ENDOUROLOGY AND STONE DISEASE Febuxostat Promoted Dissolution of Radiolucent Nephrolithiasis in Patients with Hyperuricemia Mao Yunhua1, Zhang Hao1, Li Ke1, Huang Wentao1, Li Xiaokang1, Situ Jie1* Purpose: This study aimed to investigate the efficacy and safety of febuxostat in patients with radiolucent neph- rolithiasis. Materials and Methods: From March 2016 to June 2018, data of 96 patients with radiolucent nephrolithiasis and hyperuricemia who referred to the Third Affiliated Hospital of Sun Yat-sen University were retrospectively ana- lyzed. These patients were divided into allopurinol 300mg/d (control), febuxostat 40mg/d (F40) and 80mg/d (F80) groups respectively. All patients took potassium citrate as a combination treatment and had been followed up for at least 6 months. Before treatment and on after 1st, 3rd and 6th month, complete blood count, serum uric acid (sUA), hepatic and renal function as well as ultrasound were carried out. Arthritic and gastrointestinal symptoms were also monitored. Computed tomography was performed before treatment and 6 months after medication. Results: Compared with allopurinol group, F40 group showed no difference in urate-lowering effect, while F80 had the best effect across all the visits (P<0.01). At 6th month, 25(83.3%) cases of F80 group achieved sUA<6mg/ dL, which was better than allopurinol group (18 cases, 58.1%) and F40 group (17 cases, 58.6%). In the dissolution effect of radiolucent calculi, F80 had the best effect, followed by F40 and then allopurinol (P<0.05). No statistical difference was observed in adverse events among three groups. Conclusion: Febuxostat significantly decreased sUA, promoted radiolucent stone dissolution and reduced the total stone number, whereas it did not increase the adverse events. Keywords: Nephrolithiasis; hyperuricemia; febuxostat; allopurinol INTRODUCTION Uric acid (UA) is the end chemical product of pu-rine degradation in human. Since approximately 2/3 of uric acid passes out in urine, hyperuricemia usu- ally cause high concentration of UA in the urine, which is called hyperuricosuria. When urine is supersaturated with undissolved UA, UA stones which are radiolucent form subsequently. Studies also demonstrated that hy- peruricosuria promotes not only the UA stones but also the calcium oxalate stones(1-3). It was reported that up to 10-15% of urinary stones and most of the radiolucent stones are UA stones(4-6). Thus, lowering the serum UA (sUA) is an important intervention for nephrolithiasis treatment. The two main approaches to lowering sUA are pro- moting the excretion and inhibiting the production(6,7). Drugs promoting UA excretion, such as benzbromar- one, usually exacerbate UA stones, for which reason they are contraindicated for patients with hyperurice- mia and nephrolithiasis. Xanthine oxidase inhibitors, such as allopurinol and febuxostat, remarkably decrease hyperuricemia and hyperuricosuria and are beneficial in the treatment of UA stones(8). Although the efficacy of febuxostat has been examined in primary gout, there are still no reports concerning the efficacy and safety of febuxostat as well as its advantages over allopurinol in radiolucent nephrolithiasis(9). Herein, this study pre- Department of Urology, the 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. *Correspondence: Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University, No.600, Tianhe Road, Guangzhou, China, 510630. Phone: +86-20-85252660. Fax: +86-20-85252678. Email: situjie_sysu@126.com. Received September 2019 & Accepted February 2020 sents results about the efficacy and safety of febuxostat in radiolucent nephrolithiasis based on single-center retrospective study. PATIENTS AND METHODS Study population This single-center retrospective study was approved by the institutional ethics committee of 3rd Affiliated Hos- pital of Sun Yat-sen University. All patients had signed informed consents for using related information. From March 2016 to June 2018, patients with nephrolithia- sis who were referred to the 3rd Affiliated Hospital of Sun Yat-sen University were screened. Patients with radio-lucent nephrolithiasis and hyperuricemia which was defined as serum uric acid (sUA) greater than 8mg/ dL were further selected based on inclusion and exclu- sion criteria for final analysis. The inclusion criteria are:1)18-70 years old, sUA>8m/ dL, BMI<30kg/m2;2) ultrasound and CTU confirmed renal stones<2.5cm, stones were radiolucent in KUB, absence of ureteral or bladder stones or hydronephro- sis or other congenital abnormalities; 3) serum cre- atine<130umol/L; 4) receiving single urate-lowering drug (allopurinol or febuxostat) and administration with potassium citrate as a combination treatment. Based on their medication, the selected patients were divided into three groups of allopurinol 300mg/d (100mg tid, con- Urology Journal/Vol 18 No. 1/ January-February 2021/ pp. 34-39. [DOI: 10.22037/uj.v0i0.5564] Vol 18 No 1 January-February 2021 35 trol group), febuxostat 40mg/d (40mg qd, F40 group) and 80mg/d (40mg bid, F80 group). Patients were excluded when their baseline data met exclusion criteria. Exclusion criteria were:1) second- ary hyperuricemia; 2) under gout attack or frequent gout attacks;3) liver dysfunction, AST/ALT>2 upper normal limit;4) white blood cells<4.0×109/L, hemo- globin<100 mg/dL, platelets< 100×109/L;5) receiving other urate-lowering agents or receiving ;2 kinds of urate-lowering agents; 6) using glucocorticoids, immu- noimpressive agents, thiazine diuretics or other drugs that interfere with sUA; 7) a history of alcohol or drug abuse; 8) other severe or progressive diseases including cancer, heart diseases and chronic or severe infection, gastrointestinal, endocrine, pulmonary, cardiac, neuro- logical, or cerebral diseases. 9) pregnant or breastfeed- ing woman. Data Extraction and Evaluations Regularly, patients with hyperuricemia who referred to our clinics were advised to drink enough water and maintain urine volume excessing 2000ml per day. Low purine intake was also recommended. The day before treatment and the day at 1,3,6 months after treatment, blood routine test, sUA, liver/kidney functions were de- termined. Ultrasound was performed on the day before treatment and the day at 1, 3, 6 months after treatment, while computed tomography (CTU) was performed on Febuxostat in radiolucent nephrolithiasis-Yunhua et al. Table 1. Baseline data of selected patients Allopurinol 300mg/d Febuxostat 40mg/d Febuxostat 80mg/d P Patients number, n 34 30 32 - Age,median (range),years 45(23-69) 47(26-74) 48(25-76) 0.365a Gender,n(%) Male 18(52.9) 14(46.7) 17(53.1) 0.903b Female 16(47.1) 16(53.3) 15(46.9) BMI, kg/m2 23.3 ± 3.12 22.5±2.89 23.50±3.07 0.542c Gouty tophi,n(%) 5(16.1) 3(10.0) 4(12.5) 0.718d Baseline UA, median(range), mg/dL 9.72(8.1-13.6) 9.83(8.1-13.8) 9.92(8.1-14.2) 0.487 AST, mean±SD, U/L 25.56 ± 5.17 26.91 ± 4.88 24.77 ± 5.02 0.762 ALT, mean±SD, U/L 22.34 ± 5.34 24.98 ± 4.67 23.68 ± 4.89 0.469 Cr, mean±SD, umol/L 65.12 ± 9.24 68.34 ± 8.55 69.38 ± 10.12 0.387 a, Cruskal-Wallis test. b, χ2 test. c, ANOVA test. d, Fisher exact test. Abbreviations: BMI: body max index. UA: uric acid. AST: aspartate transaminase. ALT: Alanine aminotransferase. CR: Creatine. Figure 1. Flowchart of patients through the study. AEs, adverse events. the day before treatment and the day at 6 months after treatment. Hypersensitivity, gastrointestinal and cardi- ac symptoms, arthralgia, and gout flares were recorded. Patients who did not have complete data were excluded, but those who discontinued medication due to severe adverse events still remained in adverse events analy- sis so as not to underestimate the incidence of adverse events. End points: 1) the change in sUA; 2) stones changes, including the maximum diameter and stone numbers; 3) adverse events. Patients whose maximum stone diame- ter decreased by >50% or the numbers of stones with diameter>5mm decreased were regarded as significant- ly effective cases. Statistical analysis Category variables were presented as frequencies or percent, statistical differences between groups were analyzed with χ2 test or Fisher exact test. Continuous variables were presented as mean ± standard deviation (SD) or s median (range), statistical differences among three groups were analyzed using Kruskal-Wallis test or ANOVA test, and statistical differences between two groups were performed using students’t test or Mann– Whitney U test. Pairwise comparisons were performed to analyze the changes of sUA levels, stones diameters, and numbers in each group before and after treatment. Two tailed P < 0.05 indicated statistical significance. RESULTS Patients’ characteristics In this study, a total of 96 patients were selected for final analysis, including 34, 30 and 32 cases for allopurinol group, F40 group and F80 group respectively. Howev- er, there were 3,1 and 2 patients who didn’t complete medication for at least 6 months due to severe adverse events (Figure 1). Therefore, these patients were not included in the final efficacy analysis of serum uric acid (sUA) changes and stones changes, but still remained in adverse events analysis so as not to underestimate the incidence of adverse events. For all the eligible patients, the median (range) of age was 46 (23-76) years old, the median (range) sUA level was 9.87 (8.1-14.2) mg/dL, and gouty tophi were found in 12 patients. Baseline data for each group were shown in Table 1. Serum uric acid (sUA) change There were 31, 29 and 30 cases for allopurinol group, F40 group and F80 group respectively in the efficacy analysis of sUA change. The baseline median (range) sUA were 9.72(8.1-13.6), 9.83(8.1-13.8), and 9.92(8.1- 14.2) mg/dL for allopurinol, F40 and F80 group respec- tively, with no statistical differences among groups. After treatment, sUA decline velocities were similar in allopurinol group and F40 group, whereas sUA dropped the fastest across the time (Figure 2). At the 1st month after treatment, the average decline of sUA were 2.42 ± 0.34, 2.58 ± 0.46 and 3.18 ± 0.52 mg/dL. At the 3rd month, the average decline of sUA were 3.96 ± 0.94, 4.11± 0.89 and 4.89 ± 1.32 mg/dL. At the 6th month, patients with sUA<6mg/dL were 25 (83.3%) in F80 group, which was much better than Allopurinol group (18 cases, 58.1%, P < 0.01) and F40 group (17 cases, 58.6%, P < 0.01). Since all the patients were medicated with potassium citrate as the combination therapy and the urine pH is effective for examining the effects of citrate, we com- pared the urinary parameters at baseline and 6 months after treatment. Results of 24-hour urine collections are reported in Table 2. Although urine was remarkably al- kalized by potassium citrate in each group (P < 0.001), there were no significant differences among three groups in pH at baseline or at the 6th month (P = 0.659 and 0.987). This means that the differences of treatment effects were mainly caused by urate-lowering drugs. Stone changes There were 31, 29 and 30 cases for allopurinol group, F40 group and F80 group respectively in the efficacy analysis of stones changes. The maximum diameter and the total number of the stones were used to evaluate the Table 2. Changes in urinary parameters for one-day urine collection measurements Parameters Allopurinol(n=23) Febuxostat 40mg/d(n=25) Febuxostat 80mg/d(n=23) Pb pH Baseline 5.93 (0.54) 5.83 (0.53) 5.78 (0.64) 0.659 Month 6 6.86 (0.48) 6.98-0.2 (0.49) 6.92 (0.65) 0.987 Pa < 0.001 < 0.001 < 0.001 Potasium(mEq/d) Baseline 85.0 (18.1) 82.3 (17.1) 84.2 (25.4) 0.708 Month 6 97.6 (18.8) 96.4 (23.9) 93.3 (29.7) 0.823 Pa 0.005 0.023 0.003 Sodium(mEq/d) Baseline 231.1(45.6) 244.7 (35.4) 261.1(45.1) 0.06 Month 6 190.1(53.6) 192.4 (43.7) 201.9 (45.5) 0.672 Pa 0.009 < 0.001 0.001 Citrate(mg/d) Baseline 558.1(143.8) 578.6 (132.2) 595.9 (122.3) 0.631 Month 6 628.5(127.3) 621.6 (112.3) 628.4 (109.0) 0.972 Pa 0.115 0.019 0.039 Calcium(mg/d) Baseline 231.0 (61.9) 281.4 (60.5) 259.0 (34.3) 0.008 Month 6 227.1(44.7) 250.3 (67.2) 272.4 (27.3) 0.012 Pa 0.684 0.101 0.068 Uric acid(mg/d) Baseline 946.8 (208.2) 932.2 (203.3) 954.2 (180.0) 0.923 Month 6 535.5 (108.6) 526.2 (130.9) 440.3 (112.0) 0.012 Pa < 0.001 < 0.001 < 0.001 a, the differences at baseline and at month 6 in each group were compared using pairwise t test. b, the differences among groups at the same timepoint were compared using one-way ANOVA test. Febuxostat in radiolucent nephrolithiasis-Yunhua et al. Endourology and Stones diseases 36 Vol 18 No 1 January-February 2021 37 stone burden. At the 6th month, the reduced maximum diameters were 5.1 mm (39.8%), 5.3mm (40.1%) and 7.6mm (56.7%) for allopurinol group, F40 and F80 groups respectively. There were 16(51.6%), 17(58.6%) and 22(73.3%) patients whose stones became smaller by more than 50%. Changes of the maximum diameter of stones showed no difference between the allopurinol group and the F40 group (P = 0.11). Among the three groups, F80 reduced the stone size the most significant- ly (P < 0.05). Regarding the stone number, there were 61, 58 and 64 stones in the allopurinol group, F40 and F80 groups respectively. After 6 months of treatment, there were 16 (26.2%), 14 (24.1%), and 31 (48.4%) stones being reduced, indicating F80 had the best re- duction rate, followed by F40 and then the allopurinol group (Table 3). When significantly effective cases were defined as patients whose maximum stone diame- ter decreased by >50% or the stone number with diame- ter>5mm decreased, there were 18 (58.1%), 19 (65.5%) and 24 (80.0%%) cases with significant efficacy for each group (Table 2). Therefore, patients medicated with febuxostat 40mg twice daily had the best treatment efficacy in stone dissolution. Adverse events (AEs) In order to avoid underestimating the incidence of ad- verse events (AEs), those patients discontinued medica- tion due to severe AEs and progressive symptoms still remained in AEs analysis. Data on AEs were summa- rized in Table 4. Among 96 patients, 32 (33.3%) pa- tients experienced a total of 63 AEs. There were 24, 17, 22 events in allopurinol, F40 and F80 groups, re- spectively. There were 12/34 (35.3%), 9/30(30.0%) and 11/32(34.4%) patients of each group who experienced at least one AE (P = 0.927), suggesting the incidence of AEs in patients were similar among the three groups. Only 3 subjects in the allopurinol group discontinued medication, including 2 cases of hypersensitivity and 1 case of repeated gout attack, which required hospi- talization. In the F40 group, 1 case of hypersensitivity stopped medications. Two patients discontinued med- ications in the F80 group, with 1 case of hypersensi- tivity and 1 case of abnormal myoenzymes that was suspected of myocardiopathy. Among all the AEs, liver dysfunction was the most common, but all recovered to normal liver function within 2 – 4 weeks and were able to switch to other urate-lowering agents (Table 4). Patients medicated with febuxostat 80mg/d experi- enced similar AEs with patients who medicated with febuxostat 40mg/d, indicating increasing febuxostat to 80mg/d could achieve better urate-lowering effect but did not increase AEs incidence. DISCUSSION Approximately 2/3 of uric acid is excreted through urine. Hyperuricemia results in elevated uric acid in urine, which is called hyperuricosuria. When the uric acid becomes saturated, it forms crystals thus uric acid stones reside in renal pelvis(10). Uric acid stones are ra- diolucent in the X-ray. Allopurinol and febuxostat, as two classic urate-lowering drugs, inhibit xanthine oxi- dase to reduce serum uric acid, which results in lower uric acid excretion in urine(11). Since allopurinol has a purine-like backbone, it affects enzymatic activity re- lated to purine and pyrimidine metabolism and could Table 3. Stone changes after treatment Allopurinol 300mg/d Febuxostat 40mg/d Febuxostat 80mg/d Patients included in analysis, n 31 29 30 Stone size, mm Baseline Mean(SD) 12.8 (6.3) 13.2 (5.8) 13.4 (7.1) Median(range) 12 (6-24) 13 (6-26) 13.1(6-29) At 6 mon Mean(SD) 7.7 (5.5) 7.9 (5.9) 5.8 (4.3) a,b Median(range) 7 (3-21) 8 (3-20) 5.8 (3-19) a,b Stone numbers Baseline, n 61 58 64 Mean(SD) 2.0 (0.4) 2.0 (0.5) 2.1 (0.7) Median 2 (1-4) 2 (1-5) 3 (1-5) At 6 mon, n 45 44 33 a,b Mean(SD) 1.5 (0.3) 1.5 (0.5) 1.1(0.3) a,b Median 1(0-5) 1(0-5) 1(0.4) Dissolved stones, n(%) 16 (26.2) 14 (24.1) 31(48.4)a,b a, P < 0.05 when compared with allopurinol group. b, P < 0.05 when compared with group of febuxostat 40mg/d. Allopurinol 300mg/d, n=34 Febuxostat 40mg/d, n=30 Febuxostat 80mg/d, n=32 Liver dysfunction 7 8 9 Nonobstrunctive renal dysfunction 1 1 1 Abnormal complete blood count 2 2 1 Hyperlipidemia 1 3 6 Abnormal myoenzymes 0 1 2 Hypersensitivity 7 1 1 Gastrointestinal symptoms 6 1 2 Total AEs, n 24 17 22 Patients with AEs, n (%) 12(35.3) 9(30) 11(34.4) Abbreviation: AEs, adverse events Table 4. Adverse events in the three groups Febuxostat in radiolucent nephrolithiasis-Yunhua et al. be reincorporated into nucleotides, thus reducing its urate-lowering effect and increasing adverse events. However, febuxostat has a different configuration from purine, which gives it a better inhibitory effect and specificity(12). It selectively occupies the access chan- nel to the molybdenum-pterin active site of the enzyme. Furthermore, febuxostat is primarily metabolized in the liver, and renal elimination plays a minor role in febux- ostat pharmacokinetics. Although reports have clarified the efficacy of allopurinol in nephrolithiasis(13,14), the ef- ficacy and safety of febuxostat especially in radiolucent stones remains unclear(9). This study is a single-center retrospective study aiming to compare the efficacy and safety of allopurinol and febuxostat in radiolucent nephrolithiasis. The results demonstrated that febuxostat 40mg/d achieved a similar urate-lowering effect with allopurinol 300mg/d. More- over, febuxostat 80mg/d had a better treatment effect than allopurinol and febuxostat 40mg/d while the inci- dences of adverse events were similar. Our study sug- gests that febuxostat is an effective and safe urate-low- ering agent for radiolucent nephrolithiasis. It has been reported that hyperuricosuria contributes not only uric acid nephrolithiasis but also calcium oxalate stones, both of which comprise about 90% of nephro- lithiasis(15,16). Therefore, urate-lowering agents may pro- mote the dissolution of a large part of urinary stones. A randomized multicenter clinical trial by David S. Gold- farb et al. demonstrated that febuxostat 80mg/d or al- lopurinol 300mg/d promoted dissolution of calcium ox- alate stones, and that both agents had similar treatment effects(4). Our results revealed that febuxostat 80mg/d was better for radiolucent stones dissolution. Several reasons explain why febuxostat promoted stone disso- lution in our study. On one hand, febuxostat inhibited uric acid production, thus lowering uric acid concen- tration in the urine and preventing uric acid crystal for- mation in the renal pelvis. On the other hand, a combi- nation therapy of potassium citrate increased urine pH, which increased the solubility of uric acid. Based on these results, we proposed that lowering uric acid might be helpful for the dissolution of calcium oxalate stones or radiolucent stones. Balancing the drug effect and adverse events is of top priority in practice. Our results showed that when in- creasing drug dose from 40mg/ to 80mg/d, febuxostat significantly reduced serum uric acid in a shorter time, but its adverse events were similar to allopurinol 300mg/d. Although studies suggested that increment of allopurinol dose correlated with improved urate-lower- ing effect, the adverse events would also increase pro- portionally(17). To date, 300mg/d of allopurinol is most regarded as a safe dose, further dose increment was not recommended because the risks are over the merits(18). As for febuxostat 80mg/d, it did not cause more ad- verse events while achieving a better treatment effect, suggesting febuxostat had a bigger dose window(19). It should be noted that liver dysfunction was the most common adverse event in our study, which could be explained by that febuxostat is metabolized by oxida- tion and glucuronidation in the liver. Recently, studies reported that febuxostat could cause higher mortality in patients with gout and cardiovascular diseases(20,21). In our study, 1 case of suspected cardiomyopathy was observed in patients medicated with febuxostat 80mg/d. Therefore, cardiovascular adverse events should be strictly monitored when using high dose of febuxostat. There were several limitations of this study. Firstly, the sample size was relatively small for a common dis- ease like nephrolithiasis. Since it was a single-centered retrospective study, bias was inevitably introduced to some extent, but results were statistically significant Figure 2. Changes of serum uric acid levels after treatment. Febuxostat in radiolucent nephrolithiasis-Yunhua et al. Endourology and Stones diseases 38 and efficient to draw a conclusion. Secondly, the follow up period of 6 months was relatively short. Dissolution of large stones needs a long time, and therefore the clearance rate of large stones couldn’t be evaluated. In this study, we defined effective cases as patients whose maximum stone diameter decreased by >50% or the numbers of stones with diameter>5mm reduced, which would help in treatment efficacy evaluation. Theoreti- cally, the pure uric acid stones could be dissolved and passed to achieve total clearance at last. We will con- tinue to follow up these patients and evaluate the long- term treatment of febuxostat. Finally, only one kind of urine-alkalized agent potassium citrate was used in this study. In practice, urine alkalization directly affects the treatment effect, thus urate-lowering agents are usually combined with urine-alkalized agents to improve the excretion. We didn’t compare which urine-alkalized agent would be better in combination with febuxostat. CONCLUSIONS This single-center retrospective study compared the treatment efficacy and safety of allopurinol 300mg/d, febuxostat 40mg/d, and febuxostat 80mg/d in radiolu- cent nephrolithiasis. Our results demonstrated that com- pared with allopurinol, febuxostat achieved much better efficacy while keeping a similar incidence of adverse events. Febuxostat in combination with urine-alkalized agents is better recommended in the treatment of radi- olucent stones. ACKNOWLEDGEMENT This work was financially supported by Science and Technology Planning & Social Development Project of Guangdong Province of China (2017A020215027). CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Engl J Med. 1974; 291:1344-50. 2. Spivacow FR, Del Valle EE, Lores E, et al. Kidney stones: Composition, frequency and relation to metabolic diagnosis. Medicina (B Aires). 2016; 76:343-8. 3. Moe OW, Xu LHR. Hyperuricosuric calcium urolithiasis. J Nephrol. 2018. 31:189-96. 4. Goldfarb DS, MacDonald PA, Gunawardhana L, et al. 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