Patients on cyclosporin A (CsA) often develop hyperuricaemia and gout. In transplant patients the use of uricosuric drugs for treating hyperuricaemia may be preferable to allopurinol because of the known interaction of the latter with azathioprine. We therefore prospectively studied the uricosuric efficacy of 100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treated renal transplant patients with stable graft function and hyperuricaemia (>359 μmol/l for females, >491 μmol/l for males). Benzbromarone decreased plasma uric acid from 579±18 μmol/l to 313±24 μmol/l (mean±SEM; P25 ml/min. Due to its excellent efficacy and lack of significant side-effects, benzbromarone appears to be preferable to allopurinol in CsA-treated renal transplant recipients with a creati nine clearance over 25 ml/mi

Bock, H. A.

Thiel, G.

Zürcher, R. M.

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Nephrol Dial Transplant (1994) 9: 548-551Original ArticleNephroloqyDialysisTransplantationExcellent uricosuric efficacy of benzbromarone in cyclosporin-A-treatedrenal transplant patients: a prospective studyR. M. Ztlrcher, H. A. Bock, G. ThielDivision of Nephrology, Department of Medicine, University Hospital Basel, SwitzerlandAbstract. Patients on cyclosporin A (CsA) oftendevelop hyperuricaemia and gout. In transplantpatients the use of uricosuric drugs for treating hyperu-ricaemia may be preferable to allopurinol because ofthe known interaction of the latter with azathioprine.We therefore prospectively studied the uricosuric effi-cacy of 100 mg benzbromarone (Bbr;Desuric®) dailyin 25 CsA-treated renal transplant patients with stablegraft function and hyperuricaemia (> 359 umol/1 forfemales, >491 umol/1 for males).Benzbromarone decreased plasma uric acid from579± 18 umol/1 to 313±24 umol/1 (mean + SEM; P<0.001) and thereby normalized plasma uric acid in 21of 25 patients. The remaining four patients had creatin-ine clearances between 21 and 25 ml/min, the lowestof the entire study group. Mean fractional clearanceof uric acid increased from 5.4 ±0.4% to 17.2 ±1.0%(i><0.001). The relative decrease of plasma uric acidclosely correlated with baseline creatinine clearance(r = 0.67; P<0.001). CsA trough values were not influ-enced. None of the patients experienced any significantside-effects. As an unexpected find-ing, urinary uricacid excretion increased from 2082+ 175 umol/24 h to3233 ±232 umol/24 h after 4 weeks' treatment withbenzbromarone.In conclusion, benzbromarone normalized plasmauric acid in all CsA-treated renal transplant recipientswith a creatinine clearance > 25 ml/min. Due to itsexcellent efficacy and lack of significant side-effects,benzbromarone appears to be preferable to allopurinolin CsA-treated renal transplant recipients with a creati-nine clearance over 25 ml/min.Key words: cyclosporin A; kidney transplant; hyperur-icaemia; uric acid excretion; benzbromarone; uricos-uric efficacyIntroductionTransplant patients on cyclosporin A (CsA) have agreater prevalence of hyperuricaemia than patients onCorrespondence and offprint requests to: Regula Zurcher MD,Department of Internal Medicine, HCUG, CH-12U Geneve 14,Switzerlandconventional immunosuppression [1]. Asymptomatichyperuricaemia occurs in up to 80% of patients, goutin 5-24% of patients [2,3]. A substantial number ofpatients therefore need treatment for hyperuricaemia.Since hyperuricaemia in these patients is mainly dueto reduced renal uric acid clearance and not toincreased uric acid production [3], increasing uric acidelimination via the kidney is a sensible approach.Moreover the interaction of allopurinol with azathio-prine, which can lead to life-threatening leukopenia,militates against the use of allopurinol in patients oncombined immunosuppression with CsA and azathio-prine. Since the efficacy of uricosuric drugs has neverbeen formally evaluated in CsA-treated renal trans-plant patients, we undertook a prospective study toanswer the following questions: does the uricosuricdrug benzbromarone effectively lower plasma uric acidin CsA-treated renal transplant patients? Is there alower limit of graft function for the uricosuric effect?Does benzbromarone cause any significant drug inter-action or side-effects in these patients?Subjects and methodsTwenty-five consecutive CsA-treated renal transplant patients(10 females, 15 males) with stable graft function and hyperur-icaemia were studied prospectively after giving writteninformed consent. Inclusion criteria were: (1) CsA therapywith (n = 14) or without (n = 11) azathioprine and/or prednis-one, (2) hyperuricaemia (>359|imol/l for females,>491 |imol/l for males), (3) stable graft function. Exclusioncriteria were: (1) current treatment with any uricosuric drugor allopurinol, (2) unstable graft function, (3) known poorcompliance. Two patients in the study group had a historyof gout. After baseline measurements, the patients received100 mg of benzbromarone daily for 4 weeks in addition totheir established medication. No specific prescriptions regard-ing minimal fluid intake or urine alkalinization were given.Patients were asked for side-effects at 1 and 4 weeks oftreatment. The following laboratory tests were performed atthe beginning and at the end of the study: whole bloodchemistry profile; platelet, red and white blood cell count;CsA blood trough levels; 24-h urine excretion of creatinine,urea, uric acid, protein, and calcium; microscopic examina-tion of urine sediment. In addition the same examinations© 1994 European Dialysis and Transplant Association-European Renal AssociationUricosuric efficacy of benzbromaroneexcept 24-h urine analysis were performed after 1 week oftreatment to detect early signs of toxicity or drug interaction.Laboratory methodsUric acid concentrations in plasma and urine were measuredusing a uncase method (Hitachi 737, Boehringer Mannheim),plasma and urine creatinine concentrations by a creatininaseassay (Wako Chemicals GmbH, Neuss; Hitachi 737,Boehringer Mannheim). CsA whole blood 12 h trough valueswere measured with a TDx-FPIA-method (Abbott TDxcyclosporin monoclonal).Statistical analysisStatistical evaluation was performed using Student's pairedt test. Correlations were evaluated using linear least squaresregression; /><0.05 was considered significant and two-sidedtests were used throughout. Data are given as mean ± SEM.ResultsPlasma creatinine of the study patients ranged between82 umol/1 and 276 umol/1, creatinine clearance between21 and 78 ml/min. Graft function remained stablethroughout the study period (Table 1).Benzbromarone significantly decreased mean plasmauric acid from 579± 18 umol/1 to 313 ±24 umol/1(P< 0.001; Table 1). Fall of plasma uric acid was rapidand sustained in all but two patients (Figure 1), andthere was no significant change beyond the first weekfor the group as a whole. For 21 of 25 patients thisdecrease meant normalization of plasma uric acid.Fractional uric acid clearance increased from5.4±0.4% to 17.2 + 1.0% (/><0.001; Table 1). Therewas a good correlation between the percent decreaseof plasma uric acid and both plasma creatinine (r =-0.68; P< 0.001; Figure 2) and creatinine clearance(r = 0.67; P<0.001; Figure 3). Similarly, the increaseof fractional uric acid clearance correlated well withcreatinine (r=-0.54; P< 0.005) and creatinine clear-ance (r = 0.58; P<0.005). The four patients in whomnormalization of plasma uric acid was not achievedhad creatinine clearances between 21 and 25 ml/min,the lowest of the whole study group.While 24-h urinary creatinine excretion remainedunchanged (9885 ±2540 umol/24 h versus 9971 ±2377Table 1. Results549CCR (ml/min)P-UA (umol/1)fCUA (%)UVUA (umol/24 h)UVCreat (umol/24 h)CsA trough level (ug/1)Before Bbr49 ±4579±185.4 ±0.42082 ±1759885 ±2541162±801 week Bbr281 ±20*"4 weeks Bbr47 ±4313±24*«*17.2±1.0*"3233 ±232**9971 ±2377162 ±72Data are given as mean±SEM; **P<0.01; ***/><0.001.Creatinine clearance (CCR), plasma uric acid (P-UA), fractionalclearance of uric acid (fCUA), urinary excretion of uric acid(UVUA), urinary excretion of creatinine (UVCreat).Plasma uric addpmol/l800600400200Begin Bbr0 1 2 3 4Study weeksFig. 1. Plasma uric (umol/1) acid before, during, and at the end ofbenzbromarone (Bbr) treatment.% decrease ofplasma uric add80%,60%40%20% r = -0.68p<0.00160 100 160 200 260Plasma creatinJna, pmol/l300Fig. 2. Relative decrease (in percent of initial values) of plasma uricacid in function of plasma creatinine.umol/24 h), urinary uric acid excretion was signific-antly increased at the end of the 4 weeks treatment(2082 +175 umol/24 h before Bbr, 3233 + 232umol/24 h after 4 weeks of Bbr, P< 0.001). Only twopatients' uric acid excretion, however, was in thehyperuricosuric (> 4800 umol/24 h) range, namely4862 umol/24 h and 7105 umol/24 h. Microscopicevaluation of urine sediment revealed no pathologicalmicrohaematuria nor crystalluria during treatment.There were no changes of CsA trough levels (162 ± 80before versus 162 ± 72 ug/1 after Bbr) and no signs oftoxicity in the haematological or in the blood chemistryprofile. Except for one patient with known irritablecolon who reported increased diarrhoea, no side-effects550% decrease ofplasma uric acid60%40%20%0%••1•• |••••• ••• ™ •r = 0.67p<0.00120 40 60 80Creatinine clearance, ml/mtn100Fig. 3. Relative decrease (in percent of initial values) of plasma uricacid in function of creatinine clearance.were noted. There were no episodes of gout or anyevidence of urolithiasis.DiscussionThe efficacy of uricosuric drugs, well-documented ingouty, non-transplant patients [4], has not been form-ally evaluated in CsA-treated renal transplant patientsso far. The use of uricosurics in these patients couldbe questioned because (a) reduced GFR [5,6] and (b)impaired tubular handling of uric acid due to CsA-induced proximal tubular dysfunction [7-11] couldpotentially impair their effect. The present data, how-ever, demonstrate an excellent efficacy of benzbroma-rone in lowering plasma uric acid within 1 week in allpatients with a creatinine clearance > 25 ml/min. Evenin the four patients with a creatinine clearance< 25 ml/min there was still a moderate effect at 1 week(fall of plasma uric acid 17-41%). The fact that thiseffect was not sustained in two of these patients, maybe due to non-compliance. Similar results have beenreported in non-transplant patients with comparablerenal function [6,12,13] as well as in a group of renaltransplant patients on conventional immunosuppres-sion [14]. There is therefore no evidence for impaireduricosuric efficacy of benzbromarone in CsA-treatedrenal transplant patients. That benzbromarone is lesseffective in patients with low creatinine clearances mostprobably reflects diminished postsecretory reabsorp-tion in the renal tubule such as occurs with increasingrenal failure [15,16]. Postsectretory reabsorption is thepresumptive site of action of uricosuric drugs [17].The 50% increase of urinary uric acid excretion(Table 1) after 4 weeks of benzbromarone representsan interesting, albeit unanticipated finding. Ourexpectation was that despite the increment in clearance,urinary excretion of uric acid would return to baselineR. M. Zurchere/a/.by reaching a new steady state after 4 weeks' treatmentwith benzbromarone. Two possible mechanisms maybe considered: either steady state conditions were notyet achieved because some of the patients were stillmobilizing uric acid from soft tissue microdeposits, orextrarenal (mainly intestinal) uric acid excretion mighthave decreased with decreasing plasma uric acid [18,19]and therefore a higher percentage of daily uric acidload was excreted via the kidney. Still, true hyperurico-suria (>4500 umol/24 h for females, >4800 umol/24 hfor men) occurred in only two patients. Microscopicanalysis of urine sediment never gave any evidence ofincreased crystalluria or haematuria. Since intratubularflow in the distal nephron of renal transplant patients(having only one functioning kidney) is greater thanin normals, their risk of stone formation is probablylower at any degree of uric acid excretion. Of course,a larger and longer study would be required to ascertainthat this risk is indeed not increased. In our personalexperience, following 12 renal transplant patients forat least 1.5 years (median 4 years, range 1.5-6 years),we never observed any stone formation.We conclude that benzbromarone is an efficaciousand safe drug for treating hyperuricaemia in CsA-treated renal transplant patients with a creatinine clear-ance over 25 ml/min. In patients with creatinineclearances below 25 ml/min or plasma creatinine overapproximately 250 umol/1, allopurinol probablyremains the preferred drug. Either treatment, however,should be given to symptomatic patients only.References1. European Multicenter Trial Group. Cyclosporin in cadavericrenal transplantation: one-year follow-up of a multicentre trial.Lancet 1983; 2: 986-9892. Noordzij TC, Leunissen KML, van Hooff JP. Renal handlingof urate and the incidence of gouty arthritis during cyclosporineand diuretic use. Transplantation 1991; 52: 64-673. Lin HY, Rocher LL, Me Quillan MA el al. Cyclosporine-induced hyperuricemia and gout. NEJM 1989; 321: 287-2924. Zollner W, Grobner W, Grosser U. Purinstoffwechsel,Unkosurika, Urikostatika. Pharmakotherapie der Gicht. In:Forth W, Henschler D, Rummel W et al, eds. Allgemeine undspezielle Pharmakologie und Toxikologie. Wissenschaftsverlag,Mannheim; 1992: 495-5025. Mertz DP. Veranderungen der Serumkonzentration vonHarnsflure unter der Wirkung von Benzbromaron. MMW 1969;9: 491-4956. Begemann H, Neu I. Die Behandlung der Urikopathie mitBenzbromaron unter besonderer Berucksichtigung derNiereninsuffizienz. Therapiewoche 1975; 25: 2184-21927. Versluis DJ, Wenting GJ, Jeekel J et al. Cyclosporin A-relatedproximal tubular dysfunction: impaired handling of uric acid.Transplant Proc 1987; 19: 4029-40308. Tiller DJ, Hall BM, Horvarth JS et al. Gout and hyperuricaemiain patients on cyclosporin A and diuretics. Lancet 1: 1985; 4539. Cohen SL, Boner G, Rosenfeld JB et al. The mechanism ofhyperuricemia in cyclopsorin-treated renal transplant recipients.Transplant Proc 1987; 19: 1829-183010. Noordzij TC, Leunissen KML, van HoofT JP. letter. NEJM1990; 322: 33511. Chapman JR, Harding NGL, Griffiths D. Reversibility of cyclo-sporin nephrotoxicity after three months' treatment. Lancet 1:1985; 128-12912. KOthe E, BOttner C, Quellhorst E et al. Behandlung derUricosuric efficacy of benzbromaroneHyperurikamie bei Niereninsuffizienz mit Benzbromaron.Therapiewoche 1973; 23: 2927-293313. Charbonnet F, Rossier J. La benzbromarone dans le traitementde lTiyperuricemie. Schweiz Rundsch Med Prax 1973; 44:1337-134414. Flury W, Ruch HR, Montandon A. Zur Behandlung derHyperurikamie nach Nierentransplantation. Schweiz MedWochenschr 1977; 107: 1339-134115. Garryfallos A, Maoula I, Tsapas G. Evaluation of the renalmechanism for urate homeostasis in uremic patients by probene-cid and pyrazinamide test. Nephron 1987; 46: 273-28055116. Steele TH, Rieselbach RE. The contribution of residual nephronswithin the chronically diseased kidney to urate homeostasis inman. Am J Med 1967; 43: 876-88617. Fox IH, Sinclair DS. The pharmacology of the hypouricemkeffect of benzbromarone. Adv Exp Med Biol 1977; 76B: 328-33318. Sorensen SB. Extrarenal disposal of uric acid. In: Kelley WN,Weiner IM, eds. Uric Acid. Springer Verlag, Berlin; 1978:325-33619. Vaziri ND, Freel RW, Hatch M. Enhanced enteric excretion ofurate in chronic renal failure in rats. JASN; 1992; 3: 753(Abstract)Received for publication 15.3.93Accepted in revised form 14.9.93

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

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