研究背景
根據調查台灣成人痛風盛行率約5.2%，高尿酸血症盛行率為15 %，相較歐美國家盛行率介於1至5%，顯示台灣為痛風與高尿酸血症高盛行率的國家。顯見這兩種疾病對台灣的重要性。由於正常生理中三分之二的尿酸經腎臟排除，慢性腎臟病與高尿酸血症、痛風為常見共病症，然而這群合併慢性腎臟病與高尿酸血症、痛風的病人治療上卻會面臨一些限制。促尿酸排除藥物的效果隨腎功能降低而減弱，因此sulfinpyrazone、probenecid不建議用於Creatinine clearance (CrCl) <30 ml/min的病人，benzbromarone不建議用於CrCl <20 ml/min的病人。除此之外，促尿酸排除藥物還要考慮尿結石問題。Allopurinol雖然可用於嚴重腎功能不全的病人，慢性腎臟病、年齡、漢族群等卻是Allopurinol sensitivity syndrome (AHS) 的危險因子，使得臨床上allopurinol處方的劑量受限制而效果不彰。Febuxostat是近40年唯一新研發的降尿酸藥物，它的作用機轉為抑制尿酸生成，在臨床試驗中可安全且有效地用於輕至中度腎功能不全病人，且無須調整劑量。然而由於臨床試驗排除嚴重腎功能不全的病人，且febuxostat上市後只有一些樣本數較少、觀察時間短或是無對照組的研究納入嚴重腎功能不全的病人，febuxostat用於嚴重腎功能不全病人的療效及安全性資料仍不充足，且無任何相關劑量建議。

研究目的
根據上段研究背景，本研究的研究目的如下：
1. Febuxostat與allopurinol用於慢性腎臟病第三至五期病人的療效與安全性之比較
2. Febuxostat與allopurinol延緩腎功能惡化效果之比較
 
研究方法
以國立成功大學醫學院附設醫院新處方febuxostat、allopurinol且年齡大於20歲、血中尿酸濃度 >6.0 mg/dl合併慢性腎臟病第三至五期的病人為觀察對象，進行歷史對照－回溯性世代研究。Allopurinol組自2011年11月1日至2013年5月31日收案，febuxostat組自2014年3月1日至2015年6月30日收案，觀察對象自處方febuxostat或allopurinol當日開始追蹤直到兩年或發生停止追蹤事件為止。研究材料為觀察對象之病歷及檢驗數據，紀錄項目包括觀察對象的基本資料、共病症、併用藥品、追蹤期間病人的藥物劑量與檢驗數據變化狀況以及導致停藥的原因。

研究結果
本研究febuxostat組納入270人，allopurinol組納入252人，兩組的基本特性分布存在差異，其中febuxostat組年齡較allopurinol組大 (68.2 ± 13.6 vs 65.5 ± 13.7歲)、血中尿酸濃度基礎值較低 (9.7 ± 1.8 vs 10.1 ± 1.9 mg/dl)、腎功能較差 (29.5 ± 14.4 vs 32.0 ± 15.1 mg/dl)、前三個月使用其他降尿酸藥物的比例較高 (28 % vs 9 %)。以存活分析分析兩組降尿酸效果差異，febuxostat達治療目標 (血中尿酸濃度 <6.0 mg/dl) 的機率為allopurinol 的6.92倍 (HR: 6.92; 95 % CI: 5.09 -9.41; P <0.0001)。由於基本特性存在差異，研究進一步以血中尿酸濃度基礎值、基礎腎功能分層，結果顯示無論血中尿酸濃度基礎值與腎功能狀況，febuxostat的降尿酸效果皆顯著優於allopurinol，且當病人的血中尿酸濃度基礎值較高或基礎腎功能較差時兩組的差距增加。此外本研究也發現febuxostat的降尿酸效果有隨腎功能變差而增加的趨勢 (第12個月血中尿酸自基礎值降低比例－慢性腎臟病第三期: 35.6%; 第四期: 42.0 %; 第五期: 47.5 %; P= 0.10)。研究中起始及觀察終止前最常處方的febuxostat劑量皆為40 mg/day，觀察終止前各慢性腎臟病分期病人皆有20 % 使用20 mg/day的劑量。
在安全性方面febuxostat組與allopurinol組分別有有9位、21位病人因不良反應停藥，febuxostat組皆屬於輕度不良反應，其中6位為輕微皮膚反應。Allopurinol組有中至重度的不良反應，包括3位病人發生藥疹 (drug eruption)、1位因毒性表皮溶解症 (Toxic epidermal necrosis) 而死亡。
另外本研究中febuxostat組與allopurinol組第6個月腎功能變化量 (eGFR) 分別為0.34 ± 4.90、0.30 ± 6.24 ml/min/1.73m2；第12個月腎功能變化量為 -0.50 ± 6.77、 -0.32 ± 6.90 ml/min/1.73m2，兩組腎功能隨時間的變化無統計差異 (P= 0.23)。

研究結論
本研究結果顯示febuxostat用於慢性腎臟病第三至五期病人是極有效且安全的，因此建議嚴重腎功能不全的病人治療高尿酸血症或痛風可處方febuxostat。在處方劑量部分，多數病人使用febuxostat 40 mg/day極有良好的效果，部分病人甚至需要減量為20 mg/day。台灣目前只有80 mg/tab的劑型，因此也建議台灣可引進40 mg/tab的劑型以符合臨床需求。

SUMMARY
The aim of this study is to provide further evidence of the effectiveness and safety of febuxostat in patients with chronic kidney disease (CKD), especially those with severe CKD. We performed a new user design, historical controlled, and retrospective cohort study using data from Cheng Kung University Hospital. Our results showed that febuxostat was significantly more effective than allopurinol. Besides, a trend of increase in renal function caused by febuxostat in patients with severe CKD was found. There were no moderate or severe adverse effects in the febuxostat group regardless of the severity of CKD during the study. In contrast, three patients were diagnosed with drug eruption, one died from toxic epidermal necrosis (TEN) in the allopurinol group, implicating that febuxostat was safer than allopurinol. In summary, our study supports the effectiveness and safety of febuxostat in patients with CKD.

INTRODUCTION
Taiwan is one of the countries with high prevalence of hyperuricemia and gout. According to previous reports, the prevalence of gout in Taiwan is 6.24 %, which is higher than western countries. In addition, there are almost 2,000,000 patients diagnosed with hyperuricemia. These data show the importance of controlling the occurrence of hyperuricemia in Taiwan. Chronic kidney disease (CKD) and hyperuricemia or gout are common comorbidities due to two-thirds of uric acid is eliminated by the kidneys. However, there are some challenges to treat this population. The efficacy of uricosuric agents declines in patients with renal dysfunctions. Furthermore, allopurinol, while can be used in patients with renal dysfunction, possess a concern of severe adverse event- Allopurinol hypersensitivity syndrome (AHS). This restricts the prescription dosage hence affecting the performance of this medication on patients. Febuxostat is the only new urate-lowering agent over the past few decades, with impressive performance in patients with mild to moderate renal impairment in clinical studies. However, only limited studies with small sample size, short study period or non-controlled evidence have reviewed the efficacy and safety of febuxostat in patients with severe CKD. Therefore, the main purpose of this study is to further evaluate the effectiveness and safety of febuxostat in patients with moderate to severe CKD.

MATERIALS AND METHODS
We performed a historical controlled, retrospective cohort study, collecting data from the National Cheng Kung University Hospital archives. Patients above 20 years old, with moderate to severe CKD, who received new prescription of allopurinol from 2011 to 2013 or febuxostat from 2014 to 2015 were enrolled. We further excluded patient diagnosed with cancer, HIV and kidney transplantation, without baseline uric acid level and eGFR data, and patients without further uric acid data during observational periods. All patients were followed up to two years or until the occurrence of censored events.

RESULTS AND DISCUSSION
A total of 252 patients in the allopurinol group, and 272 patients in the febuxostat group were enrolled. Differences were observed in the baseline characteristics of patients between groups, such as age, gender, baseline uric acid level and renal function. Therefore, we stratified patients to eliminate the influence of these imbalances. The result of survival analysis showed that febuxostat is significantly more effective than allopurinol (HR for uric acid less than 6.0 mg/dl: 6.92; 95 % CI: 5.09- 9.41; P <0.0001). The advantages of febuxostat sustained after the stratification. We also found a trend of increase in performance of febuxostat in patients with worsen renal function, although there was no statistical significance. The percentage changes from the baseline uric acid level compared to CKD stage 3, 4 and 5 in the febuxostat group were 35.6%, 42.0%, and 47.5 % respectively (P = 0.10). Most patients in the febuxostat group in the present study were prescribed with 40 mg daily, with some of them given only 20 mg daily. We did not find any moderate to severe adverse events in the febuxostat group, only some mild skin rashes reactions were observed. There was also no drug-related liver injury in the febuxostat group. On the contrary, three patients were observed with drug eruption and one died from toxic epidermal necrosis (TEN) observed in the allopurinol group, indicating that febuxostat seems to be safer than allopurinol in patients with CKD.

CONCLUSION
Our results support the effectiveness and the safety of febuxostat in patients with CKD, including those with severe CKD. This suggests that febuxostat could be used in these populations. Besides, we suggest approving the formulation of 40 mg/tab to fit the need for clinical practice.

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