Febuxostat in patients with hyperuricemia and severe chronic kidney disease

Febuxostat is a non-purine, selective inhibitor of both isoforms of xanthine oxido-reductase (XOR). Its pharmacokinetics is not dependent on renal clearance, and it may be advantageous in patients with chronic kidney disease (CKD). Although febuxostat is effective in patients with mild-to-moderate CKD, its efficacy and safety in patients with severe CKD remain unclear. This retrospective study included patients with an estimated glomerular filtration rate (eGFR) of < 30 ml/min/1.73 m 2 and hyperuricemia, who received febuxostat. The study was performed at Kaohsiung Medical University Hospital between January, 2015 and December, 2015. Changes were observed in the serum uric acid level, rate of achieving the target uric acid level (<6.0 mg/dL), changes in the eGFR, treatment dosage, and adverse events. 217 patients (65.9 ± 15.1 yrs, 145 males and 72 females) with severe CKD and hyperuricemia were included. Febuxostat significantly lowered the serum uric acid level (9.4 ± 1.9 at baseline and 5.6 ± 1.9 ml/min after treatment, P < 0.001). The serum uric acid level was <6 mg/dl in 126 patients (58.1%). There were no significant changes in eGFR (17.6 ± 7.4 at baseline and 17.8 ± 8.9 ml/min after treatment, P = 0.642) or indices of liver dysfunction. Adverse events were found in 5 patients, all adverse events improved after discontinuing febuxostat. This study demonstrated that febuxostat is efficacious and well tolerated in severe CKD patients with hyperuricemia, although renal function monitoring may be needed.


INTRODUCTION
Hyperuricemia is common in patients with chronic kidney disease (CKD).Previous studies have shown that hyperuricemia is associated with an increased plasma creatinine level, which is a risk factor for a low estimated glomerular filtration rate (eGFR), and can affect the progress of renal disease (Sircar et al., 2015).The risk of kidney failure is eight times higher in patients with serum uric acid (sUA) levels >8.5 mg/dl than in those with sUA levels of 5.0 to 6.4 mg/dl (Saag et al., 2016).A previous epidemiological study in Japan showed that hyperuricemia is significantly associated with the incidence of end-stage renal disease (ESRD), and sUA E-mail: 1000563@ms.kmuh.org.tw.Tel: 886-7-3121101*7174 or 7175 and 886-910-860226.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License levels >6 mg/dl are considered to be an independent predictor of ESRD in women (Iseki et al., 2004).
The 2016 European League Against Rheumatism (EULAR) recommended that the target of urate-lowering treatment should be to achieve sUA levels <6 mg/dl in all gout patients or sUA levels <5 mg/dl in severe gout patients (Richette et al., 2016).Allopurinol is a first-line drug in the treatment of hyperuricemia, and it is mainly excreted via urine.Its metabolite, oxypurinol, may accumulate in the body of patients with insufficient renal function (GFR <50 ml/min/1.73m 2 ) and produce toxicity; therefore, dosage adjustments are necessary during treatment.However, treatment efficacy is associated with dosage, and a decrease in the dosage may cause difficulty in achieving the treatment goal of controlling sUA levels (Hira et al., 2015).
Febuxostat is a selective inhibitor of xanthine oxidase.It was approved by the US FDA in 2009 for treating gout patients with hyperuricemia (Chohan, 2011).Febuxostat is metabolized mainly in the liver.Previous studies have shown that tolerance toward febuxostat is good in mildto-moderate renal insufficiency patients.To increase the clinical use and safety of febuxostat, several recent studies focused on its efficacy and safety in patients with severe CKD.However, the number of included patients was low (Saag et al., 2016;Hira et al., 2015;Juge et al., 2017;Shibagaki et al., 2014).The present study assessed the efficacy and safety of febuxostat in controlling hyperuricemia in patients with severe CKD.

Patients
This retrospective study included severe CKD patients treated with febuxostat at Kaohsiung Medical University Hospital in Taiwan between January 1, 2015 and December 31, 2015.Patient data were collected using the electronic medical record system of the hospital.Patient data included demographic data (age and sex), medical history (mainly focused on cardiovascular and liver diseases), history of gout, and medication record on gout treatment (types of drugs and their dosages).Additionally, data on plasma creatinine levels and changes in the sUA level before and after medication were collected.Since aspartate transaminase is an index for liver function, its value was monitored for adverse reactions.Through follow-up in the outpatient clinic, the adverse reactions of febuxostat during treatment were recorded.This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E (I)-20170001).This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.The inclusion criteria were age >20 years, severe CKD (GFR <30 ml/min/1.73m 2 ), and febuxostat use.The exclusion criteria were sUA levels <6 mg/dl before treatment, acute gout attack within 2 weeks, acute kidney failure, abnormal liver function, kidney transplantation, pregnancy or lactation, and anti-cancer or immunosuppressive treatment.
The treatment goal was set as a sUA level <6 mg/dl within 12 weeks.Changes in the sUA level before and after treatment were recorded, and the overall ratio of patients who achieved the goal and the association between different dosages and their efficacy were analyzed.Changes in serum creatinine levels before and after treatment were compared to evaluate the safety of febuxostat and its effect on the kidneys.eGFR is estimated GFR calculated by the abbreviated MDRD (modification of diet in renal disease) equation: 186 × (creatinine/88.4)-1.154 × (age) -0.203 × (0.742 if female) × (1.210 if black).Serum aspartate transaminase levels over twice the normal value were considered to indicate liver damage.Adverse drug reaction symptoms were monitored, and reports on adverse drug reactions were evaluated for causality using the Naranjo score.If the evaluation result is possible, the possibility cannot be ruled out, but the relative probability is low.If the result is probable, the relative probability is high.In addition, the safety end point was the follow-up cardiovascular event after 24 months.

Statistical analysis
Quantitative variables are expressed as mean ± SD, and qualitative variables are expressed in percentage.A paired t-test was used to compare changes in sUA, creatinine, and aspartate transaminase levels before and after treatment.The chi-square test was used to analyze the correlation between age/medical history and posttreatment sUA levels that achieved the treatment goal and for any value <5, the Fisher test was used.The independent sample t-test was used to compare differences in continuous variables within groups.Analysis results with a P-value < 0.05 were considered statistically significant.

RESULTS
Between January 1, 2015 and December 31, 2015, 235 patients met the severe CKD diagnostic criteria (eGFR <30 ml/min/1.73m 2 ) and other study criteria, and of these, 8 patients were kidney transplantation and 10 patients had sUA levels <6 mg/dl before treatment and were thus excluded.Consequently, the study finally included 217 patients, and grouped according to renal function (130 patients with CKD stage 4 and 87 patients with CKD stage 5) (Table 1).The mean patient age was 65.9 ± 15.1 years, and 123 patients (56.7%) were aged >65 years.The study included 7 patients who underwent hemodialysis (HD) and 4 patients who underwent peritoneal dialysis (PD).The percentages of patients with histories of cardiovascular-related diseases are listed in Table 1.Among the included patients, 20 patients had a history of liver disease (diagnosed as chronic hepatitis) and 11 patients had a history of hepatitis B, 2 patients had hepatitis C. The mean alanine transaminase level was 21.8 ± 10.4 IU/L, and there was no acute attack of hepatitis.Within 3 months before treatment, 103 patients (47.5%) did not use any medication for UA.The numbers of patients with gout history are shown in Table 2.The starting dosage of febuxostat was 40 mg/day in 191 patients (88.0%), and the mean dosage was 40.2 ± 9.8 mg/day.The mean sUA level was 9.4 ± 1.9 (range, 6.1 to 18.3) mg/dl before treatment.

Efficacy
The mean sUA level after treatment was 5.6 ± 1.9 (range, 1.7 to 9.9) mg/dl.In the study, 126 patients (58.1%) reached the treatment goal (sUA level <6 mg/dl), and 87 of these patients (40.1%) had sUA levels <5 mg/dl.The mean difference in the sUA level before and after treatment was 3.8 ± 0.0 mg/dl, which was statistically significant (P < 0.001) (Figure 1).During the course of treatment, the dosages were adjusted in some patients along with differences in their treatment effects, and the final mean dosage used was 37.7 ± 7.9 mg/day.Patients were divided into two groups based on whether they achieved the treatment goal (sUA < 6 mg/dl).Renal function and sUA levels before treatment, and dosages used were compared between the two groups (Table 3).

Safety
The mean follow-up eGFR after treatment was 17.8 ± 8.9 (range, 2.9 to 49.4) ml/min/1.73m 2 .There were no significant changes in eGFR (P = 0.642).In the decline in renal function during and before febuxostat treatment, there was a tendency towards improvement in eGFR during and after febuxostat treatment (Figure 2).The mean follow-up ALT value as an index for liver function was 22.5 ± 15.5 (range, 16 to 82) IU/L.Liver function before and after treatment did not show statistically significant differences (P = 0.481).Five patients experienced adverse reactions (Table 4), and their symptoms showed improvement after treatment discontinuation.Further treatment was discontinued.The safety end point was a follow-up cardiovascular event after 24 months (Table 2).

DISCUSSION
Febuxostat was approved by the US FDA in 2009, for use in the treatment of hyperuricemia-induced gout.On August 1, 2016, the National Health Insurance Administration in Taiwan relaxed the restriction on insurance paid for febuxostat use in gout patients with CKD.However, previous information on the efficacy and safety of febuxostat use in CKD patients above stage 3 is limited.Several studies explored the efficacy and safety of using febuxostat for treating patients undergoing advanced CKD treatment (Table 5) (Sircar et al., 2015;Saag et al., 2016;Hira et al., 2015;Juge et al., 2017;Shibagaki et al., 2014;Sakai et al., 2014).However, because of the limited number of patients included in this study and lower dosages used, further research is required for verifying the results.

Efficacy
With regard to the efficacy of drug treatment, 126 patients (58.1%) achieved sUA levels <6 mg/dl and 87 patients (40.1%) achieved sUA levels <5 mg/dl.The result in this study is lower compared with the finding in the retrospective study by Juge et al (65.1% patients achieved sUA levels <6 mg/dl and 58.9% patients achieved sUA levels <5 mg/dl) (Juge et al., 2017).Nevertheless, dosages used in the two studies were slightly different.In the study by Juge et al (2017), 24.6% of patients used 40 mg/day, 68.1% used 80 mg/day, and  7.3% used 120 mg/day, whereas in this study, most patients (88.0%) used 40 mg/day.In the study by Lim et al, approximately 76% used 40 mg/day and 23% used 80 mg/day (Lim et al., 2016).The difference in therapeutic dosage may be related to population differences, efficacy results, disease severity of the included patients, and individualities.Additionally, this study excluded patients who experienced acute gout  attack within the past 2 weeks and evaluation information on chronic kidney stone was lacking, which may have resulted in the underestimation of disease severity.
Nearly half of the patients (103 patients, 47.5%) did not use any gout medication before the study.Allopurinol requires dosage adjustments; however, its efficacy is correlated with dosage.The adjusted dosage may not be able to achieve the treatment goal.Previous studies have also shown that patients with the HLA-B*5801 gene are more susceptible to allergic reactions; therefore, gene screening is needed before treatment.Consequently, the National Health Insurance Administration in Taiwan relaxed the restriction for febuxostat payment to increase its clinical efficacy and decrease the incidence of adverse reactions.
Patients were divided into two groups based on whether they achieved the treatment goal (sUA <6 mg/dl).The study showed that differences for successful treatment are significantly related to pre-treatment sUA level.However, there was no significant difference between the two groups with regard to age, renal function, and therapeutic dosage.Thus, the outcome difference may be related to patient individuality, disease severity, and combined drug use during treatment.The study by Juge et al. showed that differences for successful treatment is significantly related to gout disease and dosages used (Juge et al., 2017).
Topiroxostat is another novel xanthine oxidoreductase Yang 199  al., 2016;Hira et al., 2015;Juge et al., 2017;Shibagaki et al., 2014;Sakai et al., 2014).The results indicate the safety of febuxostat use in CKD patients.Ten patients previously had allergic reactions to allopurinol, and no adverse reaction occurred after switching to febuxostat.The most common adverse reactions to febuxostat were skin rashes, joint pain, nausea, and liver malfunction Using the Naranjo score for adverse reactions in this study, the evaluation presented all the results as possible, that is, the probability cannot be excluded, but relative probability is low.The study included severe CKD and dialysis patients, and common symptoms included fatigue, weakness, and reduced urine volume.The patient's self-described senses of fatigue and intolerance were subjective feelings, lacking objective data supporting their correlations with the treatment.With regard to liver function, no significant changes in liver function before and after treatment were observed in this study.
In drug safety communication released on November 15, 2017 by the Food and Drug Administration (USA), the incidence of heart-related events caused by febuxostat administration was reported to be higher than that caused by allopurinol administration.In this study, the safety end points were the follow-up of cardiovascular and death events at 24 months (Table 2).The cardiovascular events are nonfatal in nature.Three patients died, but no objective data are present that support the association of this outcome with febuxostat administration.The findings of the clinical study by WB et al. indicate a higher risk of total and cardiovascular mortality with febuxostat than with allopurinol administration.The preclinical studies of febuxostat have shown no cardiovascular toxic effects.A large number of patients discontinued participation in the trial, and in the intention-to-treat analysis includes merely 10% of patients (White et al., 2018).It is therefore recommended that, within the clinical setting, related risk factors should be monitored for increasing the safety of the drug treatment.
The present study had several limitations, mainly because of the lack of comparative data with a control group in its retrospective design.Although whole blood cell counts and biochemical results were regularly monitored, mild adverse reactions may have been overlooked, or the incidence may have been underestimated owing to differences in patient tolerance.In addition, patients who had undergone kidney transplantation were not included.The number of patients was small, and their time was short.In the future, long-term, large-scale, multi-center controlled studies are needed to explore the efficacy and safety of febuxostat in patients with severe CKD and those undergoing dialysis.

Conclusion
The study showed that febuxostat treatment in patients with hyperuricemia and severe chronic kidney disease effectively reduced sUA levels with no significant adverse reaction, and patient tolerance to the drug was good.Whether febuxostat has a damaging or protecting effect on the kidneys remains debatable.Continuous monitoring of related variables is required for increasing the safety of the drug treatment.

Figure 1 .
Figure 1.Change in serum uric acid slope (mean ± SD) before and after febuxostat treatment (when is follow up)(number in parentheses indicates number of patients).

Figure 2 .
Figure 2. Change in estimated glomerular filtration rate slope (mean ± SD) before and after febuxostat treatment (when is follow up)(number in parentheses indicates number of patients).

Table 2 .
Gout history and CKD progression and safety end points.

Table 3 .
Differences in clinical characteristics and febuxostat treatment regimen between high and low efficacy groups.

Table 5 .
Compared with other studies of febuxostat use in patients with chronic kidney disease.