- Email: [email protected]
Hyperuricemia and renal insufficiency associated with malignant disease: Urate oxidase as an efficient therapy?
CASE REPORT
Hyperuricemia and Renal Insufficiency Associated With Malignant Disease: Urate Oxidase as an Efficient Therapy? Gunter Wolf, MD, Susanne Hegewisch-Becker, MD, Dieter K. Hossfeld, MD, and Rolf A.K. Stahl, MD ● Hyperuricemia is a common finding in patients with malignant diseases. Chemotherapy can induce lifethreatening tumor lysis syndrome with severe hyperuricemia, other metabolic abnormalities, and acute renal failure. Intrarenal precipitation of uric acid contributes to renal insufficiency in this situation. Allopurinol, by preventing the conversion of hypoxanthine and xanthine to uric acid, has been long considered the standard pharmacological approach to hyperuricemia and prevention of tumor lysis syndrome. However, allopurinol itself may facilitate precipitation of xanthine crystals and has little influence on already-formed uric acid crystals deposited in the kidney. Urate oxidase further oxidizes uric acid to the highly water-soluble allantoin in mammals, except humans, who lack this enzyme. We report four cases of hyperuricemia (initial serum uric acid concentrations, 14.0 to 25.0 mg/dL) associated with malignant diseases treated with exogenous urate oxidase. Two of the patients showed full-blown tumor lysis syndrome. A single urate oxidase infusion (1,000 U) readily reduced serum uric acid levels in all patients. Furthermore, renal insufficiency, determined by serum creatinine concentrations, improved in three of the four patients. No adverse effects were observed. Currently, a recombinant urate oxidase is undergoing clinical testing and may make this efficient therapy more widely available. We believe that treatment with urate oxidase is a safe and efficient therapy for patients with cancer-associated hyperuricemia and may be effective even in individuals with only moderately elevated serum uric acid concentrations. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Tumor lysis syndrome; hyperuricemia; renal failure; hyperphosphatemia; urate oxidase; allantoin; allopurinol.
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UMOR LYSIS SYNDROME is a clinical entity characterized by hyperkalemia, hyperuricemia, hyperxanthinemia (especially in patients treated with allopurinol), hyperphosphatemia, hypocalcemia, lactic acidosis, and often acute renal insufficiency.1-3 Because the homeostasis of these substances depends on the integrity of the kidney, a reduction in renal function makes tumor lysis syndrome a life-threatening metabolic emergency in clinical oncology.1 Although the destruction of malignant cells by radiotherapy may occasionally cause these metabolic abnormalities,4 tumor lysis syndrome is more often triggered by cytotoxic chemotherapy that induces cell death, with concomitant release of intracellular substances.2,3 Under certain conditions, such as in patients with non-Hodgkin’s lymphomas or acute lymphocytic leukemias, administration of low doses of corticosteroids may induce tumor lysis syndrome.5,6 Furthermore, hyperuricemia and occasionally other features of tumor lysis syndrome may be present even in cancer patients without specific therapy because of the high turnover of malignant cells.1 Tumor lysis syndrome–induced acute renal failure is caused by at least three different pathophysiological processes that may occur in paral-
lel. (1) Acute uric acid nephropathy. The mechanism of hyperuricemia-induced acute renal failure is believed to be intratubular precipitations of uric acid crystals facilitated by an increase in concentration and change of urine pH, but other pathogenic processes of uric acid crystals, such as proinflammatory effects, also have been proposed.7,8 (2) Massive hyperphosphatemia is frequently observed in patients with tumor lysis syndrome.9 Intrarenal precipitations of calcium phosphate, as well as direct toxic effects of phosphate, may contribute to acute renal insufficiency.9,10 (3) Although xanthine nephropathy is rarely seen, this complication must be considFrom the Department of Medicine, Division of Nephrology and Osteology, and the Division of Oncology and Hematology, University of Hamburg, Hamburg, Germany. Received March 31, 1999; accepted in revised form August 3, 1999. G.W. is supported in part by a Heisenberg fellowship of the Deutsche Forschungsgemeinschaft. Address reprint requests to Gunter Wolf, MD, University of Hamburg, University Hospital Eppendorf, Department of Medicine, Division of Nephrology and Osteology, Pavilion 61, Martinistraße 52, D-20246 Hamburg, Germany. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3405-0020$3.00/0
American Journal of Kidney Diseases, Vol 34, No 5 (November), 1999: E20
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ered in patients developing tumor lysis syndrome who have been pretreated with allopurinol.11-14 The therapeutic dilemma of hyperuricemia is the potential aggravation of other consequences of tumor lysis syndrome. For example, alkalinization of the urine to increase uric acid solubility facilitates precipitation of calcium phosphate. Conversely, pretreatment with high doses of such xanthine oxidase inhibitors as allopurinol bears the intrinsic risk for xanthine nephropathy and cannot be used for patients with hypersensitivity reactions to this substance. Administration of the enzyme urate oxidase (Uricozyme; Sanofi-Winthrop, Gentilly, France) induces oxidation of uric acid into highly soluble allantoin. We report here our experience with this treatment strategy. CASE REPORTS
Case 1 An acute leukemia without further differentiation was diagnosed in another hospital in a previously healthy 72-yearold man. Radiographic examination of the chest showed a large mediastinal mass. The patient was treated in this hospital with a single 200-mg dose of prednisolone and was subsequently transferred to our hospital. Immunohistochemical and molecular studies of bone marrow cells established the diagnosis of a T-cell acute lymphocytic leukemia. On admission, the patient showed all features of tumor lysis syndrome with acute renal failure (uric acid, 23.2 mg/dL [normal, 2.5 to 6.0 mg/dL]; creatinine, 6.0 mg/dL [normal, 0.6 to 1.4 mg/dL]; calcium, 4.04 mg/dL [normal, 9.0 to 10.5 mg/dL]; and phosphate, 22.42 mg/dL [normal, 2.6 to 4.5 mg/dL]). The patient received a single dose of 1,000 U urate oxidase as infusion and supportive therapy (careful fluid substitution, allopurinol treatment). Although the uric acid concentration rapidly decreased after the administration of urate oxidase, the serum creatinine level further increased (Fig 1). The clinical status of the patient deteriorated. No dialysis was initiated because of the poor prognosis. The patient developed septic shock and died. Autopsy showed no evidence of the mediastinal tumor, suggesting rapid melting of this large mass after corticosteroid treatment with concomitant development of tumor lysis syndrome.
Case 2 A previously healthy 40-year-old man reported abdominal discomfort on the right side and radiating pain into the right shoulder. On physical examination, the liver was palpable and tender, and jaundice was present. Abdominal sonography showed multiple irregular echo-dense liver nodules. Immunohistological examination of a liver biopsy specimen showed metastasis of a neuroendocrine tumor. No primary tumor could be detected, and a course of carboplatin chemotherapy (600 mg intravenously) was started. The patient showed no sign of volume depletion at the time of chemother-
Fig 1. Serum uric acid (䊉—䊉) and creatinine (䊐—䊐) concentrations of patients 1 through 3. The arrow points to a single infusion of 1,000 U urate oxidase.
apy. He received allopurinol (two doses of 300 mg/d initially; later, 100 mg/d because of developing renal insufficiency) and a 2,500-mL/d infusion of crystalloid fluids. Before chemotherapy, laboratory values were: sodium, 131 mmol/L (normal, 135 to 145 mmol/L); potassium, 3.4 mmol/L (normal, 3.5 to 5.0 mmol/L); calcium, 8.90 mg/dL; phosphate, 5.60 mg/dL; blood urea nitrogen, 19 mg/dL (normal, 8 to 26 mg/dL); creatinine, 1.2 mg/dL; uric acid, 3.1 mg/dL; and total bilirubin, 26.8 mg/dL (normal, 0.2 to 1.0 mg/dL). Serum enzyme levels were: lactate dehydrogenase, 6,455 U/L (normal, 40 to 240 U/L); aspartate aminotransferase, 85 U/L (normal, 3 to 18 U/L); and g-glutamyltransferase, 165 U/L (normal, 6 to 28 UL). Despite appropriate fluid substitution, uric acid concentration increased to 14 mg/dL, and serum creatinine level increased to 3.9 mg/dL at day 3 after infusion of carboplatin (Fig 1). At this time, laboratory values were serum phosphate, 17.09 mg/dL; calcium, 7.70 mg/dL; and lactate dehydrogenase, 16,440 U/L, suggesting acute tumor lysis syndrome. A single dose of urate oxidase, 1,000 U, was infused. As shown in Fig 1, the uric acid level rapidly decreased and serum creatinine level normalized. The patient was discharged on day 10 after chemotherapy with normal uric acid, creatinine,
HYPERURICEMIA AND URATE OXIDASE
calcium, and phosphate levels. A partial remission was obtained, and a second course of carboplatin therapy was uneventful, without changes in serum creatinine and uric acid concentrations.
Case 3 A 61-year-old woman presented with pulmonary metastasis of a rectal carcinoma that had been diagnosed 7 years before. Six courses of palliative chemotherapy with 5-fluorouracil-folinic acid were administered without a major effect on tumor regression. She was admitted to our hospital because of a decline in renal function accompanied by hyperuricemia (creatinine level, 2.9 mg/dL; uric acid, 14.8 mg/dL). There was no clinical evidence of volume depletion. Kidney sonography showed no obstruction. An infusion of urate oxidase, 1,000 U, was administered. Uric acid level decreased and renal function improved (Fig 1). The patient was discharged with a serum creatinine level of 1.7 mg/dL and an uric acid concentration of 1.3 mg/dL 4 days after administration of urate oxidase.
Case 4 Two months before admission, a 78-year-old man had symptoms of a common cold (headache, sore throat, fever) with a very slow recovery. A blood count showed the following values: hemoglobin, 10.4 g/dL (normal, 14.0 to 17.5 g/dL); erythrocytes, 2.9 ⫻ 106/mL (normal, 4.5 to 5.9 ⫻ 106/mL); leukocytes, 95.9/nL (normal, 4.0 to 11.5/ nL); and platelets, 91/nL (normal, 170 to 410/nL. A blood
Fig 2. Catabolic pathway of purines. Hypoxanthine and xanthine, released during cell lysis, are metabolized by xanthine oxidase to uric acid (shown here in the enol form). This enzyme is inhibited by allopurinol. Although decreasing the production of uric acid, allopurinol treatment may lead to accumulation of hypoxanthine and xanthine, with the risk for intrarenal crystallization. Humans lack the enzyme urate oxidase (represented by the interrupted arrow). However, uric acid is further metabolized to the highly water-soluble allantoin in other mammals. Administration of exogenous urate oxidase may reconstitute this missing pathway in humans, leading to an oxidation of uric acid to allantoin.
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smear examination showed numerous monoblasts and myeloblasts. The patient was admitted, and a bone marrow biopsy confirmed the diagnosis of acute myeloid leukemia (type M4 according to the French-American-British classification). On admission, serum creatinine level was 2.6 mg/dL, and uric acid level, 19.6 mg/dL. Because of an assumed heavy tumor load with imminent tumor lysis syndrome, a single 1,000-U dose of urate oxidase was infused before planned chemotherapy. During the next 3 days, uric acid level decreased to 13.1 mg/dL, whereas serum creatinine level decreased to 2.2 mg/dL. Just before initiation of chemotherapy, the patient developed a cardiac arrest with unsuccessful resuscitation.
DISCUSSION
Uric acid is the end product of purine metabolism in birds, reptiles, primates, and humans and is produced in the liver by oxidation of xanthine and hypoxanthine (Fig 2). In all other mammals, uric acid is further oxidized by the enzyme urate oxidase to allantoin (Fig 2). However, humans lack this enzyme. Allantoin, because of its lost pyrimidine ring, shows a more than 20-times greater water solubility than uric acid.1,2 In vitro solubility of allantoin in water at room temperature is more than 260 times greater than that of
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uric acid.15 In some fish, allantoin is further metabolized to urea. In terms of comparative physiology, excretion of relative insoluble uric acid may serve as a mechanism to conserve water. Uric acid has a pKa of 5.75 of the hydrogen atom of the imidazole ring, which is ionized, whereas the pyrimidine ring hydrogen (pKa 10.3) remains undissociated. Consequently, nearly all uric acid in blood is present as monourate, whereas in acid urine, a substantial amount is undissociated. Renal handling of uric acid is complex and requires glomerular filtration, reabsorption of filtered urate, tubular secretion, and finally postsecretory reabsorption.16,17 Hyperuricemia regularly occurs as part of tumor lysis syndrome.2 More rarely, a substantial spontaneous increase in serum uric acid concentration may be seen in patients with heavy tumor load, even in the absence of radiotherapy or chemotherapy, because of exaggerated proliferation and necrosis of cells, with subsequent catabolism of released purines into uric acid.1 It has been suggested that patients with such malignant lymphoblastic diseases as acute lymphocytic leukemia may have the greatest risk for acute hyperuricemia because these cells contain considerable amounts of purines.3 In these pathophysiological conditions of hyperuricemia, acute uric acid nephropathy is the consequence of uric acid crystal deposition in distal tubules and collecting ducts.17,18 Further outflow obstruction could be caused by precipitation of uric acid in the renal pelvis and ureter.17 Although somewhat controversial, there is evidence that uric acid crystal deposition in the tubulointerstitium may ignite an inflammatory reaction with cytokine release and additional compromise of renal function.7 Predisposing factors for renal deposition are an increased urinary uric acid concentration, volume depletion, and concentrated and acidic urine. Precipitation of calcium phosphate and probably direct tubular toxicity of phosphate further contribute to renal insufficiency in patients with tumor lysis syndrome. The prevention and treatment of hyperuricemia-induced acute renal failure caused by a malignant disease is a considerable challenge, and its therapy is currently unsatisfactory for the following reasons. Allopurinol (4-hydroxypurinol), an analogue of xanthine, is currently considered the standard
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pharmacological therapy for hyperuricemia.7,17 This drug, after being converted to oxypurinol, binds to and inhibits xanthine oxidase, the pivotal enzyme that catalyzes the conversion of hypoxanthine and xanthine to uric acid (Fig 2). As a consequence, uric acid biosynthesis is inhibited, and xanthine, as well as hypoxanthine, concentrations increase. However, allopurinol does not influence the metabolism of uric acid that is already present and deposited intrarenally as crystals. Although the solubility of xanthine and hypoxanthine is only slightly greater than that of uric acid, purines are divided into xanthine, hypoxanthine, and uric acid during allopurinol treatment. Because each of these catabolic products shows its independent solubility, it is assumed that urinary concentration of uric acid decreases below its solubility. However, during excessive catabolism of purines, allopurinol therapy may lead to intrarenal precipitation of hypoxanthine and xanthine, with further aggravation of acute renal failure, and this situation has been well documented in clinical practice.11-14 In addition, allopurinol can exert severe toxic effects, including cutaneous hypersensitivity reactions, leukopenia, and hepatomegaly.17 This drug has been also implicated in the induction of tubulointerstitial nephritis.19 Finally, urate oxidase would be useful when patients are treated with azathioprine because allopurinol interferes with the metabolism of certain drugs, including azathioprine, which could increase bone marrow toxicity.20 All these adverse effects make allopurinol less desirable for the treatment of acute hyperuricemia in tumor patients.20 Conversely, uric acid, as well as phosphate, can be effectively removed by dialysis and, as recently proposed, by continuous arteriovenous hemodialysis.21 However, these extracorporeal treatment modalities may be problematic in patients with malignancies because of the risk for severe bleeding caused by thrombocytopenia or the need for anticoagulation. Furthermore, vascular catheter access represents a risk factor for fatal infections that should not be underestimated in these already-immunocompromised patients.22 Treatment with exogenous urate oxidase, the enzyme that humans lack, could convert uric acid into the highly water-soluble allantoin. Furthermore, urate oxidase, if adequately filtered
HYPERURICEMIA AND URATE OXIDASE
into the urine, may even dissolve alreadyprecipitated uric acid crystals and could improve renal function.23-26 Urate oxidase, extracted from Aspergillus flavus through a complex manufacturing process, has been commercially available in France since 1975 and in Italy since the early 1980s.27-29 Although pediatric oncologists are well aware of the potential advantages of urate oxidase,23,24,29 this therapy surprisingly has not been widely recognized in the renal community, and even recent reviews on tumor lysis syndrome failed to mention urate oxidase treatment.1,3,8 An obstacle for a more general application of urate oxidase in hyperuricemia may be the complicated manufacturing process of the enzyme involving fermentation, extraction, and purification, which clearly limits its commercial availability, as well as the standardization of enzyme activity. Urate oxidase is only available in a few countries, currently limiting the use of this therapy. However, more recently, a complementary DNA clone encoding urate oxidase was isolated from A flavus, and the recombinant enzyme is expressed in yeast, making mass production feasible. This recombinant urate oxidase is currently undergoing phase II studies and is not yet commercially available.26 We used the nonrecombinant urate oxidase in our patients. Two of our four patients (patients 1 and 2) showed the classic signs of tumor lysis syndrome after chemotherapy, whereas patient 4 had a high serum uric acid concentration associated with decreased renal function before therapy for his acute myeloid leukemia. Patient 3 at presentation showed only an intermediate degree of hyperuricemia. A single dose of urate oxidase readily decreased serum uric acid concentrations in all four patients. Although some of our patients also received additional allopurinol therapy, the rapid decrease of serum uric acid concentrations after urate oxidase injection suggests a stimulated conversion into allantoin, rather than the inhibition of formation by allopurinol. Moreover, allopurinol had no initial effect on hyperuricemia in patient 2, who continuously received this drug from day 1. Application of urate oxidase improved renal function, determined by serum creatinine levels in patients 2 through 4. Although we cannot rule out that renal function improved in our patients because of a better control of adequate fluid intake in the hospital
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setting, the patients initially showed no clinical signs of volume depletion at admission, and no drugs of known renal toxicity were given. We would rather like to hypothesize that urate oxidase treatment may have induced solution of potential renal uric acid deposits, as previously suggested in the literature.23,26 Alternatively, a fast reduction in serum uric acid levels may have additionally improved renal function by inhibition of proinflammatory effects. Only patient 1 failed to achieve improvement of renal function after a single dose of urate oxidase, and repetitive application may have been necessary. It is also possible that intrarenal precipitation of calcium phosphate contributed to this persistent renal insufficiency because this patient showed hyperphosphatemia and a reduced serum calcium level. Moreover, the patient developed pneumonia and died of sepsis, which certainly contributed to the maintenance of renal insufficiency. A recent small study showed that a much higher infusion of urate oxidase (100 U/kg of body weight) on up to 5 consecutive days led to full resolution of acute renal failure induced by tumor lysis syndrome.24 However, our experience suggests that a much lower single dose may be equally effective. We did not observe side effects of urate oxidase infusion in our four patients. Only a few allergic side effects have been described in the limited literature.23-25,27-29 However, the true incidence of these allergic reactions is not known, and this uncertainty may have contributed to the previous limited use of the enzyme preparations. Urate oxidase should not be given to patients with glucose-6-phosphate dehydrogenase deficiency, because of intracellular erythrocyte lysis caused by generated hydrogen peroxide, or to pregnant women.23 In conclusion, we believe that in patients with malignancy-associated hyperuricemia, a single infusion of urate oxidase is already efficient to considerably reduce serum uric acid levels and to improve renal function. Treatment of tumor lysis syndrome with the recombinant enzyme currently under clinical study shows encouraging results.26 This should provoke a more widespread use and acceptance of this effective therapy in hyperuricemia-associated renal failure in patients with malignant diseases. However, con-
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trolled trials are necessary to prove this hypothesis. ACKNOWLEDGMENT The authors did not receive financial or other support from the manufacturer of urate oxidase.
REFERENCES 1. Silverman P, Distelhorst CW: Metabolic emergencies in clinical oncology. Semin Oncol 16:504-515, 1989 2. Chasty RC, Liu-Yin JA: Acute tumour lysis syndrome. Br J Hosp Med 49:488-492, 1993 3. Lorigan PC, Woodings PL, Morgenstern GR, Scarffe JH: Tumour lysis syndrome: Case report and review of the literature. Ann Oncol 7:631-636, 1996 4. Bedrna A, Poleak J: Akuter Harnleiterverschluβ nach Bestrahlung chronischer Leuka¨mien mit Ro¨ntgenstrahlen. Med Klinik 44:1700-1701, 1929 5. Sparano J, Ramirez M, Wiernik PH: Increasing recognition of corticosteroid-induced tumor lysis syndrome in non-Hodgkin’s lymphoma. Cancer 65:1072-1073, 1990 6. Hande KR, Garrow GC: Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 94:133-139, 1993 7. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB: Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 33:225-234, 1999 ¨ hler L, Watzke H, Bo¨hmig G, Prokesch R, 8. Haas M, O Druml W: The spectrum of acute renal failure in tumour lysis syndrome. Nephrol Dial Transplant 14:776-779, 1999 9. Boles JM, Dutel JL, Briere J, Mialon P, Robasckiewicz M, Garre M, Brierre J: Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer 53:2425-2429, 1984 10. Zager RA: Hyperphosphatemia: A factor that provokes severe experimental acute renal failure. J Lab Clin Med 100:230-239, 1982 11. Hande KR, Perini E, Hixon C, Magrath I, Chabner B: Post-chemotherapy hyperxanthinuria in lymphoma patients on allopurinol: A potential cause of nephropathy. Clin Res 27:386A, 1979 (abstr) 12. Band PR, Silverberg DS, Henderson JF, Ulan RA, Wensel RH, Banerjee TK, Little AS: Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 283:354-357, 1970 13. Hande KR, Hixson CV, Chabner BA: Postchemotherapy purine excretion in lymphoma patients receiving allopurinol. Cancer Res 41:2273-2279, 1981 14. Albin A, Stephens BG, Hirata T, Wilson K, Williams HE: Nephropathy, xanthinuria, and orotic aciduria complicat-
ing Burkitt’s lymphoma treated with chemotherapy and allopurinol. Metabolism 21:771-778, 1972 15. Dawson RMC, Elliott DC, Elliott WH, Jones KM: Data for Biochemical Research (ed 2). Oxford, England, Oxford University Press, 1974, p 6 16. Holmes EW, Kelley WN, Wyngaarden JB: The kidney and uric acid excretion in man. Kidney Int 2:115-118, 1972 17. Verberchmoes R: Uric acid and the kidney, in Cameron S, Davison AM, Gru¨nfeld JP, Kerr D, Ritz E (eds): Oxford Textbook of Clinical Nephrology. Oxford, England, Oxford University Press, 1992, pp 825-837 18. Robinson RR, Yarger WE: Acute uric acid nephropathy. Arch Intern Med 137:839-840, 1977 19. Neilson EG: Pathogenesis and therapy of interstitial nephritis. Kidney Int 35:1257-1270, 1989 20. Ippoliti G, Negri M, Campana C, Vigano M: Urate oxidase in hyperuricemic heart transplant recipients treated with azathioprine. Transplantation 63:1370-1371, 1997 21. Pichette V, Leblanc M, Bonnardeaux A, Ouimet D, Geadah D, Cardinal J: High dialysate flow rate continuous arteriovenous hemodialysis: A new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 23:591-596, 1994 22. Raad I: Intravascular catheter-related infections. Lancet 351:893-898, 1998 23. Mahmoud HH, Leverger G, Patte C, Harvey E, Lascombes F: Advances in the management of malignancyassociated hyperuricaemia. Br J Cancer 77:S18-S20, 1998 (suppl 4) 24. Leach M, Parsons RM, Reilly JT, Winfiled DA: Efficacy of urate oxidase (Uricozyme) in tumour lysis induced urate nephropathy. Clin Lab Haematol 20:169-172, 1998 25. Piu CH, Relling MV, Lascombes F, Harrison PL, Struxiano A, Mondesir JM, Ribeiro RC, Sandlund JT, Rivera GK, Evans WE, Mahmoud HH: Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia 11:1813-1816, 1997 26. Abstracts. International Symposium: Technological Advances in the Treatment of Malignancy-Associated Hyperuricemia, April 10, 1997, Atlanta, GA, pp 1-7 27. Kissel P, Mauuary G, Royer R, Toussain P: Treatment of malignant haemopathies and urate oxidase. Lancet I:229, 1975 28. Davis S, Park YK, Abuchowski A, Davis FF: Hypouricaemic effect of polyethyleneglycol modified urate oxidase. Lancet II:281-283, 1981 29. Masera G, Jankovic M, Zurio MG, Locasciulli A, Rossi MR, Uderzo C, Recchia M: Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia. J Pediatr 100:152-155, 1982
Hyperuricemia and Renal Insufficiency Associated With Malignant Disease: Urate Oxidase as an Efficient Therapy? Gunter Wolf, MD, Susanne Hegewisch-Becker, MD, Dieter K. Hossfeld, MD, and Rolf A.K. Stahl, MD ● Hyperuricemia is a common finding in patients with malignant diseases. Chemotherapy can induce lifethreatening tumor lysis syndrome with severe hyperuricemia, other metabolic abnormalities, and acute renal failure. Intrarenal precipitation of uric acid contributes to renal insufficiency in this situation. Allopurinol, by preventing the conversion of hypoxanthine and xanthine to uric acid, has been long considered the standard pharmacological approach to hyperuricemia and prevention of tumor lysis syndrome. However, allopurinol itself may facilitate precipitation of xanthine crystals and has little influence on already-formed uric acid crystals deposited in the kidney. Urate oxidase further oxidizes uric acid to the highly water-soluble allantoin in mammals, except humans, who lack this enzyme. We report four cases of hyperuricemia (initial serum uric acid concentrations, 14.0 to 25.0 mg/dL) associated with malignant diseases treated with exogenous urate oxidase. Two of the patients showed full-blown tumor lysis syndrome. A single urate oxidase infusion (1,000 U) readily reduced serum uric acid levels in all patients. Furthermore, renal insufficiency, determined by serum creatinine concentrations, improved in three of the four patients. No adverse effects were observed. Currently, a recombinant urate oxidase is undergoing clinical testing and may make this efficient therapy more widely available. We believe that treatment with urate oxidase is a safe and efficient therapy for patients with cancer-associated hyperuricemia and may be effective even in individuals with only moderately elevated serum uric acid concentrations. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Tumor lysis syndrome; hyperuricemia; renal failure; hyperphosphatemia; urate oxidase; allantoin; allopurinol.
T
UMOR LYSIS SYNDROME is a clinical entity characterized by hyperkalemia, hyperuricemia, hyperxanthinemia (especially in patients treated with allopurinol), hyperphosphatemia, hypocalcemia, lactic acidosis, and often acute renal insufficiency.1-3 Because the homeostasis of these substances depends on the integrity of the kidney, a reduction in renal function makes tumor lysis syndrome a life-threatening metabolic emergency in clinical oncology.1 Although the destruction of malignant cells by radiotherapy may occasionally cause these metabolic abnormalities,4 tumor lysis syndrome is more often triggered by cytotoxic chemotherapy that induces cell death, with concomitant release of intracellular substances.2,3 Under certain conditions, such as in patients with non-Hodgkin’s lymphomas or acute lymphocytic leukemias, administration of low doses of corticosteroids may induce tumor lysis syndrome.5,6 Furthermore, hyperuricemia and occasionally other features of tumor lysis syndrome may be present even in cancer patients without specific therapy because of the high turnover of malignant cells.1 Tumor lysis syndrome–induced acute renal failure is caused by at least three different pathophysiological processes that may occur in paral-
lel. (1) Acute uric acid nephropathy. The mechanism of hyperuricemia-induced acute renal failure is believed to be intratubular precipitations of uric acid crystals facilitated by an increase in concentration and change of urine pH, but other pathogenic processes of uric acid crystals, such as proinflammatory effects, also have been proposed.7,8 (2) Massive hyperphosphatemia is frequently observed in patients with tumor lysis syndrome.9 Intrarenal precipitations of calcium phosphate, as well as direct toxic effects of phosphate, may contribute to acute renal insufficiency.9,10 (3) Although xanthine nephropathy is rarely seen, this complication must be considFrom the Department of Medicine, Division of Nephrology and Osteology, and the Division of Oncology and Hematology, University of Hamburg, Hamburg, Germany. Received March 31, 1999; accepted in revised form August 3, 1999. G.W. is supported in part by a Heisenberg fellowship of the Deutsche Forschungsgemeinschaft. Address reprint requests to Gunter Wolf, MD, University of Hamburg, University Hospital Eppendorf, Department of Medicine, Division of Nephrology and Osteology, Pavilion 61, Martinistraße 52, D-20246 Hamburg, Germany. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3405-0020$3.00/0
American Journal of Kidney Diseases, Vol 34, No 5 (November), 1999: E20
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ered in patients developing tumor lysis syndrome who have been pretreated with allopurinol.11-14 The therapeutic dilemma of hyperuricemia is the potential aggravation of other consequences of tumor lysis syndrome. For example, alkalinization of the urine to increase uric acid solubility facilitates precipitation of calcium phosphate. Conversely, pretreatment with high doses of such xanthine oxidase inhibitors as allopurinol bears the intrinsic risk for xanthine nephropathy and cannot be used for patients with hypersensitivity reactions to this substance. Administration of the enzyme urate oxidase (Uricozyme; Sanofi-Winthrop, Gentilly, France) induces oxidation of uric acid into highly soluble allantoin. We report here our experience with this treatment strategy. CASE REPORTS
Case 1 An acute leukemia without further differentiation was diagnosed in another hospital in a previously healthy 72-yearold man. Radiographic examination of the chest showed a large mediastinal mass. The patient was treated in this hospital with a single 200-mg dose of prednisolone and was subsequently transferred to our hospital. Immunohistochemical and molecular studies of bone marrow cells established the diagnosis of a T-cell acute lymphocytic leukemia. On admission, the patient showed all features of tumor lysis syndrome with acute renal failure (uric acid, 23.2 mg/dL [normal, 2.5 to 6.0 mg/dL]; creatinine, 6.0 mg/dL [normal, 0.6 to 1.4 mg/dL]; calcium, 4.04 mg/dL [normal, 9.0 to 10.5 mg/dL]; and phosphate, 22.42 mg/dL [normal, 2.6 to 4.5 mg/dL]). The patient received a single dose of 1,000 U urate oxidase as infusion and supportive therapy (careful fluid substitution, allopurinol treatment). Although the uric acid concentration rapidly decreased after the administration of urate oxidase, the serum creatinine level further increased (Fig 1). The clinical status of the patient deteriorated. No dialysis was initiated because of the poor prognosis. The patient developed septic shock and died. Autopsy showed no evidence of the mediastinal tumor, suggesting rapid melting of this large mass after corticosteroid treatment with concomitant development of tumor lysis syndrome.
Case 2 A previously healthy 40-year-old man reported abdominal discomfort on the right side and radiating pain into the right shoulder. On physical examination, the liver was palpable and tender, and jaundice was present. Abdominal sonography showed multiple irregular echo-dense liver nodules. Immunohistological examination of a liver biopsy specimen showed metastasis of a neuroendocrine tumor. No primary tumor could be detected, and a course of carboplatin chemotherapy (600 mg intravenously) was started. The patient showed no sign of volume depletion at the time of chemother-
Fig 1. Serum uric acid (䊉—䊉) and creatinine (䊐—䊐) concentrations of patients 1 through 3. The arrow points to a single infusion of 1,000 U urate oxidase.
apy. He received allopurinol (two doses of 300 mg/d initially; later, 100 mg/d because of developing renal insufficiency) and a 2,500-mL/d infusion of crystalloid fluids. Before chemotherapy, laboratory values were: sodium, 131 mmol/L (normal, 135 to 145 mmol/L); potassium, 3.4 mmol/L (normal, 3.5 to 5.0 mmol/L); calcium, 8.90 mg/dL; phosphate, 5.60 mg/dL; blood urea nitrogen, 19 mg/dL (normal, 8 to 26 mg/dL); creatinine, 1.2 mg/dL; uric acid, 3.1 mg/dL; and total bilirubin, 26.8 mg/dL (normal, 0.2 to 1.0 mg/dL). Serum enzyme levels were: lactate dehydrogenase, 6,455 U/L (normal, 40 to 240 U/L); aspartate aminotransferase, 85 U/L (normal, 3 to 18 U/L); and g-glutamyltransferase, 165 U/L (normal, 6 to 28 UL). Despite appropriate fluid substitution, uric acid concentration increased to 14 mg/dL, and serum creatinine level increased to 3.9 mg/dL at day 3 after infusion of carboplatin (Fig 1). At this time, laboratory values were serum phosphate, 17.09 mg/dL; calcium, 7.70 mg/dL; and lactate dehydrogenase, 16,440 U/L, suggesting acute tumor lysis syndrome. A single dose of urate oxidase, 1,000 U, was infused. As shown in Fig 1, the uric acid level rapidly decreased and serum creatinine level normalized. The patient was discharged on day 10 after chemotherapy with normal uric acid, creatinine,
HYPERURICEMIA AND URATE OXIDASE
calcium, and phosphate levels. A partial remission was obtained, and a second course of carboplatin therapy was uneventful, without changes in serum creatinine and uric acid concentrations.
Case 3 A 61-year-old woman presented with pulmonary metastasis of a rectal carcinoma that had been diagnosed 7 years before. Six courses of palliative chemotherapy with 5-fluorouracil-folinic acid were administered without a major effect on tumor regression. She was admitted to our hospital because of a decline in renal function accompanied by hyperuricemia (creatinine level, 2.9 mg/dL; uric acid, 14.8 mg/dL). There was no clinical evidence of volume depletion. Kidney sonography showed no obstruction. An infusion of urate oxidase, 1,000 U, was administered. Uric acid level decreased and renal function improved (Fig 1). The patient was discharged with a serum creatinine level of 1.7 mg/dL and an uric acid concentration of 1.3 mg/dL 4 days after administration of urate oxidase.
Case 4 Two months before admission, a 78-year-old man had symptoms of a common cold (headache, sore throat, fever) with a very slow recovery. A blood count showed the following values: hemoglobin, 10.4 g/dL (normal, 14.0 to 17.5 g/dL); erythrocytes, 2.9 ⫻ 106/mL (normal, 4.5 to 5.9 ⫻ 106/mL); leukocytes, 95.9/nL (normal, 4.0 to 11.5/ nL); and platelets, 91/nL (normal, 170 to 410/nL. A blood
Fig 2. Catabolic pathway of purines. Hypoxanthine and xanthine, released during cell lysis, are metabolized by xanthine oxidase to uric acid (shown here in the enol form). This enzyme is inhibited by allopurinol. Although decreasing the production of uric acid, allopurinol treatment may lead to accumulation of hypoxanthine and xanthine, with the risk for intrarenal crystallization. Humans lack the enzyme urate oxidase (represented by the interrupted arrow). However, uric acid is further metabolized to the highly water-soluble allantoin in other mammals. Administration of exogenous urate oxidase may reconstitute this missing pathway in humans, leading to an oxidation of uric acid to allantoin.
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smear examination showed numerous monoblasts and myeloblasts. The patient was admitted, and a bone marrow biopsy confirmed the diagnosis of acute myeloid leukemia (type M4 according to the French-American-British classification). On admission, serum creatinine level was 2.6 mg/dL, and uric acid level, 19.6 mg/dL. Because of an assumed heavy tumor load with imminent tumor lysis syndrome, a single 1,000-U dose of urate oxidase was infused before planned chemotherapy. During the next 3 days, uric acid level decreased to 13.1 mg/dL, whereas serum creatinine level decreased to 2.2 mg/dL. Just before initiation of chemotherapy, the patient developed a cardiac arrest with unsuccessful resuscitation.
DISCUSSION
Uric acid is the end product of purine metabolism in birds, reptiles, primates, and humans and is produced in the liver by oxidation of xanthine and hypoxanthine (Fig 2). In all other mammals, uric acid is further oxidized by the enzyme urate oxidase to allantoin (Fig 2). However, humans lack this enzyme. Allantoin, because of its lost pyrimidine ring, shows a more than 20-times greater water solubility than uric acid.1,2 In vitro solubility of allantoin in water at room temperature is more than 260 times greater than that of
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uric acid.15 In some fish, allantoin is further metabolized to urea. In terms of comparative physiology, excretion of relative insoluble uric acid may serve as a mechanism to conserve water. Uric acid has a pKa of 5.75 of the hydrogen atom of the imidazole ring, which is ionized, whereas the pyrimidine ring hydrogen (pKa 10.3) remains undissociated. Consequently, nearly all uric acid in blood is present as monourate, whereas in acid urine, a substantial amount is undissociated. Renal handling of uric acid is complex and requires glomerular filtration, reabsorption of filtered urate, tubular secretion, and finally postsecretory reabsorption.16,17 Hyperuricemia regularly occurs as part of tumor lysis syndrome.2 More rarely, a substantial spontaneous increase in serum uric acid concentration may be seen in patients with heavy tumor load, even in the absence of radiotherapy or chemotherapy, because of exaggerated proliferation and necrosis of cells, with subsequent catabolism of released purines into uric acid.1 It has been suggested that patients with such malignant lymphoblastic diseases as acute lymphocytic leukemia may have the greatest risk for acute hyperuricemia because these cells contain considerable amounts of purines.3 In these pathophysiological conditions of hyperuricemia, acute uric acid nephropathy is the consequence of uric acid crystal deposition in distal tubules and collecting ducts.17,18 Further outflow obstruction could be caused by precipitation of uric acid in the renal pelvis and ureter.17 Although somewhat controversial, there is evidence that uric acid crystal deposition in the tubulointerstitium may ignite an inflammatory reaction with cytokine release and additional compromise of renal function.7 Predisposing factors for renal deposition are an increased urinary uric acid concentration, volume depletion, and concentrated and acidic urine. Precipitation of calcium phosphate and probably direct tubular toxicity of phosphate further contribute to renal insufficiency in patients with tumor lysis syndrome. The prevention and treatment of hyperuricemia-induced acute renal failure caused by a malignant disease is a considerable challenge, and its therapy is currently unsatisfactory for the following reasons. Allopurinol (4-hydroxypurinol), an analogue of xanthine, is currently considered the standard
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pharmacological therapy for hyperuricemia.7,17 This drug, after being converted to oxypurinol, binds to and inhibits xanthine oxidase, the pivotal enzyme that catalyzes the conversion of hypoxanthine and xanthine to uric acid (Fig 2). As a consequence, uric acid biosynthesis is inhibited, and xanthine, as well as hypoxanthine, concentrations increase. However, allopurinol does not influence the metabolism of uric acid that is already present and deposited intrarenally as crystals. Although the solubility of xanthine and hypoxanthine is only slightly greater than that of uric acid, purines are divided into xanthine, hypoxanthine, and uric acid during allopurinol treatment. Because each of these catabolic products shows its independent solubility, it is assumed that urinary concentration of uric acid decreases below its solubility. However, during excessive catabolism of purines, allopurinol therapy may lead to intrarenal precipitation of hypoxanthine and xanthine, with further aggravation of acute renal failure, and this situation has been well documented in clinical practice.11-14 In addition, allopurinol can exert severe toxic effects, including cutaneous hypersensitivity reactions, leukopenia, and hepatomegaly.17 This drug has been also implicated in the induction of tubulointerstitial nephritis.19 Finally, urate oxidase would be useful when patients are treated with azathioprine because allopurinol interferes with the metabolism of certain drugs, including azathioprine, which could increase bone marrow toxicity.20 All these adverse effects make allopurinol less desirable for the treatment of acute hyperuricemia in tumor patients.20 Conversely, uric acid, as well as phosphate, can be effectively removed by dialysis and, as recently proposed, by continuous arteriovenous hemodialysis.21 However, these extracorporeal treatment modalities may be problematic in patients with malignancies because of the risk for severe bleeding caused by thrombocytopenia or the need for anticoagulation. Furthermore, vascular catheter access represents a risk factor for fatal infections that should not be underestimated in these already-immunocompromised patients.22 Treatment with exogenous urate oxidase, the enzyme that humans lack, could convert uric acid into the highly water-soluble allantoin. Furthermore, urate oxidase, if adequately filtered
HYPERURICEMIA AND URATE OXIDASE
into the urine, may even dissolve alreadyprecipitated uric acid crystals and could improve renal function.23-26 Urate oxidase, extracted from Aspergillus flavus through a complex manufacturing process, has been commercially available in France since 1975 and in Italy since the early 1980s.27-29 Although pediatric oncologists are well aware of the potential advantages of urate oxidase,23,24,29 this therapy surprisingly has not been widely recognized in the renal community, and even recent reviews on tumor lysis syndrome failed to mention urate oxidase treatment.1,3,8 An obstacle for a more general application of urate oxidase in hyperuricemia may be the complicated manufacturing process of the enzyme involving fermentation, extraction, and purification, which clearly limits its commercial availability, as well as the standardization of enzyme activity. Urate oxidase is only available in a few countries, currently limiting the use of this therapy. However, more recently, a complementary DNA clone encoding urate oxidase was isolated from A flavus, and the recombinant enzyme is expressed in yeast, making mass production feasible. This recombinant urate oxidase is currently undergoing phase II studies and is not yet commercially available.26 We used the nonrecombinant urate oxidase in our patients. Two of our four patients (patients 1 and 2) showed the classic signs of tumor lysis syndrome after chemotherapy, whereas patient 4 had a high serum uric acid concentration associated with decreased renal function before therapy for his acute myeloid leukemia. Patient 3 at presentation showed only an intermediate degree of hyperuricemia. A single dose of urate oxidase readily decreased serum uric acid concentrations in all four patients. Although some of our patients also received additional allopurinol therapy, the rapid decrease of serum uric acid concentrations after urate oxidase injection suggests a stimulated conversion into allantoin, rather than the inhibition of formation by allopurinol. Moreover, allopurinol had no initial effect on hyperuricemia in patient 2, who continuously received this drug from day 1. Application of urate oxidase improved renal function, determined by serum creatinine levels in patients 2 through 4. Although we cannot rule out that renal function improved in our patients because of a better control of adequate fluid intake in the hospital
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setting, the patients initially showed no clinical signs of volume depletion at admission, and no drugs of known renal toxicity were given. We would rather like to hypothesize that urate oxidase treatment may have induced solution of potential renal uric acid deposits, as previously suggested in the literature.23,26 Alternatively, a fast reduction in serum uric acid levels may have additionally improved renal function by inhibition of proinflammatory effects. Only patient 1 failed to achieve improvement of renal function after a single dose of urate oxidase, and repetitive application may have been necessary. It is also possible that intrarenal precipitation of calcium phosphate contributed to this persistent renal insufficiency because this patient showed hyperphosphatemia and a reduced serum calcium level. Moreover, the patient developed pneumonia and died of sepsis, which certainly contributed to the maintenance of renal insufficiency. A recent small study showed that a much higher infusion of urate oxidase (100 U/kg of body weight) on up to 5 consecutive days led to full resolution of acute renal failure induced by tumor lysis syndrome.24 However, our experience suggests that a much lower single dose may be equally effective. We did not observe side effects of urate oxidase infusion in our four patients. Only a few allergic side effects have been described in the limited literature.23-25,27-29 However, the true incidence of these allergic reactions is not known, and this uncertainty may have contributed to the previous limited use of the enzyme preparations. Urate oxidase should not be given to patients with glucose-6-phosphate dehydrogenase deficiency, because of intracellular erythrocyte lysis caused by generated hydrogen peroxide, or to pregnant women.23 In conclusion, we believe that in patients with malignancy-associated hyperuricemia, a single infusion of urate oxidase is already efficient to considerably reduce serum uric acid levels and to improve renal function. Treatment of tumor lysis syndrome with the recombinant enzyme currently under clinical study shows encouraging results.26 This should provoke a more widespread use and acceptance of this effective therapy in hyperuricemia-associated renal failure in patients with malignant diseases. However, con-
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trolled trials are necessary to prove this hypothesis. ACKNOWLEDGMENT The authors did not receive financial or other support from the manufacturer of urate oxidase.
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ing Burkitt’s lymphoma treated with chemotherapy and allopurinol. Metabolism 21:771-778, 1972 15. Dawson RMC, Elliott DC, Elliott WH, Jones KM: Data for Biochemical Research (ed 2). Oxford, England, Oxford University Press, 1974, p 6 16. Holmes EW, Kelley WN, Wyngaarden JB: The kidney and uric acid excretion in man. Kidney Int 2:115-118, 1972 17. Verberchmoes R: Uric acid and the kidney, in Cameron S, Davison AM, Gru¨nfeld JP, Kerr D, Ritz E (eds): Oxford Textbook of Clinical Nephrology. Oxford, England, Oxford University Press, 1992, pp 825-837 18. Robinson RR, Yarger WE: Acute uric acid nephropathy. Arch Intern Med 137:839-840, 1977 19. Neilson EG: Pathogenesis and therapy of interstitial nephritis. Kidney Int 35:1257-1270, 1989 20. Ippoliti G, Negri M, Campana C, Vigano M: Urate oxidase in hyperuricemic heart transplant recipients treated with azathioprine. Transplantation 63:1370-1371, 1997 21. Pichette V, Leblanc M, Bonnardeaux A, Ouimet D, Geadah D, Cardinal J: High dialysate flow rate continuous arteriovenous hemodialysis: A new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 23:591-596, 1994 22. Raad I: Intravascular catheter-related infections. Lancet 351:893-898, 1998 23. Mahmoud HH, Leverger G, Patte C, Harvey E, Lascombes F: Advances in the management of malignancyassociated hyperuricaemia. Br J Cancer 77:S18-S20, 1998 (suppl 4) 24. Leach M, Parsons RM, Reilly JT, Winfiled DA: Efficacy of urate oxidase (Uricozyme) in tumour lysis induced urate nephropathy. Clin Lab Haematol 20:169-172, 1998 25. Piu CH, Relling MV, Lascombes F, Harrison PL, Struxiano A, Mondesir JM, Ribeiro RC, Sandlund JT, Rivera GK, Evans WE, Mahmoud HH: Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia 11:1813-1816, 1997 26. Abstracts. International Symposium: Technological Advances in the Treatment of Malignancy-Associated Hyperuricemia, April 10, 1997, Atlanta, GA, pp 1-7 27. Kissel P, Mauuary G, Royer R, Toussain P: Treatment of malignant haemopathies and urate oxidase. Lancet I:229, 1975 28. Davis S, Park YK, Abuchowski A, Davis FF: Hypouricaemic effect of polyethyleneglycol modified urate oxidase. Lancet II:281-283, 1981 29. Masera G, Jankovic M, Zurio MG, Locasciulli A, Rossi MR, Uderzo C, Recchia M: Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia. J Pediatr 100:152-155, 1982