Vogt, Bruno

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Nephrol Dial Transplant (2005) 20: 431–433doi:10.1093/ndt/gfh629Case ReportUrate oxidase (rasburicase) for treatment of severe tophaceous goutBruno VogtDivision of Nephrology and Hypertension, University Hospital Inselspital, Berne, SwitzerlandKeywords: cyclosporine; gout; gout tophi;hyperuricaemia; kidney transplant; rasburicase;urate oxidaseIntroductionGout is a clinical disorder caused by deposition of uratecrystals in a joint leading to acute inﬂammatory res-ponse with acute pain. In severe and longstanding gout,the crystals accumulate in soft tissues such as cartilage,subcutaneous tissue or even veins leading to thedevelopment of tophi responsible for very large depositformations and disability. Most cases of gout presentwith the sudden onset of severe acute arthritis in aperipheral joint in the leg.Urate oxidase, or uricase (EC 1.7.3.3), is a per-oxisomal liver enzyme that catalyses the enzymaticoxidation of uric acid into the more water-solubleallantoin (Figure 1). Urate oxidase is an endogenousenzyme found in most mammals but not in humans.During primate evolution, the inactivation of thehominoid urate oxidase gene was caused by indepen-dent nonsense or frameshift mutations and has takena two-step deterioration process, ﬁrst in the promotorand second in the coding region [1]. Two nonsensemutations were found in the human urate oxidase gene,which conﬁrms, at the molecular level, that the urateoxidase gene in humans is non-functional [2–3].Because uric acid is a powerful scavenger of freeradicals, it has been proposed that uric acid plays animportant role in protection hominoids from oxidativedamage and the prolonged live span [1,4].Urate oxidase is used in humans for the controlof increased serum uric acid in patients with acutetumour lysis syndrome after receiving chemotherapy.Rasburicase (SR 29142), a recombinant urate oxidaseexpressed in Saccharomyces cerevisiae, has beendemonstrated to be superior to allopurinol in thecontrol of uric acid in a randomized trial of paediatricand adult patients at risk of acute tumour lysissyndrome [5,6]. However, only few case reports addressthe potential role of urate oxidase for treatment ofsevere tophaceous gout. A French group treated threeheart transplant patients with uncontrollable gout withnon-recombinant urate oxidase and observed shrinkingof tophi and improved mobility of the ﬁngers in allthree patients [7]. Phillips and co-workers used rasburi-case for treatment of severe tophaceous gout refractoryto high-dose allopurinol in a patient with end-stagerenal disease and observed a regression of gout tophi[8]. The treatment was well tolerated in all reportedpatients and produced no adverse effects.We analysed efﬁcacy and safety of rasburicase in thelong-term control of hyperuricaemia in an adult kidneytransplant patient with severe tophaceous gout.Case reportA 33-year-old female patient suffered from severetophaceous gout. Kidney transplantation was per-formed 8 years ago for end-stage renal disease causedby bilateral vesico-ureteral reﬂux disease in childhood.Renal function remained stable (creatinine clearance30ml/min). Hyperuricemia was present since the timeof end stage renal failure with eight to 12 gout attacksper year treated with steroids and colchicine.Allopurinol was not given because of allopurinolallergy. Anorectic behaviour and therapy with cyclos-porine together with loop diuretics contributed tohyperuricemia. During the last 6 years, severe tophac-eous gout developed with large deposits in all ﬁngers ofboth hands as well as in the feet. The tophi recurreddespite repetitive surgical removal and led to signiﬁcantdisability due to previous sensory loss (Figure 2).A therapy with the recombinant urate oxidaserasburicase (Fasturtec, i.e. SR29142 from Sanoﬁ-Synthelabo, Geneva, Switzerland) 0.15mg/kg bodyweight i.v. every second week was started. Serum uricacid decreased from base line levels of 850 mM tovalues below 50 mM during the ﬁrst week after therapyand increased steadily during the subsequent weeksto levels before therapy during the ﬁrst 6 monthCorrespondence and offprint requests to: Bruno Vogt, MD, Divisionof Nephrology and Hypertension, Inselspital, University of Berne,Freiburgstrasse 15, 3010, Berne, Switzerland.Email: bruno.vogt@insel.chNephrol Dial Transplant Vol. 20 No. 2  ERA–EDTA 2005; all rights reservedtreatment period. Thereafter, and for the rest of the 3years of monthly rasburicase therapy, serum uric aciddecreased from 850 to 658 mM (mean of three values).Following rasburicase injection, serum uric aciddecreased despite a concomitant decrease in urinaryexcretion of uric acid (fractional excretion of uric aciddecrased from 8% to 3%), indicating metabolism ofuric acid unrelated to renal elimination. In the presenceof decreased fractional excretion of uric acid, onepotential mechanism for the decrease in serum uric acidis the elimination of uric acid metabolites by transportmechanisms similar to that of uric acid. Proteinuria of0.20–0.35 g/24 h remained stable during the 3 years oftherapy. Rasburicase therapy was well tolerated andproduced no adverse effects besides occasional episodesof inﬂammation observed during the ﬁrst 2 monthsof therapy. These episodes of mild inﬂammation ofmultiple joints (symmetrically ﬁngers, knees and feet)disappeared when the dose was lowered and theinterval between two doses was prolonged. With0.15mg/kg body weight of rasburicase every fourthweek, the patient remained without side effects during3 years of follow-up. No gout attack occurred sincethe start of rasburicase therapy. The size of the tophidecreased substantially and the patient’s functionalcapacity improved dramatically (Figure 3).DiscussionUrate oxidase is an enzyme that catalyses the conver-sion of uric acid into allantoin, which is 10 times moresoluble than uric acid and more readily eliminated bythe kidney. Humans and certain primates lack thisenzyme. Administered intravenously, urate oxidase is apotent and fast-acting urate-lowering drug used for theprevention of acute urate nephropathy during tumourlysis following cytolytic therapy. As demonstrated inthis patient, to the best of our knowledge the ﬁrst renaltransplant patient, urate oxidase can be used to reduceserum uric acid to a degree that will facilitate theresorption of tophi and improve functional capacity inpatients with severe gout who have allopurinol intol-erance to.Rasburicase, a recombinant urate oxidase, which isan urolytic agent, and has been developed for theprevention and treatment of chemotherapy-inducedhyperuricemia and acute renal failure induced bytumour lysis [6,9]. In this indication, the recommendeddosage is 0.20mg/kg per day for 5–7 days. Signiﬁcantreductions from baseline in plasma uric acid levels wereseen in a randomized comparative trial of rasburicaseversus allopurinol in pediatric patients at high risk oftumour lysis syndrome. The efﬁcacy and safety ofrasburicase for the prevention and treatment of hyper-uricaemia during induction chemotherapy of aggressivenon-Hodgkin’s lymphoma has been demonstrated inseveral clinical studies such as the recent GRAAL1(Groupe d’Etude des Lymphomes de l’Adulte Trial onRasburicase Activity in Adult Lymphoma) study [5].Rasburicase was well tolerated in clinical trials, withskin rashes reported in <2% of patients [6]. Therefore,short-term administration of rasburicase can beregarded as well tolerated with very few side effects.However, to date no experience of long-term therapyALLOPURINOLXANTHINEXANTHINE  OXIDASEURIC  ACID(urinary  excretion)rasburicase (urate oxidase)ALLANTOIN(urinary excretion)Purine pathwayPurine catabolismnormal endpoint of purine catabolism in humansRasburicase: mechanism of actionFig. 1. Purin pathway. Allopurinol blocks the conversion ofxanthine to uric acid. The urate oxidase rasburicase catalyses theoxidation of uric acid to allantoin, a highly water-soluble metabolitereadily excreted by the kidney.bFig. 2. Left and right hand from the 33-years-old female patient withsevere gout tophi on both hands leading to pain and functionaldisability.a432 B. Vogtwith rasburicase exists. In this regard, our patientrepresents the ﬁrst report on a 3 year rasburicasetherapy. The very few side effects observed at thebeginning of therapy disappeared after 2 months oftreatment, and then the patient was event free for theremaining 3 years. Two reasons may account for this:ﬁrst, the immunosuppressive therapy with cyclosporineA and prednisone administered concomitantly mightfacilitate the excellent tolerance, and second, rasburi-case has a high degree of purity since the structure ofthe molecule is maintained by a speciﬁc puriﬁcationprocess [10].The dramatic regression of gout tophi in the ﬁngertips indicates that a substantial amount of uric acidtissue deposits can be mobilized by long-term rasburi-case therapy.Treatment of severe gout remains a challenge inmedicine. Today, therapeutic options to decrease serumuric acid consist of diet and uricostatic agents likeallopurinol [11]. Drugs known to increase serum uricacid like diuretics and cyclosporine A usually cannot beavoided as in the present case. Benzbromarone, anuricosuric drug, is not in use any more because itsassociation with fulminant liver failure. Therefore,urate oxidase agents might open new therapeuticpossibilities in patients with severe uncontrolled gout.Furthermore, allopurinol allergy, albeit rare, representsanother interesting indication for these patients [12].Despite the excellent tolerance for 3 years of thepatient described above, allergic reactions remain apossible threat that need to be addressed in furtherstudies with the urate oxidase rasburicase.Acknowledgements. The author thanks Dr Stefan Kohler, Geneva,Switzerland, for suggestions and critical reading of the manuscript.This work was supported by a grant from the Swiss NationalFoundation for Scientiﬁc Research (No. 32-57205.99) and aresearch grant from Sanoﬁ-Synthelabo, Geneva, Switzerland. Partof this work was presented in abstract form at the Annual Meetingof the Swiss Society of Nephrology 2002, St Gallen, Switzerland.Conﬂict of interest statement. None declared.References1. Oda M, Satta Y, Takenaka O, Takahata N. Loss of urateoxidase activity in hominoids and its evolutionary implications.Mol Biol Evol 2002; 19: 640–6532. Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase:primary structure and evolutionary implications. Proc NatlAcad Sci USA 1989; 86: 9412–94163. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independentmutational events in the loss of urate oxidase during hominoidevolution. J Mol Evol 1992; 34: 78–844. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uricacid provides an antioxidant defense in humans againstoxidant- and radical-caused aging and cancer: a hypothesis.Proc Natl Acad Sci USA 1981; 78: 6858–68625. Coifﬁer B, Mounier N, Bologna S et al. Efﬁcacy and safety ofrasburicase (recombinant urate oxidase) for the prevention andtreatment of hyperuricemia during induction chemotherapy ofaggressive non-Hodgkin’s lymphoma: results of the GRAAL1(Groupe d’Etude des Lymphomes de l’Adulte Trial onRasburicase Activity in Adult Lymphoma) study. J ClinOncol 2003; 21: 4402–44066. Goldman SC, Holcenberg JS, Finklestein JZ et al. Arandomized comparison between rasburicase and allopurinolin children with lymphoma or leukemia at high risk for tumorlysis. Blood 2001; 97: 2998–30037. Rozenberg S, Roche B, Dorent R et al. Urate-oxidase forthe treatment of tophaceous gout in heart transplant recipients.A report of three cases. Rev Rhum Engl Ed 1995; 62: 392–3948. Phillips M, Hunt RE, Shergy WJ, Hernandez J. Urate-oxidasein the treatment of severe tophaceous gout with hyperuricemiaerfractory to high-dose allopurinol: case report and review.Artritis Rheumatol 2000; 43: S401 [Abstract]9. Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A,Schreiber MJ. Pathophysiology, clinical consequences, andtreatment of tumor lysis syndrome.Am JMed 2004; 116: 546–55410. Bayol A, Capdevielle J, Malazzi P et al. Modiﬁcation of areactive cysteine explains differences between rasburicase andUricozyme, a natural Aspergillus ﬂavus uricase. Biotechnol ApplBiochem 2002; 36: 21–3111. Snaith ML. Gout: diet and uric acid revisited. Lancet 2001;358: 52512. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity.Description and guidelines for prevention in patients with renalinsufﬁciency. Am J Med 1984; 76: 47–56Received for publication: 16.8.04Accepted in revised form: 12.11.04bFig. 3. Left and right hand from the 33-year-old female patient after12 months of therapy with the urate oxidase rasburicase.aUrate oxidase and gout 433

Urate oxidase (rasburicase) for treatment of severe tophaceous gout

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