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OBJECTIVE: Gout flares during urate-lowering therapy (ULT) initiation are common, but predictors of these flares are poorly understood. The aim of this study was to determine whether serum CA72-4 is an independent predictor for gout flares during ULT initiation. METHODS: A prospective cohort study was conducted between March 2021 and January 2022. Men with gout, at least one gout flare in the past year, and at least three serum CA72-4 measurements in the previous six months were enrolled. Participants were grouped according to their highest recorded serum CA72-4 levels (above or within the normal range). All participants took oral febuxostat 20 mg daily without flare prophylaxis therapy, and attended face-to-face visits every four weeks until 24 weeks. The incidence of gout flare was compared between the two groups. Backward stepwise logistic regression analyses were used to identify risk factors associated with flares. Receiver operating characteristic curve analysis was used to evaluate prediction efficacy. RESULTS: A total of 193 completed the study (79 with high CA72-4; 114 with normal CA72-4). The cumulative incidence of at least one gout flare was 48.1% (62.1% in the high CA72-4 group, 38.4% in the normal CA72-4 group, P = 0.001), and recurrent (≥2) flares was 33.0% (47.1% in the high CA72-4 group, 23.2% in the normal CA72-4, P < 0.001). High CA72-4, disease duration, intra-articular tophus size, glucose, high-density lipoprotein-cholesterol and ESR were independent risk factors for gout flares. Serum CA72-4 alone predicted recurrent flares with an area under the curve of 0.63 (95% CI = 0.54, 0.71), and 0.78 (95% CI = 0.71, 0.85) when combined with other independent variables. CONCLUSION: High serum CA72-4 predicts the risk of gout flares during ULT initiation. TRIAL REGISTRATION: ChiCTR; https://www.chictr.org.cn/; ChiCTR2100043573.
Subject(s)
Gout , Male , Humans , Uric Acid , Gout Suppressants/therapeutic use , Prospective Studies , Symptom Flare UpABSTRACT
Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.
Subject(s)
Cadmium , Gastrointestinal Microbiome , Animals , Mice , Cadmium/metabolism , Liver , Metabolomics , Homeostasis , Disease Models, AnimalABSTRACT
Excitons in two-dimensional (2D) materials have attracted the attention of the community to develop improved photoelectronic devices. Previous reports are based on direct excitation where the out-of-plane illumination projects a uniform single-mode light spot. However, because of the optical diffraction limit, the minimal spot size is a few micrometers, inhibiting the precise manipulation and control of excitons at the nanoscale level. Herein, we introduced the in-plane coherent surface plasmonic interference (SPI) field to excite and modulate excitons remotely. Compared to the out-of-plane light, a uniform in-plane SPI suggests a more compact spatial volume and an abundance of mode selections for a single or an array of device modulation. Our results not only build up a fundamental platform for operating and encoding the exciton states at the nanoscale level but also provide a new avenue toward all-optical integrated valleytronic chips for future quantum computation and information applications.
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OBJECTIVES: COVID-19 vaccination often triggers a constellation of transitory inflammatory symptoms. Gout is associated with several comorbidities linked to poor outcomes in COVID-19, and gout flares can be triggered by some vaccinations. We analysed the risk of gout flares in the first 3 months after COVID-19 vaccination with inactivated virus, and whether colchicine can prevent gout flares following post-COVID-19 vaccination. METHODS: A clinical delivery population-based cross-sectional study was conducted in the Gout Clinic at the Affiliated Hospital of Qingdao University between February and October 2021. Study participants were selected using a systematic random sampling technique among follow-up patients with gout. We collected data, including vaccinations and potential risk factors, using a combination of interviews, health QR codes and medical records. Logistic regression was used to adjust for covariates. RESULTS: We enrolled 549 gout participants (median age 39 years, 84.2% vaccinated). For the 462 patients who received COVID-19 vaccine, 203 (43.9%) developed at least one gout flare in the 3 months after vaccination. Most of these flares were experienced within 1 month after the first (99/119 (83.2%)) or second (70/115 (60.9%)) dose of vaccine. Compared with unvaccinated participants, COVID-19 vaccination was associated with higher odds of gout flare within 3 months (adjusted OR 6.02; 95% CI 3.00 to 12.08). Colchicine use was associated with 47% less likelihood of postvaccine gout flare. CONCLUSION: COVID-19 vaccination was associated with increased odds of gout flare, which developed mainly in month 1 after each vaccine dose, and was negatively associated with colchicine prophylaxis.
Subject(s)
COVID-19 Vaccines , COVID-19 , Colchicine , Gout Suppressants , Gout , Symptom Flare Up , Adult , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Colchicine/therapeutic use , Cross-Sectional Studies , Gout/drug therapy , Gout Suppressants/therapeutic use , Humans , Vaccination , Vaccines/therapeutic useABSTRACT
Resonant integrated optical gyroscopes (RIOGs) can integrate discrete optical components as a promising candidate for high-performance micro-optical gyroscopes. However, the current RIOG still consists of discrete elements due to the difficulty and complexity of heterogeneous integration of resonator and modulators. This paper presents on-chip integration of optical functional components including modulator, resonator, beam splitter, and coupler for the organic-polymer-based RIOG. Simple integrated optical processes such as spin coating, lithography, and etching can realize RIOG chips with low cost, size, weight, and power (CSWaP) features. Thereinto, the electro-optic modulator (EOM) fabricated by self-synthesized electro-optic (EO) polymer (side chain bonded polyurethane imide) exhibits less than 2 V half-wave voltage, which is half of the lithium niobate (LiNbO3) modulator. With respect to the resonator, a quality factor of approximately million was achieved using low-loss fluorinated polymer. In addition, the angular velocity sensing of RIOG was also investigated. By demonstrating the monolithic integration of the resonator and modulators, such an all-polymer RIOG chip prototype builds the technical foundation for the precision fully integrated optical gyroscope.
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OBJECTIVES: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment. METHODS: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12). RESULTS: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred. CONCLUSION: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks. TRIAL REGISTRATION: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.
Subject(s)
Benzbromarone/therapeutic use , Citrates/therapeutic use , Gout/drug therapy , Sodium Bicarbonate/therapeutic use , Uricosuric Agents/therapeutic use , Adult , Benzbromarone/administration & dosage , China , Citrates/adverse effects , Drug Administration Schedule , Glomerular Filtration Rate/drug effects , Gout/urine , Humans , Hydrogen-Ion Concentration , Incidence , Kidney Calculi/chemically induced , Kidney Calculi/epidemiology , Occult Blood , Prospective Studies , Sodium Bicarbonate/adverse effects , Uricosuric Agents/administration & dosageABSTRACT
Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT1 receptor being most over-expressed at 24 h after MI, we developed a nanovector (AT1-PEG-DGL) anchored with AT1 targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT1-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT1 targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment.
Subject(s)
Dendrimers/chemistry , Genetic Therapy , MicroRNAs/antagonists & inhibitors , Myocardial Infarction/therapy , Nanoparticles/administration & dosage , Receptor, Angiotensin, Type 1/chemistry , Animals , Apoptosis , Male , Mice , Mice, Inbred C57BL , MicroRNAs/genetics , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardium/metabolism , Myocardium/pathology , Nanoparticles/chemistry , Receptor, Angiotensin, Type 1/geneticsABSTRACT
Acute lung injury (ALI) is a frequent complication of sepsis, with pyroptosis playing a pivotal role. Analysis of Gene Expression Omnibus (GEO) mouse sepsis datasets revealed the upregulation of sphingosine kinase 1 (SphK1) in septic mouse lung tissues, which was validated in lipopolysaccharide (LPS)-treated mice. Therefore, this study aimed to explore the potential role and underlying mechanisms of SphK1, the primary kinase responsible for catalyzing the formation of the bioactive lipid sphingosine-1-phosphat, in sepsis development. Mice received an intraperitoneal injection of SphK1 inhibitor prior to LPS administration. Mouse lung vascular endothelial cells (MLVECs) were exposed to LPS and SphK1 inhibitor. The SphK1 inhibitor mitigated ALI, as evidenced by hematoxylin and eosin (H&E) staining and the wet-to-dry (W/D) weight ratio and reduced Evans blue dye leakage. Furthermore, the SphK1 inhibitor inhibited the activation of the NOD-like receptor protein 3 inflammasome and the subsequent induction of pyroptosis both in vivo and in vitro. Intriguingly, using co-immunoprecipitation (Co-IP) combined with mass spectrometry, our findings revealed that SphK1 associates with pyruvate kinase M2 (PKM2), facilitating PKM2 phosphorylation and its nuclear translocation. TEPP-46, which has the ability to stabilize PKM2 and inhibit the phosphorylation and nuclear translocation of PKM2, markedly reduced the expression of pyroptosis-associated markers and alleviated lung injury. Concludingly, our results suggest that targeting SphK1 is a promising therapeutic strategy for ALI.
Subject(s)
Acute Lung Injury , Phosphotransferases (Alcohol Group Acceptor) , Sepsis , Animals , Mice , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Endothelial Cells/metabolism , Lipopolysaccharides/toxicity , Lung/metabolism , Pyroptosis , SphingosineABSTRACT
OBJECTIVE: To assess post-COVID-19 vaccination gout flare risk with differing baseline flare burden. METHODS: We prospectively studied gout patients with infrequent or frequent flares, defined as ≤1 flare/year or ≥2 flares/year, respectively. COVID-19 vaccine-naive patients managed with urate-lowering therapy between February and June 2021 were included and voluntarily decided on vaccination. Participants were followed for 12 weeks after enrollment or first vaccine dose. Gout flares and risk factors were compared between groups. RESULTS: Of 530 participants, 308 (58.1%) had infrequent flares and 222 (41.9%) had frequent flares at baseline, with 248 (142 infrequent and 106 frequent) receiving two-dose COVID-19 vaccination. Vaccination increased cumulative flare incidence at 12 weeks in the infrequent but not the frequent flare group (26.1% vs 10.8%, P = 0.001, compared with 60.4% vs 65.5%, P = 0.428). Flare incidence in the final 4 weeks of observation decreased significantly only in the vaccinated infrequent flare group (4.3% vs 12.0%, P = 0.017). Multivariable analyses showed that vaccination (odds ratio [OR] 2.82, 95% confidence interval [95% CI] 1.50-5.30, P = 0.001), flare in the preceding year (OR 1.95, 95% CI 1.03-3.71, P = 0.04), and body mass index (OR 1.09, 95% CI 1.01-1.19, P = 0.03) were independently associated with increased flare risk in the infrequent flare group. Baseline serum urate (mg/dl) was an independent risk factor in the frequent flare group (OR 1.23, 95% CI 1.05-1.45, P = 0.012). CONCLUSION: COVID-19 vaccination was associated with increased early gout flares only in patients with previously infrequent flares.
Subject(s)
COVID-19 Vaccines , COVID-19 , Gout , Humans , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Gout/drug therapy , Gout/epidemiology , Gout Suppressants/therapeutic use , Prospective Studies , Symptom Flare Up , Uric Acid , Vaccination/adverse effectsABSTRACT
Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (UoxCKO) mouse using the Cre/loxP gene targeting system. These UoxCKO mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the UoxCKO mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in UoxCKO mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old UoxCKO mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, UoxCKO mice are a stable model of human hyperuricemia. Activated DNPB in the UoxCKO mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.
Subject(s)
Hyperuricemia , Kidney Diseases , Humans , Animals , Mice , Hyperuricemia/genetics , Uric Acid/metabolism , Gene Knockout Techniques , Mice, Knockout , Urate Oxidase/genetics , Urate Oxidase/metabolism , Kidney Diseases/genetics , Disease Models, Animal , Liver/metabolismABSTRACT
OBJECTIVE: There is an unmet need for simpler urate-lowering therapy (ULT) regimens that achieve the serum urate target and improve the overall quality of gout care. We report a comparative effectiveness trial of febuxostat monotherapy versus benzbromarone add-on to low-dose febuxostat in gout specifically with combined renal urate underexcretion and overload. METHODS: A prospective randomized trial was conducted on patients with combined-type hyperuricemia and estimated glomerular filtration rate >60 mL/min/1.73 m2 1:1 randomly assigned to febuxostat and benzbromarone combination therapy (initially febuxostat at 20 mg/day, with benzbromarone at 25 mg/day added onto 20 mg/day of febuxostat if not at target) or febuxostat monotherapy (initially 20 mg/day, escalating to 40 mg/day if not at target). The primary end point at 12 weeks was the proportion achieving a serum urate (SU) level <360 µmol/L. Other outcomes included altered liver and kidney function, new-onset urolithiasis, and gout flares. RESULTS: There were 250 participants randomized; 219 completed 12-week treatment. More patients in the febuxostat and benzbromarone combination group achieved the SU target compared to patients in the febuxostat monotherapy group (75.5% vs 47.7%; odds ratio 3.37 [95% confidence interval 1.90-5.98]). Safety profiles were comparable between the two groups. CONCLUSION: Simply adding on low-dose benzbromarone (25 mg/day) to low-dose (20 mg/day) febuxostat showed superior urate lowering compared to febuxostat monotherapy in gout with a combined-type hyperuricemia. For selected patients, expedited achievement of the SU target in more than 75% of patients using one titration step and low xanthine oxidase inhibitor and uricosuric doses is a potential alternative to standard ULT regimens.
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OBJECTIVE: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. METHODS: Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. RESULTS: Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. CONCLUSION: Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.
Subject(s)
Gout , Hyperuricemia , Phenotype , Polymorphism, Single Nucleotide , Uric Acid , Humans , Gout/genetics , Hyperuricemia/genetics , Male , Middle Aged , Uric Acid/blood , Female , Adult , Kidney , Aged , Genetic Predisposition to Disease , Age of Onset , Genotype , Asian People/geneticsABSTRACT
OBJECTIVES: To evaluate whether ultrasound findings of monosodium urate (MSU) crystal deposition predict frequent gout flares in index joints over 12 months. METHODS: This single-center study enrolled people with at least one gout flare involving the MTP1, ankle or knee joint. The most painful or most frequently joint was identified as index joint for analysis. All participants were started on urate-lowering therapy and had an ultrasound scan of the index joints at the baseline visit. OMERACT scores (for tophus, double contour sign and aggregates) were used to analyze whether ultrasound scores predicted frequent (≥2) gout flares in the index joint over 12 months. RESULTS: Frequent flares were significantly higher in those with ultrasound findings in all index joints (MTP1: tophus: 85.0% vs 46.0%, P < 0.001, aggregates: 78.8% vs 59.0%, P < 0.01; ankle: tophus: 54.6% vs 20.8%, P < 0.001; aggregates: 60.0% vs 35.9%, P < 0.05; knee: tophus: 68.4% vs 28.6%, P < 0.05). For the MTP1, for each 1-point increase in tophus score, the odds of frequent gout flares increased by 5.19 [(95%CI: 1.26-21.41), 7.91 [(95%CI: 2.23-28.14), and 13.79 [(95%CI: 3.79-50.20)] fold respectively. For the ankle, a tophus score of 3 markedly improved the prediction of the frequent flares [OR= 9.24 (95%CI=2.85-29.91)]. Semi-quantitative sum scores were associated with frequent flares with an OR (95%CI) of 13.66 (3.44-54.18), P < 0.001 at the MTP1, 7.05 (1.98-25.12), P < 0.001 at the ankle. CONCLUSION: Ultrasound features of MSU crystal deposition at the MTP1 and knee predict subsequent risk of frequent gout flares in the same joints following initiation of urate-lowering therapy, with the highest risk in those with high tophus scores.
Subject(s)
Gout Suppressants , Gout , Ultrasonography , Uric Acid , Humans , Male , Gout/diagnostic imaging , Gout/drug therapy , Gout/blood , Female , Middle Aged , Prospective Studies , Gout Suppressants/therapeutic use , Uric Acid/blood , Symptom Flare Up , Aged , Knee Joint/diagnostic imaging , Adult , Ankle Joint/diagnostic imaging , Predictive Value of TestsABSTRACT
OBJECTIVE: Mechanisms underlying the adolescent-onset and early-onset gout are unclear. This study aimed to discover variants associated with early-onset gout. METHODS: We conducted whole-genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low-frequency single-nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early-onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta-analysis was performed with the discovery and replication cohorts to identify loci associated with early-onset gout. Transcriptome and epigenomic analyses, quantitative real-time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated the regulation and function of candidate gene RCOR1. RESULTS: In addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified two novel loci (Pmeta < 5.0 × 10-8): rs12887440 (RCOR1) and rs35213808 (FSTL5-MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low-frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. CONCLUSION: This is the first comprehensive genetic characterization of adolescent-onset gout. The identified risk loci of early-onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.
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Purpose: Higher baseline serum urate or higher initial urate-lowering medication dose increased risk of gout flares during urate-lowering therapy (ULT) initiation. The decrease in serum urate may play a crucial role in this process. Therefore, we aim to explore the relationship between decrease in serum urate and the risk of gout flares during ULT initiation. Patients and Methods: A 12-week prospective cohort study of Chinese male gout patients was conducted at Shandong Provincial Clinical Research Center for Immune Diseases and Gout in China. Patients were grouped by baseline serum urate (7-7.9 mg/dL, 8-8.9 mg/dL and ≥9 mg/dL). All patients received febuxostat 20 mg daily during weeks 0-4, then escalated to 40mg during weeks 4-12 if serum urate >6mg/dL. The main outcomes were the number of gout flares and the decrease in serum urate. Poisson regression was performed. Results: A total of 282 participants were enrolled, of whom 260 completed (84, 87 and 89 in each group) from March 2021 to December 2021. A 44.2% of all participants experienced at least one gout flare. In the multivariate Poisson regression 1, Δ serum urate 0-12 weeks (IRR 1.184, 95% CI, 1.062-1.320; P=0.002), the number of gout flares before treatment 1 year (1.017, 1.010-1.024; P<0.001) and tophus (1.580, 1.023-2.440; P=0.039) were independently associated with the number of gout flares. While in the multivariate Poisson regression 2, baseline serum urate (1.256, 1.050-1.503; P=0.013) and the number of gout flares before treatment 1 year (1.014, 1.007-1.022; P<0.001) were independently associated with the number of gout flares, Δ serum urate 0-12 weeks (1.055, 0.923-1.207; P=0.433) was no longer a risk factor. Conclusion: ULT-induced gout flares depend on the degree of decrease in serum urate, which is affected by baseline serum urate. Higher baseline serum urate and greater decrease in serum urate lead to higher risk of gout flares.
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BACKGROUND: Low urine pH, which may be mediated by metabolic syndrome (MetS), is common in gout. Tart cherries are shown to improve MetS symptoms and possess anti-inflammatory properties. However, the efficacy of tart cherry supplements on urine pH has yet to be studied. OBJECTIVES: This study aimed to investigate the efficacy and safety of tart cherry supplementary citrate (TaCCi) mixture on urine pH, serum urate (sUA), C-reactive protein (CRP), and gout flares in gout patients initiating urate-lowering therapy (ULT), in comparison to citrate mixture and sodium bicarbonate. METHODS: A prospective, randomized (1:1:1), open-label, parallel-controlled trial was conducted among 282 men with gout and fasting urine pH ≤ 6, who were initiating ULT with febuxostat (initially 20 mg daily, escalating to 40 mg daily if serum urate ≥ 360 µmol/L). Participants were randomized to groups taking either sodium bicarbonate, citrate mixture, or TaCCi mixture. All participants were followed every 4 weeks until week 12. Urine pH and sUA were co-primary outcomes, with various biochemical and clinical secondary endpoints. RESULTS: Urine pH increased to a similar extent in all three groups. SUA levels declined in all three groups as well, with no significant differences observed between the groups. At week 12, the TaCCi mixture group exhibited a greater reduction in the urine albumin/creatinine ratio (UACR) compared to the other two groups (p < 0.05). Participants taking TaCCi mixture or citrate mixture experienced fewer gout flares than those in the sodium bicarbonate group over the study period (p < 0.05). Additionally, the TaCCi mixture group had a lower CRP level at week 12 relative to the other two groups (p < 0.01). Adverse events were similar across all three groups. CONCLUSION: The TaCCi mixture had similar efficacy and safety on urine alkalization and sUA-lowering as the citrate mixture and sodium bicarbonate in patients with gout. However, the TaCCi mixture resulted in greater improvements in UACR and CRP, which suggests that tart cherry supplements may provide additional benefits for renal protection and reduce inflammation in gout, particularly when starting ULT. TRIAL REGISTRATION: This project was registered in ChiCTR ( www.chictr.org.cn ), with the registration number: ChiCTR2100050749.
Subject(s)
Gout , Metabolic Syndrome , Prunus avium , Male , Humans , Citric Acid , Prospective Studies , Sodium Bicarbonate/therapeutic use , Uric Acid , Citrates , Gout/drug therapy , C-Reactive ProteinABSTRACT
BACKGROUND: While xanthine oxidase inhibitors target uric acid production, renal urate underexcretion is the predominant subtypes in gout. This study was to compare treatment response to the XOI febuxostat in a gout cohort according to clinical subtypes of hyperuricemia. METHODS: A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (initially 20 mg daily, escalating to 40 mg daily if not at target) in 644 gout patients with the three major clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal overload subtype, the renal underexcretion subtype, or the combined subtype based on UUE > or ≤ 600 mg/d/1.73 m2 and FEUA < or ≥ 5.5%. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12. RESULTS: Fewer participants with combined subtype achieved the SU target, 45.5% compared with 64.8% with overload subtype (P = 0.007), and 56.6% with underexcretion subtype (P = 0.022). More participants with combined subtype (82%) had febuxostat escalated to 40 mg than those with overload (62%, P = 0.001) or underexcretion subtype (68%, P = 0.001). In all participants, combined subtype hyperuricemia (OR = 0.64, 95%CI 0.41-0.99, P = 0.048) and baseline SU (OR = 0.74, 95%CI 0.62-0.89, P = 0.001) were independently associated with lower rates of achieving SU target. CONCLUSIONS: People with combined subtype have a lower response to febuxostat, compared to those with either overload or underexcretion subtype. Assessment of hyperuricemia subtype may provide useful clinical data in predicting febuxostat response.
Subject(s)
Gout , Hyperuricemia , Humans , Febuxostat/therapeutic use , Uric Acid , Gout Suppressants/therapeutic use , Prospective Studies , Thiazoles/therapeutic use , Xanthine Oxidase/therapeutic useABSTRACT
The objective of this study is to evaluate the efficacy of ibandronate (IBN) in prevention and treatment of glucocorticoid-induced osteoporosis in rabbits. A total of 60 New Zealand white rabbits were randomly allocated into six groups. Twenty rabbits in the control group were injected with saline. Forty rabbits received dexamethasone (DX) treatment at a dose of 3 mg/kg twice weekly during the first 6 weeks, while 10 of these rabbits (group IBN&DX) were injected additionally with IBN at a dose of 2 mg/kg before DX treatment. At week 6, the rabbits from IBN&DX group, 10 rabbits from control group (group CNTR-1) and 10 rabbits treated with DX (group DX6) were killed. Half (10) of the remaining rabbits in DX group were continued for DX treatment at a dose of 3 mg/kg once weekly (group DX12), while the other half (10) rabbits (group DX&IBN) additionally received IBN injection (2 mg/kg) once before continuing DX treatment. The remaining rabbits (10) in an additional of control group (group CNTR-2) continuously received saline. At week 12, all rabbits were killed for bone biomechanical analysis and histological examination. At week 6, the analysis of bone biomechanical and histological results of group CNTR-1 and DX6 showed that GIOP rabbit models were successfully established. Compared with group DX6, bone volume/tissue volume (BV/TV), trabecular number (Tb.N) and trabecular thickness (Tb.Th) of lumbar spine in group IBN&DX were increased by 100, 45.74 and 40.55%, respectively (P < 0.01). Meanwhile, BV/TV and Tb.N of femoral neck were increased by 30.29 and 16.86%, respectively (P < 0.01). The maximum compressive load, the maximum bending stress and the maximum torque were increased by 24.19, 29.91 and 37.24%, respectively (P < 0.01). At week 12, in comparison of the results between group DX12 and group DX6, the histomorphometric and mechanical analysis demonstrated that prolonged DX treatment could lead to further loss of bone mass and strength. Compared with group DX12, BV/TV, Tb.N and Tb.Th of lumbar spine in group DX&IBN were increased by 73.34, 39.02 and 23.87%, respectively (P < 0.05), the parameters of femoral neck were increased by 88.75, 31.29 and 42.01%, respectively (P < 0.01), and the biomechanical parameters were increased by 54.36, 21.38 and 105.75%, respectively (P < 0.05). IBN could effectively prevent and treat high-dosing glucocorticoid-induced loss of bone mass and strength in rabbits.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Animals , Bone Density/drug effects , Bone Density/physiology , Bone Density Conservation Agents/pharmacology , Diphosphonates/pharmacology , Femur Neck/drug effects , Femur Neck/pathology , Glucocorticoids , Ibandronic Acid , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/pathology , Osteoporosis/chemically induced , Osteoporosis/pathology , Rabbits , Weight-BearingABSTRACT
BACKGROUND: Patients with gout frequently have low urinary pH, which is associated with the nephrolithiasis. However, the specific distribution of urinary pH and potential relationship of acidic urine pH to broader manifestations of kidney disease in gout are still poorly understood. METHODS: A 2016-2020 population-based cross-sectional study was conducted among 3565 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University to investigate the association between low urinary pH and kidney disease. We studied patients that we defined to have "primary gout", based on the absence of > stage 2 CKD. All subjects underwent 14 days of medication washout and 3-day standardized metabolic diet. We obtained general medical information, blood and urine biochemistries, and renal ultrasound examination on the day of the visit. The primary readouts were urine pH, eGFR, nephrolithiasis, renal cysts, microhematuria, and proteinuria. Patients were assigned into 5 subgroups (urine pH ≤5.0, 5.0
Subject(s)
Gout , Kidney Calculi , China/epidemiology , Cross-Sectional Studies , Gout/complications , Gout/diagnosis , Gout/epidemiology , Humans , Hydrogen-Ion Concentration , Kidney/physiology , Kidney Calculi/complications , Kidney Calculi/epidemiology , Prospective Studies , Uric AcidABSTRACT
OBJECTIVE: The predominant mechanism driving hyperuricemia in gout is renal uric acid underexcretion; however, the standard urate-lowering therapy (ULT) recommendation is first-line xanthine oxidase inhibitor (XOI), irrespective of the cause of hyperuricemia. This comparative effectiveness clinical trial was undertaken to compare first-line nontitrated low-dose benzbromarone (LDBen) uricosuric therapy to XOI ULT with low-dose febuxostat (LDFeb) in gout patients with renal uric acid underexcretion. METHODS: We conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2 ). A total of 196 participants were randomly assigned to receive LDBen 25 mg daily or LDFeb 20 mg daily for 12 weeks. All participants received daily urine alkalization with oral sodium bicarbonate. The primary end point was the rate of achieving the serum urate target of <6 mg/dl. RESULTS: More participants in the LDBen group achieved the serum urate target than those in the LDFeb group (61% compared to 32%, P < 0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the LDFeb group (4% for LDBen compared to 15% for LDFeb, P = 0.008). CONCLUSION: Compared to LDFeb, LDBen has superior urate-lowering efficacy and similar safety in treating relatively young and healthy patients with renal uric acid underexcretion-type gout.