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Treatment of Uric Acid Urolithiasis With Allopurinol: A Xanthine Oxidase Inhibitor
Vol. 97, Feb. Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright
© 1967 by The Williams & Wilkins Co.
TREATiVIE~T OF URIC ACID UROLITHIASIS WITH ALLOPURINOL: A XANTHINE OXIDASE INHIBITOR STEVEN ALEXANDER
AND
HERBERT BRENDLER
From the Department of Urology, Mount Sinai Hospital and School of Medicine, New York, New York
Uric acid urolithiasis presents a difficult diagnostic and therapeutic problem for the urologist. The uricosuric drugs are of established value in reducing serum urate levels and in the treatment and prevention of tophaceous gout. However, there are limitations to their usefulness. Decreased serum uric acid concentration is achieved by enhanced renal excretion of this compound. 1 This is mediated by suppression of tubular reabsorption of urate filtered at the glomerulus. This process increases the likelihood of urolithiasis. Moreover, uricosuric drugs often fail to lower serum uric acid when renal function is impaired, and in gouty subjects in whom there is an overwhelming production of uric acid. This also may occur in patients with neoplastic diseases of the hematopoietic system in whom the turnover rate of nucleic acids is extremely high causing a release of uric acid into the urine. 2 Allopurinol is a xanthine oxidase inhibitor which was originally used in the treatment of leukemia to suppm,s the oxidative degradation of 6-mercaptopurine to the therapeutically inert compound, 6-thiouric acid. 3 It has also been found to inhibit the catalytic effect of xanthine oxidase on the metabolic conversion of hypoxanthine and xanthine to uric acid (fig. 1), thereby causing a sharp derline in serum and urinary levels of uric acid:' In the treatment of gout and other conditions Accepted for publication June 30, 1966. Read in part at annual Residents' Meeting of New York Section, American Urological Association, Inc., New York, :New York, March 30, 1966. 1 Yi.\, T. F. and Gutman, A. B.: Effect of allopurinol (4-hydroxypyrazolo-(3, 4-d) pyrimidine) on serum and urina1y uric acid in primary and secondary gout. Amer. J. Med., 37: 885-898, 1964. 2 Krakoff, I. H. and Meyer, R. L.: Prevention of hyperuricemia in leukemia and lymphoma; use of allopurinol, a xanthine oxidase inhibitor. J.A.M.A., 193: 1-G, 1965. 3 Rundles, R. W., Wyngaarden, J.B., Hitching, G. II., Elion, G. B. and Silberman, H. R.: Effects of xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Trans. Ass. Amer. Phys., 76: 126-140, 1963. 4 I-Iall, A. P., Holloway, V. P. and Scott, J. T.: 4-Hydroxypyrazolo (3,4-d) pyrimidine (HPP) in the treatment of gout; preliminary observations. Ann. Rheum. Dis., 23: 439-44(j, 1964.
where hyperuricemia is a prominent feature, allopurinol in average daily doses of 300 mg. has significantly reduced serum and urinary uric acid levels within 5 to 10 clays. This has been associated with increased urinary oxypurine excretion, consisting of approximately equal am.ounts of hypoxanthine and xanthine. There has been no evidence of hematologic, hepatic, gastrointestinal or renal toxicity. 5 The following case report illustrates a dramatic response to allopurinol therapy in a seriously-ill boy adm.itted in uremia clue to renal complications of primary, familial hyperuricemia. ADENINE
GUANINE
1
J(guanase)
(adenase)
HYPOXANTHINE
--------+
XANTHINE
(xanthine oxidase)
1
URIC ACID
Fm. 1. Xanthine oxidase catalyzes conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol blocks this action. CASE REPORT
J. B., No. 264063, a 16-year-old male patient was transferred to the urological service of the J\Iount Sinai Hospital on October 7, 1964 because of rapidly rising blood urea nitrogen (DUN) following cystoscopy elsewhere. He had been admitted to that hospital because of left renal colic, chills, fever and gross hematuria. Heavy uric acid crystalluria was present. An excretory urogram demonstrated marked delay in excretion of the dye. Bilateral nephrograms were obtained, but neither collecting systen1 could be visualized. The BUN on admission was 74 mg. per cent and the serum creatinine 5.6 mg. per cent. At cystoscopy, no efflux was observed from the ureteral orifices. The left orifice 5 Wyngaarden, J. B., Rundles, R. vV., Silberman, H. R. and Hunter, S.: Control of hypernricemia with hydroxypyrazolopyrimidine, a purine analog which inhibits uric acid synthesis. Arthr. & Rheumat., 6: 306-307, 1963.
340
URIC ACID UROLITHIASIS
Frn. 2. A, excretory nrogram on admission reveals bilateral nephrogrnm at 2 honrs. ~o calc11li arc seen. B, excretory urogram after 1 week of allopurinol shows normal kidneys (15-minnte film). C, excretory urogram 3 weeks after allopnrinol had been discontinued. Xo vis11aliaa1ion of left kidne:,· 011 20-mimite film. D, excretory nrogram 1 week after allopurinol w,1s resumed. I-kt urn of fun ct ion clll ldt. side (5-minu1e film).
342
ALEXANDER AND BRENDLER
Data for patient J. B. Treated with HPP Serum Uric Acid
24-Hour Urine Uric Acid
(mg.%)
(mg.%)
1060
33
17.8 9.0 8.2
20 20
17.8 7.5
975 750
Blood
BUN
Pressure
(mg.%)
On admission 3 days of HPP therapy 1 week of HPP therapy
180/100 140/90 140/70
100
3 weeks after HPP therapy discontinued 1 week after HPP therapy resumed
110/70 110/70
was reported to be reddened and edematous, some brownish, sandy material was observed in its vicinity. Catheters were passed easily to both renal pelves and a small amount of dark urine was obtained. Bilateral retrograde pyelograms demonstrated normal intrarenal collecting systems and ureters. The day following cystoscopy, the boy became lethargic. His BUN was found to have risen to 169 mg. per cent. The serum uric acid was 16.9 mg. per cent. No infonnation was available as to the patient's urinary output. He was thereupon transferred to the Mount Sinai Hospital. A review of the past history disclosed several episodes of back pain, fever and hematuria during the preceding 4 years, without passage of stones. There was a documented familial history of hyperuricemia. The patient's father and 3 uncles on his mother's side were known to have elevated serum uric acid levels and a history of intermittent urolithiasis. One of the uncles was also under treatment for gouty arthritis. On admission, the patient was responsive, but weak and chronically ill in appearance. Temperature, pulse and respirations were normal. The blood pressure was elevated (180 /100). The abdomen was soft, non-tender and no masses were felt. Both flanks and costovertebral angles were negative. Neither kidney was palpable. The bladder was not distended. The remainder of the physical examination was negative. The admission urine was acid, specific gravity 1.010, and contained 1 plus albumin. l\ficroscopically, the sediment revealed innumerable red blood cells, a few white blood cells and nmny uric acid crystals. Hen1oglobin was 13.3 gm. per cent. Mild leukocytosis was present (12,300/ cu. mm.). The BUN was 96 mg. per cent and the serum creatinine 7.2 mg. per cent. Serum uric acid was 17.8 mg. per cent. The 24-hour urinary
730
24-Hour Oxypurines (mg.%)
295 (elevated)
excretion of uric acid was subsequently reported as 1060 mg. per cent, a significant elevation. Serum calciun1. was 9.8 mg. per cent, phosphorus 8.3 mg. per cent. Mild acidosis was present (CO2 combining power 20.5 meq/L); serum electrolytes were otherwise normal. Excretory urography shortly after admission showed no visualization of either collecting system. A bilateral nephrogram was present at 2 hours. No calculi were seen (fig. 2, A). The patient was immediately begun on allopurinol 200 mg. daily. He also received sodium bicarbonate and chloramphenicol. After 3 days, his serum uric acid had fallen to 9.0 mg. per cent; by the end of the fast week it was 8.2 mg. per cent. The BUN at the same time had decreased to 33 mg. per cent; the urinary urate excretion had also decreased markedly to a value of 730 mg. per cent. As expected, the urinary excretion of hypoxanthine and xanthine increased. (See table.) Rapid clinical improvement occurred simultaneously. Daily urinary volumes were normal. No febrile episodes occurred. The blood pressure fell to 140 /90 by the third day and was never again elevated. An excretory urogram 1 week after start of therapy revealed essentially normal kidneys (fig. 2, B). The patient was discharged on a daily maintenance dose of 200 mg. allopurinol. He remained well for the next 6 months. His blood pressure stayed in the range of 110/70. His urinary output of uric acid continued to diminish. He had no complaints and returned to school. Six months after leaving the hospital, allopurinol was discontinued. Three weeks later the patient suddenly had sharp left renal colic and was readmitted to the hospital. The admission BUN was 20 mg. per cent. An emergency excretory urogram disclosed a normal
343
URIC ACID UROLITHIASIS
right kidney but no visualization on the left side (fig. 2, C). Serum uric acid was again elevated (17.8 mg. per cent). Uric acid crystalluria was again present. Treatment with allopurinol was thereupon reinstituted. Sodium bicarbonate was started but had to be discontinued because of nausea. The patient again responded rapidly (table). One week later an excretory urogram demonstrated return of function on the left side (fig. 2, D). The patient has been followed at regular intervals since leaving the hospital in June 1965. He has continued allopurinol therapy without interruption. There have been no further attacks of renal colic. Serum uric acid values have been maintained at approximately 7.0 mg. per cent. The latest excretory urogram (May 20, 1966) reveals bilaterally normal kidneys. DISCUSSION
No significant toxic manifestations have been observed in patients receiving allopurinol over extended periods. Perhaps the most troublesome problem encountered has been the precipitation of acute gouty arthritis. 6 This reaction has occasionally been observed in patients receiving uricosuric drugs. No satisfactory explanation has been proposed for its occurrence in patients on allopurinol. The attacks can generally be effectively controlled with colchicine. Allopurinol does not possess anti-rheumatic powers. It is ineffective in relieving the pain of chronic gout. However, salicylates can be given concurrently because they do not interfere with the action of allopurinol as they do with the uricosuric agents. Because of the enhanced excretion of oxypurines with allopurinol, the possibility of forma6 DeConti, R. C. and Calabresi, P.: Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. New Engl. J. Med., 274: 481-486, 1966.
tion of stones composed of these substances must be considered. 7 To our knowledge, no instances of this have been reported, nor have we seen it in other patients receiving allopurinol for longstanding gout. Considerable experience on the medical service of the Mount Sinai Hospital has shown that no improvement in renal function can be expected from allopurinol therapy in those patients suffering from gouty nephropathy. 8 However, fairly prompt cessation of uric acid stone formation has occurred. In the case reported, dramatic improvement in renal function was noted shortly after allopurinol administration was begun. Although no information was available as to the patient's actual urinary output prior to admission to the Mount Sinai Hospital, all evidence points to the fact that he was oliguric at that time. However, at no time was there evidence of the true nephropathy of gout. It is significant that the hyperuricemia and consequent renal obstruction recurred promptly after discontinuance of allopurinol. This was quickly reversed upon resumption of the drug. SUMMARY
Allopurinol (4-hydroxypyrazolo-(3, 4-d) pyrimidine, HPP) is a potent xanthine oxidase inhibitor which effectively suppresses uric acid formation and thereby lowers urinary excretion of urate. Its use has not been associated with serious toxic manifestations. It would appear to be worthy of trial in the prevention and treatment of uric acid stone-formation due to increased urate concentrations in the urine. 7 Klinenberg, J. R., Goldfinger, S. E. and Seegmiller, J. E.: The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann. Intern. Med., 62: 639-647, 1965. 8 Wyngaarden, J.B., Rundles, R. vV. and Metz, E. N.: Allopurinol in the treatment of gout. Ann. Intern. Med., 62: 842-847, 1965.
THE JOURNAL OF UROLOGY
Copyright
© 1967 by The Williams & Wilkins Co.
TREATiVIE~T OF URIC ACID UROLITHIASIS WITH ALLOPURINOL: A XANTHINE OXIDASE INHIBITOR STEVEN ALEXANDER
AND
HERBERT BRENDLER
From the Department of Urology, Mount Sinai Hospital and School of Medicine, New York, New York
Uric acid urolithiasis presents a difficult diagnostic and therapeutic problem for the urologist. The uricosuric drugs are of established value in reducing serum urate levels and in the treatment and prevention of tophaceous gout. However, there are limitations to their usefulness. Decreased serum uric acid concentration is achieved by enhanced renal excretion of this compound. 1 This is mediated by suppression of tubular reabsorption of urate filtered at the glomerulus. This process increases the likelihood of urolithiasis. Moreover, uricosuric drugs often fail to lower serum uric acid when renal function is impaired, and in gouty subjects in whom there is an overwhelming production of uric acid. This also may occur in patients with neoplastic diseases of the hematopoietic system in whom the turnover rate of nucleic acids is extremely high causing a release of uric acid into the urine. 2 Allopurinol is a xanthine oxidase inhibitor which was originally used in the treatment of leukemia to suppm,s the oxidative degradation of 6-mercaptopurine to the therapeutically inert compound, 6-thiouric acid. 3 It has also been found to inhibit the catalytic effect of xanthine oxidase on the metabolic conversion of hypoxanthine and xanthine to uric acid (fig. 1), thereby causing a sharp derline in serum and urinary levels of uric acid:' In the treatment of gout and other conditions Accepted for publication June 30, 1966. Read in part at annual Residents' Meeting of New York Section, American Urological Association, Inc., New York, :New York, March 30, 1966. 1 Yi.\, T. F. and Gutman, A. B.: Effect of allopurinol (4-hydroxypyrazolo-(3, 4-d) pyrimidine) on serum and urina1y uric acid in primary and secondary gout. Amer. J. Med., 37: 885-898, 1964. 2 Krakoff, I. H. and Meyer, R. L.: Prevention of hyperuricemia in leukemia and lymphoma; use of allopurinol, a xanthine oxidase inhibitor. J.A.M.A., 193: 1-G, 1965. 3 Rundles, R. W., Wyngaarden, J.B., Hitching, G. II., Elion, G. B. and Silberman, H. R.: Effects of xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Trans. Ass. Amer. Phys., 76: 126-140, 1963. 4 I-Iall, A. P., Holloway, V. P. and Scott, J. T.: 4-Hydroxypyrazolo (3,4-d) pyrimidine (HPP) in the treatment of gout; preliminary observations. Ann. Rheum. Dis., 23: 439-44(j, 1964.
where hyperuricemia is a prominent feature, allopurinol in average daily doses of 300 mg. has significantly reduced serum and urinary uric acid levels within 5 to 10 clays. This has been associated with increased urinary oxypurine excretion, consisting of approximately equal am.ounts of hypoxanthine and xanthine. There has been no evidence of hematologic, hepatic, gastrointestinal or renal toxicity. 5 The following case report illustrates a dramatic response to allopurinol therapy in a seriously-ill boy adm.itted in uremia clue to renal complications of primary, familial hyperuricemia. ADENINE
GUANINE
1
J(guanase)
(adenase)
HYPOXANTHINE
--------+
XANTHINE
(xanthine oxidase)
1
URIC ACID
Fm. 1. Xanthine oxidase catalyzes conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol blocks this action. CASE REPORT
J. B., No. 264063, a 16-year-old male patient was transferred to the urological service of the J\Iount Sinai Hospital on October 7, 1964 because of rapidly rising blood urea nitrogen (DUN) following cystoscopy elsewhere. He had been admitted to that hospital because of left renal colic, chills, fever and gross hematuria. Heavy uric acid crystalluria was present. An excretory urogram demonstrated marked delay in excretion of the dye. Bilateral nephrograms were obtained, but neither collecting systen1 could be visualized. The BUN on admission was 74 mg. per cent and the serum creatinine 5.6 mg. per cent. At cystoscopy, no efflux was observed from the ureteral orifices. The left orifice 5 Wyngaarden, J. B., Rundles, R. vV., Silberman, H. R. and Hunter, S.: Control of hypernricemia with hydroxypyrazolopyrimidine, a purine analog which inhibits uric acid synthesis. Arthr. & Rheumat., 6: 306-307, 1963.
340
URIC ACID UROLITHIASIS
Frn. 2. A, excretory nrogram on admission reveals bilateral nephrogrnm at 2 honrs. ~o calc11li arc seen. B, excretory urogram after 1 week of allopurinol shows normal kidneys (15-minnte film). C, excretory urogram 3 weeks after allopnrinol had been discontinued. Xo vis11aliaa1ion of left kidne:,· 011 20-mimite film. D, excretory nrogram 1 week after allopurinol w,1s resumed. I-kt urn of fun ct ion clll ldt. side (5-minu1e film).
342
ALEXANDER AND BRENDLER
Data for patient J. B. Treated with HPP Serum Uric Acid
24-Hour Urine Uric Acid
(mg.%)
(mg.%)
1060
33
17.8 9.0 8.2
20 20
17.8 7.5
975 750
Blood
BUN
Pressure
(mg.%)
On admission 3 days of HPP therapy 1 week of HPP therapy
180/100 140/90 140/70
100
3 weeks after HPP therapy discontinued 1 week after HPP therapy resumed
110/70 110/70
was reported to be reddened and edematous, some brownish, sandy material was observed in its vicinity. Catheters were passed easily to both renal pelves and a small amount of dark urine was obtained. Bilateral retrograde pyelograms demonstrated normal intrarenal collecting systems and ureters. The day following cystoscopy, the boy became lethargic. His BUN was found to have risen to 169 mg. per cent. The serum uric acid was 16.9 mg. per cent. No infonnation was available as to the patient's urinary output. He was thereupon transferred to the Mount Sinai Hospital. A review of the past history disclosed several episodes of back pain, fever and hematuria during the preceding 4 years, without passage of stones. There was a documented familial history of hyperuricemia. The patient's father and 3 uncles on his mother's side were known to have elevated serum uric acid levels and a history of intermittent urolithiasis. One of the uncles was also under treatment for gouty arthritis. On admission, the patient was responsive, but weak and chronically ill in appearance. Temperature, pulse and respirations were normal. The blood pressure was elevated (180 /100). The abdomen was soft, non-tender and no masses were felt. Both flanks and costovertebral angles were negative. Neither kidney was palpable. The bladder was not distended. The remainder of the physical examination was negative. The admission urine was acid, specific gravity 1.010, and contained 1 plus albumin. l\ficroscopically, the sediment revealed innumerable red blood cells, a few white blood cells and nmny uric acid crystals. Hen1oglobin was 13.3 gm. per cent. Mild leukocytosis was present (12,300/ cu. mm.). The BUN was 96 mg. per cent and the serum creatinine 7.2 mg. per cent. Serum uric acid was 17.8 mg. per cent. The 24-hour urinary
730
24-Hour Oxypurines (mg.%)
295 (elevated)
excretion of uric acid was subsequently reported as 1060 mg. per cent, a significant elevation. Serum calciun1. was 9.8 mg. per cent, phosphorus 8.3 mg. per cent. Mild acidosis was present (CO2 combining power 20.5 meq/L); serum electrolytes were otherwise normal. Excretory urography shortly after admission showed no visualization of either collecting system. A bilateral nephrogram was present at 2 hours. No calculi were seen (fig. 2, A). The patient was immediately begun on allopurinol 200 mg. daily. He also received sodium bicarbonate and chloramphenicol. After 3 days, his serum uric acid had fallen to 9.0 mg. per cent; by the end of the fast week it was 8.2 mg. per cent. The BUN at the same time had decreased to 33 mg. per cent; the urinary urate excretion had also decreased markedly to a value of 730 mg. per cent. As expected, the urinary excretion of hypoxanthine and xanthine increased. (See table.) Rapid clinical improvement occurred simultaneously. Daily urinary volumes were normal. No febrile episodes occurred. The blood pressure fell to 140 /90 by the third day and was never again elevated. An excretory urogram 1 week after start of therapy revealed essentially normal kidneys (fig. 2, B). The patient was discharged on a daily maintenance dose of 200 mg. allopurinol. He remained well for the next 6 months. His blood pressure stayed in the range of 110/70. His urinary output of uric acid continued to diminish. He had no complaints and returned to school. Six months after leaving the hospital, allopurinol was discontinued. Three weeks later the patient suddenly had sharp left renal colic and was readmitted to the hospital. The admission BUN was 20 mg. per cent. An emergency excretory urogram disclosed a normal
343
URIC ACID UROLITHIASIS
right kidney but no visualization on the left side (fig. 2, C). Serum uric acid was again elevated (17.8 mg. per cent). Uric acid crystalluria was again present. Treatment with allopurinol was thereupon reinstituted. Sodium bicarbonate was started but had to be discontinued because of nausea. The patient again responded rapidly (table). One week later an excretory urogram demonstrated return of function on the left side (fig. 2, D). The patient has been followed at regular intervals since leaving the hospital in June 1965. He has continued allopurinol therapy without interruption. There have been no further attacks of renal colic. Serum uric acid values have been maintained at approximately 7.0 mg. per cent. The latest excretory urogram (May 20, 1966) reveals bilaterally normal kidneys. DISCUSSION
No significant toxic manifestations have been observed in patients receiving allopurinol over extended periods. Perhaps the most troublesome problem encountered has been the precipitation of acute gouty arthritis. 6 This reaction has occasionally been observed in patients receiving uricosuric drugs. No satisfactory explanation has been proposed for its occurrence in patients on allopurinol. The attacks can generally be effectively controlled with colchicine. Allopurinol does not possess anti-rheumatic powers. It is ineffective in relieving the pain of chronic gout. However, salicylates can be given concurrently because they do not interfere with the action of allopurinol as they do with the uricosuric agents. Because of the enhanced excretion of oxypurines with allopurinol, the possibility of forma6 DeConti, R. C. and Calabresi, P.: Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. New Engl. J. Med., 274: 481-486, 1966.
tion of stones composed of these substances must be considered. 7 To our knowledge, no instances of this have been reported, nor have we seen it in other patients receiving allopurinol for longstanding gout. Considerable experience on the medical service of the Mount Sinai Hospital has shown that no improvement in renal function can be expected from allopurinol therapy in those patients suffering from gouty nephropathy. 8 However, fairly prompt cessation of uric acid stone formation has occurred. In the case reported, dramatic improvement in renal function was noted shortly after allopurinol administration was begun. Although no information was available as to the patient's actual urinary output prior to admission to the Mount Sinai Hospital, all evidence points to the fact that he was oliguric at that time. However, at no time was there evidence of the true nephropathy of gout. It is significant that the hyperuricemia and consequent renal obstruction recurred promptly after discontinuance of allopurinol. This was quickly reversed upon resumption of the drug. SUMMARY
Allopurinol (4-hydroxypyrazolo-(3, 4-d) pyrimidine, HPP) is a potent xanthine oxidase inhibitor which effectively suppresses uric acid formation and thereby lowers urinary excretion of urate. Its use has not been associated with serious toxic manifestations. It would appear to be worthy of trial in the prevention and treatment of uric acid stone-formation due to increased urate concentrations in the urine. 7 Klinenberg, J. R., Goldfinger, S. E. and Seegmiller, J. E.: The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann. Intern. Med., 62: 639-647, 1965. 8 Wyngaarden, J.B., Rundles, R. vV. and Metz, E. N.: Allopurinol in the treatment of gout. Ann. Intern. Med., 62: 842-847, 1965.