Effects of Adding Urinary Alkalizer Citrate Mixture to Febuxostat in Gout Patients with Combined-type Hyperuricemia and Acidic Urine: A Prospective Cohort Study

Effects of Adding Urinary Alkalizer Citrate Mixture to Febuxostat in Gout Patients with Combined-type Hyperuricemia and Acidic Urine: A Prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Adding Urinary Alkalizer Citrate Mixture to Febuxostat in Gout Patients with Combined-type Hyperuricemia and Acidic Urine: A Prospective Cohort Study Kai Guo, Changgui Li, Robert Terkeltaub, Nicola Dalbeth, Xuefeng Wang, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7578472/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Arthritis Research & Therapy → Version 1 posted 11 You are reading this latest preprint version Abstract Background People with gout and combined-type hyperuricemia, defined as renal urate overload and renal urate under-excretion, have diminished responsiveness to urate-lowering therapy. Emerging observational data suggest that urine alkalization might improve responsiveness to febuxostat. Hence, this prospective study evaluated the urate-lowering efficacy of citrate mixture added to febuxostat in people with gout and combined-type hyperuricemia. Methods Patients with combined-type hyperuricemia and low urine pH (< 6.2) were prospectively enrolled from a gout clinic. All were treated with febuxostat (initially 20 mg daily, escalated to 40 mg daily if serum urate (SU) ≥ 360µmol/L). Citrate mixture (3.5g twice daily, open label) was added according to shared decision of both physician and patient (alkalization vs. non-alkalization). Participants were followed for 12 weeks, with primary endpoint being achievement of SU < 360 µmol/L at final assessment. Results We enrolled 234 eligible patients, with 194 completing 12 weeks follow-up (98 non-alkalization and 96 with alkalization). At week 12, more patients in the alkalization group achieved SU < 360µmol/L (57% vs. 40%, P < 0.05), with significantly increased renal urate excretion, and lower febuxostat doses (mean ± S.D, 31.88 ± 9.88 vs. 34.69 ± 8.88 mg, P < 0.05). Additionally, metabolic measures including the triglyceride concentration and triglyceride-glucose index were lower, and high-density lipoprotein cholesterol concentration as well as insulin sensitivity were higher in the alkalization group. The incidence of adverse events was similar between groups. Conclusions In people with gout and combined-type hyperuricemia, adjunctive urine alkalization with febuxostat demonstrated superior urate-lowering response, along with improvement in metabolic abnormalities. Trial registration ChiCTR, http://www.chictr.org.cn , ChiCTR2100043573. gout combined-type hyperuricemia urine alkalization serum urate gout flare Figures Figure 1 Figure 2 Figure 3 Introduction Gout, a chronic disease characterized by recurrent arthritis flares, is caused by the deposition of monosodium urate (MSU) crystals in joints and soft tissues [ 1 ]. Urate-lowering therapy (ULT) is the cornerstone of gout management [ 2 , 3 ], and successfully treating to serum urate (SU) target is disease-modifying and can lead to disease remission [ 4 – 6 ]. Recent research evaluating response patterns to the xanthine oxidase inhibitor (XOI) febuxostat among distinct gout phenotypes revealed that patients with the combined-type hyperuricemia (exhibiting both renal urate overload and under-excretion) exhibited the least favorable treatment outcomes, as evidenced by significantly lower rates of achieving SU target compared to other types [ 7 ]. Combined-type hyperuricemia is present in approximately 30% of people with gout [ 8 ], and is typically associated with higher polygenic risk scores [ 9 ] and the highest genetic complexity among all hyperuricemia types [ 10 ]. This constellation of multiple genetic defects may lead to comprehensive dysregulation of urate production and elimination pathways through additive/synergistic effects, rendering hyperuricemia more resistant to monotherapy targeting a single mechanism (e.g., XOI) [ 9 , 11 ]. Furthermore, gout patients with combined-type hyperuricemia present with more severe clinical manifestations than for other hyperuricemia phenotypes, including higher baseline SU levels, earlier gout disease onset, and more pronounced metabolic syndrome (MetS) components, all factoring into synergistic exacerbation of inflammatory responses, thereby compounding therapeutic challenges [ 7 , 9 ]. Notably, people with combined-type hyperuricemia experience significantly more frequent ULT agent hepatotoxicity, compared to other hyperuricemia types [ 7 ]. A previous prospective randomized clinical trial indicated that adding low-dose benzbromarone (25 mg/day) to low-dose (20 mg/day) febuxostat had superior urate lowering efficacy to febuxostat monotherapy in people with combined-type hyperuricemia [ 8 ]. However, benzbromarone can cause urolithiasis, and the rare side effect of fulminant hepatotoxicity [ 12 – 14 ]. Hence, there is an unmet need for a simpler and safer ULT regimen that consistently reduces the SU to target, particularly for those with combined-type hyperuricemia. Notably, many people with gout have acidic urine [ 15 ]. A cross-sectional study involving 3565 people with primary gout, detected decreased urine pH (pH < 6.2) in 76.2% of subjects, which independently associated with renal damage indicators [ 16 ]. Acidic urine is commonly associated with MetS, type 2 diabetes, high dietary animal protein, and some diuretics. However, due to insufficient evidence, recommendations for urinary alkalization in gout management are inconsistent, and have focused mainly on urolithiasis prevention in those initiating uricosuric drug ULT [ 17 – 20 ]. Interest is now growing in urine alkalization adjunctive to ULT with XOIs [ 21 , 22 ]. Specifically, the urine alkalizer citrate facilitated SU reduction and renal function improvement in people with chronic kidney disease and hyperuricemia treated with allopurinol [ 21 ]. In a cohort of people with gout unselected for type of hyperuricemia, citrate mixture also improved gout clinical outcomes, including renal damage index, gout flare frequency, MetS traits, and response to febuxostat, without significantly affecting SU levels [ 22 ]. At present, it is unclear whether urine alkalization therapy with citrate mixture enhances urate-lowering effect of febuxostat in people with combined-type hyperuricemia. This study examined whether adding citrate mixture to febuxostat could enhance clinical outcomes in patients with gout and combined-type hyperuricemia. Methods Study Design and Participants This single-center prospective cohort study was conducted at the Gout Clinic in the Affiliated Hospital of Qingdao University. Patients met the 2015 ACR/EULAR gout classification criteria [ 23 ] were screened between February 2023 and June 2024. Male patients, aged between 18 and 70 years, with combined-type hyperuricemia and fasting urine pH < 6.2 were eligible for this study. From 824 screened candidates meeting inclusion criteria, 234 eligible participants were enrolled (Fig. 1 ). Febuxostat was initiated in all participants, and citrate mixture was administered according to shared decision-making by the patient and treating physician, which precluded randomization. The distinct taste of the citrate mixture necessitated an open-label rather than blinded study. The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University. The study was registered at the China Clinical Trial Registration Center ( www.chictr.org.cn ) with registration number: ChiCTR2100043573. Written informed consents were obtained from all participants. Combined-type hyperuricemia was defined as 24-hour urinary uric acid excretion (24h-UUE) > 600 mg/d/1.73m 2 and fractional excretion of uric acid (FEUA) < 5.5%, assessed using 24-hour urine samples [ 24 ], and was present in 28.4% of screened study candidates. The exclusion criteria included UUE ≤ 600 mg/d/1.73m 2 or FEUA ≥ 5.5%, on ULT or experienced gout flare in the 14 days prior recruitment, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m 2 , baseline SU 2-fold the upper limit of normal (ULN), taking other drugs affecting SU levels and/or urine pH, allergic to any drugs or ingredients involved in this study, and secondary gout. Treatment and Data Collection To optimally screen for combined-type hyperuricemia, people with gout underwent a 14-day washout period for drugs with urate-lowering capacity, accompanied by the imposition of a low-purine diet. All 234 participants were prescribed with febuxostat 20 mg daily, escalating to 40 mg daily if SU ≥ 360 µmol/L at week 4. Of those, 118 participants chose addition of citrate mixture (citric acid 50%, sodium citrate 10%, potassium citrate 10%, sodium carbonate 20% and excipient 10%) 3.5 g twice a day [ 15 ]. Participants were followed every 4 weeks till week 12. Gout flare prophylaxis medications and other drugs with urate-lowering capacity were not used during the study period. Standard anti-inflammatory therapy was permitted in patients experiencing a self-reported or physician-managed gout flare [ 18 ]. Clinical information, fasting urine pH and biochemistry parameters were collected at baseline and the follow-up visits. Clinical information included body mass index (BMI), subcutaneous tophi, histories of nephrolithiasis, metabolic dysfunction-associated steatohepatitis (MASH), hypertension and MetS [ 25 , 26 ]. Blood and urine parameters included SU, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting blood glucose (FBG), serum creatinine (CREA), eGFR and fasting urine pH. The urine pH was determined with a pH electrode (FE28-STANDARD, METTLER Toledo Company, Zurich, Switzerland), using spot morning fasting urine sample. UUE and FEUA were evaluated at baseline and week 12. Metabolic status was evaluated using several models assessing insulin resistance (IR) indices at baseline and week 12. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) = FBG (mmol/L) * Insulin (µU/mL) / 22.5; Triglyceride-Glucose Index (TyG) = ln (TG [mg/dL] * FBG[mg/dl]/2); Quantitative Insulin Sensitivity Check Index (QUICKI) = 1/ (log FBG [mg/dL] + log Insulin [µU/mL]); Insulin Sensitivity Index (ISI) = 1 / (FBG [mmol/L] * Insulin [µU/mL]). FBG (mg/dL) = FBG (mmol/L) * 18.016; TG (mg/dL) = TG (mmol/L) * 88.545. Dual energy computed tomography (DECT) of the affected joints, ultrasonography (US) of the kidneys and affected joints were collected at baseline and week 12. US examination was performed using an ALOKA 70 machine (HITACHI, Tokyo, Japan) equipped with a multi-frequency linear transducer (9–13 MHz). The first metatarsophalangeal (MTP) joints, ankles, knees, elbows, wrists, and metacarpals were scanned by sonographers who was trained for musculoskeletal US examination. According to the OMERACT ultrasound guidelines [ 23 ], the representative US images of each individual elementary lesion presented in the longitudinal and transverse scans from each joint were collected, and to observe the changes of joint tophi, the maximum diameter of tophi was recorded. For DECT, all symptomatic joints were scanned on a dual x-ray tube 128-detector-row scanner (Somatom Definition Flash, Siemens Healthineers, Forchheim, Germany), with tube A 140kVp/55mAs and tube B 80kVp/255mAs, acquisition at 128×0.6mm, reconstruction at 0.6mm. Urate volumes were automatically calculated by DECT syngo. via Gout program (Siemens Healthineers, Germany). Imaging assessors were blinded to the alkalization group. Adverse events (AEs) were monitored and managed during the study period. Gout flare was defined as patient-reported joint pain with pain visual analogue scale (VAS) score > 3 of 0–10 scale [ 27 ], or physician-witnessed gout flare. Serum potassium (K + ) was monitored at baseline and week 12. Outcomes The primary outcome was the proportion of patients achieving target (SU < 360 µmol/L) after 12 weeks of treatment. The secondary outcome was was the proportion of patients achieving SU < 300 µmol/L. Other outcomes of interest included: the incidence of gout flares, changes in FEUA and UUE, DECT MSU crystal volume and detected maximum diameter of ultrasonic tophus; eGFR, CREA and urine pH; Diastolic Blood Pressure (DBP), Systolic Blood Pressure (SBP), BMI, FBG, blood lipids and IR Indices. AEs included changes of serum K + level, new-onset nephrolithiasis, in the treatment period, transaminase elevation and other AEs leading to treatment interruption or hospitalization. Sample Size Determination of sample size was based on the primary endpoint (percent of patients reaching target < 360µmol/L at week 12). In a separate pilot study conducted in our center, 29 participants in non-alkalization group and 28 participants in alkalization group were included using the same inclusion/exclusion criteria, the rate of SU target achievement was 41.12% and 60.78% in the non-alkalization and alkalization group, respectively. To achieve a 5% two-sided significance level and 80% power to detect the differences between the two groups, patient allocation was set as 1:1 in these two groups respectively. Therefore, 95 participants were required in each group. Factoring in an expected dropout rate of 20%, at least 114 participants in each group were required. Statistical Analysis All data were analyzed using IBM SPSS Statistics version 22.0 (IBM SPSS, Chicago, USA). Standard descriptive statistical methods summarized the demographic and clinical characteristics, with continuous variables reported as mean ± standard deviation (S.D) or median (interquartile range (IQR)), and categorical variables as percentages. Baseline comparisons were conducted using independent samples t-tests or the Mann-Whitney U test. Categorical data comparisons employed the chi-square test. Follow-up data were analyzed using a repeated measures model to assess trends between these two groups. Within-group comparisons pre- and post-treatment were performed using paired t-tests or Wilcoxon signed-rank tests. A linear mixed-effects model evaluated changes over time within groups at each follow-up compared to baseline. For skewed variables, appropriate data transformations or nonparametric mixed models were applied. Bonferroni correction was utilized for post-hoc pairwise comparisons. All patients who completed the 12-week follow-up were included in the statistical analysis. A two-sided test was applied, with a significance threshold of P < 0.05 indicating statistical significance. Results Participants and Baseline Characteristics As shown in Fig. 1 , 98/116 participants in the non-alkalization group, and 96/118 in the alkalization group completed the 12-week study. At baseline, the demographic and clinical characteristics were comparable between the two groups (Table 1 ). The SU level (mean ± S.D, 556.05 ± 59.82 µmol/L vs . 552.31 ± 52.41 µmol/L) and the baseline urine pH (median (IQR), 5.55 (5.35, 5.90) vs . 5.58 (5.33, 5.83) were similar between the non-alkalization and alkalization groups. There were 68.37% participants in the non-alkalization group and 67.71% participants in the alkalization group with MetS. Table 1 Baseline demographics and clinical features of participants who completed the 12-week follow-up Non-alkalization group (n = 98) Alkalization group (n = 96) Demographic and clinical characteristics Age, mean ± S.D, years 43.20 ± 10.81 43.30 ± 12.26 Male, no. (%) of patients 98 (100) 96 (100) Height, mean ± S.D, cm 175.52 ± 5.75 176.26 ± 6.03 Body weight, mean ± S.D, kg 85.35 ± 11.46 86.04 ± 13.38 Body mass index, mean ± S.D, kg/m 2 27.64 ± 2.90 27.61 ± 3.36 Systolic blood pressure, mean ± S.D, mmHg 139.26 ± 14.40 137.24 ± 14.55 Diastolic blood pressure, mean ± S.D, mmHg 90.20 ± 10.04 88.77 ± 9.45 Gout characteristics Age of onset, mean ± S.D, years 35.54 ± 8.56 36.33 ± 10.26 Duration of gout, mean ± S.D, years 7.66 ± 5.94 6.97 ± 5.18 Tophi, n (%) 45 (45.92) 53 (55.21) Laboratory parameters Serum urate, mean ± S.D, µmol/L 556.05 ± 59.82 552.31 ± 52.41 Fasting glucose, mean ± S.D, mmol/L 5.77 ± 0.60 5.88 ± 0.58 Total cholesterol, mean ± S.D, mmol/L 5.32 ± 0.93 5.24 ± 0.92 Triglyceride, median (IQR), mmol/L 2.24 (1.71, 2.81) 2.25 (1.70, 3.00) HDL-C, median (IQR), mmol/L 1.13 (1.02, 1.27) 1.2 (1.04, 1.32) LDL-C, mean ± S.D, mmol/L 3.67 ± 0.88 3.69 ± 0.90 AST, median (IQR), U/L 21 (18, 25.75) 22 (18, 28) ALT, median (IQR), U/L 26.5 (21.25, 40.75) 28 (20, 46) Serum creatinine, median(IQR), µmol/L 81 (74.25, 91.5) 80 (74, 87) eGFR, mean ± S.D, ml/minute/1.73 m 2 96.99 ± 17.08 97.77 ± 14.78 Urine pH 5.55 (5.35, 5.90) 5.58 (5.33, 5.83) Coexisting conditions, no. (%) of patients Metabolic syndrome, n (%) 67 (68.37) 65 (67.71) Obesity, n (%) 39 (39.80) 37 (38.54) MASH, n (%) 43 (43.88) 42 (43.75) Hypertension, n (%) 60 (61.22) 57 (59.38) Data were shown as mean ± standard derivation (S.D); median (interquartile range (IQR)) or number (percentage, %). HDL-C, High-Density Lipoprotein Cholesterol; LDL-C, Low-Density Lipoprotein Cholesterol; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; eGFR, estimated Glomerular Filtration Rate; MASH, Metabolic dysfunction-associated steatohepatitis. Urate-lowering Efficacy The proportion of participants achieving the SU target < 360 µmol/L was lower in the non-alkalization group than in the alkalization group at week 4 (27% vs . 41%, P < 0.05), week 8 (30% vs. 47%, P < 0.05), and week 12 (40% vs. 57%, P < 0.05) (Fig. 2 A). The proportion of participants reaching a target SU < 300 µmol/L was higher in the alkalization group at week 12 (19% vs . non-alkalization group 8%, P < 0.05) (Fig. 2 B). Mean SU concentration during the entire study period was lower in the alkalization group ( P < 0.05) (Fig. 2 C, Table 2 ). At week 12, the mean decline in SU levels (ΔSU = [(baseline SU level - visit SU level)/baseline SU level]*100%) was also higher in the alkalization group (37.50% vs . non-alkalization group 32.49%, P < 0.05) (Fig. 3 A). The average febuxostat dose was lower in the alkalization group (mean ± S.D, 31.88 ± 9.88 vs. non-alkalization group 34.69 ± 8.88 mg, P < 0.05) (Fig. 2 D). At week 12, both FEUA and 24h-UUE were higher in the alkalization group ( P < 0.001) (Fig. 2 E-F, Table 2 ). Table 2 Major clinical parameters during the study in participants who completed the 12-week follow-up Baseline Week 4 Week 8 Week 12 Serum urate, mean ± S.D, µmol/L Non-alkalization group 556.05 ± 59.82 417.20 ± 87.91 ***### 383.71 ± 75.09 *### 373.13 ± 68.54 *### Alkalization group 552.31 ± 52.41 376.46 ± 65.70 ### 354.03 ± 50.67 ### 343.47 ± 48.66 ### Urine pH, median (IQR) Non-alkalization group 5.55 (5.35, 5.90) 5.72 (5.44, 6.00) *** 5.68 (5.37, 6.03) *** 5.67 (5.45, 6.10) ** Alkalization group 5.58 (5.33, 5.83) 5.91 (5.60, 6.50) ### 6.02 (5.69, 6.45) ### 6.04 (5.64, 6.39) ### Body mass index, mean ± S.D, kg/m 2 Non-alkalization group 27.64 ± 2.90 27.59 ± 2.89 27.59 ± 2.93 27.58 ± 3.05 Alkalization group 27.61 ± 3.36 27.64 ± 3.27 27.60 ± 3.29 27.66 ± 3.28 Systolic blood pressure, mean ± S.D, mmHg Non-alkalization group 139.26 ± 14.40 138.21 ± 15.72 137.3 ± 15.53 136.30 ± 17.16 Alkalization group 137.24 ± 14.55 136.86 ± 13.86 137 ± 13.46 135.17 ± 14.92 Diastolic blood pressure, mean ± S.D, mmHg Non-alkalization group 90.20 ± 10.04 88.57 ± 9.77 89.35 ± 11.24 88.80 ± 10.83 Alkalization group 88.77 ± 9.45 88.20 ± 9.10 88.36 ± 9.74 87.79 ± 11.06 Fasting blood glucose, mean ± S.D, mmol/L Non-alkalization group 5.77 ± 0.60 5.69 ± 0.58 5.64 ± 0.57 5.61 ± 0.50 Alkalization group 5.88 ± 0.58 5.75 ± 0.59 5.66 ± 0.54 5.78 ± 0.55 Fractional excretion of uric acid, median (IQR), % Non-alkalization group 4.19 (3.48, 4.68) - - 3.65 (2.98, 4.18) **### Alkalization group 4.25 (3.39, 4.68) - - 4.13 (3.27, 4.53) 24-hour urinary uric acid excretion, mean ± S.D, mg/d/1.73 m 2 Non-alkalization group 810.16 ± 227.17 - - 440.32 ± 203.78 **### Alkalization group 797.52 ± 233.69 - - 538.26 ± 203.85 ### Total cholesterol, mean ± S.D, mmol/L Non-alkalization group 5.32 ± 0.93 5.16 ± 0.84 5.20 ± 0.89 5.17 ± 0.87 Alkalization group 5.24 ± 0.92 5.18 ± 1.00 5.19 ± 0.98 5.18 ± 0.93 Triglyceride, median (IQR), mmol/L Non-alkalization group 2.24 (1.70, 2.82) 2.23 (1.61, 2.89) 2.27 (1.54, 3.05) 2.29 (1.62, 3.01) * Alkalization group 2.25 (1.69, 3.09) 1.85 (1.38, 2.39) 1.82 (1.32, 2.31) 1.65 (1.32, 2.27) # High-density lipoprotein cholesterol, median (IQR), mmol/L Non-alkalization group 1.13 (1.02, 1.27) 1.13 (0.98, 1.27) 1.12 (1.02, 1.26) *** 1.14 (1.00, 1.32) *** Alkalization group 1.2 (1.04, 1.32) 1.18 (1.00, 1.37) 1.29 (1.16, 1.48) # 1.32 (1.19, 1.46) ### Low-density lipoprotein cholesterol, mean ± S.D, mmol/L Non-alkalization group 3.67 ± 0.88 3.51 ± 0.91 3.53 ± 0.85 3.54 ± 0.88 Alkalization group 3.69 ± 0.90 3.62 ± 1.04 3.67 ± 0.98 3.69 ± 0.98 Aspartate aminotransferase, median(IQR), U/L Non-alkalization group 21 (18, 25.75) 23 (19, 28) 24 (19, 29) 23 (19.25, 27) Alkalization group 22 (18, 28) 22 (19, 30) 23 (19, 28) 22 (18, 29) Alanine aminotransferase, median(IQR), U/L Non-alkalization group 26.5 (21.25, 40.75) 27 (20, 44.75) 30 (21, 45.75) 31.5 (22.25, 41.75) Alkalization group 28 (20, 46) 29.5 (20, 45) 28.5 (21, 41.25) 27.5 (20, 36.25) Serum creatinine, median(IQR), µmol/L Non-alkalization group 81 (74.25, 91.5) 83.5 (75, 91.75) 79.5 (73.25, 90.75) 82 (76, 87) Alkalization group 80 (74, 87) 82 (74, 89.25) 80 (73, 86) 83.5 (76, 89.25) estimated glomerular filtration rate (eGFR), mean ± S.D, ml/minute/1.73m 2 Non-alkalization group 96.99 ± 17.08 95.41 ± 15.63 98.66 ± 17.12 97.06 ± 16.90 Alkalization group 97.77 ± 17.78 97.11 ± 16.54 99.53 ± 16.50 94.57 ± 15.70 Homeostasis model assessment of insulin resistance (HOMA-IR) Index, median(IQR) Non-alkalization group 3.47 (2.48, 4.97) - - 3.48 (2.57, 4.73) Alkalization group 3.28 (2.35, 4.90) - - 2.69 (1.82, 4.23) ## Triglyceride-glucose (TyG) index, mean ± S.D Non-alkalization group 9.24 ± 0.47 - - 9.24 ± 0.49 *** Alkalization group 9.90 ± 0.45 - - 8.98 ± 0.50 ### LN (Insulin Sensitivity index (ISI)) Index, mean ± S.D Non-alkalization group -4.32 ± 0.54 - - -4.33 ± 0.55* Alkalization group -4.39 ± 0.58 - - -4.11 ± 0.55 ## Quantitative Insulin Sensitivity Check Index (QUICKI) Index, mean ± S.D Non-alkalization group 0.32 ± 0.03 - - 0.32 ± 0.03 * Alkalization group 0.32 ± 0.02 - - 0.33 ± 0.03 ## Data were shown as mean ± standard derivation (S.D) or median (interquartile range (IQR)). LN, Natural Logarithm transform. Compared to baseline, # P < 0.05, ## P < 0.01, and ### P < 0.001; Compared between groups, * P < 0.05, ** P < 0.01 and *** P < 0.001. Gout Related Clinical Outcomes There was no statistically significant difference between the two groups in gout flare incidence (ie, 40.82% in the non-alkalization group and 29.17% in the alkalization group) (Table 3 ). In addition, at week 12, no significant between-group differences were observed in either the maximum diameter of tophi detected by ultrasound or MSU crystal volume quantified by DECT (Fig. 3 B-C). Table 3 The number of patients with adverse events during the 12-week follow-up. Non-alkalization group (n = 98) Alkalization group (n = 96) Gout flare ≥ 1 40 (40.82) 28 (29.17) New onset AST level elevation (Total) 9 (9.18) 10 (10.42) 1–2-times elevation 9 (9.18) 10 (10.42) 2–3-times elevation 0 (0) 0 (0) >3 times elevation 0 (0) 0 (0) New onset ALT level elevation (Total) 13 (13.27) 5 (5.21) 1–2-times elevation 12 (12.63) 4 (4.17) 2–3-times elevation 1 (1.02) 1 (0) >3 times elevation 0 (0) 0 (0) Hyperkalemia 0 (0) 0 (0) eGFR < 60 ml/min/1.73 m 2 3 (3.16) 0 (0) Nephrolithiasis 4 (4.08) 1 (1.04) Edema 0 (0) 0 (0) Values are the number (%) of patients. AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; eGFR, estimated Glomerular Filtration Rate. MetS and Renal Related Outcomes Urine pH in both groups was detected to be elevated since week 4, compared to baseline, and it was higher in the alkalization group after week 4 ( P < 0.01) (Table 2 ). At week 12, the mean TG concentration and TyG index were lower ( P < 0.05), and the mean HDL-C concentration and Quicki index were higher ( P < 0.05) in the alkalization group (Table 2 ). Safety Events During the 12-week study period, the incidence of AEs was similar between the two groups. No serious adverse reactions were reported in either group (Table 3 ), such as fulminant hepatitis, cardiovascular events, or severe rashes. Finally, no cases of hyperkalemia were observed in either group. Discussion Combined-type hyperuricemia is found in approximately 30% of the gout population in Asia [ 28 ], likely reflecting, in part, the markedly high frequency (ie 25.7 ~ 32.2%) of the allele encoding dysfunctional Q141K variant of the intestinal and renal urate-eliminating transporter ATP-binding cassette subfamily G member 2 (ABCG2) particular to multiple East and Southeast Asian populations [ 29 ]. People with gout and combined-type hyperuricemia commonly exhibit decreased response and lowered tolerance to febuxostat [ 7 , 8 ]. This study evaluated the efficacy and safety of citrate mixture-febuxostat combination therapy in people with gout and this specific hyperuricemia type as well as decreased urine pH. After 12 weeks of treatment, patients treated with adjunctive alkalization therapy demonstrated superior urate-lowering effects compared to febuxostat monotherapy. Notably, the combined-type hyperuricemia patients exclusively included in the current study, had significantly increased FEUA and elevated 24-h UUE in the alkalization group relative to febuxostat monotherapy group, but the alkalization group lacked significant improvement in gout flare over 12 weeks compared to monotherapy controls. Hence, the collective results for combined-type hyperuricemia in the current study differed from findings in the prior gout cohort unselected for type of hyperuricemia in a similarly designed prospective cohort study of febuxostat titration and adjunctive citrate mixture [ 22 ]. Specifically, in the prior study, the alkalization group required a significantly lower febuxostat dose (by ~ 20%) to achieve SU target, but there was no significant difference in SU at target with 12 weeks treatment, nor significant elevation of FEUA and 24-hour UUE [ 22 ]. Febuxostat robustly inhibits ABCG2 [ 30 ] and "renal urate overload" is linked to ABCG2 dysfunction, since ABCG2 Q141K markedly decreases urate transport into the intestinal tract, where urate disposition occurs via gut microbial uricolysis [ 31 ] and fecal urate excretion 24 . In vitro studies suggested that the function of the ABCG2 transporter is reduced by an acidic microenvironment [ 32 ], and pre-clinical studies have demonstrated that potassium citrate reduces SU levels and modulates ABCG2 levels in potassium oxonate-induced hyperuricemic mice [ 33 ]. Moreover, renal urate re-absorption is pH-sensitive [ 34 ], and a crossover study involving healthy females showed an increase in UUE that positively correlated with a rise in urinary pH [ 35 ]. Alkaline pH-sensitive inhibition of re-absorptive anion and dicarboxylate exchange transport by the apical renal proximal tubule membrane molecule organic anion transporter 4 (OAT4) [ 36 ], and potentially effects on other urate reabsorbing transporters and on renal tubular urate solubility, could have contributed to the substantial increases in FEUA and 24-hour UUE seen in combined-type hyperuricemia subjects receiving alkalization. Metabolic profile associated with MetS improved significantly in the adjunctive alkalization group. This study suggests that the febuxostat-citrate combination therapy may provide benefits for both urate dysregulation and metabolic comorbidities in people with gout and combined-type hyperuricemia. MetS is a highly prevalent gout comorbidity, especially in those with combined-type hyperuricemia [ 37 ]. IR is recognized a key etiopathogenic factor in these related conditions [ 38 – 40 ]. In this study, the baseline prevalence of MetS was comparable between groups, while after 12 weeks of treatment, the alkalization group showed significant improvements in IR-related indicator TyG. IR has been shown to enhance hepatic very-low-density lipoprotein TG synthesis, contributing to hypertriglyceridemia [ 41 , 42 ]. It also associates with up-regulation of hepatic triglyceride lipase, which may accelerate high-density lipoprotein catabolism, leading to reduced HDL-C levels [ 41 , 42 ]. Furthermore, Petillo et al. demonstrated that high exogenous citrate could suppresses the ATP-citrate lyase (ACLY) activity, thereby reducing fatty acid production by inhibiting ACLY through feedback mechanism [ 43 ]. Numerous studies have shown a reciprocal relationship between hyperuricemia and MetS, and speculated IR as a driving factor for several metabolic dysfunction associated conditions including gout, nonalcoholic steatohepatitis and cardio-renal diseases [ 38 , 44 – 46 ]. IR can modulate urate re-absorption by activating sodium-dependent anion co-transporters in the proximal renal tubules, down-regulating ABCG2 expression, and stimulating Glucose Transporter 9 (GLUT9) and other urate transporters, leading to increased uric acid reabsorption [ 47 – 51 ]. Moreover, IR impairs oxidative phosphorylation, promoting systemic adenosine accumulation by increasing intracellular levels of long-chain fatty acid coenzyme A esters. Chronically elevated extracellular adenosine concentrations may further exacerbate hyperuricemia by enhancing urate production [ 48 , 52 ]. Mendelian randomization analysis demonstrated a unidirectional causal effect of IR on hyperuricemia and gout, which suggests that mitigating IR could effectively reduce SU concentrations and the risk of gout [ 38 ]. These findings may partially explain the simultaneous reduction in SU levels with improvements in MetS components, which buttresses the rationale for urinary alkalization application in people with gout and combined-type hyperuricemia. This study has several limitations. First, this was a non-randomized open-label study, which may introduce confounding factors. Second, this study had a relatively short observation period, limiting evaluation of cardio-renal effects and long-term safety. Third, the study only recruited patients with preserved renal function (eGFR ≥ 60 mL/min/1.73m²). Hence, the findings may not be generalized to those with severely impaired renal function. Future studies should aim to include patients with eGFR < 60 ml/min/1.73m² to expand the applicability of the results. Conclusions This 12-week study assessed febuxostat-alkalization combination therapy in people with gout and combined-type hyperuricemia. The combination regimen demonstrated superior urate-lowering efficacy compared to febuxostat monotherapy, and it also significantly improved the metabolic profile. This study demonstrates that the febuxostat-alkalization combination regimen could be an effective treatment regimen to address both urate dysregulation and metabolic comorbidities in the gout sub-population with combined-type hyperuricemia and low urine pH studied in this study. Abbreviations MSU Monosodium Urate ULT Urate-lowering Therapy SU Serum Urate XOI Xanthine Oxidase Inhibitor MetS Metabolic Syndrome 24h-UUE 24-hour Urinary Uric acid Excretion FEUA Fractional Excretion of Uric Acid eGFR estimated Glomerular Filtration Rate ULN Upper Limit of Normal BMI Body Mass Index MASH Metabolic dysfunction-associated steatohepatitis TG Triglycerides TC Total Cholesterol HDL-C High-Density Lipoprotein Cholesterol LDL-C Low-Density Lipoprotein Cholesterol AST aspartate aminotransferase ALT alanine aminotransferase FBG Fasting Blood Glucose CREA serum creatinine IR Insulin Resistance HOMA-IR Homeostatic Model Assessment of Insulin Resistance TyG Triglyceride-Glucose Index QUICKI Quantitative Insulin Sensitivity Check Index LN (ISI) Natural Logarithm (Insulin Sensitivity Index) DECT Dual Energy Computed Tomography US ultrasonography MTP metatarsophalangeal AEs Adverse Events VAS Visual Analogue Scale K + serum potassium DBP Diastolic Blood Pressure SBP Systolic Blood Pressure S.D Standard Deviation IQR interquartile range ABCG2 ATP-binding Cassette subfamily G member 2 OAT4 Organic Anion Transporter 4 ACLY ATP-Citrate lyase GLUT9 Glucose Transporter 9 Declarations Acknowledgement: We sincerely thank all the participants who took part in this study, as well as the contributions and efforts made by all authors involved in this work. Author contributions: C.L, M.S, contributed to the study design and critical revision of the manuscript; R.T, N.D, contributed to critical revision of the manuscript; K.G, C.W, contributed to study performing, data collecting, drafting and critical revision of the manuscript; X.W, X.J, Y.C, L.C, Z.L, X.L, Y.H, J.L, W.S, L.H, H.Z, A.J contributed to the study performing, and data collecting of the manuscript, and all authors approved the final version for publication. Funding: This study was funded by the National Natural Science Foundation of China (Grant No. 82301003), the National Key Research and Development Program of China (Grant Nos. 2022YFC2503300, 2022YFE0107600), the NSFC Projects for International Cooperation and Exchanges (Grant No. 82220108015), Shandong Provincial Natural Science Foundation ZR2023MH213 and Qingdao Science and Technology Benefiting the People Demonstration Special Program 25-1-5-smjk-20-nsh. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate: This study received approval from the Ethics Committee of the Affiliated Hospital of Qingdao University. Consent for publication: Not applicable Competing interests: The authors declare no conflicts of interest. References Dalbeth N, Gosling AL, Gaffo A, et al. Gout Lancet. 2021;397(10287):1843–55. https://doi.org/10.1016/S0140-6736(21)00569-9 . Perez-Ruiz F. Treating to target: a strategy to cure gout. Rheumatology (Oxford). 2009;48(Suppl 2):i9–14. https://doi.org/10.1093/rheumatology/kep087 . Terkeltaub R. Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review. Drugs. 2023;83(16):1501–21. https://doi.org/10.1007/s40265-023-01944-y . Stamp LK, Dalbeth N. Critical appraisal of serum urate targets in the management of gout. 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07:11:40","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":185064,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7578472/v1/709d3b11e07bb94439ad6c01.html"},{"id":97656362,"identity":"a3a1d74f-11da-4bd1-9de1-2f295c4ba4a5","added_by":"auto","created_at":"2025-12-08 07:11:40","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":627382,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of the study design.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eULT, urate-lowering therapy. UUE, 24-hour urinary uric acid excretion. FEUA, fractional excretion of uric acid. SU, serum urate. eGFR, estimated glomerular filtration rate. ULN, upper limit of normal.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7578472/v1/b82af9190ba16cf4ce88ae5c.jpeg"},{"id":97656363,"identity":"d9463e55-bd40-468c-9006-638013b8b286","added_by":"auto","created_at":"2025-12-08 07:11:40","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":432069,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy of alkalization treatment in people with gout and combined-type hyperuricemia. \u003c/strong\u003eA, B: Proportion of participants with serum urate (SU) levels \u0026lt; 360μmol/L (A) and \u0026lt; 300μmol/L (B), at weeks 4, 8, and 12 after the initiation of treatment. Values at the top of the bars show the percentage of participants. C: Mean ± S.D level of SU at weeks 4, 8, and 12. D: Mean ± S.D dosage of febuxostat at weeks 4 and 12. E: Mean ± S.D of FEUA at baseline and week 12. F: Mean ± S.D of 12h-UUE at baseline and week 12. *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05. **\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001. ***\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7578472/v1/3386c4db06e88339bd526928.jpeg"},{"id":97675018,"identity":"f7dbff03-df9c-48ab-9d0c-82847c1cd932","added_by":"auto","created_at":"2025-12-08 09:45:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":16382,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy of alkalization treatment in people with gout andcombined-type hyperuricemia.\u003c/strong\u003e A: Percentage change in serum urate (SU) levels at weeks 4, 8, and 12, calculated as ΔSU = [(baseline SU level - visit SU level)/baseline SU level]*100%. B: Mean ± S.D maximum diameter of tophus by ultrasound (US) at baseline and week 12. C: Mean ± S.D volume of MSU crystal measured by dual-energy CT (DECT) at baseline and week 12 (after LN transformation). *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ***\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7578472/v1/378da321b53ede102c578e7b.png"},{"id":103251865,"identity":"2db5f5ee-345c-4237-8630-8b11c68bdcb9","added_by":"auto","created_at":"2026-02-23 16:12:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2771696,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7578472/v1/e28aa342-c037-49a4-acad-89ddda4e9848.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Adding Urinary Alkalizer Citrate Mixture to Febuxostat in Gout Patients with Combined-type Hyperuricemia and Acidic Urine: A Prospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGout, a chronic disease characterized by recurrent arthritis flares, is caused by the deposition of monosodium urate (MSU) crystals in joints and soft tissues [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Urate-lowering therapy (ULT) is the cornerstone of gout management [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and successfully treating to serum urate (SU) target is disease-modifying and can lead to disease remission [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recent research evaluating response patterns to the xanthine oxidase inhibitor (XOI) febuxostat among distinct gout phenotypes revealed that patients with the combined-type hyperuricemia (exhibiting both renal urate overload and under-excretion) exhibited the least favorable treatment outcomes, as evidenced by significantly lower rates of achieving SU target compared to other types [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCombined-type hyperuricemia is present in approximately 30% of people with gout [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and is typically associated with higher polygenic risk scores [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and the highest genetic complexity among all hyperuricemia types [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This constellation of multiple genetic defects may lead to comprehensive dysregulation of urate production and elimination pathways through additive/synergistic effects, rendering hyperuricemia more resistant to monotherapy targeting a single mechanism (e.g., XOI) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, gout patients with combined-type hyperuricemia present with more severe clinical manifestations than for other hyperuricemia phenotypes, including higher baseline SU levels, earlier gout disease onset, and more pronounced metabolic syndrome (MetS) components, all factoring into synergistic exacerbation of inflammatory responses, thereby compounding therapeutic challenges [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Notably, people with combined-type hyperuricemia experience significantly more frequent ULT agent hepatotoxicity, compared to other hyperuricemia types [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA previous prospective randomized clinical trial indicated that adding low-dose benzbromarone (25 mg/day) to low-dose (20 mg/day) febuxostat had superior urate lowering efficacy to febuxostat monotherapy in people with combined-type hyperuricemia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, benzbromarone can cause urolithiasis, and the rare side effect of fulminant hepatotoxicity [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Hence, there is an unmet need for a simpler and safer ULT regimen that consistently reduces the SU to target, particularly for those with combined-type hyperuricemia.\u003c/p\u003e\u003cp\u003eNotably, many people with gout have acidic urine [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A cross-sectional study involving 3565 people with primary gout, detected decreased urine pH (pH\u0026thinsp;\u0026lt;\u0026thinsp;6.2) in 76.2% of subjects, which independently associated with renal damage indicators [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Acidic urine is commonly associated with MetS, type 2 diabetes, high dietary animal protein, and some diuretics. However, due to insufficient evidence, recommendations for urinary alkalization in gout management are inconsistent, and have focused mainly on urolithiasis prevention in those initiating uricosuric drug ULT [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInterest is now growing in urine alkalization adjunctive to ULT with XOIs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Specifically, the urine alkalizer citrate facilitated SU reduction and renal function improvement in people with chronic kidney disease and hyperuricemia treated with allopurinol [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a cohort of people with gout unselected for type of hyperuricemia, citrate mixture also improved gout clinical outcomes, including renal damage index, gout flare frequency, MetS traits, and response to febuxostat, without significantly affecting SU levels [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. At present, it is unclear whether urine alkalization therapy with citrate mixture enhances urate-lowering effect of febuxostat in people with combined-type hyperuricemia.\u003c/p\u003e\u003cp\u003eThis study examined whether adding citrate mixture to febuxostat could enhance clinical outcomes in patients with gout and combined-type hyperuricemia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Participants\u003c/h2\u003e\u003cp\u003eThis single-center prospective cohort study was conducted at the Gout Clinic in the Affiliated Hospital of Qingdao University. Patients met the 2015 ACR/EULAR gout classification criteria [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] were screened between February 2023 and June 2024. Male patients, aged between 18 and 70 years, with combined-type hyperuricemia and fasting urine pH\u0026thinsp;\u0026lt;\u0026thinsp;6.2 were eligible for this study. From 824 screened candidates meeting inclusion criteria, 234 eligible participants were enrolled (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Febuxostat was initiated in all participants, and citrate mixture was administered according to shared decision-making by the patient and treating physician, which precluded randomization. The distinct taste of the citrate mixture necessitated an open-label rather than blinded study. The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University. The study was registered at the China Clinical Trial Registration Center (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.chictr.org.cn\" target=\"_blank\"\u003ewww.chictr.org.cn\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with registration number: ChiCTR2100043573. Written informed consents were obtained from all participants.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCombined-type hyperuricemia was defined as 24-hour urinary uric acid excretion (24h-UUE)\u0026thinsp;\u0026gt;\u0026thinsp;600 mg/d/1.73m\u003csup\u003e2\u003c/sup\u003e and fractional excretion of uric acid (FEUA)\u0026thinsp;\u0026lt;\u0026thinsp;5.5%, assessed using 24-hour urine samples [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and was present in 28.4% of screened study candidates. The exclusion criteria included UUE\u0026thinsp;\u0026le;\u0026thinsp;600 mg/d/1.73m\u003csup\u003e2\u003c/sup\u003e or FEUA\u0026thinsp;\u0026ge;\u0026thinsp;5.5%, on ULT or experienced gout flare in the 14 days prior recruitment, estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, baseline SU\u0026thinsp;\u0026lt;\u0026thinsp;420 \u0026micro;mol/L, fasting urine pH\u0026thinsp;\u0026ge;\u0026thinsp;6.2, transaminase\u0026thinsp;\u0026gt;\u0026thinsp;2-fold the upper limit of normal (ULN), taking other drugs affecting SU levels and/or urine pH, allergic to any drugs or ingredients involved in this study, and secondary gout.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment and Data Collection\u003c/h3\u003e\n\u003cp\u003eTo optimally screen for combined-type hyperuricemia, people with gout underwent a 14-day washout period for drugs with urate-lowering capacity, accompanied by the imposition of a low-purine diet. All 234 participants were prescribed with febuxostat 20 mg daily, escalating to 40 mg daily if SU\u0026thinsp;\u0026ge;\u0026thinsp;360 \u0026micro;mol/L at week 4. Of those, 118 participants chose addition of citrate mixture (citric acid 50%, sodium citrate 10%, potassium citrate 10%, sodium carbonate 20% and excipient 10%) 3.5 g twice a day [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Participants were followed every 4 weeks till week 12. Gout flare prophylaxis medications and other drugs with urate-lowering capacity were not used during the study period. Standard anti-inflammatory therapy was permitted in patients experiencing a self-reported or physician-managed gout flare [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eClinical information, fasting urine pH and biochemistry parameters were collected at baseline and the follow-up visits. Clinical information included body mass index (BMI), subcutaneous tophi, histories of nephrolithiasis, metabolic dysfunction-associated steatohepatitis (MASH), hypertension and MetS [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Blood and urine parameters included SU, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting blood glucose (FBG), serum creatinine (CREA), eGFR and fasting urine pH. The urine pH was determined with a pH electrode (FE28-STANDARD, METTLER Toledo Company, Zurich, Switzerland), using spot morning fasting urine sample. UUE and FEUA were evaluated at baseline and week 12.\u003c/p\u003e\u003cp\u003eMetabolic status was evaluated using several models assessing insulin resistance (IR) indices at baseline and week 12. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)\u0026thinsp;=\u0026thinsp;FBG (mmol/L) * Insulin (\u0026micro;U/mL) / 22.5; Triglyceride-Glucose Index (TyG)\u0026thinsp;=\u0026thinsp;ln (TG [mg/dL] * FBG[mg/dl]/2); Quantitative Insulin Sensitivity Check Index (QUICKI)\u0026thinsp;=\u0026thinsp;1/ (log FBG [mg/dL]\u0026thinsp;+\u0026thinsp;log Insulin [\u0026micro;U/mL]); Insulin Sensitivity Index (ISI)\u0026thinsp;=\u0026thinsp;1 / (FBG [mmol/L] * Insulin [\u0026micro;U/mL]). FBG (mg/dL)\u0026thinsp;=\u0026thinsp;FBG (mmol/L) * 18.016; TG (mg/dL)\u0026thinsp;=\u0026thinsp;TG (mmol/L) * 88.545.\u003c/p\u003e\u003cp\u003eDual energy computed tomography (DECT) of the affected joints, ultrasonography (US) of the kidneys and affected joints were collected at baseline and week 12. US examination was performed using an ALOKA 70 machine (HITACHI, Tokyo, Japan) equipped with a multi-frequency linear transducer (9\u0026ndash;13 MHz). The first metatarsophalangeal (MTP) joints, ankles, knees, elbows, wrists, and metacarpals were scanned by sonographers who was trained for musculoskeletal US examination. According to the OMERACT ultrasound guidelines [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], the representative US images of each individual elementary lesion presented in the longitudinal and transverse scans from each joint were collected, and to observe the changes of joint tophi, the maximum diameter of tophi was recorded. For DECT, all symptomatic joints were scanned on a dual x-ray tube 128-detector-row scanner (Somatom Definition Flash, Siemens Healthineers, Forchheim, Germany), with tube A 140kVp/55mAs and tube B 80kVp/255mAs, acquisition at 128\u0026times;0.6mm, reconstruction at 0.6mm. Urate volumes were automatically calculated by DECT syngo. via Gout program (Siemens Healthineers, Germany). Imaging assessors were blinded to the alkalization group.\u003c/p\u003e\u003cp\u003eAdverse events (AEs) were monitored and managed during the study period. Gout flare was defined as patient-reported joint pain with pain visual analogue scale (VAS) score\u0026thinsp;\u0026gt;\u0026thinsp;3 of 0\u0026ndash;10 scale [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], or physician-witnessed gout flare. Serum potassium (K\u003csup\u003e+\u003c/sup\u003e) was monitored at baseline and week 12.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the proportion of patients achieving target (SU\u0026thinsp;\u0026lt;\u0026thinsp;360 \u0026micro;mol/L) after 12 weeks of treatment. The secondary outcome was was the proportion of patients achieving SU\u0026thinsp;\u0026lt;\u0026thinsp;300 \u0026micro;mol/L. Other outcomes of interest included: the incidence of gout flares, changes in FEUA and UUE, DECT MSU crystal volume and detected maximum diameter of ultrasonic tophus; eGFR, CREA and urine pH; Diastolic Blood Pressure (DBP), Systolic Blood Pressure (SBP), BMI, FBG, blood lipids and IR Indices. AEs included changes of serum K\u003csup\u003e+\u003c/sup\u003e level, new-onset nephrolithiasis, in the treatment period, transaminase elevation and other AEs leading to treatment interruption or hospitalization.\u003c/p\u003e\n\u003ch3\u003eSample Size\u003c/h3\u003e\n\u003cp\u003eDetermination of sample size was based on the primary endpoint (percent of patients reaching target\u0026thinsp;\u0026lt;\u0026thinsp;360\u0026micro;mol/L at week 12). In a separate pilot study conducted in our center, 29 participants in non-alkalization group and 28 participants in alkalization group were included using the same inclusion/exclusion criteria, the rate of SU target achievement was 41.12% and 60.78% in the non-alkalization and alkalization group, respectively. To achieve a 5% two-sided significance level and 80% power to detect the differences between the two groups, patient allocation was set as 1:1 in these two groups respectively. Therefore, 95 participants were required in each group. Factoring in an expected dropout rate of 20%, at least 114 participants in each group were required.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll data were analyzed using IBM SPSS Statistics version 22.0 (IBM SPSS, Chicago, USA). Standard descriptive statistical methods summarized the demographic and clinical characteristics, with continuous variables reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (S.D) or median (interquartile range (IQR)), and categorical variables as percentages. Baseline comparisons were conducted using independent samples t-tests or the Mann-Whitney U test. Categorical data comparisons employed the chi-square test. Follow-up data were analyzed using a repeated measures model to assess trends between these two groups. Within-group comparisons pre- and post-treatment were performed using paired t-tests or Wilcoxon signed-rank tests. A linear mixed-effects model evaluated changes over time within groups at each follow-up compared to baseline. For skewed variables, appropriate data transformations or nonparametric mixed models were applied. Bonferroni correction was utilized for post-hoc pairwise comparisons. All patients who completed the 12-week follow-up were included in the statistical analysis. A two-sided test was applied, with a significance threshold of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicating statistical significance.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eParticipants and Baseline Characteristics\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, 98/116 participants in the non-alkalization group, and 96/118 in the alkalization group completed the 12-week study. At baseline, the demographic and clinical characteristics were comparable between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The SU level (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, 556.05\u0026thinsp;\u0026plusmn;\u0026thinsp;59.82 \u0026micro;mol/L \u003cem\u003evs\u003c/em\u003e. 552.31\u0026thinsp;\u0026plusmn;\u0026thinsp;52.41 \u0026micro;mol/L) and the baseline urine pH (median (IQR), 5.55 (5.35, 5.90) \u003cem\u003evs\u003c/em\u003e. 5.58 (5.33, 5.83) were similar between the non-alkalization and alkalization groups. There were 68.37% participants in the non-alkalization group and 67.71% participants in the alkalization group with MetS.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline demographics and clinical features of participants who completed the 12-week follow-up\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eDemographic and clinical characteristics\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.20\u0026thinsp;\u0026plusmn;\u0026thinsp;10.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.30\u0026thinsp;\u0026plusmn;\u0026thinsp;12.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, no. (%) of patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98 (100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96 (100)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeight, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e175.52\u0026thinsp;\u0026plusmn;\u0026thinsp;5.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e176.26\u0026thinsp;\u0026plusmn;\u0026thinsp;6.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody weight, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, kg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85.35\u0026thinsp;\u0026plusmn;\u0026thinsp;11.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86.04\u0026thinsp;\u0026plusmn;\u0026thinsp;13.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody mass index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.61\u0026thinsp;\u0026plusmn;\u0026thinsp;3.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystolic blood pressure, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e139.26\u0026thinsp;\u0026plusmn;\u0026thinsp;14.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e137.24\u0026thinsp;\u0026plusmn;\u0026thinsp;14.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiastolic blood pressure, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90.20\u0026thinsp;\u0026plusmn;\u0026thinsp;10.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.77\u0026thinsp;\u0026plusmn;\u0026thinsp;9.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGout characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge of onset, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.54\u0026thinsp;\u0026plusmn;\u0026thinsp;8.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36.33\u0026thinsp;\u0026plusmn;\u0026thinsp;10.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of gout, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.66\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.97\u0026thinsp;\u0026plusmn;\u0026thinsp;5.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTophi, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (45.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53 (55.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLaboratory parameters\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum urate, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, \u0026micro;mol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e556.05\u0026thinsp;\u0026plusmn;\u0026thinsp;59.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e552.31\u0026thinsp;\u0026plusmn;\u0026thinsp;52.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFasting glucose, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal cholesterol, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTriglyceride, median (IQR), mmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.24 (1.71, 2.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.25 (1.70, 3.00)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHDL-C, median (IQR), mmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.13 (1.02, 1.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.2 (1.04, 1.32)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDL-C, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAST, median (IQR), U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (18, 25.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (18, 28)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT, median (IQR), U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.5 (21.25, 40.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (20, 46)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum creatinine, median(IQR), \u0026micro;mol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (74.25, 91.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80 (74, 87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, ml/minute/1.73 m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.99\u0026thinsp;\u0026plusmn;\u0026thinsp;17.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.77\u0026thinsp;\u0026plusmn;\u0026thinsp;14.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine pH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.55 (5.35, 5.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.58 (5.33, 5.83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCoexisting conditions, no. (%) of patients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolic syndrome, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67 (68.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65 (67.71)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObesity, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (39.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37 (38.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMASH, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (43.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (43.75)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 (61.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57 (59.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eData were shown as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard derivation (S.D); median (interquartile range (IQR)) or number (percentage, %). HDL-C, High-Density Lipoprotein Cholesterol; LDL-C, Low-Density Lipoprotein Cholesterol; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; eGFR, estimated Glomerular Filtration Rate; MASH, Metabolic dysfunction-associated steatohepatitis.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eUrate-lowering Efficacy\u003c/h3\u003e\n\u003cp\u003eThe proportion of participants achieving the SU target\u0026thinsp;\u0026lt;\u0026thinsp;360 \u0026micro;mol/L was lower in the non-alkalization group than in the alkalization group at week 4 (27% \u003cem\u003evs\u003c/em\u003e. 41%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), week 8 (30% \u003cem\u003evs.\u003c/em\u003e 47%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and week 12 (40% \u003cem\u003evs.\u003c/em\u003e 57%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The proportion of participants reaching a target SU\u0026thinsp;\u0026lt;\u0026thinsp;300 \u0026micro;mol/L was higher in the alkalization group at week 12 (19% \u003cem\u003evs\u003c/em\u003e. non-alkalization group 8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Mean SU concentration during the entire study period was lower in the alkalization group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At week 12, the mean decline in SU levels (ΔSU = [(baseline SU level - visit SU level)/baseline SU level]*100%) was also higher in the alkalization group (37.50% \u003cem\u003evs\u003c/em\u003e. non-alkalization group 32.49%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The average febuxostat dose was lower in the alkalization group (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, 31.88\u0026thinsp;\u0026plusmn;\u0026thinsp;9.88 \u003cem\u003evs.\u003c/em\u003e non-alkalization group 34.69\u0026thinsp;\u0026plusmn;\u0026thinsp;8.88 mg, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). At week 12, both FEUA and 24h-UUE were higher in the alkalization group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE-F, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMajor clinical parameters during the study in participants who completed the 12-week follow-up\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWeek 4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWeek 8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWeek 12\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSerum urate, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, \u0026micro;mol/L\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e556.05\u0026thinsp;\u0026plusmn;\u0026thinsp;59.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e417.20\u0026thinsp;\u0026plusmn;\u0026thinsp;87.91\u003csup\u003e***###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e383.71\u0026thinsp;\u0026plusmn;\u0026thinsp;75.09\u003csup\u003e*###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e373.13\u0026thinsp;\u0026plusmn;\u0026thinsp;68.54\u003csup\u003e*###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e552.31\u0026thinsp;\u0026plusmn;\u0026thinsp;52.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e376.46\u0026thinsp;\u0026plusmn;\u0026thinsp;65.70\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e354.03\u0026thinsp;\u0026plusmn;\u0026thinsp;50.67\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e343.47\u0026thinsp;\u0026plusmn;\u0026thinsp;48.66\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUrine pH, median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.55 (5.35, 5.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.72 (5.44, 6.00)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.68 (5.37, 6.03)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.67 (5.45, 6.10)\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.58 (5.33, 5.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.91 (5.60, 6.50)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.02 (5.69, 6.45)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6.04 (5.64, 6.39)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBody mass index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.59\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27.59\u0026thinsp;\u0026plusmn;\u0026thinsp;2.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.61\u0026thinsp;\u0026plusmn;\u0026thinsp;3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27.66\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSystolic blood pressure, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmHg\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e139.26\u0026thinsp;\u0026plusmn;\u0026thinsp;14.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e138.21\u0026thinsp;\u0026plusmn;\u0026thinsp;15.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e137.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e136.30\u0026thinsp;\u0026plusmn;\u0026thinsp;17.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e137.24\u0026thinsp;\u0026plusmn;\u0026thinsp;14.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e136.86\u0026thinsp;\u0026plusmn;\u0026thinsp;13.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e137\u0026thinsp;\u0026plusmn;\u0026thinsp;13.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e135.17\u0026thinsp;\u0026plusmn;\u0026thinsp;14.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiastolic blood pressure, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmHg\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90.20\u0026thinsp;\u0026plusmn;\u0026thinsp;10.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.57\u0026thinsp;\u0026plusmn;\u0026thinsp;9.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89.35\u0026thinsp;\u0026plusmn;\u0026thinsp;11.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e88.80\u0026thinsp;\u0026plusmn;\u0026thinsp;10.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88.77\u0026thinsp;\u0026plusmn;\u0026thinsp;9.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.20\u0026thinsp;\u0026plusmn;\u0026thinsp;9.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88.36\u0026thinsp;\u0026plusmn;\u0026thinsp;9.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e87.79\u0026thinsp;\u0026plusmn;\u0026thinsp;11.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFasting blood glucose, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFractional excretion of uric acid, median (IQR), %\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.19 (3.48, 4.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.65 (2.98, 4.18)\u003csup\u003e**###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.25 (3.39, 4.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.13 (3.27, 4.53)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003e24-hour urinary uric acid excretion, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mg/d/1.73 m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e810.16\u0026thinsp;\u0026plusmn;\u0026thinsp;227.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e440.32\u0026thinsp;\u0026plusmn;\u0026thinsp;203.78\u003csup\u003e**###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e797.52\u0026thinsp;\u0026plusmn;\u0026thinsp;233.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e538.26\u0026thinsp;\u0026plusmn;\u0026thinsp;203.85\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal cholesterol, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTriglyceride, median (IQR), mmol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.24 (1.70, 2.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.23 (1.61, 2.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.27 (1.54, 3.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.29 (1.62, 3.01)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.25 (1.69, 3.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.85 (1.38, 2.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.82 (1.32, 2.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.65 (1.32, 2.27)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHigh-density lipoprotein cholesterol, median (IQR), mmol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.13 (1.02, 1.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.13 (0.98, 1.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.12 (1.02, 1.26)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.14 (1.00, 1.32)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.2 (1.04, 1.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.18 (1.00, 1.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.29 (1.16, 1.48)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.32 (1.19, 1.46)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLow-density lipoprotein cholesterol, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, mmol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAspartate aminotransferase, median(IQR), U/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (18, 25.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (19, 28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 (19, 29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e23 (19.25, 27)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (18, 28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (19, 30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23 (19, 28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e22 (18, 29)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlanine aminotransferase, median(IQR), U/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.5 (21.25, 40.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (20, 44.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (21, 45.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e31.5 (22.25, 41.75)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (20, 46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.5 (20, 45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.5 (21, 41.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27.5 (20, 36.25)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum creatinine, median(IQR), \u0026micro;mol/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (74.25, 91.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83.5 (75, 91.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e79.5 (73.25, 90.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e82 (76, 87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (74, 87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82 (74, 89.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e80 (73, 86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e83.5 (76, 89.25)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eestimated glomerular filtration rate (eGFR), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, ml/minute/1.73m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.99\u0026thinsp;\u0026plusmn;\u0026thinsp;17.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95.41\u0026thinsp;\u0026plusmn;\u0026thinsp;15.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e98.66\u0026thinsp;\u0026plusmn;\u0026thinsp;17.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97.06\u0026thinsp;\u0026plusmn;\u0026thinsp;16.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.77\u0026thinsp;\u0026plusmn;\u0026thinsp;17.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.11\u0026thinsp;\u0026plusmn;\u0026thinsp;16.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.53\u0026thinsp;\u0026plusmn;\u0026thinsp;16.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e94.57\u0026thinsp;\u0026plusmn;\u0026thinsp;15.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHomeostasis model assessment of insulin resistance (HOMA-IR) Index, median(IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.47 (2.48, 4.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.48 (2.57, 4.73)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.28 (2.35, 4.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.69 (1.82, 4.23)\u003csup\u003e##\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTriglyceride-glucose (TyG) index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLN (Insulin Sensitivity index (ISI)) Index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-4.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-4.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-4.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-4.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003csup\u003e##\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQuantitative Insulin Sensitivity Check Index (QUICKI) Index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkalization group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003csup\u003e##\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData were shown as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard derivation (S.D) or median (interquartile range (IQR)). LN, Natural Logarithm transform. Compared to baseline, \u003csup\u003e#\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003csup\u003e##\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, and \u003csup\u003e###\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Compared between groups, \u003csup\u003e*\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 and \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGout Related Clinical Outcomes\u003c/h2\u003e\u003cp\u003eThere was no statistically significant difference between the two groups in gout flare incidence (ie, 40.82% in the non-alkalization group and 29.17% in the alkalization group) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, at week 12, no significant between-group differences were observed in either the maximum diameter of tophi detected by ultrasound or MSU crystal volume quantified by DECT (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB-C).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe number of patients with adverse events during the 12-week follow-up.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-alkalization group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAlkalization group (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGout flare\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (40.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (29.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNew onset AST level elevation (Total)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (9.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (10.42)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u0026ndash;2-times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (9.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (10.42)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u0026ndash;3-times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;3 times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNew onset ALT level elevation (Total)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (13.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (5.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u0026ndash;2-times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (12.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (4.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u0026ndash;3-times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (1.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;3 times elevation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHyperkalemia\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.73 m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (3.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNephrolithiasis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (4.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.04)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEdema\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eValues are the number (%) of patients. AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; eGFR, estimated Glomerular Filtration Rate.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eMetS and Renal Related Outcomes\u003c/h2\u003e\u003cp\u003eUrine pH in both groups was detected to be elevated since week 4, compared to baseline, and it was higher in the alkalization group after week 4 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At week 12, the mean TG concentration and TyG index were lower (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the mean HDL-C concentration and Quicki index were higher (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the alkalization group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSafety Events\u003c/h2\u003e\u003cp\u003eDuring the 12-week study period, the incidence of AEs was similar between the two groups. No serious adverse reactions were reported in either group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), such as fulminant hepatitis, cardiovascular events, or severe rashes. Finally, no cases of hyperkalemia were observed in either group.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCombined-type hyperuricemia is found in approximately 30% of the gout population in Asia [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], likely reflecting, in part, the markedly high frequency (ie 25.7\u0026thinsp;~\u0026thinsp;32.2%) of the allele encoding dysfunctional Q141K variant of the intestinal and renal urate-eliminating transporter ATP-binding cassette subfamily G member 2 (ABCG2) particular to multiple East and Southeast Asian populations [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. People with gout and combined-type hyperuricemia commonly exhibit decreased response and lowered tolerance to febuxostat [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This study evaluated the efficacy and safety of citrate mixture-febuxostat combination therapy in people with gout and this specific hyperuricemia type as well as decreased urine pH.\u003c/p\u003e\u003cp\u003eAfter 12 weeks of treatment, patients treated with adjunctive alkalization therapy demonstrated superior urate-lowering effects compared to febuxostat monotherapy. Notably, the combined-type hyperuricemia patients exclusively included in the current study, had significantly increased FEUA and elevated 24-h UUE in the alkalization group relative to febuxostat monotherapy group, but the alkalization group lacked significant improvement in gout flare over 12 weeks compared to monotherapy controls. Hence, the collective results for combined-type hyperuricemia in the current study differed from findings in the prior gout cohort unselected for type of hyperuricemia in a similarly designed prospective cohort study of febuxostat titration and adjunctive citrate mixture [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Specifically, in the prior study, the alkalization group required a significantly lower febuxostat dose (by ~\u0026thinsp;20%) to achieve SU target, but there was no significant difference in SU at target with 12 weeks treatment, nor significant elevation of FEUA and 24-hour UUE [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFebuxostat robustly inhibits ABCG2 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and \"renal urate overload\" is linked to ABCG2 dysfunction, since ABCG2 Q141K markedly decreases urate transport into the intestinal tract, where urate disposition occurs via gut microbial uricolysis [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and fecal urate excretion\u003csup\u003e24\u003c/sup\u003e. In vitro studies suggested that the function of the ABCG2 transporter is reduced by an acidic microenvironment [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and pre-clinical studies have demonstrated that potassium citrate reduces SU levels and modulates ABCG2 levels in potassium oxonate-induced hyperuricemic mice [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Moreover, renal urate re-absorption is pH-sensitive [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and a crossover study involving healthy females showed an increase in UUE that positively correlated with a rise in urinary pH [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Alkaline pH-sensitive inhibition of re-absorptive anion and dicarboxylate exchange transport by the apical renal proximal tubule membrane molecule organic anion transporter 4 (OAT4) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and potentially effects on other urate reabsorbing transporters and on renal tubular urate solubility, could have contributed to the substantial increases in FEUA and 24-hour UUE seen in combined-type hyperuricemia subjects receiving alkalization.\u003c/p\u003e\u003cp\u003eMetabolic profile associated with MetS improved significantly in the adjunctive alkalization group. This study suggests that the febuxostat-citrate combination therapy may provide benefits for both urate dysregulation and metabolic comorbidities in people with gout and combined-type hyperuricemia. MetS is a highly prevalent gout comorbidity, especially in those with combined-type hyperuricemia [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. IR is recognized a key etiopathogenic factor in these related conditions [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In this study, the baseline prevalence of MetS was comparable between groups, while after 12 weeks of treatment, the alkalization group showed significant improvements in IR-related indicator TyG. IR has been shown to enhance hepatic very-low-density lipoprotein TG synthesis, contributing to hypertriglyceridemia [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. It also associates with up-regulation of hepatic triglyceride lipase, which may accelerate high-density lipoprotein catabolism, leading to reduced HDL-C levels [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Furthermore, Petillo \u003cem\u003eet al.\u003c/em\u003e demonstrated that high exogenous citrate could suppresses the ATP-citrate lyase (ACLY) activity, thereby reducing fatty acid production by inhibiting ACLY through feedback mechanism [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNumerous studies have shown a reciprocal relationship between hyperuricemia and MetS, and speculated IR as a driving factor for several metabolic dysfunction associated conditions including gout, nonalcoholic steatohepatitis and cardio-renal diseases [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. IR can modulate urate re-absorption by activating sodium-dependent anion co-transporters in the proximal renal tubules, down-regulating ABCG2 expression, and stimulating Glucose Transporter 9 (GLUT9) and other urate transporters, leading to increased uric acid reabsorption [\u003cspan additionalcitationids=\"CR48 CR49 CR50\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Moreover, IR impairs oxidative phosphorylation, promoting systemic adenosine accumulation by increasing intracellular levels of long-chain fatty acid coenzyme A esters. Chronically elevated extracellular adenosine concentrations may further exacerbate hyperuricemia by enhancing urate production [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Mendelian randomization analysis demonstrated a unidirectional causal effect of IR on hyperuricemia and gout, which suggests that mitigating IR could effectively reduce SU concentrations and the risk of gout [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. These findings may partially explain the simultaneous reduction in SU levels with improvements in MetS components, which buttresses the rationale for urinary alkalization application in people with gout and combined-type hyperuricemia.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, this was a non-randomized open-label study, which may introduce confounding factors. Second, this study had a relatively short observation period, limiting evaluation of cardio-renal effects and long-term safety. Third, the study only recruited patients with preserved renal function (eGFR\u0026thinsp;\u0026ge;\u0026thinsp;60 mL/min/1.73m\u0026sup2;). Hence, the findings may not be generalized to those with severely impaired renal function. Future studies should aim to include patients with eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.73m\u0026sup2; to expand the applicability of the results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis 12-week study assessed febuxostat-alkalization combination therapy in people with gout and combined-type hyperuricemia. The combination regimen demonstrated superior urate-lowering efficacy compared to febuxostat monotherapy, and it also significantly improved the metabolic profile. This study demonstrates that the febuxostat-alkalization combination regimen could be an effective treatment regimen to address both urate dysregulation and metabolic comorbidities in the gout sub-population with combined-type hyperuricemia and low urine pH studied in this study.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMSU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMonosodium Urate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eULT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUrate-lowering Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSerum Urate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eXOI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eXanthine Oxidase Inhibitor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMetS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMetabolic Syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e24h-UUE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e24-hour Urinary Uric acid Excretion\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFEUA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFractional Excretion of Uric Acid\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eestimated Glomerular Filtration Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eULN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUpper Limit of Normal\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBody Mass Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMASH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMetabolic dysfunction-associated steatohepatitis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTriglycerides\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTotal Cholesterol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHDL-C\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHigh-Density Lipoprotein Cholesterol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLDL-C\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLow-Density Lipoprotein Cholesterol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003easpartate aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ealanine aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFBG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFasting Blood Glucose\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCREA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eserum creatinine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInsulin Resistance\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHOMA-IR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHomeostatic Model Assessment of Insulin Resistance\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTyG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTriglyceride-Glucose Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eQUICKI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eQuantitative Insulin Sensitivity Check Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLN (ISI)\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNatural Logarithm (Insulin Sensitivity Index)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDECT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDual Energy Computed Tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eultrasonography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMTP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emetatarsophalangeal\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdverse Events\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eVAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eVisual Analogue Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eK\u003csup\u003e+\u003c/sup\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eserum potassium\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiastolic Blood Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSystolic Blood Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eS.D\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStandard Deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003einterquartile range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eABCG2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eATP-binding Cassette subfamily G member 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOAT4\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOrganic Anion Transporter 4\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eACLY\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eATP-Citrate lyase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGLUT9\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGlucose Transporter 9\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank all the participants who took part in this study, as well as the contributions and efforts made by all authors involved in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.L, M.S, contributed to the study design and critical revision of the manuscript; R.T, N.D, contributed to critical revision of the manuscript; K.G, C.W, contributed to study performing, data collecting, drafting and critical revision of the manuscript; X.W, X.J, Y.C, L.C, Z.L, X.L, Y.H, J.L, W.S, L.H, H.Z, A.J contributed to the study performing, and data collecting of the manuscript, and all authors approved the final version for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the National Natural Science Foundation of China (Grant No. 82301003), the National Key Research and Development Program of China (Grant Nos. 2022YFC2503300, 2022YFE0107600), the NSFC Projects for International Cooperation and Exchanges (Grant No. 82220108015), Shandong Provincial Natural Science Foundation ZR2023MH213 and Qingdao Science and Technology Benefiting the People Demonstration Special Program 25-1-5-smjk-20-nsh.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received approval from the Ethics Committee of the Affiliated Hospital of Qingdao University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDalbeth N, Gosling AL, Gaffo A, et al. 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Atherosclerosis. 2001;155(2):283\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0021-9150(00)00745-0\u003c/span\u003e\u003cspan address=\"10.1016/s0021-9150(00)00745-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"gout, combined-type hyperuricemia, urine alkalization, serum urate, gout flare","lastPublishedDoi":"10.21203/rs.3.rs-7578472/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7578472/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePeople with gout and combined-type hyperuricemia, defined as renal urate overload and renal urate under-excretion, have diminished responsiveness to urate-lowering therapy. Emerging observational data suggest that urine alkalization might improve responsiveness to febuxostat. Hence, this prospective study evaluated the urate-lowering efficacy of citrate mixture added to febuxostat in people with gout and combined-type hyperuricemia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePatients with combined-type hyperuricemia and low urine pH (\u0026lt;\u0026thinsp;6.2) were prospectively enrolled from a gout clinic. All were treated with febuxostat (initially 20 mg daily, escalated to 40 mg daily if serum urate (SU)\u0026thinsp;\u0026ge;\u0026thinsp;360\u0026micro;mol/L). Citrate mixture (3.5g twice daily, open label) was added according to shared decision of both physician and patient (alkalization vs. non-alkalization). Participants were followed for 12 weeks, with primary endpoint being achievement of SU\u0026thinsp;\u0026lt;\u0026thinsp;360 \u0026micro;mol/L at final assessment.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eWe enrolled 234 eligible patients, with 194 completing 12 weeks follow-up (98 non-alkalization and 96 with alkalization). At week 12, more patients in the alkalization group achieved SU\u0026thinsp;\u0026lt;\u0026thinsp;360\u0026micro;mol/L (57% \u003cem\u003evs.\u003c/em\u003e 40%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with significantly increased renal urate excretion, and lower febuxostat doses (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D, 31.88\u0026thinsp;\u0026plusmn;\u0026thinsp;9.88 \u003cem\u003evs.\u003c/em\u003e 34.69\u0026thinsp;\u0026plusmn;\u0026thinsp;8.88 mg, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, metabolic measures including the triglyceride concentration and triglyceride-glucose index were lower, and high-density lipoprotein cholesterol concentration as well as insulin sensitivity were higher in the alkalization group. The incidence of adverse events was similar between groups.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn people with gout and combined-type hyperuricemia, adjunctive urine alkalization with febuxostat demonstrated superior urate-lowering response, along with improvement in metabolic abnormalities.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eChiCTR, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chictr.org.cn\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, ChiCTR2100043573.\u003c/p\u003e","manuscriptTitle":"Effects of Adding Urinary Alkalizer Citrate Mixture to Febuxostat in Gout Patients with Combined-type Hyperuricemia and Acidic Urine: A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 07:11:35","doi":"10.21203/rs.3.rs-7578472/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T08:27:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-20T20:52:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-17T09:34:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T07:55:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81544490249560467152306594795823402379","date":"2025-12-05T08:11:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4263038705584633505789748666946077353","date":"2025-12-03T07:09:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53698920908724454545593213664544283778","date":"2025-12-03T01:48:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-03T00:53:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-11T12:04:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-11T10:27:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Arthritis Research \u0026 Therapy","date":"2025-09-10T03:52:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"40e9167e-75a6-4fdf-9e8b-9ec2558ac6b0","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-23T16:08:19+00:00","versionOfRecord":{"articleIdentity":"rs-7578472","link":"https://doi.org/10.1186/s13075-026-03768-z","journal":{"identity":"arthritis-research-and-therapy","isVorOnly":false,"title":"Arthritis Research \u0026 Therapy"},"publishedOn":"2026-02-19 15:59:14","publishedOnDateReadable":"February 19th, 2026"},"versionCreatedAt":"2025-12-08 07:11:35","video":"","vorDoi":"10.1186/s13075-026-03768-z","vorDoiUrl":"https://doi.org/10.1186/s13075-026-03768-z","workflowStages":[]},"version":"v1","identity":"rs-7578472","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7578472","identity":"rs-7578472","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}