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Nephrolithiasis and urine ion changes in ulcerative colitis patients undergoing colectomy and endorectal ileal pullthrough
JOURNAL
OF SURGICAL
RESEARCH
48,552-556
(1990)
Nephrolithiasis and Urine Ion Changes in Ulcerative Colitis Patients Undergoing Colectomy and Endorectal lleal Pullthrough MATTHIAS STELZNER, M.D., J. DUNCAN PHILLIPS, M.D., SALEH SALEH, M.D.,* AND ERIC W. FONKALSRUD, M.D.l The Departments
of Surgery and *Medicine,
Presented at the Annual Meeting
of the Association
UCLA School of Medicine,
for Academic Surgery, Louisville,
Press,
Kentucky,
90024
November
15-18, 1989
with inflammatory bowel disease who have undergone colectomy and construction of a permanent ileostomy [ 7, 81. Bambach et al. [8] found stones in 27 of 305 patients (8.9%) who had undergone proctocolectomy and ileostomy without small bowel resection, and in 9 of 61 patients (14.8%) with an additional partial small bowel resection. During the past decade over 2500 patients with ulcerative colitis have undergone total colectomy, mucosal proctectomy, and endorectal pullthrough with construction of an ileal reservoir (PTR) in the United States. It appears that this new operation may offer several physiologic advantages over standard ileostomy, including the prolongation of small intestinal transit time and increased intestinal water absorption with reduced fecal fluid loss [9, lo]. Whether the PTR procedure influences the incidence of urinary stone formation has not been determined. The present investigation was designed to obtain information regarding changes in the urinary ion excretion in patients with ulcerative colitis who undergo a PTR operation in order to estimate their risk of urinary stone formation.
Nephrolithiasis occurs in 5 to 13% of patients with ulcerative colitis (UC) who undergo colectomy and abdominal ileostomy, presumably from chronic dehydration and urinary concentration. Whether endorectal ileal pullthrough with ileal reservoir (PTR) changes the incidence of stones (primarily calcium oxalate) after colectomy is not known. Urinary excretion of Na2+, K+, Ca2+, Mg2+, phosphate, urate, oxalate, and citrate was measured in a prospective study of 12 UC patients undergoing PTR with temporary end ileostomy. Twenty-four-hour urine samples were obtained before colectomy (tJ, after colectomy but before ileostomy closure (t2), and 5 months after ileostomy closure (t3). Urine volumes decreased from 831 * 101 cc (mean + SE) at tI to 715 f 101 cc at t2 and then increased to 1278 f 421 cc at t3 (significant, with P < 0.01 by t test). Urinary excretions of Mg’+, oxalate, and citrate were low in UC patients compared to those in controls (15 healthy adult volunteers). Excretion of Ca2+ increased significantly following temporary ileostomy while excretion of Mg2+ fell. Excretion of Ca2’ fell and excretion of Mg2+ and citrate increased following PTR. We conclude that PTR patients have increased urine volumes and urinary ion changes known to decrease the risk of developing renal stones. o 1990 Academic
Los Angeles, California
METHODS
Inc.
Informed consent for voluntary study participation was obtained from 12 patients (7 males, 5 females) with ulcerative colitis undergoing the PTR procedure, in accordance with the Helsinki Declaration of 1975. Twentyfour-hour urine volumes and excretion of sodium, potassium, calcium, magnesium, phosphate, urate, oxalate, and citrate were measured in a prospective controlled fashion and compared to those of 15 healthy adult controls. Study patients ranged in age from 18 to 58 years (mean = 32.2). All patients had a history of long-standing ulcerative colitis with a mean duration of 8.3 years. Nine of the 12 patients had pancolitis. Each of the 12 had received highdose corticosteroid therapy for more than 4 months. The operation was performed in two stages separated by an interval of 4 months, as previously described [ll]. During the first operation, total colectomy, mucosal proctectomy, and creation of a 15-cm-lateral ileal reservoir
INTRODUCTION The incidence of nephrolithiasis is believed to be increased in patients with ulcerative colitis (UC) and Crohn’s disease, as well as certain other gastrointestinal disorders particularly in association with high urine oxalate levels [l, 21. Although some earlier reports do not mention nephrolithiasis as a complication in patients with UC [3-51, others have reported that nephrolithiasis develops in 2.0 to 6.4% of these patients [l, 6, 71. Nephrolithiasis occurs even more frequently in those patients 1 To whom correspondence and reprint requests should be addressed at Rm 72-126 CHS, Division of Pediatric Surgery, Dept. of Surgery, UCLA School of Medicine, Los Angeles, CA 90024. 0022-4804/90 $1.50 Copyright 0 1990 by Academic Press, All rights of reproduction in any form
552 Inc. reserved.
STELZNER
ET AL.: URINE
IONS
IN ULCERATIVE
COLITIS
TABLE Urine
Ion Excretion
mole/mole, creatinine Na+ K+ Ca2+ (X100) M$f (X100) Phosphate (X100) Urate (X100) Oxalate (X100) Citrate (X100) pH (pH units)
+ + f f f f f f
5 0.5** 5 3* 13” 5 0.4* 1**
5.60 rt 0.115**
UNDERGOING
and pH in Patients
with
Ulcerative
Colitis
tz 16 4 85 16 83 20 1 7
553
COLECTOMY
1
h 22 3 36 23 54 25 2 5
PATIENTS
+ * f f f f f f
6 0.5* 26* 4* 23* 4 0.3* 2*
5.53 f 0.097**
t3 63 5 32 24 62 22 2 14
k h f + f f f f
15* 1.0 7 4* lo** 3 0.3* 3*
5.70 f 0.165**
N 12 f 8 7f2 34 * 5 48 f 8 264 2~55 26 f 5 3 f 1.2 28 f 7 6.10 k 0.100
Note. ti, before colectomy; tP, after cutaneous ileostomy; t3, after PTR; N, normal controls. Values expressed as means f SEM; *, significantly different from N with P < 0.05; **, significantly different from N with P < 0.01.
was performed. The reservoir was drawn through the rectal muscularis and sutured to the anal mucosa. A temporary end ileostomy was constructed. During the second operation, the ileostomy was mobilized and an ileo-ileal anastomosis was performed. Perioperative corticosteroids and antibiotics were given according to a standardized regimen. Other postoperative medications including antidiarrheals or bulk-forming agents were given intermittently as necessary. For urine ion excretion, 24-hr urine specimens were obtained from each patient 2 days prior to both the first stage (tr) and the second stage operations (tz). A third urine specimen was obtained 4 months after cutaneous ileostomy closure (ts). All patients were consuming their regular home diets during the entire sampling periods. Patients did not receive any recommendations regarding oral fluid intake in order to obtain unbiased urine volume values reflecting actual “normal life” conditions. All urine samples were stored at 4°C and measurements were performed within 24 hr. Values of sodium, potassium, calcium, magnesium, phosphate, creatinine, chloride, uric acid, oxalate, citrate, and pH were measured using standard laboratory methods: sodium and potassium by flame emission photometry, calcium and magnesium by atomic absorption spectrophotometry, phosphate and creatinine by autoanalyzer, chloride by automated chloride titration, and pH by pH meter. Uric acid [12], oxalate [13], and citrate [14] were measured by techniques described previously. Results are expressed as moles of ion per mole of creatinine. Oral fluid intakes were not recorded. Saturation of the urine was calculated as relative supersaturation on a log 10 scale as described by Marshall and Robertson [15]. Relative supersaturation values for calcium oxalate, brushite, octocalcium phosphate, uric acid, and sodium acid urate were calculated using nomograms described previously by these authors. On this supersaturation scale, a urine at the solubility product has a value of zero and a urine at the formation product has the value of one. Negative values indicate undersat-
uration of the urine for the particular substrate and a very low probability of crystal formation. Values between zero and one are characteristic for the metastable region of supersaturation where growth of free existing crystal may occur but spontaneous crystal formation is unlikely if there are no nucleating agents. Values greater than one reflect the region of absolute supersaturation and indicate that there is a high probability of spontaneous precipitation of the particular substrate. Results are expressed as means + SEM. Statistical comparisons were made using the Student t test, with P < 0.05 considered significant. RESULTS
All 12 patients underwent the PTR procedure without major complications. Before ileostomy closure, two patients developed rectal strictures successfully treated by transanal dilatation. They continued to use anal dilators intermittently for 3 months following closure of the ileostomy and showed a satisfactory evacuation pattern during the long-term postoperative follow-up. When the- third urine sample was taken, all patients considered themselves to be continent. However, three patients experienced fecal staining once or twice a week and one patient had nocturnal fecal staining more than twice a week. The mean stool frequency was 7.9 per 24 hr. None of the patients experienced reservoir inflammation during the period of study. At the time of the third urine collection (t3), only four patients were still using psyllium hydrophilic mucilloid (Metamucil), diphenoxylate hydrochloride with atropine sulfate (Lomotil), or other antidiarrheal agents regularly. Patients with functioning ileal reservoirs demonstrated significantly increased sodium excretion compared to normal controls (Table 1). Potassium excretion was low preoperatively when compared to normal control values and after cutaneous ileostomy. However, potassium excretion increased to control values after PTR. During the
554
JOURNAL
OF SURGICAL
RESEARCH:
ileostomy period, patients showed a marked hypercalcuria, which returned to normal levels with the functioning reservoir. Magnesium excretion was low, compared to controls, at all time points. Excretions of phosphate increased slightly with the ileostomy, but remained far below normal values. Uric acid excretion showed minimal change during the entire period of study. Patients with a functioning ileal reservoir (t3) showed significantly higher urine citrate concentrations than those during the ti and t2 periods, but their citrate concentrations were less than half of normal values. Urine pH values were significantly lower in the three groups of patients than in controls (Table 1). The 24-hr urine volume was lowest during the ileostomy period, but increased by almost 80% once intestinal continuity was restored and the ileal reservoir was functioning (Table 2). The saturation of urine with calcium oxalate, uric acid, sodium urate, and calcium phosphate was calculated (Fig. 1). In all three groups of patients, metastable urine concentrations were found for calcium oxalate. Uric acid and sodium urate crystal formation appeared more likely in patients with ulcerative colitis or an ileostomy than in those with an ileal reservoir. Urine concentrations were below the solubility product for calcium phosphates in all three groups of patients. None of the 12 patients developed urinary stones during the 7-month study period. DISCUSSION
In this prospective study, changes in urinary ion excretion were measured in 12 patients undergoing colectomy and the PTR procedure. Patients with active ulcerative colitis and those following ileostomy creation had significantly reduced urine volumes compared to those of patients after the PTR procedure and to those of normal controls. The reduced volume in ileostomy patients was accompanied by an increased urinary excretion of calcium, but not of oxalate or uric acid. Changes in urine volumes may have been influenced by changes in medications, since the majority of patients received corticosteroids before colectomy and 4 patients continued to use antidiarrheals in varying dosages at the end of the study. Urine saturation, expressed by an activity product ratio, can be precisely calculated after obtaining activity prod-
TABLE Urine
Volume per 24 hr (ml)
Volume
in Patients
2 with
Ulcerative
Colitis
h
tz
t3
N
831 + 101*
715 f 101*
1278 f 420
1300f65
Note. tl, before colectomy; t2, after cutaneous ileostomy; t3, after PTR; N, normal controls. Values expressed as means f SEM, *, significantly different from N by t test, with 2’ <* 0.01.
VOL. 48, NO. 6, JUNE
Calcium
1990
cap0 4
malate
FIG. 1. Urine saturation
levels in patients
ca (PO) 3 42 with ulcerative
colitis
(tl, before colectomy; t2,after cutaneous ileostomy; t3,after PTR). Values expressed as means f SEM.
ucts by chemical analysis of at least nine urine constituents and by calculation of their 22 or 31 complexes using computer programs [16, 171. However, the number of these complexes is often uncertain, as are some of their stability constants. We used nomograms to estimate relative saturation of the urine samples of several substances. As demonstrated by the relative supersaturation values, oxalate is the most likely constituent to precipitate with calcium. Two main factors have been shown to determine the risk of developing calcium-containing stones: (i) the degree of urinary saturation of calcium oxalate and calcium phosphate and (ii) the level of protective inhibitory activity against crystallization of calcium oxalate. Major determinants of calcium stone formation are known to be the urine concentrations of acid mucopolysaccharides (AMPS), magnesium, and citrate [18-211. In addition, increased uric acid concentration may interfere with the inhibitory activity of AMPS and promote calcium oxalate stone formation [22]. Although AMPS concentrations were not determined in this study, it appears that the slight decrease in oxalate excretion in our patients may be balanced out by the significant increase in hydrogen ion excretion as reflected by the low pH value. Thus, calcium oxalate crystal formation appeared more likely in all three patient groups than in controls. Conversely, the probability of calcium phosphate stone formation was very low due to a markedly low phosphate excretion found at all three time points. Magnesium has been shown to exert a major inhibitory effect on the formation of calcium stones in vitro [23,24]. Clinical studies indicate that magnesium therapy may be effective in the treatment of individuals with calciumcontaining renal stones [25-271. It has been suggested that magnesium binds oxalate competitively and increases the solubility of calcium oxalate [28]. Thus, the low urine magnesium excretions found in ulcerative colitis and
STELZNER
ET AL.: URINE
IONS
IN ULCERATIVE
postoperative patients may increase the risk of stone formation. Biochemical and clinical evidence suggest that urine citrate also represents an important preventive factor against crystallization of calcium salts [29,30]. By forming complexes with calcium, citrate may inhibit growth of calcium oxalate and calcium phosphate crystals [31]. The patients in the present study showed low citrate excretion at all time points which might increase their susceptibility to calcium stone formation. The demonstration of the persistently acid urine and unchanged uric acid concentrations in the patients at the three different perioperative time periods confirms findings of Clarke and McKenzie that an ileostomy causes the persistent loss of water and bicarbonate and thus produces changes which favor the production of uric acid stones [32]. The pK of uric acid is 5.42; 6 of the 12 patients at tl, 4 at tz, and 3 at t3 had urinary pH values below this value. Uric acid concentrations were without influence on stone formation, as they remained normal at all three time points. Four of the patients stated that they consumed considerably more salt than other family members. This may offer an explanation of why sodium excretion was significantly elevated post ileostomy closure. However, this increase in sodium excretion did not result in supersaturation. Following PTR, patients had the lowest saturation values compared to those of time points tl and t2. According to the nomograms used, this was mainly attributed to the increase in pH. We conclude that it appears likely that there will be an increased incidence of calcium oxalate and uric acid stones in patients with ulcerative colitis, ileostomy patients, and those with a PTR. Low urine volumes, low urine pH values, and low excretions of magnesium and citrate are the determinants that lead to an increased risk of calcium oxalate and urate precipitation. Thus, the risk of stone formation appears to be lowest in patients with an ileal reservoir, primarily due to an increase in urine volume and pH. The risk of forming calcium oxalate or uric acid stones in this group of patients appears to be less than in patients with active ulcerative colitis, and in those with colectomy and a temporary ileostomy. Two factors appear to establish the functional superiority of the ileal reservoir. First, the intestinal transit time is markedly increased in patients with an ileal reservoir [lo]. The ileal reservoir allows for fecal storage and maintains the thyme in contact with the ileal mucosa for a longer period of time. Second, increased water absorption and more semisolid stool consistency appears to develop [33]. Sodium and potassium absorption may never be as effective as in normal individuals since the ileal active transport mechanisms for these ions are not able to work against as high a gradient as are colonic transporters [34]. Thus the ileum is not able to completely substitute for the removed colon. A certain number of cations are lost persistently, although this status of cation
COLITIS
PATIENTS
UNDERGOING
COLECTOMY
555
depletion appears to improve as ileal reservoir adaptation progresses. In a retrospective study of the last 147 patients with either ulcerative colitis or familial polyposis coli who underwent colectomy and a PTR operation at the UCLA Medical Center, 14 had a history of nephrolithiasis. The mean postoperative follow-up was 3.8 years. Three patients with ulcerative colitis had stones before and after the PTR procedure; all 3 had more than three episodes of recurrent stones. Eight patients (7 with ulcerative colitis and 1 with familial polyposis) who had stones during their active colonic disease did not develop stones after colectomy and PTR. Three other ulcerative colitis patients developed stones after colectomy and PTR. One of these patients has documented hyperparathyroidism. Calcium oxalate stones were identified in 5 patients and uric acid stones were found in 3. The results from the present study suggest that colectomy and PTR do not prevent, but may reduce, the likelihood of developing nephrolithiasis in patients with ulcerative colitis. Further studies are necessary to determine whether the incidence of renal stones in patients with ulcerative colitis who require proctocolectomy can in fact be reduced by performing a PTR operation. REFERENCES 1.
Gelzayd, E. A., Breuer, R. I., and Kirsner, J. B. Nephrolithiasis in inflammatory bowel disease. Amer. J. Dig. Dis. 13: 1027, 1968. 2. Smith, L. H., Fromm, H., and Hofmann, A. F. Acquired hyperoxaluria, nephrolithiasis, and intestinal disease. Description of a syndrome. N. Engl. J. Med. 286: 1371,1972.
3. Brown, M. L., Kasick, A. M., and Weingarten, of chronic ulcerative
B. Complications colitis. Amer. J. Dig. Dis. 18: 52, 1951.
4. Hightower,
N. C., Broders, A. C., Haines, R. D., McKenney, J. F., and Sommer, A. W. Chronic ulcerative colitis. II. Complications. Amer. J. Dig. Dis. 3: 861, 1958.
5. Barron, R. A., and Ruel, R. E. Serious complications colitis:
Review of cases, 1950-1961. Harper
of ulcerative Hosp. Bull. 21: 70,
1963. 6. Deren, J. J., Porush, J. G., Levitt,
M. F., and Khilnani, M. T. Nephrolithiasis as a complication of ulcerative colitis and regional enteritis. Ann. Intern. Med. 56: 843, 1962. Maratka, Z., and Nedbal, J. Urolithiasis as a complication surgical treatment of ulcerative colitis. Gut 5: 214, 1964.
of the
8. Bambach, C. P., Robertson, W. G., Peacock, M., and Hill, G. L. Effect of intestinal surgery on the risk of urinary Gut22: 257, 1981.
stone formation.
9.
Mibu, R., Itoh, H., and Nakayama, F. Effect of total colectomy and mucosal proctectomy on intestinal absorptive capacity in dogs. Dis. Colon Rectum 30: 47, 1987.
10.
Soper, N. J., Orkin, B. A., Kelly, K. A., Phillips, S. F., and Brown, M. L. Gastrointestinal transit after proctocolectomy with ileal pouch-anal anastomosis or ileostomy. J. Surg. Res. 46: 300, 1989.
11.
Fonkalsrud, E. W. Update on clinical experience with different surgical techniques of the endorectal pullthrough operation for colitis and polyposis. Surg. Gynecol. O&et. 165: 309, 1987. 12. Liddle, L., Seegmiller, J. E., and Laster, L. The enzymatic spectrophotometric method for determination of uric acid. J. Lab. Clin. Med. 54: 903, 1959.
556 13. 14. 15.
16.
JOURNAL
OF SURGICAL
RESEARCH:
Olthuls, F. M. F. G., Markslag, A. M. G., and Klein Elhorst, J. T. Urinary oxalate estimation. Clin. Chim. Acta 75: 123, 1977. Nielsen, T. T. A method for the enzymatic determination of citrate in serum and urine. Scund. J. Lab. Znuest. 56: 513, 1976. Marshall, R. W., and Robertson, W. G. Nomograms for the estimation of the saturation of urine with calcium oxalate, calcium phosphate, magnesium ammonium phosphate, uric acid, sodium acid urate, ammonium acid, and cystine. Clin. Chim. Actu 72: 253, 1976. Robertson, W. G., Peacock, M., and Nordin, B. E. C. Activity products in stone-forming and non-stone-forming urine. Clin. Sci.
34: 579,196s. 17. Marangella,
M., Daniele, P. G., Ronzani, M., Sonego, S., and Linari, F. Urine saturation with calcium salts in normal subjects and ideopathic calcium stone formers estimated by an improved computer model system. Ural. Res. 13: 189, 1985. 18. Robertson, W. G., and Nordin, B. E. C. Physiochemical factors governing stone formation. In D. I. Williams and G. D. Chisholm (Eds.), Foundations of Urology. London: Heinemann, 1976. Pp.
254-267. Kohri, K., Garside, J., and Blacklock, N. J. The role of magnesium in calcium oxalate urolithiasis. &it. J. Ural. 61: 107, 1988. 20. Aroldi, A., Soriani, N., Zubani, R., Catelnovo, C., and Graziani, G. Urinary citrate in recurrent stone-forming patients. Co&rib. Nephrol. 58: 39, 1987. 21. Robertson, G., Peacock, M., Heyburn, P. J., Marshall, D. H., and Clark, P. B. Risk factors in calcium stone disease of the urinary tract. J. Ural. 50: 449, 1978. 22. Robertson, W. G., Knowles, C. F., and Peacock, M. Urinary acid mucopolysaccharide inhibitors of calcium oxalate crystallisation. In H. Fleisch, W. G. Robertson, C. H. Smith, and W. Vahlensieck (Eds.), Urolithiasis Research. New York: Plenum, 1976. Pp. 33119.
334. 23. Desmars, J. F., and Tawashi, R. Dissolution oxalate monohydrate. I. Effect Biophys. Acta 213: 256, 1973.
and growth of calcium of magnesium and pH. Biochim.
VOL. 48, NO. 6, JUNE
1990
24. Meyer, J. L. The relative importance of calcium phosphate urinary inhibitors. In P. 0. Schwille, L. H. Smith, W. G. Robertson, and W. Vahlensieck (Eds.), Urolithiasis and Related Clinical Research. New York: Plenum, 1985. Pp. 811-814.
25. Kohler, F. P., and Uhle, C. A. Oral magnesium intake and its effect on various urinary constituents J. Ural. 96: 812, 1966.
in the prophylaxis
or urolithiasis.
26. Melnick,
I., Landes, R. R., Hoffman, A. A., and Burch, J. F. Magnesium therapy for recurring calcium oxalate urinary calculi. J. Ural. 105: 119, 1971.
27. Johansson,
G., Backman, U., Danielson, B. G., Fellstrom, B., Ljunghall, S., and Wilkstrom, B. Biochemical and clinical effects of the prophylactic treatment of renal calcium stones with magnesium hydroxide. J. Ural. 124: 770, 1980.
28. Hammarsten,
G. On calcium oxalate and its solubility in the presence of inorganic salts with special reference to the occurrence of oxaluria. C. R. Lab. Curlsberg 17: 1, 1929.
29. Marangella,
M., Bianco, O., Grande, M. L., Petrarulo, M., Valente, D., Vitale, C., and Linari, F. Patterns of citrate excretion in healthy subjects and patients with idiopathic stone disease. Co&rib. Nephrol. 58: 34, 1987.
30. Hallson, P. C., Rose, G. A., and Sulaiman, S. Raising urinary citrate lowers calcium oxalate and calcium phosphate in whole urine. Ural. Znt. 38: 179, 1983.
crystal
formation
31. Kok, D. J., Papapoulos, S. E., and Bijvoet, 0. L. M. Low inhibition of crystal agglomeration and citrate excretion in recurrent oxalate stone formers. Contrib. Nephrol. 58: 73, 1987.
32. Clarke, A. M., and McKenzie, urinary
R. G. Ileostomy uric acid stones. Lancet 2: 395, 1969.
calcium
and the risk of
33. Fonkalsrud,
E. W., Stelzner, M., and McDonald, N. Construction of an ileal reservoir in patients with a previous straight ileal pullthrough. Ann. Surg. 208: 50, 1988.
34. Powell, D. W. Intestinal
water and electrolyte transport. In L. R. Johnson (Ed.), Physiology of the Gastrointestinal Tract. New York: Raven Press,1987.Pp.1267-1305.
OF SURGICAL
RESEARCH
48,552-556
(1990)
Nephrolithiasis and Urine Ion Changes in Ulcerative Colitis Patients Undergoing Colectomy and Endorectal lleal Pullthrough MATTHIAS STELZNER, M.D., J. DUNCAN PHILLIPS, M.D., SALEH SALEH, M.D.,* AND ERIC W. FONKALSRUD, M.D.l The Departments
of Surgery and *Medicine,
Presented at the Annual Meeting
of the Association
UCLA School of Medicine,
for Academic Surgery, Louisville,
Press,
Kentucky,
90024
November
15-18, 1989
with inflammatory bowel disease who have undergone colectomy and construction of a permanent ileostomy [ 7, 81. Bambach et al. [8] found stones in 27 of 305 patients (8.9%) who had undergone proctocolectomy and ileostomy without small bowel resection, and in 9 of 61 patients (14.8%) with an additional partial small bowel resection. During the past decade over 2500 patients with ulcerative colitis have undergone total colectomy, mucosal proctectomy, and endorectal pullthrough with construction of an ileal reservoir (PTR) in the United States. It appears that this new operation may offer several physiologic advantages over standard ileostomy, including the prolongation of small intestinal transit time and increased intestinal water absorption with reduced fecal fluid loss [9, lo]. Whether the PTR procedure influences the incidence of urinary stone formation has not been determined. The present investigation was designed to obtain information regarding changes in the urinary ion excretion in patients with ulcerative colitis who undergo a PTR operation in order to estimate their risk of urinary stone formation.
Nephrolithiasis occurs in 5 to 13% of patients with ulcerative colitis (UC) who undergo colectomy and abdominal ileostomy, presumably from chronic dehydration and urinary concentration. Whether endorectal ileal pullthrough with ileal reservoir (PTR) changes the incidence of stones (primarily calcium oxalate) after colectomy is not known. Urinary excretion of Na2+, K+, Ca2+, Mg2+, phosphate, urate, oxalate, and citrate was measured in a prospective study of 12 UC patients undergoing PTR with temporary end ileostomy. Twenty-four-hour urine samples were obtained before colectomy (tJ, after colectomy but before ileostomy closure (t2), and 5 months after ileostomy closure (t3). Urine volumes decreased from 831 * 101 cc (mean + SE) at tI to 715 f 101 cc at t2 and then increased to 1278 f 421 cc at t3 (significant, with P < 0.01 by t test). Urinary excretions of Mg’+, oxalate, and citrate were low in UC patients compared to those in controls (15 healthy adult volunteers). Excretion of Ca2+ increased significantly following temporary ileostomy while excretion of Mg2+ fell. Excretion of Ca2’ fell and excretion of Mg2+ and citrate increased following PTR. We conclude that PTR patients have increased urine volumes and urinary ion changes known to decrease the risk of developing renal stones. o 1990 Academic
Los Angeles, California
METHODS
Inc.
Informed consent for voluntary study participation was obtained from 12 patients (7 males, 5 females) with ulcerative colitis undergoing the PTR procedure, in accordance with the Helsinki Declaration of 1975. Twentyfour-hour urine volumes and excretion of sodium, potassium, calcium, magnesium, phosphate, urate, oxalate, and citrate were measured in a prospective controlled fashion and compared to those of 15 healthy adult controls. Study patients ranged in age from 18 to 58 years (mean = 32.2). All patients had a history of long-standing ulcerative colitis with a mean duration of 8.3 years. Nine of the 12 patients had pancolitis. Each of the 12 had received highdose corticosteroid therapy for more than 4 months. The operation was performed in two stages separated by an interval of 4 months, as previously described [ll]. During the first operation, total colectomy, mucosal proctectomy, and creation of a 15-cm-lateral ileal reservoir
INTRODUCTION The incidence of nephrolithiasis is believed to be increased in patients with ulcerative colitis (UC) and Crohn’s disease, as well as certain other gastrointestinal disorders particularly in association with high urine oxalate levels [l, 21. Although some earlier reports do not mention nephrolithiasis as a complication in patients with UC [3-51, others have reported that nephrolithiasis develops in 2.0 to 6.4% of these patients [l, 6, 71. Nephrolithiasis occurs even more frequently in those patients 1 To whom correspondence and reprint requests should be addressed at Rm 72-126 CHS, Division of Pediatric Surgery, Dept. of Surgery, UCLA School of Medicine, Los Angeles, CA 90024. 0022-4804/90 $1.50 Copyright 0 1990 by Academic Press, All rights of reproduction in any form
552 Inc. reserved.
STELZNER
ET AL.: URINE
IONS
IN ULCERATIVE
COLITIS
TABLE Urine
Ion Excretion
mole/mole, creatinine Na+ K+ Ca2+ (X100) M$f (X100) Phosphate (X100) Urate (X100) Oxalate (X100) Citrate (X100) pH (pH units)
+ + f f f f f f
5 0.5** 5 3* 13” 5 0.4* 1**
5.60 rt 0.115**
UNDERGOING
and pH in Patients
with
Ulcerative
Colitis
tz 16 4 85 16 83 20 1 7
553
COLECTOMY
1
h 22 3 36 23 54 25 2 5
PATIENTS
+ * f f f f f f
6 0.5* 26* 4* 23* 4 0.3* 2*
5.53 f 0.097**
t3 63 5 32 24 62 22 2 14
k h f + f f f f
15* 1.0 7 4* lo** 3 0.3* 3*
5.70 f 0.165**
N 12 f 8 7f2 34 * 5 48 f 8 264 2~55 26 f 5 3 f 1.2 28 f 7 6.10 k 0.100
Note. ti, before colectomy; tP, after cutaneous ileostomy; t3, after PTR; N, normal controls. Values expressed as means f SEM; *, significantly different from N with P < 0.05; **, significantly different from N with P < 0.01.
was performed. The reservoir was drawn through the rectal muscularis and sutured to the anal mucosa. A temporary end ileostomy was constructed. During the second operation, the ileostomy was mobilized and an ileo-ileal anastomosis was performed. Perioperative corticosteroids and antibiotics were given according to a standardized regimen. Other postoperative medications including antidiarrheals or bulk-forming agents were given intermittently as necessary. For urine ion excretion, 24-hr urine specimens were obtained from each patient 2 days prior to both the first stage (tr) and the second stage operations (tz). A third urine specimen was obtained 4 months after cutaneous ileostomy closure (ts). All patients were consuming their regular home diets during the entire sampling periods. Patients did not receive any recommendations regarding oral fluid intake in order to obtain unbiased urine volume values reflecting actual “normal life” conditions. All urine samples were stored at 4°C and measurements were performed within 24 hr. Values of sodium, potassium, calcium, magnesium, phosphate, creatinine, chloride, uric acid, oxalate, citrate, and pH were measured using standard laboratory methods: sodium and potassium by flame emission photometry, calcium and magnesium by atomic absorption spectrophotometry, phosphate and creatinine by autoanalyzer, chloride by automated chloride titration, and pH by pH meter. Uric acid [12], oxalate [13], and citrate [14] were measured by techniques described previously. Results are expressed as moles of ion per mole of creatinine. Oral fluid intakes were not recorded. Saturation of the urine was calculated as relative supersaturation on a log 10 scale as described by Marshall and Robertson [15]. Relative supersaturation values for calcium oxalate, brushite, octocalcium phosphate, uric acid, and sodium acid urate were calculated using nomograms described previously by these authors. On this supersaturation scale, a urine at the solubility product has a value of zero and a urine at the formation product has the value of one. Negative values indicate undersat-
uration of the urine for the particular substrate and a very low probability of crystal formation. Values between zero and one are characteristic for the metastable region of supersaturation where growth of free existing crystal may occur but spontaneous crystal formation is unlikely if there are no nucleating agents. Values greater than one reflect the region of absolute supersaturation and indicate that there is a high probability of spontaneous precipitation of the particular substrate. Results are expressed as means + SEM. Statistical comparisons were made using the Student t test, with P < 0.05 considered significant. RESULTS
All 12 patients underwent the PTR procedure without major complications. Before ileostomy closure, two patients developed rectal strictures successfully treated by transanal dilatation. They continued to use anal dilators intermittently for 3 months following closure of the ileostomy and showed a satisfactory evacuation pattern during the long-term postoperative follow-up. When the- third urine sample was taken, all patients considered themselves to be continent. However, three patients experienced fecal staining once or twice a week and one patient had nocturnal fecal staining more than twice a week. The mean stool frequency was 7.9 per 24 hr. None of the patients experienced reservoir inflammation during the period of study. At the time of the third urine collection (t3), only four patients were still using psyllium hydrophilic mucilloid (Metamucil), diphenoxylate hydrochloride with atropine sulfate (Lomotil), or other antidiarrheal agents regularly. Patients with functioning ileal reservoirs demonstrated significantly increased sodium excretion compared to normal controls (Table 1). Potassium excretion was low preoperatively when compared to normal control values and after cutaneous ileostomy. However, potassium excretion increased to control values after PTR. During the
554
JOURNAL
OF SURGICAL
RESEARCH:
ileostomy period, patients showed a marked hypercalcuria, which returned to normal levels with the functioning reservoir. Magnesium excretion was low, compared to controls, at all time points. Excretions of phosphate increased slightly with the ileostomy, but remained far below normal values. Uric acid excretion showed minimal change during the entire period of study. Patients with a functioning ileal reservoir (t3) showed significantly higher urine citrate concentrations than those during the ti and t2 periods, but their citrate concentrations were less than half of normal values. Urine pH values were significantly lower in the three groups of patients than in controls (Table 1). The 24-hr urine volume was lowest during the ileostomy period, but increased by almost 80% once intestinal continuity was restored and the ileal reservoir was functioning (Table 2). The saturation of urine with calcium oxalate, uric acid, sodium urate, and calcium phosphate was calculated (Fig. 1). In all three groups of patients, metastable urine concentrations were found for calcium oxalate. Uric acid and sodium urate crystal formation appeared more likely in patients with ulcerative colitis or an ileostomy than in those with an ileal reservoir. Urine concentrations were below the solubility product for calcium phosphates in all three groups of patients. None of the 12 patients developed urinary stones during the 7-month study period. DISCUSSION
In this prospective study, changes in urinary ion excretion were measured in 12 patients undergoing colectomy and the PTR procedure. Patients with active ulcerative colitis and those following ileostomy creation had significantly reduced urine volumes compared to those of patients after the PTR procedure and to those of normal controls. The reduced volume in ileostomy patients was accompanied by an increased urinary excretion of calcium, but not of oxalate or uric acid. Changes in urine volumes may have been influenced by changes in medications, since the majority of patients received corticosteroids before colectomy and 4 patients continued to use antidiarrheals in varying dosages at the end of the study. Urine saturation, expressed by an activity product ratio, can be precisely calculated after obtaining activity prod-
TABLE Urine
Volume per 24 hr (ml)
Volume
in Patients
2 with
Ulcerative
Colitis
h
tz
t3
N
831 + 101*
715 f 101*
1278 f 420
1300f65
Note. tl, before colectomy; t2, after cutaneous ileostomy; t3, after PTR; N, normal controls. Values expressed as means f SEM, *, significantly different from N by t test, with 2’ <* 0.01.
VOL. 48, NO. 6, JUNE
Calcium
1990
cap0 4
malate
FIG. 1. Urine saturation
levels in patients
ca (PO) 3 42 with ulcerative
colitis
(tl, before colectomy; t2,after cutaneous ileostomy; t3,after PTR). Values expressed as means f SEM.
ucts by chemical analysis of at least nine urine constituents and by calculation of their 22 or 31 complexes using computer programs [16, 171. However, the number of these complexes is often uncertain, as are some of their stability constants. We used nomograms to estimate relative saturation of the urine samples of several substances. As demonstrated by the relative supersaturation values, oxalate is the most likely constituent to precipitate with calcium. Two main factors have been shown to determine the risk of developing calcium-containing stones: (i) the degree of urinary saturation of calcium oxalate and calcium phosphate and (ii) the level of protective inhibitory activity against crystallization of calcium oxalate. Major determinants of calcium stone formation are known to be the urine concentrations of acid mucopolysaccharides (AMPS), magnesium, and citrate [18-211. In addition, increased uric acid concentration may interfere with the inhibitory activity of AMPS and promote calcium oxalate stone formation [22]. Although AMPS concentrations were not determined in this study, it appears that the slight decrease in oxalate excretion in our patients may be balanced out by the significant increase in hydrogen ion excretion as reflected by the low pH value. Thus, calcium oxalate crystal formation appeared more likely in all three patient groups than in controls. Conversely, the probability of calcium phosphate stone formation was very low due to a markedly low phosphate excretion found at all three time points. Magnesium has been shown to exert a major inhibitory effect on the formation of calcium stones in vitro [23,24]. Clinical studies indicate that magnesium therapy may be effective in the treatment of individuals with calciumcontaining renal stones [25-271. It has been suggested that magnesium binds oxalate competitively and increases the solubility of calcium oxalate [28]. Thus, the low urine magnesium excretions found in ulcerative colitis and
STELZNER
ET AL.: URINE
IONS
IN ULCERATIVE
postoperative patients may increase the risk of stone formation. Biochemical and clinical evidence suggest that urine citrate also represents an important preventive factor against crystallization of calcium salts [29,30]. By forming complexes with calcium, citrate may inhibit growth of calcium oxalate and calcium phosphate crystals [31]. The patients in the present study showed low citrate excretion at all time points which might increase their susceptibility to calcium stone formation. The demonstration of the persistently acid urine and unchanged uric acid concentrations in the patients at the three different perioperative time periods confirms findings of Clarke and McKenzie that an ileostomy causes the persistent loss of water and bicarbonate and thus produces changes which favor the production of uric acid stones [32]. The pK of uric acid is 5.42; 6 of the 12 patients at tl, 4 at tz, and 3 at t3 had urinary pH values below this value. Uric acid concentrations were without influence on stone formation, as they remained normal at all three time points. Four of the patients stated that they consumed considerably more salt than other family members. This may offer an explanation of why sodium excretion was significantly elevated post ileostomy closure. However, this increase in sodium excretion did not result in supersaturation. Following PTR, patients had the lowest saturation values compared to those of time points tl and t2. According to the nomograms used, this was mainly attributed to the increase in pH. We conclude that it appears likely that there will be an increased incidence of calcium oxalate and uric acid stones in patients with ulcerative colitis, ileostomy patients, and those with a PTR. Low urine volumes, low urine pH values, and low excretions of magnesium and citrate are the determinants that lead to an increased risk of calcium oxalate and urate precipitation. Thus, the risk of stone formation appears to be lowest in patients with an ileal reservoir, primarily due to an increase in urine volume and pH. The risk of forming calcium oxalate or uric acid stones in this group of patients appears to be less than in patients with active ulcerative colitis, and in those with colectomy and a temporary ileostomy. Two factors appear to establish the functional superiority of the ileal reservoir. First, the intestinal transit time is markedly increased in patients with an ileal reservoir [lo]. The ileal reservoir allows for fecal storage and maintains the thyme in contact with the ileal mucosa for a longer period of time. Second, increased water absorption and more semisolid stool consistency appears to develop [33]. Sodium and potassium absorption may never be as effective as in normal individuals since the ileal active transport mechanisms for these ions are not able to work against as high a gradient as are colonic transporters [34]. Thus the ileum is not able to completely substitute for the removed colon. A certain number of cations are lost persistently, although this status of cation
COLITIS
PATIENTS
UNDERGOING
COLECTOMY
555
depletion appears to improve as ileal reservoir adaptation progresses. In a retrospective study of the last 147 patients with either ulcerative colitis or familial polyposis coli who underwent colectomy and a PTR operation at the UCLA Medical Center, 14 had a history of nephrolithiasis. The mean postoperative follow-up was 3.8 years. Three patients with ulcerative colitis had stones before and after the PTR procedure; all 3 had more than three episodes of recurrent stones. Eight patients (7 with ulcerative colitis and 1 with familial polyposis) who had stones during their active colonic disease did not develop stones after colectomy and PTR. Three other ulcerative colitis patients developed stones after colectomy and PTR. One of these patients has documented hyperparathyroidism. Calcium oxalate stones were identified in 5 patients and uric acid stones were found in 3. The results from the present study suggest that colectomy and PTR do not prevent, but may reduce, the likelihood of developing nephrolithiasis in patients with ulcerative colitis. Further studies are necessary to determine whether the incidence of renal stones in patients with ulcerative colitis who require proctocolectomy can in fact be reduced by performing a PTR operation. REFERENCES 1.
Gelzayd, E. A., Breuer, R. I., and Kirsner, J. B. Nephrolithiasis in inflammatory bowel disease. Amer. J. Dig. Dis. 13: 1027, 1968. 2. Smith, L. H., Fromm, H., and Hofmann, A. F. Acquired hyperoxaluria, nephrolithiasis, and intestinal disease. Description of a syndrome. N. Engl. J. Med. 286: 1371,1972.
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