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Bilateral Acetylsulfapyridine Nephrolithiasis Associated with Chronic Sulfasalazine Therapy
0022-;)'.147 /94/l 5 l 6-1605$03.00/0 Vol. 151, 1605· 1606, June 1994
'THE ,JOURNAL OF UHOLO(;Y
Copyright
Printed in US.A
1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Case Reports BILATERAL ACETYLSULFAPYRIDINE NEPHROLITHIASIS ASSOCIATED WITH CHRONIC SULFASALAZINE THERAPY ERDAL ERTURK,* JEFFREY B. CASEMENTO, KEVIN R. GUERTIN AND ANDREWS. KENDE From the Departments of Urology and Chemistry, University of Rochester, Rochester, New York
ABSTRACT
We report on formation of bilateral renal calculi secondary to sulfasalazine therapy for juvenile rheumatoid arthritis. The condition was successfully treated with extracorporeal shock wave lithotripsy. Analysis of the fragments with thin layer chromatography and nuclear magnetic resonance revealed acetylsulfapyridine, a metabolite of sulfasalazine. KEY WORDS: salicylazosulfapyridine, kidney calculi, extracorporeal shockwave lithotripsy
Urinary stone formation related to drug therapy has been previously reported. The most common drug that is associated with stone formation is triamterene, 1 although other drugs have been implicated. To our knowledge we report the first case of bilateral kidney stone formation associated with chronic sulfasalazine therapy. The patient was successfully treated with extracorporeal shock wave lithotripsy (ESWL t). CASE REPORT
A 19-year-old white woman presented to the emergency room with right flank pain. Physical examination was significant for marked left costovertebral angle tenderness and urinalysis
Accepted for publication October 22, 1993. * Requests for reprints: Department of Urology, 601 Elmwood Ave., Box 656, Rochester, New York 14642. t Dornier Medical Systems, Inc., Marietta, Georgia.
showed microhematuria. An excretory urogram revealed a 2 cm. moderately obstructing, poorly calcified stone at the left ureteropelvic junction and a 2.5 cm. stone in the right renal pelvis (fig. 1). Medical history was significant for juvenile rheumatoid arthritis. The patient, who denied a personal or family history of urolithiasis, was taking sulfasalazine, prednisone, meclofenamate sodium and iron sulfate. Serum chemistry studies revealed a creatinine of 0.6 mg./dl. (normal 0.8 to 1.3), calcium 9.2 mg./dl. (normal 8.8 to 10.1), phosphate 3.9 mg./dl. (normal 2.2 to 4.1) and mate 3.9 mg./dl. (normal 4.0 to 8.5). Urinalysis showed a pH of 7.0 and fewer than 50 erythrocytes with 7 to 10 leukocytes per high power field. Urine culture yielded no growth. The patient underwent cystoscopy and insertion of a left Double-J:j: ureteral stent, and left ESWL with the Dornier HM3 unit. The stone fragmented well and numerous gold colored fragments were passed. Following clear-
+Medical Engineering Corp., New York, New York.
FIG. 1. A, bilateral poorly calcified renal stones (arrows). B, delayed excretory urogram shows significant obstruction of left kidney by stone at ureteropelvic junction.
1605
1606
BILATERAL ACETYLSULFAPYRIDINE NEPHROLITHIASIS
so-O-N•N-0-so,HN v
BDOC
--3
1
2
FIG. 2. Metabolism of sulfasalazine 1, salicylazosulfapyridine. 2, sulfapyridine. 3, 5-aminosalycylic acid. 4, N-acetylsulfapyridine.
ance of all fragments right ESWL was performed without stenting. A film of the kidney, ureters and bladder 1 month posttreatment showed no residual fragments. The initial stone analysis with infrared spectroscopy was reported as a drug metabolite, possibly sulfa in origin. Fragments were further analyzed at our chemistry department. Thin layer chromatography identified the chemical composition of the fragments as acetylsulfapyridine, a metabolite of the parent compound, sulfasalazine. Nuclear magnetic resonance confirmed the initial findings. The patient was advised to discontinue sulfasalazine and no other metabolic evaluation was performed. DISCUSSION
Although the calculogenic potential of certain drugs has been recognized, emphasis on stone analysis has been lacking. Triamterene stones have been studied in some detail but the physiological basis for stone formation is still poorly understood. 2· 3 In 1 series in which the incidence of drug induced stones was found to be 2.5% glafenine, piridoxylate and triamterene were associated with stone formation. 4 Other rare products, such as phenazopyridine hydrochloride, N -acetylsulfamethoxazole hydrochloride, N-acetylsulfaguanidine, flumequine, oxolinic acid, silica and calcite, are also reportedly associated with stone formation. 5 Although urinary stones have been associated with sulfa drugs, such as sulfamethoxazoletrimethoprim, 6 to our knowledge an association with sulfasalazine has not been reported. Sulfasalazine (salicylazosulfapyridine) is indicated in the treatment of ulcerative colitis. Although the mode of action is poorly understood, the drug is thought to exert an effect through anti-inflammatory properties. 7 The parent compound, salicylazosulfapyridine (fig. 2, 1 ), is broken down into sulfapyridine (fig. 2, 2) and 5-aminosalicylic acid (fig. 2, 3) by colonic bacteria through reductive cleavage of the azo linkage. Most of the sulfapyridine is adsorbed, metabolized and excreted in the urine as N-acetylsulfapyridine (fig. 2, 4). 8 Stone fragments in our case were examined using thin layer chromatography and were found to be homogeneous with only 1 ultraviolet active component detectable. The compound was
identified as N-acetylsulfapyridine by comparing its thin layer chromatography mobility in a variety of solvent systems with literature values. 9 Identification was confirmed by examining the nuclear magnetic resonance spectrum, which clearly revealed the presence of an N-acetyl group and was consistent with the structure of N-acetylsulfapyridine (fig. 2, 4). We believe that our patient was receiving this medication for rheumatoid arthritis due to its anti-inflammatory properties. Since urinary excretion of its metabolites is not affected by acid or alkali urine,8 sulfasalazine was discontinued. The patient has been followed for approximately 2 years and stone disease has not recurred. Although rare, urinary stone formation has been associated with drugs and their metabolites. Results of treatment of these types of stones with ESWL are not well known. However, the type of stone in our case fragmented well with the lithotriptor. Discontinuing the drug usually prevents stone recurrence. Our case illustrates the importance of careful analysis of stones from patients who are on chronic medication. Generally, stone composition may be accurately identified using infrared spectroscopy or x-ray diffraction. 10 However, in our case thin layer chromatography was necessary to identify correctly the drug compound. REFERENCES 1.
2. 3. 4. 5.
6. 7.
8. 9. 10.
Carr, M. C., Prien, E. L., Jr. and Babayan, R. K.: Triamterene nephrolithiasis: renewed attention is warranted. J. Ural., 144: 1339, 1990. Ettinger, B.: Excretion oftriamterene and its metabolites in triamterene stone patients. J. Clin. Pharm., 25: 365, 1985. White, D. J. and Nancollas, G. H.: Triamterene and renal stone formation; the influence oftriamterene stones on calcium oxalate crystallization. Calcif. Tissue Int., 40: 79, 1987. Teillac, P., Daudon, M., deDreuzy, 0., Nguyen, H. V., Reveillaud, R. J. and LeDuc, A.: 13 cases of drug-induced calculi. Ann. d'Urol., 22: 278, 1988. Bellanato, J.: Infrared spectroscopy of urinary calculi. In: Renal Tract Stone. Metabolic Basis and Clinical Practice. Edited by J. E. A. Wickham and A. C. Buck. New York: Churchill Livingstone, vol. 1, chapt. 4B, pp. 45-57, 1990. Siegel, W. H.: Unusual complication of therapy with sulfamethoxazole-trimethoprim. J. Ural., 117: 397, 1977. van Hogezand, R. A., Van Balen, H. C., van Schaik, A., Tangerman, A., van Hees, P. A., Zwanenburg, B. and van Tongeren, J. H.: Determination of sodium azodisalicylate, salazosulphapyridine and their metabolites in serum, urine and faeces by high-performance liquid chromatography. J. Chromat., 305: 470, 1984. Schroder, H. and Campbell, E. S.: Absorption, metabolism, and excretion of salicylazosulfapyridine in man. Clin. Pharmacol. Ther., 13: 539, 1972. Peppercorn, M.A. and Goldman, P.: The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther., 181: 555, 1972. Rebentisch, G. and Berg, W.: Comparison of methods and guaranteeing quality of analyses of urinary calculi-5th international ring test. Ural. Int., 44: 298, 1989.
'THE ,JOURNAL OF UHOLO(;Y
Copyright
Printed in US.A
1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Case Reports BILATERAL ACETYLSULFAPYRIDINE NEPHROLITHIASIS ASSOCIATED WITH CHRONIC SULFASALAZINE THERAPY ERDAL ERTURK,* JEFFREY B. CASEMENTO, KEVIN R. GUERTIN AND ANDREWS. KENDE From the Departments of Urology and Chemistry, University of Rochester, Rochester, New York
ABSTRACT
We report on formation of bilateral renal calculi secondary to sulfasalazine therapy for juvenile rheumatoid arthritis. The condition was successfully treated with extracorporeal shock wave lithotripsy. Analysis of the fragments with thin layer chromatography and nuclear magnetic resonance revealed acetylsulfapyridine, a metabolite of sulfasalazine. KEY WORDS: salicylazosulfapyridine, kidney calculi, extracorporeal shockwave lithotripsy
Urinary stone formation related to drug therapy has been previously reported. The most common drug that is associated with stone formation is triamterene, 1 although other drugs have been implicated. To our knowledge we report the first case of bilateral kidney stone formation associated with chronic sulfasalazine therapy. The patient was successfully treated with extracorporeal shock wave lithotripsy (ESWL t). CASE REPORT
A 19-year-old white woman presented to the emergency room with right flank pain. Physical examination was significant for marked left costovertebral angle tenderness and urinalysis
Accepted for publication October 22, 1993. * Requests for reprints: Department of Urology, 601 Elmwood Ave., Box 656, Rochester, New York 14642. t Dornier Medical Systems, Inc., Marietta, Georgia.
showed microhematuria. An excretory urogram revealed a 2 cm. moderately obstructing, poorly calcified stone at the left ureteropelvic junction and a 2.5 cm. stone in the right renal pelvis (fig. 1). Medical history was significant for juvenile rheumatoid arthritis. The patient, who denied a personal or family history of urolithiasis, was taking sulfasalazine, prednisone, meclofenamate sodium and iron sulfate. Serum chemistry studies revealed a creatinine of 0.6 mg./dl. (normal 0.8 to 1.3), calcium 9.2 mg./dl. (normal 8.8 to 10.1), phosphate 3.9 mg./dl. (normal 2.2 to 4.1) and mate 3.9 mg./dl. (normal 4.0 to 8.5). Urinalysis showed a pH of 7.0 and fewer than 50 erythrocytes with 7 to 10 leukocytes per high power field. Urine culture yielded no growth. The patient underwent cystoscopy and insertion of a left Double-J:j: ureteral stent, and left ESWL with the Dornier HM3 unit. The stone fragmented well and numerous gold colored fragments were passed. Following clear-
+Medical Engineering Corp., New York, New York.
FIG. 1. A, bilateral poorly calcified renal stones (arrows). B, delayed excretory urogram shows significant obstruction of left kidney by stone at ureteropelvic junction.
1605
1606
BILATERAL ACETYLSULFAPYRIDINE NEPHROLITHIASIS
so-O-N•N-0-so,HN v
BDOC
--3
1
2
FIG. 2. Metabolism of sulfasalazine 1, salicylazosulfapyridine. 2, sulfapyridine. 3, 5-aminosalycylic acid. 4, N-acetylsulfapyridine.
ance of all fragments right ESWL was performed without stenting. A film of the kidney, ureters and bladder 1 month posttreatment showed no residual fragments. The initial stone analysis with infrared spectroscopy was reported as a drug metabolite, possibly sulfa in origin. Fragments were further analyzed at our chemistry department. Thin layer chromatography identified the chemical composition of the fragments as acetylsulfapyridine, a metabolite of the parent compound, sulfasalazine. Nuclear magnetic resonance confirmed the initial findings. The patient was advised to discontinue sulfasalazine and no other metabolic evaluation was performed. DISCUSSION
Although the calculogenic potential of certain drugs has been recognized, emphasis on stone analysis has been lacking. Triamterene stones have been studied in some detail but the physiological basis for stone formation is still poorly understood. 2· 3 In 1 series in which the incidence of drug induced stones was found to be 2.5% glafenine, piridoxylate and triamterene were associated with stone formation. 4 Other rare products, such as phenazopyridine hydrochloride, N -acetylsulfamethoxazole hydrochloride, N-acetylsulfaguanidine, flumequine, oxolinic acid, silica and calcite, are also reportedly associated with stone formation. 5 Although urinary stones have been associated with sulfa drugs, such as sulfamethoxazoletrimethoprim, 6 to our knowledge an association with sulfasalazine has not been reported. Sulfasalazine (salicylazosulfapyridine) is indicated in the treatment of ulcerative colitis. Although the mode of action is poorly understood, the drug is thought to exert an effect through anti-inflammatory properties. 7 The parent compound, salicylazosulfapyridine (fig. 2, 1 ), is broken down into sulfapyridine (fig. 2, 2) and 5-aminosalicylic acid (fig. 2, 3) by colonic bacteria through reductive cleavage of the azo linkage. Most of the sulfapyridine is adsorbed, metabolized and excreted in the urine as N-acetylsulfapyridine (fig. 2, 4). 8 Stone fragments in our case were examined using thin layer chromatography and were found to be homogeneous with only 1 ultraviolet active component detectable. The compound was
identified as N-acetylsulfapyridine by comparing its thin layer chromatography mobility in a variety of solvent systems with literature values. 9 Identification was confirmed by examining the nuclear magnetic resonance spectrum, which clearly revealed the presence of an N-acetyl group and was consistent with the structure of N-acetylsulfapyridine (fig. 2, 4). We believe that our patient was receiving this medication for rheumatoid arthritis due to its anti-inflammatory properties. Since urinary excretion of its metabolites is not affected by acid or alkali urine,8 sulfasalazine was discontinued. The patient has been followed for approximately 2 years and stone disease has not recurred. Although rare, urinary stone formation has been associated with drugs and their metabolites. Results of treatment of these types of stones with ESWL are not well known. However, the type of stone in our case fragmented well with the lithotriptor. Discontinuing the drug usually prevents stone recurrence. Our case illustrates the importance of careful analysis of stones from patients who are on chronic medication. Generally, stone composition may be accurately identified using infrared spectroscopy or x-ray diffraction. 10 However, in our case thin layer chromatography was necessary to identify correctly the drug compound. REFERENCES 1.
2. 3. 4. 5.
6. 7.
8. 9. 10.
Carr, M. C., Prien, E. L., Jr. and Babayan, R. K.: Triamterene nephrolithiasis: renewed attention is warranted. J. Ural., 144: 1339, 1990. Ettinger, B.: Excretion oftriamterene and its metabolites in triamterene stone patients. J. Clin. Pharm., 25: 365, 1985. White, D. J. and Nancollas, G. H.: Triamterene and renal stone formation; the influence oftriamterene stones on calcium oxalate crystallization. Calcif. Tissue Int., 40: 79, 1987. Teillac, P., Daudon, M., deDreuzy, 0., Nguyen, H. V., Reveillaud, R. J. and LeDuc, A.: 13 cases of drug-induced calculi. Ann. d'Urol., 22: 278, 1988. Bellanato, J.: Infrared spectroscopy of urinary calculi. In: Renal Tract Stone. Metabolic Basis and Clinical Practice. Edited by J. E. A. Wickham and A. C. Buck. New York: Churchill Livingstone, vol. 1, chapt. 4B, pp. 45-57, 1990. Siegel, W. H.: Unusual complication of therapy with sulfamethoxazole-trimethoprim. J. Ural., 117: 397, 1977. van Hogezand, R. A., Van Balen, H. C., van Schaik, A., Tangerman, A., van Hees, P. A., Zwanenburg, B. and van Tongeren, J. H.: Determination of sodium azodisalicylate, salazosulphapyridine and their metabolites in serum, urine and faeces by high-performance liquid chromatography. J. Chromat., 305: 470, 1984. Schroder, H. and Campbell, E. S.: Absorption, metabolism, and excretion of salicylazosulfapyridine in man. Clin. Pharmacol. Ther., 13: 539, 1972. Peppercorn, M.A. and Goldman, P.: The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther., 181: 555, 1972. Rebentisch, G. and Berg, W.: Comparison of methods and guaranteeing quality of analyses of urinary calculi-5th international ring test. Ural. Int., 44: 298, 1989.