European Review for Medical and Pharmacological Sciences 2007; 11: 179-184 Is rasburicase an effective alternative to allopurinol for management of hyperuricemia in renal failure patients? A double blind-randomized study S. DE ANGELIS, A. NOCE, L. DI RENZO*, R. CIANCI*§, A. NATICCHIA, G.F. GIARRIZZO*, F. GIORDANO**, C. TOZZO, G. SPLENDIANI, A. DE LORENZO* Division of Nephrology, University “Tor Vergata” – Rome (Italy) *Department of Neuroscience, Division of Human Nutrition, University of “Tor Vergata" – Rome (Italy) **Division of Nephrology, Nuova I.T.O.R. – Rome (Italy) §Institute of Internal Medicine, Catholic University – Rome (Italy) Abstract. – Recent epidemiological Introduction studies provide a clear evidence that hyper- uricemia is associated with hypertension, coronary heart disease, left ventricular hyper- Hyperuricemia is defined as a serum uric acid trophy and progression of renal disease. Aim (SUA) concentration exceeding the limit of solu- of our study was to assess the effect of low dosage of recombinant urate oxidase on hype- bility, about 6.8 mg/dL (400 mmol/L). In patients ruricemia in renal failure patients that already with renal disease uric acid urinary excretion is receiving allopurinol. Our study group consist- usually decreased and whether this will give rise ed of 43 renal failure patients, 23 women and to hyperuricemia depends only on the gastroin- 20 men. The mean age was 74 years (range 36- testinal excretory compensation1. 90 years). The following variables were stud- Recent studies provide a clear evidence that ied on admission: serum creatinine, blood urea nitrogen and serum uric acid. Intravenous hyperuricemia is associated with essential hyper- rasburicase was administered at a dose of 0.02 tension, coronary heart disease, left ventricular mg/kg/day on 3 consecutive days in patients hypertrophy and progression of renal disease2. with serum uric acid between 8-10 mg/dl, on 5 The role of uric acid in the progression of re- consecutive days in patients with serum uric nal disease has been investigated by Kang et al in acid between 10-15 mg/dl and on 7 consecu- normal rats using a model of mild hyperuricemia tive days in patients with serum uric acid > 15 induced by the uricase inhibitor, oxonic acid mg/dl. Uric acid levels were assayed after 48 3 hours and 7 days after rasburicase treatment. (OA) . The major novel finding of this study was Mean values of uric acid levels after 48 hours that modest hyperuricemia markedly exacerbated were 2.47 mg/dl (± 1.58) in men and 2,77 mg/dl renal progression through activation of the renin (± 2.24) in woman, where’as mean values of angiotensin system (RAS) and vascular smooth uric acid levels after 7 days were 4.45 mg/dl (± muscle cell (VSMC) proliferation via COX-2 2.0) in men and 5.75 mg/dl (± 1.9) in woman. pathway. In this remnant kidney model of pro- No significant relationship were found be- tween uric acid and creatinine as before as gressive renal disease uric acid behave an inde- well after therapy. There were no side effects pendent risk factor for renal progression, since in all patients included in the study. After 7 hyperuricemia increased systemic blood pres- days, the rasburicase therapy showed more sure, renal afferent arteriopaty, increased antihyperuricemic effect in men (59%) than in glomerular hydrostatic pressure, proteinuria and women (46%). progressive renal scarring. The relationship between hyperuricemia and Key Words: progression of renal disease in humans has been Hyperuricemia, Chronic renal failure, Allopurinol, confirmed from the study of Iseki et al who ex- Recombinant urate oxidase. amined the significance of hyperuricemia on the Corresponding Author: Antonino De Lorenzo, MD; e-mail: [email protected] 179 S. De Angelis, A. Noce, L. Di Renzo, R. Cianci, A. Naticchia, et al. early detection of renal failure in a cohort of • presence of renal disease and serum creatinine screened subjects4. Therefore SUA should be ac- level greater 1.4 mg/dL knowledged as a significant modifiable risk fac- • stable clinical conditions in terms of general tor and a potential target for treatment, but we do health and renal function not as yet have conclusive human clinical trial • serum uric acid levels steadily over 7.6 mg/dL data to prove the utility of uric acid-lowering regimens as agents to attenuate progressive renal We excluded either patients with glucose-6- injury5. phosphate dehydrogenase deficiency, because the Usually, the average dose of allopurinol (300 usage of rasburicase in these subjects can cause mg per day) in patients with chronic kidney dis- hemolysis, or those with a history of atopy. ease, if correctly titrated to serum creatinine lev- We conducted the study between June 2005 els, resulted often inadequate to decrease SUA < and June 2006 at the Division of Nephrology of 7.60 mg/dL. Moreover, the side effects of allop- University Tor Vergata and Division of Nephrol- urinol may vary by a simple urticarial skin rash ogy of “Nuova ITOR Hospital, in Rome, Italy. A to a life-threatening toxicity that is characterized computer-generated central randomization sched- by a diffuse desquamative skin rash, fever, hepat- ule was used to assign each subject to one of two ic dysfunction, eosinophilia and worsening renal groups: Rasburicase at 0.02 mg/kg per day or Al- function. About eighty percent of the patients re- lopurinol at 300 mg per day. ported to have this syndrome had pre-existing re- Subjects already receiving urate-lowering nal failure, obviously followed by a promptly therapy underwent a one week washout period drug withdrawal6. before undergoing randomization. Approval was Intravenous recombinant urate oxidase (Ras- obtained from Institutional Ethichs Committee buricase) is considered an effective alternative to and carried out in patients that were followed up. oral allopurinol for management of hyper- All subjects gave written informed consent be- uricemia7. Advantages over allopurinol include a fore enrollement. more rapid onset and superior uric acid-lowering activity. Disavantages of rasburicase are its Patients propensity for severe hypersensitivity reactions Patients were randomly assigned in a 1:1 ratio and hemolytic anemia, although the risk of these to receive either rasburicase or allopurinol treat- complications appears relatively low. At the mo- ment, in a double-blind fashion by means of cen- ment the rasburicase is used only for tumor lysis tral, computerized system of randomisation. syndrome prevenction in cancer patients (primar- A total of 39 renal failure patients were en- ily lymphoma or leukemia) at the dosage of 0.20 rolled in the rasburicase group, 19 women and 20 mg/kg. men. The mean age of patients was 76 years Since hyperuricemia should have treated with (range 36-90 years). any uric acid lowering agent in order to improve The following variables were studied on ad- morbidity and mortality in renal patients, we mission: serum creatinine 4.5 mg/dL (SD 2.2), thought to investigate the effects of Rasburicase blood urea nitrogen 167.2 mg/dL (SD 80.4) and in patients with renal insufficiency at the dosage serum uric acid 10.7 mg/dL (SD 2.1). of 0.02 mg/kg/day, that is very lower than dosage 30 patients (77 %) had previously taken allop- that’s usually used for tumor lysis syndrome pre- urinol, that was withdrawn temporarily since 1 venction (0.20 mg/kg). week before the start of the study and was restarded at once at the end of the study, that is 1 week after the last rasburicase administration. The remaining 9 (23%) had a history of allopuri- Materials and Methods nol-related adverse event. According to distribu- tion in general population, prevalence of metabol- Study Design ic syndrome and association with hyperuricemia The Rasburicase versus Allopurinol Con- were about 12% of patients enrolled in the study. trolled Trial, a phase 3, randomized, double- The dose of rasburicase (0.02 mg/kg/day) was blind, 2 week, multicenter trial, compared the administered according to serum acid level: safety and efficacy of Rasburicase with the safety and efficacy of Allopurinol in adult subjects with • on 3 consecutive days in patients with serum the following inclusion criteria: uric acid between 8-10 mg/dl 180 Rasburicase treatment of hyperuricemia in renal failure patients • on 5 consecutive days in patients with serum End Points uric acid between 10-15 mg/dl The primary efficacy end point was serum uric • on 7 consecutive days in patients with serum acid reduction less than 5.5 mg/dL at first pro- uric acid > 15 mg/dl grammed measurement, after 48 hour. The sec- ondary efficacy end point included the propor- A total of 41 patients were enrolled in the Al- tion of subjects with serum urate levels of less lopurinol group, 15 women and 26 men. The than 5.5 mg/dL at the second programmed mea- mean age of patients was 66 years (range 35-90 surement, that is 7 days after the last rasburicase years). Following variables were studied on ad- administration. mission: serum creatinine 2.7 mg/dL (SD 1.8), blood urea nitrogen 99.0 mg/dL (SD 55.3) and Statistical Analysis serum uric Acid 7.6 mg/dL (SD 1.3). Statistical analysis was performed using All patients had previously taken allopurinol, SPSS statistical package (SPSS Chicago, IL, at the dosage that was adjusted according to version 5.0 for Windows). Descriptive values baseline renal function. Dosage of the other were expressed as mean value (standard devia- drugs were continued in both groups, according tion, SD), p value of < 0.05 was considered sta- to the individual patient’s clinical conditions. tistically significant. Differences between vari- ables were assessed using appropriate statisti- Adverse Event cal test based on the underlying distribution of A treatment-emergent adverse event was de- the variables by two-away ANOVA followed fined as an adverse event occurring during the by correction for multiple comparison (Bonfer- period between the first dose and 7 days after the roni test) and Chi-Square test.