195 J I M D C 2 0 1 8 195 Open Access F u l l L e n g t h A r t i c l e Effects of Febuxostat in the Progression of Chronic Kidney Disease in Renal Transplant Recipients Muhammad Aqeel1, Syed Sohail Tanvir2, Mariam Masud3 1 Assistant Professor, 2 Associate Professor, 3 Assistant Professor Department of Nephrology, Pakistan Institute of Medical Sciences A B S T R A C T Objective: To see the effect of febuxostat in slowing the progression that treatment with febuxostat improves eGFR in renal transplant recipients having asymptomatic hyperuricemia. Patients and Methods: This randomized controlled trial was carried out in a Department of Nephrology PIMS. A total of 106 post renal transplants recipients having asymptomatic hyperuricemia, were randomly divided into two groups of 53 each by lottery method. One group was given febuxostat for treatment of post renal transplant hyperuricemia while the other one was given a placebo. Results: The mean age of patients was 48.15 years with a male to female ratio 4.6:1. Treatment with febuxostat was linked significantly in lowering the mean uric acid level at 7.01mg/dl, 6.32mg/dl and 5.42mg/dl at 2, 4 and 6 months, respectively, and renal function was better preserved in the patients receiving febuxostat at mean eGFR of 49.74, 48.96 & 48.89 ml/min/1.73m 2 at 2, 4 and 6 months, respectively. Conclusion: In patients with postrenal transplant asymptomatic hyperuricemia, febuxostat showed significant reduction in serum uric acid level with preservation of renal function. Key words: Asymptomatic Hyperuricemia, eGFR, Febuxostat, Renal graft dysfunction, Renal transplant Author`s Contribution 1 Conception, synthesis, planning of research and manuscript writing Interpretation and discussion 2,3 Data analysis, interpretation and manuscript writing, Active participation in data collection. Address of Correspondence Mariam Masud Email: drmariam.masud@gmail.com Article info. Received: August 20, 2018 Accepted: September 10, 2018 Cite this article. Aqeel M, Tanvir S.S, Masud M. Effect of Febuxostat in progression of Chronic Kidney Disease in Renal Transplant Recipents. JIMDC.2018; 7(3):195-198 Funding Source: Nil Conflict of Interest: Nil I n t r o d u c t i o n Uric acid is a weak Acid Trioxypurine, comprising of imidazole and pyrimidine substructure with molecules of oxygen. It is made from metabolic conversion of either endogenous or dietary purines mainly in intestines, muscles and liver 1. Xanthine is the predecessor of uric acid which is metabolized into uric acid by the enzyme xanthine oxidoreductase i.e., xanthine-oxidase or xanthine dehydrogenase.2 Uric acid is mainly excreted by kidneys approx. 250-750 mg/day, which is about 70% of daily urate production.3 Post renal transplant hyperuricemia is defined as serum uric acid level >7.0mg/dl in men and >6.0mg/dl in women, having renal transplantation.4 Identification of new risk factors help in improvement of long-term outcomes. Numerous factors predisposing renal transplant recipients to hyperuricemia were reported, including treatment with diuretics, insufficient allograft function and immunosuppression with cyclosporine.5 Asymptomatic hyperuricemia is a risk factor for cardiovascular disease and for the onset and progression of chronic kidney disease in general population.6,7 Chung et al investigated whether early-onset hyperuricemia has clinical importance irrespective of graft function.8 Post renal transplant hyperuricemia is linked with the onset of O R I G I N A L A R T I C L E 196 J I M D C 2 0 1 8 196 cardiovascular disease and allograft loss in renal transplant recipients.9,10 Numerous studies have been done in kidney transplant recipients to assess the role of hyperuricemia in decreased renal function, but there has been a controversy in the results. The commonly used hypouricemic agents used in general population are Allopurinol and Benzbromarone but both of them cannot be used in post renal transplant hyperuricemia because of toxicity of the former and reduced hypouricemic effect due to chronic renal insufficiency and renal transplantation in the latter.11 Febuxostat is a non-purine selective inhibitor of xanthine oxidase and is better tolerated in patients with gout and/or moderate renal dysfunction.12,13 Metabolism of Febuxostat is mainly done by glucuronide formation and oxidation in the liver.14 However, the assessment of efficacy of febuxostat in kidney transplant recipients with asymptomatic hyperuricemia has not been done in local population so far. *Chi-square test and independent sample t-test, observed difference was statistically insignificant P a t i e n t s a n d M e t h o d s It is a prospective randomized controlled trial conducted in Department of Nephrology, Pakistan Institute of Medical Sciences, Islamabad, Pakistan over 6 months i.e., from 18th September 2017 to 17th March, 2018. Sample size was calculated using WHO sample size calculator. In total 106 patients (87 males and 19 females), selected by non- probability, consecutive sampling, were enrolled, and after informed consent were divided into 2 groups of 53 each, using lottery method. All renal transplant recipients with age from 20-60 years in PIMS nephrology OPD or ward, 3 months’ post-transplantation with asymptomatic hyperuricemia, males having serum uric acid of >7.0 mg/dl and females having serum uric acid level > 6mg/dl, eGFR > 35ml/min/1.73m 2, patients with cyclosporine levels in therapeutic range and, no previous history of gout. Group A was given febuxostat with adjusted dose according to individual eGFR of the participant using MDRD study equation. Group B was given placebo. Determination of serum uric acid levels and eGFR was done in both the groups at 2, 4 and 6 months and then both serum uric acid levels and eGFR were compared in both the groups at 2, 4 and 6 months. Nephrotoxic drugs were avoided in this time period. Patients with malignancy, hypersensitivity to febuxostat, already on any of the following drugs; probenicid, benzbromarone, fenofibrate, diuretics or azathioprine, patients having ALT and AST more than twice the upper limit of laboratory reference range, pregnancy and patients non-compliant to protein diet. R e s u l t s The mean age of the patients was 48.15±8.61 years, having 87 (82.1%) males and 19 (17.9%) female patients, with a male is to female ratio of 4.6:1. Demographic characteristic are presented in (Table 1). Treatment with febuxostat was linked with significant lowering of mean serum uric acid level at 2 months (7.01±0.35 mg/dl vs 8.69±0.74 mg/dl; p < 0.001), at 4 months (6.32 ±0.33 mg/dl vs 8.78 ± 0.78 mg/dl; p < 0.001) and at 6 months (5.42 ± 0.28 mg/dl vs 8.58 ± 0.72 mg/dl; p<0.001). It preserved renal function, which was evident from significantly higher mean eGFR with febuxostat at 2 months (49.74 ± 4.67 ml/min/1.73m2 vs 47.34 ± 5.10 ml/min/1.73m2; p<0.013), at 4 months (48.96 ± 4.88 ml/min/1.73m2 vs 43.00 ±5.43 ml/min/1.73m2; p < 0.001) and at 6 months (48.89 ± 4.72 ml/min/1.73m2 vs 40.92 ± 4.99 ml/min/1.73m2; p < 0.001) as compared with placebo (Table 2). Table 1: Baseline and Demographic Characteristics of Study Groups (n=106) Characteristics Group A Febuxostat (n=53) Group B Placebo (n=53) P value Age (years) 48.38 ±8.61 47.92 ±8.70 0.788 <45 years 22 (41.5%) 23 (43.4%) 0.844 ≥45 years 31 (58.5%) 30 (56.6%) 0.844 Gender Male 43 (81.1%) 44 (83.0%) 0.800 Female 10 (18.9%) 9 (17.0%) 0.800 Weight (Kg) 98.66 ±12.56 97.91 ±11.79 0.750 Serum creatinine (mg/dl) 1.84 ±0.27 1.85 ±0.35 0.912 eGFR using MDRD equation (ml/min/1.73m2) 50.38 ±5.23 50.13 ±5.10 0.807 Serum Uric Acid (mg/dl) 8.83 ±0.71 8.80 ±0.70 0.812 197 J I M D C 2 0 1 8 197 Table 2: Comparison of Various Laboratory Parameters between the Groups over 2, 4 and 6 Months Follow- up (n=106) Lab Parameter Characteristic 0 2 months 4 months 6 months P value Serum creatinine(mg/dl) Febuxostat 1.84±0.27 1.87±0.28 1.88±0.32 1.91±0.29 0.487 Placebo 1.85±0.35 1.99±0.35 2.05±0.30 2.25±0.38 0.006* P value 0.912 0.070 0.005* <0.001* eGFR (ml/min/1.73m2) Febuxostat 50.38±5.23 49.74±4.67 48.96±4.88 48.89±4.72 0.788 Placebo 50.13±5.10 47.34±5.10 43.00±5.43 40.92±4.99 0.028* P value 0.807 0.013* <0.001* <0.001* Serum Uric Acid (mg/dl) Febuxostat 8.83±0.71 7.01±0.35 6.32±0.33 5.42±0.28 <0.001* Placebo 8.80±0.70 8.69±0.74 8.78±0.78 8.58±0.72 0.207 P value 0.812 <0.001* <0.001* <0.001* Independent sample t-test, *observed difference was statistically significant D i s c u s s i o n In order to improve long-term outcomes of kidney transplantation, new risk factors are required to be recognized that result in poor outcomes.5 Post- transplant hyperuricemia occurs in renal transplant recipients.4 Uric acid lowering drugs help to control serum uric acid levels and improve graft function.14-17 However, the available evidence contains controversy. Moreover, there was no such local published data available that triggered the need for this study. We observed that in patients on febuxostat, serum creatinine level gradually increased over 6 months but the difference was statistically insignificant. Our results are comparable to those of Tojimbara et al, who also reported similar insignificant difference in mean serum creatinine in renal transplant patients with asymptomatic hyperuricemia on febuxostat treatment over 3 to 6 months’ interval from baseline.14 Oh et al also reported similar insignificant rise in creatinine in such patients over 6 months.16 eGFR decline in our study was also statistically insignificant. However, in present study, we found that treatment with febuxostat in post renal transplant recipients lead to significant reduction in serum uric acid level over 2, 4 and 6 months’ follow-up from baseline, (8.83±0.71 mg/dl vs. 7.01 ±0.35 mg/dl vs. 6.32 ±0.33 mg/dl vs. 5.42 ±0.28 mg/dl; p<0.001). Our observations are in line with Tojimbara et al, who also observed similar decline in serum uric acid levels in patients with post renal transplant hyperuricemia recipients treated with febuxostat over 3 and 6 months (8.0 ±0.8 vs. 6.3 ±0.9 vs. 5.7 ±0.7 mg/dl).14 Similar reduction in mean serum uric acid level has been reported by Sofue et al (8.4 0.3 vs. 6.2 0.3 vs. 6.4 0.3 vs 6.2 0.3 mg/dl; p<0.05) after 1, 3 and 6 months of treatment.15 C o n c l u s i o n The present study indicates that patients with asymptomatic hyperuricemia after 3 months of renal transplantation, febuxostat treatment was linked with significant decrease in serum uric acid level with preservation of renal function evident from insignificant difference in the mean eGFR. The present study is the first of its kind in local population and advocates the routine use of febuxostat in hyperuricemic post renal- transplant recipients. A very strong limitation to the present study was limited follow-up of 6 months. Consequently, long term results of febuxostat treatment on serum uric acid and kidney function were not considered. Studies involving long term follow-up are recommended in future research. R e f e r e n c e s 1. Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda) 2005;20(2):125-33. 198 J I M D C 2 0 1 8 198 2. Schlesinger N. Dietary factor and hyperuricemia. Curr Pharm Des 2005;11(32):4133-8. 3. Maesaka JK, Fishbane s. Regulation of renal urate excretion: a critical review. Am J Kidney Dis 1998;32(6):917-33. 4. Haririan A, Metireddy M, Cangro C. Association of serum uric acid graft survival after kidney transplantation: A time varying analysis. Am J Transplant 2011; 11(9):1943- 50. 5. Bahn A, Hagos Y, Reuter S. Identification of new urate and high affinity nicotinate transporter, Hoat10 (SCL22A13). J Biol Chem 2008; 283(24):16332-41. 6. Goicoechea M, de Vinuesa SG, Verdalles U. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5(8):1388-93. 7. Miao et al. Effect of reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension 2011; 58(1):2-7. 8. Chung BH, Kang SH, Hwang HS. Clinical significance of early onset hyperuricemia in renal transplant recipients. Nephron Clin Pract 2011;117(3):276-83. 9. Numakura K, Satoh S, Tsuchiya N. Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. Transplantation 2012;94(2):145- 51. 10. Huang Y et al. Effects of hyperuricemia on renal function of renal transplant recipients: A systematic review and meta-analysis of cohort studies. PLoS One 2012;7(6):e39457. 11. Day RO et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet 2007; 46(8): 623-44. 12. UloricR Full Prescribing information. Deerfield, IL, USA: Takeda Pharmaceuticals North America, Inc,; 2009. 13. Becker MA, Schumacher HR, Espinoza LR. The urate- lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12(2):R63. 14. Tojimbara, Nakajima, Yashima. Efficacy and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in kidney transplant recipients. Transplant Proc 2014; 46(2):511-3. 15. Sofue et al. Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients. Drug Des Devel Ther 2014;8:245-53. 16. Oh J et al. Safety and efficacy of febuxostat in advanced CKD patients with hyperuricemia. Br Med J 2017; 76(2): THU0467. 17. Nagaruju SP, Attur RP. Effect of febuxostat verses allopurinol on hyperuricemia and progression of chronic kidney disease. Nephrol Dial Transplant 2017; 32(3):205- 6.