of nephrolithiasis in association with inflammatory bowel disease has been recognized for some time. 1 It was at first believed that the resultant calculi were composed of uric acid, with the postulated pathogenesis being dehydration, sodium conservation and a consequent secretion of an acid urine. 2 In a study of 885 cases of inflammatory bowel disease Gelzayd and associates reported an incidence of stone formation of 7 .2 per cent and unexpectedly found that only 12 per cent of the analyzed stones contained uric acid. 3 In 1970 Hofmann and associates observed the combined findings of hyperoxaluria and calcium oxalate nephrolithiasis occurring in patients after ileal resections. 4 They thought that the operation led to altered bile-absorbing capabilities in the terminal ileum and allowed glycine-conjugated bile salts to enter the colon, where bacteria split off and deaminated the glycine moiety to glyoxalate, which in tum was absorbed by the gut and metabolized to oxalate in the liver. On the basis of this mechanism the therapeutic use of taurine was suggested as a means to alter the ratio oftaurine to glycine available for bile salt binding, which in tum reduced the amount of glycine available for exposure to colon bacteria. 5 Admirand and associates found that taurine reduced urinary oxalate in 7 patients who had undergone ileal resection. 6 Smith and associates were unable to confirm the beneficial effects of taurine in similar patients but were able to lower urinary oxalate to normal by the use of cholestyramine, an anion-binding resin. 7 The mechAccepted for publication July 9, 1976. Read at annual meeting of American Urological Association, Las Vegas, Nevada, May 16-20, 1976. Supported in part by the National Institute of Arthritis, Metabolism and Digestive Diseases, Grant AM18599-01, and in part by the American Urologic Research Scholar Fund. * Requests for reprints: Division of Urology, St. Louis University School of Medicine, 1325 South Grand Blvd., St. Louis, Missouri 63104. t American Urologic Research Scholar, 1975-1976.
anism postulated here was that cholestyramine bound the free bile acids, reducing the normally increased production of hepatic glycine necessary for bile salt binding in the ileal resection patients. Glyoxalate is a possible common precursor for glycine and oxalate and it was reasoned that reduction in glycine production also might act to reduce oxalate production. Using 14C-labeled glycine to measure the incorporation of bile acid glycine into oxalate, Hofmann and associates found that it was negligible in patients with ileal disease or resections, thus disproving the very mechanism that they had suggested previously. 8 Chadwick and associates confirmed this finding and, furthermore, showed that ileal resection patients had a markedly increased intestinal absorption of exogenous oxalate. 9 In 4 such hyperoxaluric patients they were able to lower the oxalate excretion to normal levels merely by the use of an oxalate-free diet. Stauffer and associates also showed a moderate increase in oxalate excretion in patients who had undergone ileal resection and were able to correct this hyperoxaluria by the use of cholestyramine, which was shown by in vitro experiments to be an oxalate-binding agent. 10 Earnest and associates performed oxalate-loading studies on patients with ileal resections and found that patients with extensive resections absorbed 30 per cent more oxalic acid and 24 per cent more dietary oxalate than did the normal control subjects. 11 This group also has shown a direct correlation between dietary fat malabsorption and urinary oxalate excretion. In view of the considerable literature relating ileal dysfunction and resection to hyperoxaluria and renal stone formation it was not unexpected that the formation ofrenal calculi would be an important complication after small bowel bypass procedures performed for morbid obesity. Various series have substantiated this expectation and have reported stone incidences ranging from 2 to 32 per cent. 12- 15 Why patients with generally reduced intestinal absorption capabilities should hyperabsorb oxalate has not been explained convincingly. One possible mechanism is that steatorrhea associated with bypasses allows intestinal fat to combine with dietary calcium, resulting in intestinal soap formation. In this manner free intraluminal calcium is reduced, thus limiting the formation of highly insoluble calcium oxalate, and in tum allows free and highly 631
632
GREGORY, PARK AND SCHOENBERG
soluble oxalate to pass across the intestinal lumen. 11 Therapeutic measures suggested for the reduction of hyperoxaluria have included low oxalate diets, 9 low fat diets, 11 calcium ingestion, 11 magnesium oxide ingestion (alone and in combination with folic acid and pyridoxine), 13 cholestyramine 10 and the use of a low caloric diet. 14 Despite recent interest the frequency of calculus formation and therapy for this condition remain uncertain. We believe that a better understanding of the calculogenesis in these patients could prove of therapeutic benefit and, at the same time, a study of this population might open investigative pathways for the study of that equally elusive but more widespread problem of idiopathic calcium oxalate calculogenesis. Since 1968, 543 small bowel bypass procedures have been performed at our university. This patient group has formed the subject pool for the present study, which is a continuation of work first reported in 1974. 15 Our purpose has been 3-fold: 1) to establish in our population the incidence and pattern of stone formation after jejuno-ileal bypass procedures, 2) to try to identify and tabulate those characteristics that differentiate normal persons and bypass patients without stones from those patients with stones and 3) to use the aforementioned criteria to evaluate the efficacy of various therapeutic measures aimed at reducing hyperoxaluria and stone formation. METHODS
Registry. A small bowel bypass registry has been established that maintains patient contact through followup examination, interviews and mail questionnaires for the purpose of supplying postoperative data of stone incidence and identifying subjects for followup studies. Parameters studied. A population of 10 normal control subjects, 10 pre-bypass obese patients, 10 postoperative patients without stones and 10 postoperative patients with stones have been evaluated in terms of the criteria suggested by the recent literature as differentiating stone forming from non-stone forming patients (table 1). Serum and urinary oxalate measurements. A gas chromatographic method for the rapid and accurate determination of plasma and urinary oxalate has been developed. 16 The normal values are in fairly close agreement with those of Zarembski and Hodgkinson (urine less than 23 mg. per 24 hours and plasma 1 to 2 µ,g. per ml.). 17 Oxalate absorption studies. Thirty-two patients (22 without and 10 with stones) were fasted for 12 hours before and after the small bowel bypass operation and then given 200 mg. oxalic acid orally, diluted in 200 cc deionized water. At 1-hour intervals voided urine specimens were collected and the patients were given an additional 100 ml. oral water. Hourly urinary oxalate determinations were made and these values were plotted against time. Calcium oxalate saturation. The rate of disappearance of small amounts of added 14 C-labeled oxalate from test urine has been used to determine the relative levels of urinary supersaturation o:r under-saturation ,vith respect to calcium oxalate. 18 In addition, a kinetic measurement of the rate of crystallization has been possible with this method in patients with supersaturated urine. According to Gill and associates paTABLE
tients in whom stones form have more highly supersaturated urine specimens with more rapid crystallization rates than do patients in whom stones do not form. 18 Urinary crystal sizes. The Coulter counter method of Robertson19 has been used to measure the number and size of crystal complexes present in freshly voided urine specimens. In this study the percentage of crystal complexes 15 mu. or greater has been calculated for normal controls and for small bowel bypass patients with and without calculi. Robertson has found that idiopathic stone formers generally have more large crystal complexes than do non-stone formers. 19 Therapeutic trial. Small bowel bypass patients who have passed renal calculi have been placed into various therapeutic groups. The agents or methods used have been those suggested by the current literature to be of benefit in reducing the incidence of stone formation after intestinal resection. Prior to the institution of the therapeutic modality those base line studies shown to best characterize patients in whom stones will form were performed. These studies included a measurement of urinary oxalate, urinary particle size, percentage saturation and urinary crystallization rates. These studies were repeated after 3 months of therapy. The therapeutic agents used were: 1) 400 mg. magnesium oxide twice a day, 2) 800 mg. calcium carbonate 5 times a day, 3) 500 mg. calcium gluconate 5 times a day, 4) a low (40 gm.) fat diet, 5) 1, 9 gm. packet cholestyramine containing 4 gm. active resin dissolved in water 5 times a day, 6) a low oxalate diet, which consisted of a standard diet with avoidance of those fruits, vegetables and beverages shown to be high in oxalate, 7) a more severe low oxalate diet, which consisted of limiting the patient's dietary intake to meats, fats and carbohydrates, with a total avoidance of fruits and vegetables, and 8) a no oxalate diet, consisting of an elemental diet that supplied complete nutritional requirements but with an oxalate content of less than 15 mg. per day. RESULTS
Patient statistics. Followup studies have been completed within the last 3 months in 70 per cent of the 543 bypass patients. Sixty patients have passed calculi that have been recovered and 6 additional patients who have a history strongly suggestive of stone passage have been included as stone formers. Therefore, the incidence of stone disease is 12 per cent as calculated on the basis of the total population or 17 per cent if based on the group reviewed. We believe the severity of stone symptoms encourages physician contact and, therefore, favors the 12 per cent incidence. Seven patients reported a history of calculi preoperatively and all but 1 of these has had postoperative calculi. Surgical extraction has been necessary in only 7 instances. Thirty-two stones have been analyzed: 30 consisted entirely of calcium oxalate and 2 consisted of ammonium urate. The first indication of stone disease occurred 1 year postoperatively in 57 per cent of the cases, 2 years postoperatively in 18 per cent, 3 years postoperatively in 18 per cent and more than 4 years postoperatively in 7 per cent. A solitary calculus was present in 59 per cent of the cases, while 2 calculi were noted in 16 per cent, 3 calculi in 12 per cent and multiple calculi in 13 per cent.
1. Results of studies done on 10 bypass patients with calculi, 10 patients 4 years after bypass operation without calculi, 10 obese patients
before bypass operation and 10 normal control subjects Pts. With Stones Mean Urine volume (ml./24 hrs.) Plasma oxalate (µg./ml.) Urine oxalate (mg./24 hrs.) Calcium oxalate supersaturation (%) 18 Crystallization rate" % Urine particles > 15 /L· 19 Urine calcium (mg./24 hrs.)
850 3 130 30 75 43 71
(range) (410-997) (2.5-3.5) (80-210) (9-50) (30-90) (10-60) (10-149)
Pts. Without Stones Mean 970 3 124 31 30 21 80
(range) (430-1,041) (2.5-3.5) (60-190) (9-40) (10-50) (0-30) (55-147)
Pre-Bypass Pts. Mean 1,800 1.8 18 24 15 11
170
(range) (870-2,200) (1-2.5) (8-25) (9-37) (0-30) (0-18) (100-260)
Normal Controls Mean 1,670 1.6 16 31 20 10 167
(range) (900-2,010) (1-2) (9-23) (10-50) (0-35) (0-25) (90-250)
633
OXALATE STONE DISEASE AFTER INTESTINAL RESECTION 24--~----~----,---r---r---,
Identification of patients in whom stones will form. Studies designed to characterize patients in whom stones will form are shown in table 1. These data show that there were no differences in the parameters studied between the normal control subjects and the pre-bypass patients. All patients studied showed increased urinary and plasma oxalate levels postoperatively, while urinary calcium excretion was reduced. There was no absolute difference in plasma or urinary oxalate levels, urinary calcium or percentage saturation between patients with and without stones but a difference in the kinetics of crystal formation (crystallization rate) was observed between the 2 groups, which also may be responsible for the observed increased number of large particles present in the urine of the stone formers. Oxalate absorption. Figure 1 shows the response to a 200 mg. oral load of oxalate in a normal person and in a patient 1 year after a small bowel bypass. The control subject absorbed 6 per cent of the oxalate load, while the bypass patient absorbed 38 per cent. This pattern of response is typical of that seen in all patients studied. Preoperatively the non-stone formers absorbed 5 to 12 per cent and the stone formers 7 to 15 per cent. Postoperatively, the non-stone formers absorbed 35 to 55 per cent and the stone formers 34 to 58 per cent. Results of therapy. Table 2 shows the lack of effect of various therapeutic regimens on those aforementioned factors to have some relationship with stone formation. Our period offollowup is too short to show any change in the pattern of stone formation in response to therapeutic measures but 1 patient who passes in excess of 2 recoverable calculi per week has been tried for at least a 2-month period on each of these regimens without change in the stone production rate (fig. 2). This patient is in serious difficulty but will not consider having the bypass reversed. He has been placed on an elemental diet containing no oxalate with immediate cessation of stone formation. Unfortunately, such a diet is not palatable for long periods. At present the patient is eating only meat, fish, carbohydrates and dairy products. The urinary oxalate has decreased from 200 to 100 mg. per 24 hours and the patient has passed 6 calculi in the last 2 months.
22
20 18
16 Bypass Patient
Urinary 14 Excretion
of Oxalic Acid Mg.
12 10
8 6
(1'
4
I
I
I
p.
\
\
\
Normal Control
\ \
/
\
/
/
b,
t
..... "0-
3
2
-
o---o
4
5
6
Hr.
Load
Fm. 1. Urinary excretion of oxalate after 200 mg. oral load of oxalic acid. Both subjects fasted for 12 hours before loading. Bypass patient is 1 year postoperative. TABLE
2. Patients with a decrease in measured parameters after 3
months of therapy No. OxPts. in Urine alate Trial Magnesium oxide Calcium carbonate Calcium gluconate Cholestyramine Low fat diet Low oxalate diet
12 11 9
14 20 30
Particle Size
Calcium Oxalate Supersaturation
Calcium Oxalate Crystallization Rate
2 1 0 0 0 2
3 1 2 1 1 3
1 1 1 1 0 1
0 1 2 3 2 4
I
+ I
Small bowel bypass patients are difficult subjects to work with. Extensive psychologic testing at our institution suggests that this group uses much denial in regard to body image and condition, and that eating is a form of addiction. For these
first stone
bypass
6/73
DISCUSSION
9/73 I
12/73 + I
I
3/74 I
6/74
9/74
12/74
3/75
I
I
I
I
low oxalate diet low fat diet
cholestyromine
mg.oxide
THERAPY
ca. 9luconote
ca. carbonate
no oxalate no fruit or vegetables
URINE OXALATE MG./24HR. 5 0 - - - -.....
100150200-
STONES/WK.
0------------..... 1-
234-
Fm. 2. Effect of various therapeutic measures on urinary oxalate excretion and stone production in 28-year-old man who weighed 410 pounds at time of bypass operation in July 1973. Current weight of patient is 195 pounds.
634
GREGORY, PARK AND SCHOENBERG
reasons patient followup and compliance with therapy are difficult to obtain. Diets are not followed and medications are ignored often. The observed 12 per cent incidence of calculogenesis is not excessive, especially if viewed in light of the fact that the majority of calculi are passed spontaneously and that to date 57 per cent of stone formers pass only 1 calculus. The fact that 6 of 7 patients who had stones preoperatively had additional stones postoperatively does underline the importance of a careful preoperative urologic history on patients undergoing small bowel bypass procedures. It is our opinion at this time that patients with a positive stone history should not have this procedure performed. As could be expected, the intestinal absorption studies show a marked increase in oxalate absorption after an intestinal bypass. It is interesting that these patients who have a mouthto-colon transit time of only 20 minutes as seen on postoperative upper gastrointestinal series have an oxalate absorption curve peak that occurs later and remains elevated for a longer time than is the case in normal patients. We interpret this as an indication that the site of intestinal oxalate absorption is different in the normal individual from that in the patient with intestinal resection. It is most likely that the site of oxalate absorption in the bypass patient is the colon, which after a bypass procedure has undergone adaptive changes to become the principal site of intestinal absorption. The mechanism of hyperabsorption of oxalate is not understood but is under investigation currently. Developments in this area could be of major therapeutic importance. Of all therapeutic measures currently available only reduced ingestion of oxalate has had beneficial results. Inasmuch as detectable oxalate exists in a large percentage of standard food products it does not appear practical to expect a reduction of oxaluria by dietary controls, especially in a population highly resistant to dieting. Even by eliminating all dietary fruits and vegetables we have been unable to reduce oxalate excretion to normal levels. In our hands no suitable agent has been successful in achieving intestinal oxalate chelation in the bypass population, despite the fact that chelation with calcium11 and also with cholestyramine 10 has been reported to be of therapeutic importance for patients who have hyperoxaluria resulting from ulcerative colitis. A possible explanation for this discrepancy is the generally lower level of oxaluria demonstrated by the patients with ulcerative colitis and bowel resections less extensive than those done in a jejuno-ileal bypass. The observed incidence of oxalate stone formation in our bypass patients is far higher than the idiopathic rate for this geographic area but it is of interest that the rate is no higher, with a marked hyperoxaluria and some degree of calcium oxalate supersaturation occurring in essentially all our postoperative patients. Obviously, other factors responsible for stone induction or for calcium inhibition are acting here. Hopefully, these factors can be defined. Toward this end we have demonstrated an increased crystallization rate in the group of bypass stone formers and believe that future investigations involving the kinetics of stone formation will prove fruitful in elaborating the mechanism of this disorder. Until the time that prevention or treatment is available it is fortunate for those patients requiring small bowel bypass and for those surgeons undertaking this procedure that the incidence of stone formation and the rate of recurrence are relatively low and that the incidence of spontaneous stone passage is quite high. REFERENCES
1. Melick, R. A. and Henneman, P. H.: Clinical and laboratory studies of 207 consecutive patients in a kidney-stone clinic. New Engl. J. Med., 259: 307, 1958. 2. Clarke, A. M. and McKenzie, R. G.: Ileostomy and the risk of urinary uric acid stones. Lancet, 2: 395, 1969.
3. Gelzayd, E. A., Breuer, R. I. andKirsner, J.B.: Nephrolithiasis in inflammatory bowel disease. Amer. J. Dig. Dis., 13: 1027, 1968. 4. Hofmann, A. F., Thomas, P. J., Smith, L. H. and McCall, J. T.: Pathogenesis of secondary hyperoxaluria in patients with ileal resection and diarrhea. Gastroenterology, 58: 960, 1970. 5. Dowling, R.H., Rose, G. A. and Sutor, D. J.: Hyperoxaluria and renal calculi in ileal disease. Lancet, 1: 1103, 1971. 6. Admirand, W. H., Earnest, D. L. and Williams, H. E.: Hyperoxaluria and bowel disease. Trans. Ass. Amer. Physicians, 84: 307, 1971. 7. Smith, L. H., Fromm, H. and Hofmann, A. F.: Acquired hyperoxaluria, nephrolithiasis, and intestinal disease. Description of a syndrome. New Engl. J. Med., 286: 1371, 1972. 8. Hofmann, A. F., Tacker, M. M., Fromm, H., Thomas, P. J. and Smith, L. H.: Acquired hyperoxaluria and intestinal disease. Evidence that bile acid glycine is not a precursor of oxalate. Mayo Clin. Proc., 48: 35, 1973. 9. Chadwick, V. S., Modha, J. and Dowling, R.H.: Mechanism for hyperoxaluria in patients with ileal dysfunction. New Engl. J. Med., 289: 172, 1973. 10. Stauffer, J. Q., Humphreys, M. H. and Weir, G. J.: Acquired hyperoxaluria with regional enteritis after ileal resection. Role of dietary oxalate. Ann. Intern. Med., 79: 383, 1973. 11. Earnest, D. L., Johnson, G., Williams, H. E. and Admirand, W. H.: Hyperoxaluria in patients with ileal resection: an abnormality in dietary oxalate absorption. Gastroenterology, 66: 1114, 1974. 12. Woodward, E. R., Payne, J. H., Salmon, P. A. and O'Leary, J. P.: Morbid obesity. Arch. Surg., 110: 1440, 1975. 13. Dickstein, S.S. and Frame, B.: Urinary tract calculi after intestinal shunt operation for the treatment of obesity. Surg., Gynec. & Obst., 136: 257, 1973. 14. O'Leary, J. P., Thomas, W. C. and Woodward, B. R.: Urinary tract stone after small bowel bypass for morbid obesity. Amer. J. Surg., 127: 142, 1974. 15. Gregory, J. G., Starkloff, E. B., Miyai, K. and Schoenberg, H. W.: Urologic complications ofileal bypass operation for morbid obesity. J. Urol., 113: 521, 1975. 16. Gregory, J. G. and Park, K. Y.: Clinical measurement of urine and plasma oxalate. In preparation. 17. Zarembski, P. M. and Hodgkinson, A.: The fluorimetric determination of oxalic acid in blood and other biological materials. Biochem. J., 96: 717, 1965. 18. Gill, W. B., Silvert, M. A. and Roma, M. J.: Supersaturation levels and crystallization rates of calcium oxalate from urines of normal humans and stone formers determined by a 14Coxalate technique. Invest. Urol., 12: 203, 1974. 19. Robertson, W. G.: A method for measuring calcium crystalluria. Clin. Chim. Acta, 26: 105, 1969. COMMENT Unfortunately, the jejuno-ileal bypass procedure has become a predictable means of inducing calcareous renal calculi in a significant number of patients. The authors have emphasized the similarity of the urinary abnormalities of patients with and without calculi, so that we still do not know why stones develop in some patients but not in the majority. The authors' pessimistic views on effective therapy of the induced stone disease are shared by many. Because of the intestinal bypass it is almost impossible for these patients to achieve a copious volume of urine. Larger amounts of calcium than used in this study will reduce urinary oxalate to within the range of normal but patient compliance is difficult to maintain and the potential ill-effects of long-term treatment are not known. If the current popularity of the bypass procedure is to persist some simple but effective means to prevent renal calculi must be devised. W.C .T. REPLY BY AUTHORS The failure of stone prevention limits the role of the urologist in small bowel bypass operations to the area of preoperative patient selection and consultation, and as therapists for those patients in whom stones eventually form. In our institution bypass reversal is recommended to patients who have passed multiple calculi and who appear to be developing a degree of renal impairment secondary to the stone disease. Despite impending renal failure acceptance of this advice frequently is not heeded and, when heeded, a return to prebypass weight invariably is seen.