A Meta-Analysis for Comparing the Effects of Febuxostat and Allopurinol on Kidney Function in Hyperuricemia Patients Complicated with Chronic Kidney Disease

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Introduction
Hyperuricemia (HUA) is a common medical condition characterized by a substantial increase in fasting serum uric acid (SUA) levels, exceeding 420 μmol/L while maintaining a standard purine-rich diet.Uric acid, a product of purine metabolism, is primarily excreted through the renal and intestinal pathways.HUA is defned by SUA levels greater than 7.0 mg/dl in males and 5.7 mg/dl in females [1].Presently, HUA has emerged as a signifcant public health issue.In the years 2015-2016, the prevalence of gout in the United States reached 3.9% among adults, with rates of 5.2% in men and 2.7% in women [2].Epidemiological data from 2015 to 2018 in China highlight the substantial burden of HUA, with an overall prevalence rate of 19.87%, encompassing rates of 28.35% in males and 9.41% in females [3].
In recent years, the mounting incidence of HUA has led to a growing understanding of its detrimental efects on the human body.A substantial body of research has elucidated the correlation between HUA and the onset and progression of various medical conditions, including kidney disease, gout, cardiovascular and cerebrovascular diseases, and metabolic syndrome [4].Among these, HUA demonstrates a signifcant and direct association with chronic kidney disease (CKD) and related kidney conditions, including endstage kidney disease, albuminuria, and elevated serum creatinine (SCr) levels [5].Elevated SUA levels in the body can instigate kidney injury by precipitating sodium urate crystal deposition in the tubular interstitium, triggering oxidative stress reactions, and activating the reninangiotensin system through increased renin expression in periglomerular cells [6].Terefore, actively managing SUA levels stands as a crucial strategy for slowing the progression of CKD, with measures primarily including lifestyle interventions and pharmaceutical treatments.
Allopurinol, a traditional medicine widely used, is effective in suppressing uric acid synthesis.Goicoechea et al. [7] reported that allopurinol can mitigate kidney injury resulting from HUA, leading to reductions in urinary protein, blood urea nitrogen (BUN), and SCr levels to some extent while also ameliorating pathological kidney tissue changes.Nonetheless, allopurinol, being a purine analog, can also afect the activity of other enzymes involved in purine metabolism and is associated with numerous adverse reactions; thus, it is not recommended in the treatment of elderly patients with moderate to severe kidney dysfunction [8].Febuxostat, on the other hand, is a nonpurine selective inhibitor of xanthine oxidase that robustly inhibits uric acid synthesis.It is excreted via both bile and the kidneys and is accompanied by fewer adverse reactions [9].Although some studies have confrmed that febuxostat can more efectively lower uric acid levels than allopurinol (in doses of 300/ 200 mg), there remains a lack of research and evidence regarding the efcacy and safety of febuxostat in the treatment of HUA patients with moderate to severe kidney dysfunction [10].
In this study, we hypothesized that treatment with febuxostat could be more efective than allopurinol in managing patients with CKD complicated by HUA.Tus, we designed this present study by conducting a metaanalysis to compare the efects of febuxostat and allopurinol and evaluate their efcacies and safety on HUA patients complicated with CKD.

Search Strategies.
Tis study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [11].Data were retrieved from the Wanfang, China National Knowledge Infrastructure (CNKI), PubMed, and Web of Science databases.Te following are efective terms and related variants used in the database searches: "Hyperuricemia," "Chronic kidney disease," "Febuxostat," and "Allopurinol.

Inclusion and Exclusion
Criteria.Te inclusion criteria comprised (1) randomized controlled trials (RCTs) as the only research design, necessitating the documentation of participants' general details, including name, age, and gender, along with the recording of biochemical indicators such as BUN, SCr, SUA, and microalbumin levels; (2) patients clinically diagnosed with CKD complicated by HUA; and (3) SUA levels exceeding 420 μmol/ L for males and 360 μmol/L for females, as well as an estimated glomerular fltration rate (eGFR) lower than ml/min/1.73m 2 .Intervention in the experimental group involved either febuxostat alone or a combination of febuxostat with other therapeutic modalities, while the control group received treatment with allopurinol or a placebo.Te outcome measures included eGFR, SCr, 24hour urinary protein quantity (24-h UTP), SUA, and BUN levels, with at least one of these measures required for inclusion in each study.
Te exclusion criteria included the following: (1) studies involving letters, reviews, animal studies, case reports, secondary analyses, and any non-RCT; (2) studies involving patients undergoing dialysis, kidney transplantation, individuals with malignant tumors, kidney failure, or those aged below 18 years; (3) lacked kidney function-related outcomes; and (4) did not provide original data or presented incomplete research data required for our present study analysis.

Literature Screening and Data Extraction.
After removing duplicate literature, two researchers independently screened the title, abstract, and full text of the potentially eligible articles.Disagreements were resolved by involving a third researcher.Data extraction was performed that included authorship, publication date, language, study duration, study population, intervention methods, sample size, and experimental endpoints.Subsequently, data from the selected literature were compared to assess the efcacy and safety of febuxostat and allopurinol in treating CKD complicated by HUA.Efcacy was evaluated based on eGFR, SCr, 24-h UTP, SUA, and BUN.Safety was assessed by monitoring adverse events and complications.Last, the Cochrane risk-of-bias tool was used to evaluate literature quality.

Statistical Analysis.
All data were analyzed using Stata 17.0 (StataCorp LLC, College Station, TX, USA).Continuous variable results are shown as the weighted mean difference (WMD) and 95% confdence interval (CI).A signifcance level of P < 0.05 was used to denote statistical signifcance, and all tests were two-tailed.Heterogeneity among the included studies was evaluated using the Q test and I 2 statistic.If I 2 exceeded 50% and P < 0.10, indicating notable heterogeneity, we used the random-efects model for data synthesis; otherwise, the fxed-efects model was utilized.Sensitivity analysis was performed to identify potential sources of heterogeneity and assess the stability of the metaanalysis results.

Search Outcomes.
Based on the search strategies, a total of 472 studies were initially identifed, with 56 retrieved from PubMed, 263 from Web of Science, 27 from Wanfang, and 126 from CNKI.Following the removal of duplicated studies, 127 were excluded based on search records, and an additional 279 were excluded based on abstracts and titles.Subsequently, the full text of 30 articles was evaluated, among which 12 records were excluded due to one instance of missing data, seven studies with mismatched research design types, and four studies being non-RCT.Tus, a total of 18 studies were included in this meta-analysis [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].Te detailed literature search process is shown in Figure 1, and Figures 2(a) and 2(b) present the risk of bias graph and the risk of bias summary, respectively.
Te basic characteristics of the eligible articles are shown in Table 1.Collectively, this meta-analysis comprised 18 RCTs, encompassing a total of 1,877 patients, with 1,039 individuals in the control group and 838 in the experimental group.Among the 18 RCTs, two were identifed from non-Chinese databases, while the remaining 16 were from Chinese databases.Te publication dates of these trials ranged from 2019 to 2022, with experimental durations ranging from 12 months to 36 months, and all trials were conducted within China.Te mean age of the patients across the studies ranged from 30.4 to 84.4 years, the ratio varied from approximately 1 : 2 to 4 : 5, and the treatment duration extended from 4 to 24 weeks.

Primary Outcome Measures.
Eleven reports [12-14, 18, 19, 22-25, 28, 29] provided data on the eGFR levels in both patient groups posttreatment and exhibited signifcant heterogeneity (I 2 � 80.1%; P < 0.1), requiring the use of the random-efects model for meta-analysis.Te analysis results demonstrated that the eGFR levels in the experimental group were signifcantly higher than those in the control group (WMD: 2.897, 95% CI: 1.336 to 4.458, P < 0.001) (Figure 3(a)).Sensitivity analysis indicated that the exclusion of any individual study did not alter the overall combined analysis results (Figure 3(b)).Moreover, the outcomes of Begg's test (P � 0.640) and Egger's test (P � 0.323) indicated the absence of publication bias in the eGFR results.

Discussion
Allopurinol is the primary therapeutic agent for HUA to reduce uric acid production by inhibiting hypoxanthine and xanthine metabolism.Nevertheless, the overall clinical effcacy of allopurinol remains suboptimal.Notably, uric acid levels often do not exhibit signifcant reductions in most patients, and complications from allopurinol are not uncommon [14].We designed this present study based on the rationale of the known association between HUA and CKD and the potential benefts of urate-lowering therapies such as febuxostat and allopurinol in managing HUA.Our results reveal that febuxostat treatment was associated with a signifcant improvement in eGFR compared to allopurinol, indicating a potential beneft for kidney function.Furthermore, febuxostat led to signifcant reductions in SCr, SUA, and BUN levels, suggesting its efectiveness in managing HUA and preserving renal function.Tese fndings may be particularly relevant for clinicians managing such patients with HUA, ofering a more efective pharmacological intervention.However, considering that there was no statistically signifcant diference in the 24-h UTP between the two treatment groups, this highlights the need for further research to confrm these observations and assess long-term safety.
Te fndings that febuxostat treatment was associated with a signifcant improvement in eGFR compared to allopurinol in HUA patients with CKD may be attributed to several potential underlying mechanisms.First, HUA is known to trigger infammatory responses in the kidneys [30], potentially leading to renal damage, and febuxostat has been suggested to have anti-infammatory properties that could help reduce infammation in the renal tissues [31].4 Journal of Clinical Pharmacy and Terapeutics capabilities [32].Second, some studies have suggested that febuxostat may improve endothelial function [33], which plays a role in regulating blood fow to the kidneys.Improved endothelial function could result in better renal perfusion and function.Tird, HUA can lead to increased oxidative stress, which can damage renal cells, and febuxostat's ability to lower SUA levels may have reduced oxidative stress in the kidneys, protecting them from injury [34].Fourth, febuxostat and allopurinol have distinct mechanisms of action.Febuxostat is a selective xanthine oxidase inhibitor, whereas allopurinol is a nonselective xanthine oxidase inhibitor [35].Te selectivity of febuxostat may make it more efective at lowering uric acid levels,

Journal of Clinical Pharmacy and Terapeutics
Zhang Qing (2020)  Journal of Clinical Pharmacy and Terapeutics glomerular hypertrophy, sclerosis, proteinuria induced by high uric acid levels, and mild tubulointerstitial fbrosis [38].Te Japanese Society of Gout and Nucleic Acid Metabolism (JSGNM) and the Dutch College of General Practitioners (DCGP) recommend lowering SUA levels below 6 mg/dL using uric acid-lowering drugs to protect kidney function in HUA patients [39,40].Quantitative measurement of urinary protein plays a vital role in the diagnosis, treatment, and outcomes of patients with CKD, with the 24-h UTP test serving as the gold standard for total urinary protein determination [41].However, the analysis did not reveal a signifcant diference in 24-h UTP levels between the experimental and control groups (WMD: −0.198, 95% CI: −0.413 to 0.016, P � 0.070).Tis lack of a signifcant diference between the two groups may be attributed to several potential factors.First, the relatively short treatment durations in the included studies (ranging from 4 to 24 weeks) might not have allowed suffcient time to observe signifcant changes in proteinuria, which often develops and progresses over a longer timeframe.For instance, in a recent study by O'Dell et al., patients with gout and HUA were randomly assigned allopurinol or febuxostat in a 72-week trial.Te trial had three phases (titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72).O'Dell et al. found that allopurinol was noninferior to febuxostat in controlling fares and similar outcomes were noted in participants with stage 3 CKD [42].However, it should be noted that although 300 mg is the most commonly prescribed dose of allopurinol, in the study of O'Dell et al., the authors used a titrateto-target protocol, and the median dose of allopurinol to achieve the target was 400 mg, while 29% of participants needed 500 mg or higher.Second, the heterogeneity in patient populations, comorbidities, and treatment regimens across the included studies may have contributed to variations in proteinuria outcomes.
Moreover, our present meta-analysis results demonstrated that the experimental group exhibited notably lower SCr levels, showed a more pronounced advantage in reducing SCr, and displayed signifcantly lower BUN levels than the control group.SCr and BUN are widely used clinical indices for assessing kidney function, and  simultaneous elevation of both indicators indicates severe kidney impairment [43].Conversely, the concurrent reduction of SCr and BUN can efectively alleviate kidney damage.Tese fndings indicate that febuxostat can improve eGFR, lower SUA levels, and enhance SCr and BUN-related parameters.Moreover, febuxostat holds substantial pharmaceutical values, which aligns closely with the fndings of another meta-analysis by Zheng and Sun [44], which indicated that febuxostat may be efective in patients with CKD and HUA.Importantly, our investigations into drug safety revealed the absence of severe adverse reactions in both treatment groups, highlighting the safety and reliability of both therapeutic approaches.However, it should be noted that the CAREs trial reported that febuxostat increased cardiovascular and all-cause mortality compared with allopurinol [45], which led the U.S. FDA to issue a boxed warning in 2019, while the FAST trial [46] and that of O'Dell et al. [42] showed no indication that febuxostat increases the risk of major adverse cardiovascular events or is associated with greater cardiovascular mortality or overall mortality.Furthermore, it should also be noted that allopurinol was studied in two trials of HUA in participants with heart failure, with conficting results [47,48].
While the meta-analysis conducted in this study provides valuable insights into the efcacy and safety of febuxostat and allopurinol in treating HUA patients complicated by CKD, there are several limitations to consider when interpreting the results of this meta-analysis.First, the inclusion of studies conducted exclusively from China and predominantly in the Chinese population may limit the generalizability of the fndings to more diverse populations.Second, the heterogeneity observed in various outcome measures, such as eGFR, SCr, 24-hour urinary protein quantity, SUA, and BUN levels, despite the use of randomefects models, suggests potential variations in study designs, patient characteristics, or interventions across the included trials.Tird, the relatively short duration of some of the trials may not capture long-term outcomes or potential adverse efects that may emerge over extended treatment periods.In addition, we did not perform a subgroup analysis for elderly individuals, who often are more likely to have multiple comorbidities and be on various medications, which could have potentially afected treatment outcomes and interactions.Tus, further research and meta-analysis, encompassing diverse populations and longer follow-up periods, are essential to validate these results and assess the safety profle of febuxostat in patients with HUA and CKD.

Conclusion
Our fndings demonstrate that febuxostat treatment was associated with signifcant improvements in key clinical parameters, including increased eGFR and reduced levels of SCr, SUA, and BUN, when compared to allopurinol.Overall, these results suggest that febuxostat may represent a more promising therapeutic approach for this specifc patient population.However, it is important to acknowledge the limitations of this study and the need for further research, encompassing diverse populations and longer follow-up periods, to validate these results and assess the safety profle of febuxostat in patients with HUA and CKD.
" Tese keywords and their corresponding MeSH terms were combined with the Boolean operators AND or OR.Te complete keyword search terms were used for PubMed were (Chronic kidney disease [Title/Abstract] OR Kidney Insufciency, Chronic [Title/Abstract] OR Chronic Renal Insufciency [Title/Abstract] OR Renal Insufciency, Chronic [Mesh]) AND (Hyperuricemia [Mesh]) AND (Allopurinol [Mesh]) AND (Febuxostat [Title/Abstract] OR Uloric [Mesh]).Chinese databases use the appropriate search terms in Chinese.Te search timeframe included records from the inception of each database up to April 2023.

Figure 2 :
Figure 2: Risk of bias graph for the included literature.(a) Risk of bias graph; seven areas were scored for risk of bias; (b) Risk of bias summary; each item of bias was scored as low (+), uncertain (?), or high risk (−).

Figure 3 :
Figure 3: Meta-analysis of eGFR of HUA patients complicated with CKD after treatment with febuxostat and allopurinol.(a, b) Te eGFR of HUA patients complicated with CKD after treatment was assessed by a forest plot (a) and a sensitivity analysis diagram (b).eGFR, estimated glomerular fltration rate; HUA, hyperuricemia; CKD, chronic kidney disease.

Figure 4 :
Figure 4: Meta-analysis of kidney function indexes of HUA patients complicated with CKD after treatment with febuxostat and allopurinol.(a-d) Forest plots for assessing the levels of SCr (a), 24-h UTP (b), SUA (c), and BUN (d) in HUA patients complicated with CKD.SCr, serum creatinine; 24-h UTP, 24-hour urinary protein quantity; SUA, serum uric acid; BUN, blood urea nitrogen; HUA, hyperuricemia.

Table 1 :
Te basic characteristics of inclusion in the literature.
[37]rnal of Clinical Pharmacy and Terapeutics diminishes uric acid production by suppressing xanthine oxidase activity[36].In contrast, febuxostat selectively targets uric acid synthesis without signifcantly impacting the activities of other enzymes related to pyrimidine or purine metabolism.Furthermore, febuxostat can interact with sodium bicarbonate, facilitating the dissolution and excretion of urate, resulting in a substantial reduction in SUA levels among CKD patients complicated with HUA[37].In addition, febuxostat has been shown to reduce or ameliorate pathological changes in aferent arterioles,