Primary Gout Research Articles

Effect of low-purine diet on the serum uric acid of gout patients in different clinical subtypes: a prospective cohort study

BackgroundThe pathogenic causes of primary gout include urate overproduction and/or renal or extra-renal urate underexcretion. The aim of this study was to evaluate the association of gout subtypes with the response to low-purine diet (LPD).MethodsThis is a single-center prospective clinical study. Gout patients visiting from 2019 to 2022, from Shandong Gout Clinic Center at the Affiliated Hospital of Qingdao University, China, assigned to three groups according to clinical subtypes, were enrolled and all treated with 2-week low-purine diet. General characteristics, serum uric acid (sUA) and other clinical biochemical variables before and after the diet were evaluated.ResultsA total of 626 gout patients (age 41.20 ± 13.41 years, male 98.0%) were included. Of these, 69 (11.0%) were overproduction type, 428 (68.37%) were underexcretion type, and 129 (20.61%) were combined type. Overall, there was a substantial decrease in sUA after a 2-week LPD (p < 0.001). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum triglycerides (TG), serum total cholesterol (TC), blood urea nitrogen (BUN) and serum creatinine (Scr) levels were lower than those at baseline (p < 0.05). On the other hand, there were significant differences in the reduction of sUA among different types, the rank order being overproduction type (− 88.81 ± 63.01 μmol/L) > combined type (− 65.22 ± 44.13 μmol/L) > underexcretion type (− 57.32 ± 61.19 μmol/L). After adjusting for age, BMI and baseline sUA and eGFR, there were still significant differences in the decline of serum uric acid among different types. Higher baseline sUA (95%CI − 0.285, − 0.191; p < 0.001) and BUN (95%CI − 6.751, − 0.602; p < 0.001) were correlated with greater decrease of sUA.ConclusionsOur findings support the protective role of low-purine diet on sUA levels in gout patients, especially overproduction type. Furthermore, LPD could exert a beneficial effect on gout patients’ blood pressure, BMI, blood lipid, BUN and Scr levels.Trial registration Registered with ChiCTR, No. ChiCTR1900022981 at 06/05/2019.

Hyperechoic Spots in the Renal Medulla as a Potential Indicator of Early Gouty Nephropathy

Introduction: The aim of the study was to explore the causes and clinical significance of hyperechoic renal medulla observed by ultrasonography in patients with primary gout. Methods: This study included 2,107 patients with primary gout treated in the Gout Clinic of our hospital from 2016 to 2022. The clinical data and biochemical data of these patients were collected and analyzed. According to the presence or absence of punctate hyperechogenicity in the renal medulla on ultrasound examination, the patients were divided into the hyperechoic medulla (HM) and the normal hypoechoic medulla (NM) groups, and the HM group was further divided into the partial HM (P-HM) and fulfilled HM (F-HM) subgroups according to the distribution range of hyperechogenicity. Results: Among the 2,107 patients with primary gout, 380 had hyperechoic renal medulla on renal ultrasound, including 106 patients with F-HM and 274 with P-HM. There were significant differences in the gout duration, urate arthropathy number, serum urate (SU) level, clinical tophi number, blood urea nitrogen, serum creatinine (sCr), and estimated glomerular filtration rate between the HM and NM groups or between the F-HM and P-HM subgroups (p < 0.05). Multivariate regression analysis showed that the presence of HM was positively correlated with gout duration, urate arthropathy number, gout attack frequency, SU, and sCr. The number of clinical tophi and sCr were closely related to F-HM. Conclusion: Ultrasound examination showed that a high medulla echo in patients with gout was often related to renal function damage. P-HM may be a transitory condition between NM and F-HM in patients with gout.

Analysis of risk factors for changes of renal artery resistance indexes in gout patients by ultrasound colour Doppler.

Gout may disturb renal hemodynamics by promoting uric acid deposition; however, this relationship has not been elucidated with adequate clinical evidence. In this study, we measured the renal artery resistance index (ARI) in patients with gout to identify the risk factors and establish predictive models for elevated renal ARI in these patients. Renal artery ultrasound examination was performed in 235 primary gout patients and 50 healthy controls (HCs); subsequently, their renal interlobar ARI (RIARI), renal segmental ARI (RSARI) and overall intrarenal ARI (OIARI) were recorded. Each ARI > 0.7 was considered elevated. RIARI, RSARI and OIARI were higher in patients with gout than in HCs (all P < 0.001). Nineteen (8.1%), 24 (10.2%) and 18 (7.7%) patients had elevated RIARI, RSARI and OIARI scores, respectively. Multivariate logistic regression analyses disclosed that: age ≥ 60 years (P = 0.000), abnormal beta2 microglobulin (β2MG) (P = 0.028), and abnormal high-density lipoprotein cholesterol (HDLC) (P = 0.030) were independently associated with elevated RIARI; age ≥ 60 years (P = 0.000), and abnormal β2MG (P = 0.013) were independently related to elevated RSARI; abnormal total protein (TP) (P = 0.014) were independently linked with elevated OIARI in gout patients. Consequently, predictive models for elevated ARI were established using nomograms based on the aforementioned independent risk factors, which showed a satisfactory value for estimating elevated RIARI [area under the curve (AUC):0.929], RSARI (AUC: 0.926) and OIARI (AUC: 0.660) in patients with gout, as validated by receiver operating characteristic curves. Renal ARI were elevated in patients with gout, whose independent risk factors included older age and abnormal β2MG, HDLC and TP levels.

Identification of potential biomarkers of gout through weighted gene correlation network analysis.

Although hyperuricemia is not always associated with acute gouty arthritis, uric acid is a significant risk factor for gout. Therefore, we investigated the specific mechanism of uric acid activity. Using the gout-associated transcriptome dataset GSE160170, we conducted differential expression analysis to identify differentially expressed genes (DEGs). Moreover, we discovered highly linked gene modules using weighted gene coexpression network analysis (WGCNA) and evaluated their intersection. Subsequently, we screened for relevant biomarkers using the cytoHubba and Mcode algorithms in the STRING database, investigated their connection to immune cells and constructed a competitive endogenous RNA (ceRNA) network to identify upstream miRNAs and lncRNAs. We also collected PBMCs from acute gouty arthritis patients and healthy individuals and constructed a THP-1 cell gout inflammatory model, RT-qPCR and western blotting (WB) were used to detect the expression of C-X-C motif ligand 8 (CXCL8), C-X-C motif ligand 2 (CXCL2), and C-X-C motif ligand 1 (CXCL1). Finally, we predicted relevant drug targets through hub genes, hoping to find better treatments. According to differential expression analysis, there were 76 upregulated and 28 downregulated mRNAs in GSE160170. Additionally, WGCNA showed that the turquoise module was most strongly correlated with primary gout; 86 hub genes were eventually obtained upon intersection. IL1β, IL6, CXCL8, CXCL1, and CXCL2 are the principal hub genes of the protein-protein interaction (PPI) network. Using RT-qPCR and WB, we found that there were significant differences in the expression levels of CXCL8, CXCL1, and CXCL2 between the gouty group and the healthy group, and we also predicted 10 chemicals related to these proteins. In this study, we screened and validated essential genes using a variety of bioinformatics tools to generate novel ideas for the diagnosis and treatment of gout.

Association Between Family History in Patients with Primary Gout and Left Ventricular Diastolic Function: A Cross-Sectional Study.

This study aimed to employ echocardiography for measuring the markers of left ventricular (LV) diastolic function to investigate the effects of family history of gout on the LV diastolic function in patients with primary gout. Two hundred and eighty-four patients with primary gout who visited the Department of Rheumatology and Immunology of the First Affiliated Hospital of Chengdu Medical College from September 2020 to July 2022 were selected and their family history of gout, general information, and laboratory markers were recorded. Parameters of LV diastolic function were measured via echocardiography. The correlation between family history and LV diastolic function markers was analyzed using univariate and multivariate regression and the receiver operating characteristic (ROC) curve analyses. LV diastolic function parameters, peak early mitral diastolic velocity (E)/peak late mitral diastolic velocity (A), and early septal mitral annulus diastolic motion velocity (Sepe'), early lateral mitral annulus diastolic motion velocity (Late') and their mean (e'), were significantly lower in patients with familial primary gout, while left atrial volume index (LAVI) and E/e' were markedly elevated in patients with sporadic primary gout. In patients with family history, the proportion of grade ≥2 LV diastolic insufficiency was distinctly higher than that in patients without family history (41.6% vs 12.3%). Even after adjusting for confounding variables, LAVI, E/A, Sepe', Late', e', E/e' were obviously associated with family history of gout. The area under ROC of family history combined with SUA level for identifying grade ≥2 LV diastolic insufficiency in patients with primary gout was 0.872 (P<0.05). Family history of gout was closely related to echocardiographic LV diastolic function parameters in patients with gout, what is more, family history of gout combined with SUA level was found to be a valuable indicator for discriminating grade ≥2 LV diastolic insufficiency in patients with primary gout.

Urolithiasis in Primary Gout, Incidence of Clinically Presented and Asymptomatic Kidney Stones: Identification of Significant Risk Factors

Background The aim of this study is to explore the prevalence of urolithiasis in patients with primary gout as well as its correlation with other associated risk factors. Methods The study was conducted on 102 patients with primary gout, they underwent ultrasonography examination and their general, clinical, and urinalysis data were recorded for further assessment and statistical analysis. Results There were 102 patients with primary gout included in our study, 69 (67.6%) males, mean age of patients was 64.3±9.7. The overall prevalence of urolithiasis in our patients with primary gout is 37.3% and 15.7% have “silent” urolithiasis. Patients with urolithiasis (Group 1) are significantly older, 68.9±7.4-years, had a long history of gout 10.3±4.5-years, presence of tophi in 9 (23.6%) patients and more than 3 gouty arthritis attacks per year in 17(44.7%) patients. Also, patients in Group 1 have a significantly lower urine pH of 5.2±0.4 compared to patients without urolithiasis (Group 2) who have a urine pH of 6.6±0.2. Results showed that obesity, diabetes, and hyperlipidemia are significantly more common in patients with urolithiasis (Group 1) while the presence of hypertension is not significantly different between groups. Correlation between urolithiasis and parameters related to disease (duration, tophi, and more than three attacks per year) and parameters related to urinalysis (pH and crystalluria) was tested and found statistically significant. Logistic regression analyses (univariate and multivariate) of tested parameters confirmed that obesity, diabetes mellitus, and hyperlipidemia are predictive factors for the presence of urolithiasis in patients with primary gout. Conclusion There is a high prevalence of urolithiasis in patients with primary gout including asymptomatic urolithiasis, associated with the age of patients, duration, and severity of gout, obesity, diabetes, and hyperlipidemia. Therefore, ultrasonographic screening as harmless and available should be recommended in order to prevent complications.

Identification of hub genes and transcription factors in patients with primary gout complicated with atherosclerosis

Evidence shows that primary gout is prone to develop to atherosclerosis, but the mechanism of its occurrence is still not fully clarified. The aim of this study was to explore the molecular mechanism of the occurrence of this complication in gout. The gene expression profiles of primary gout and atherosclerosis were downloaded from the gene expression omnibus database. Overlapping differentially expressed genes (DEGs) between gout and atherosclerosis were identified. The biological roles of common DEGs were explored through enrichment analyses. Hub genes were identified using protein–protein interaction networks. The immune infiltrations of 28 types of immune cells in gout and control samples from GSE160170 were evaluated by the ssGSEA method. Transcription factors (TFs) were predicted using Transcriptional Regulatory Relationships Unraveled by Sentence Based Text Mining (TRRUST) database. A total of 168 overlapping DEGs were identified. Functional enrichment analyses indicated that DEGs were mostly enriched in chemokine signaling pathway, regulation of actin cytoskeleton, and TNF signaling pathway. CytoScape demonstrated 11 hub genes and two gene cluster modules. The immune infiltration analysis showed that the expression of DEGs in gout was significantly upregulated in activated CD4 T cells, gamma delta T cells, T follicular helper cell, CD56dim natural killer cells, and eosinophil. TRRUST predicted one TF, RUNX family transcription factor 1. Our study explored the pathogenesis of gout with atherosclerosis and discovered the immune infiltration of gout. These results may guide future experimental research and clinical transformation.

Examining the Association of Rare Allelic Variants in Urate Transporters SLC22A11, SLC22A13, and SLC17A1 with Hyperuricemia and Gout.

Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.

Response to febuxostat according to clinical subtypes of hyperuricemia: a prospective cohort study in primary gout

BackgroundWhile 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.MethodsA 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.ResultsFewer 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.ConclusionsPeople 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.

On the venous origin of primary gout: The barotoxicity hypothesis

Gout is the oldest and the most prevalent inflammatory joint disease worldwide exhibiting a steady increase in both incidence and prevalence. Despite millennia of rigorous clinical research, specific pivotal questions still need to be fully elucidated. Presently, the exact initial defect that induces its most prevalent type—primary hyperuricemia and primary gout—remains idiopathic. Additionally, the remarkable predilection for foot involvement (podagra), its exceptionally intense pain, and the precise mechanism triggering acute gout attack all lack clear pathological processes. This manuscript aims to demystify the aforementioned dilemmas by presenting the barotoxicity hypothesis which introduces the barotoxic effect of intra-abdominal pressure on the renal and pedal venous circulations as the potential origin of primary hyperuricemia and the subsequent podagra formation in addition to presenting evidence in support of this hypothesis. If validated, the barotoxicity hypothesis could radically transform our modern understanding of this ancient ailment, reframing gout from being a metabolic arthropathy to a mechanical phlebopathy. Moreover, future therapeutic interventions could pivot towards alleviating intra-abdominal pressure and subsequent peripheral venous stasis, offering innovative preventative and therapeutic approaches.

Association of microRNA-146a rs57095329 Polymorphism with Susceptibility to Primary Gout in a Chinese Han Population.

MicroRNA-146a (miR-146a) plays a critical role in the regulation of autoinflammatory diseases, including gout. There is growing evidence that miR-146a gene single nucleotide polymorphisms (SNPs) are associated with different diseases, but no genetic relevance studies of miR-146a gene polymorphisms to gout have been reported by now. The purpose of this study was to examine the relationship between the miR-146a rs57095329 genetic polymorphism and the susceptibility to primary gout in the Chinese Han population. A case-control study was performed in this report to examine the potential association between gout and the functional rs57095329 SNP of miR-146a in a Chinese population consisting of 448 primary gout patients (containing 76 tophi patients) and 418 healthy controls. MiR-146a expression in peripheral blood mononuclear cells (PBMCs) was measured in 81 gout patients (including 32 tophi patients and 49 non-tophi patients) and 47 healthy subjects. There was no significant difference found in the distribution of miR-146a rs57095329 between 448 gout patients and 418 healthy subjects (P > 0.05). However, significant differences in genotypes and allele distributions were found between 76 gout with tophi patients and 418 healthy subjects, as well as between gout with tophi (76) and with no tophi patients (372) (P < 0.01, respectively). Gout patients with AG/GG genotypes had a 0.323-fold reduced risk for tophi than those with the AA genotype, and the G allele had a 0.362-fold reduced risk of tophi. Furthermore, in 32 tophi patients, the GG genotype was significantly associated with increased expression of miR- 146a. Our findings suggest that rs57095329 may play a protective role in tophi gout susceptibility, and rs57095329 A > G variant may modulate the expression of miR-146a in tophi patients.

Presence of tophi and carotid plaque were risk factors of MACE in subclinical artherosclerosis patients with gout: a longitudinal cohort study.

Patients with gout carry an excess risk for cardiovascular disease (CVD), but the contribution of subclinical atherosclerosis to the CVD risk has never been reported. In this study, we aimed to explore the predictive factors for incident major adverse cardiovascular events (MACE) in gout patients without a previous history of CVD or cerebral vascular disease. A single-center, long-term follow-up cohort analysis was performed to assess subclinical atherosclerosis at baseline since 2008. Patients with a previous history of CVD or cerebrovascular disease were excluded. The outcome of the study was the first MACE. The presence of subclinical atherosclerosis was assessed by carotid plaque (CP), and carotid intima-media thickness (CMIT) was determined by ultrasound. An ultrasound scan of bilateral feet and ankles was performed at baseline. The association between tophi, carotid atherosclerosis, and the risk of developing incident MACE was evaluated using Cox proportional hazards models with adjustment for the CVD risk scores. A total of 240 consecutive patients with primary gout were recruited. Their mean age was 44.0 years, with male predominance (238, 99.2%). During a median follow-up of 10.3 years, incident MACE was ascertained in 28 (11.7%) patients. In a Cox hazards model, controlling for the CV risk scores, the presence of at least two tophi (HR, 2.12-5.25, p < 0.05) and carotid plaque (HR, 3.72-4.01, p < 0.05) were identified as independent predictors of incident MACE in gout patients. The presence of at least two tophi and carotid plaque on an ultrasound could independently predict MACE in addition to conventional cardiovascular risk factors in gout patients.

Expression Profile of Pyroptosis-Related Genes and the Associated Regulatory Axis in Primary Gout Patients.

Analyzed the expression characteristics of pyroptosis-related genes (PRGs) in peripheral blood mononuclear cells (PBMCs) of gout patients by microarray, and constructed ceRNA network to explore the molecular mechanism of RNA-mediated pyroptosis regulation. Human mRNA, lncRNA, circRNA microarray data were used to identify differentially expressed in PBMCs from patients with primary gout and healthy controls. Differential PRGs in PBMCs of gout patients identified by Genecard database and mRNA microarray data. GO and KEGG enrichment analyses of these genes were then conducted. Protein-protein interaction networks and cytoHubba were used to identify hub genes. Combining the lncRNA and circRNA microarray data, a ceRNA network was constructed by Cytoscape to screen out key non-coding RNA molecules that can regulate target PRGs. Finally, the relative expression levels of target miRNA and circRNA in 60 gout patients and 40 healthy subjects were detected by qRT-PCR. The results revealed 30 differentially expressed PRGs. GO and KEGG analysis of these genes were mainly concentrated in the production and regulation of cytokines, NOD-like receptor signaling pathway and so on. Nine hub genes were screened by PPI network, including IL1B, DDX3X, NLRP3, NLRP9, AIM2, CASP8, P2XR7, CARD8 and IFI16. The has_circRNA_102906\hsa_circRNA_102910\hsa_circRNA_102911-hsa-miR-129-5p-DDX3X\NLRP3\NLRP9 regulatory network was constructed. The expression of has_circRNA_102906, hsa_circRNA_102910, hsa_circRNA_102911 were up-regulated and hsa-miR-129-5p down-regulated in PBMCs of gout patients. The relative expression of hsa_circRNA_102911 was positively correlated with clinical inflammatory indicators associated with gout, and the area under the curve of hsa_circRNA_102911 for gout diagnosis was 0.85 (95% CI: 0.775-0.925; p < 0.001). There are several differentially expressed PRGs in PBMCs of gout patients, which are involved in the regulation of gout inflammation through multiple pathways. hsa_circRNA_102911-hsa-miR-129-5p-DDX3X\NLRP3\NLRP9 may be the key regulatory pathway for pyroptosis to regulate gout inflammation, and hsa_circRNA_102911 may be a potential biomarker for the diagnosis of primary gout.

Relationship between rs4349859 and rs116488202 polymorphisms close to MHC-I region and serum urate levels in patients with gout.

Gout is the most common inflammatory rheumatic disease and elevated levels of serum urate (SU) are the main cause for its development. Major histocompatibility complex class 1 (MHC-1) plays an important role in the development of multiple inflammatory diseases; however, there is little evidence of its involvement in gout. The present study focused on evaluating the association of the rs4349859 and rs116488202 single nucleotide polymorphisms (SNPs) close to the MHC-1 region in patients with gout. One hundred and seventy-six individuals of Mexican origin were included, of which 81 were patients with primary gout and 95 were healthy controls. The rs4349859 and rs116488202 SNPs were genotyped using TaqMan probes by allelic discrimination by real-time PCR. Serum concentrations of biochemical parameters were measured with enzymatic methods. Descriptive statistics were applied and P-values < 0.05 were considered significant. It was observed that the rs4349859 and rs116488202 SNPs showed significant association with the risk of gout (OR = 146, 95%CI = 44.8-480.2, P < 0.01; OR = 2885, 95%CI = 265-31398, P < 0.01, respectively). Our results also showed significantly higher serum SU levels in gout patients with respect to controls (P < 0.01) in the carriers of the GA genotype compared with the GG genotype of the rs4349859 variant, and in the carriers of the CT genotype compared with the CC genotype of the rs116488202 variant. The study revealed that rs4349859 and rs116488202 SNPs close to MHC-I region confers strong susceptibility to gout in Mexican population, and the heterozygous genotypes of both were associated with higher levels of SU.

Sex and country differences in gout: cross-country comparison between Sweden and the UK

Objective Compare characteristics, sex differences, and management of gout in Sweden and the UK. Method The results from two separate primary care gout surveys from Sweden and the UK were compared. Participants aged ≥18 years with gout were sent a questionnaire asking about lifestyle, gout characteristics, uratelowering therapy (ULT), comorbidities, disability, and disease impact. For sex comparison, participants were pooled across countries. Results In total, 784 (80% male) participants from Sweden and 500 (87% male) from the UK were included. Swedish patients were significantly older at gout onset, mean (SD) age 72 (12) versus 63 (13) years, (p<0.0001), with more comorbidities, and more frequent use of ULT (48% vs 35%, p=0.0005, age-adjusted). Use of alcohol and diuretics was significantly more common among UK patients, who also reported a higher number of gout flares, mean (SD) 2.2 (1.7) versus 1.6 (3.6), (p=0.003) age-adjusted. Females with gout were older at gout onset, mean (SD) age 67 (13) versus 56 (15), (p<0.0001), more often obese, and reported higher use of diuretics. Furthermore, females reported greater impact of gout, more pain and physical limitations, whereas no sex differences were seen in ULT or flares. Conclusions In the UK, gout was more frequently associated with modifiable risk factors. People with gout in Sweden were more commonly taking ULT and had lower frequency of gout flares and impact of gout. Females with gout more commonly took diuretics, had higher body mass index, and reported greater physical disability, which should be considered when managing gout in women.

Recovery of patients with gout

Introduction. The incidence and prevalence of gout have increased worldwide in recent decades. Scientists at the Rochester Epidemiology Project (MN, USA) have seen a two-fold increase in the incidence of primary gout (patients without diuretic exposure) over a 20-year period, which ended in 1996. The increase of incidence may be related due to the difficulty and often unsatisfactory treatment options. The aim of the study was to systematize the recommendations on dietary treatment, and medication for patients with gout. Materials and methods. An analytical, qualitative, and secondary study was performed in the form of a synthesis article. 115 sources were identified and analyzed; from this list, 44 sources were selected according to the impact score during the publication period and according to the level of recommendations. Results. 44 articles were included. Most studies were small, retrospective analyses performed in single centers, with concerns for bias. Eleven studies (including five randomized controlled trials) reported improved patient outcomes following pharmacological interventions with known efficacy in gout, including allopurinol, prednisolone, NSAIDs and anakinra. Eight studies reported improved outcomes associated with non-pharmacological interventions: inpatient rheumatology consultation and a hospital gout management protocol. No studies to date have prospectively evaluated strategies designed to prevent re-admissions of patients hospitalized for gout flares. Conclusions. Urate crystals is completely soluble when we can lower the serum level of uric acid to normal values, but this often requires long-term treatment. The early onset of rehabilitation of affected joints helps to reduce the articular inflammatory process, the pain syndrome and it delays the progression of the underlying pathology while improving the quality of life in patients with gout. Further research is needed to enable healthcare providers to individualize and optimize gout treatment strategies, ensuring that patients with gout receive effective, safe, and high-quality care.

Effect of Berberine on Activation of TLR4-NFκB Signaling Pathway and NLRP3 Inflammasome in Patients with Gout.

To determine the effects of berberine (BBR) on the activation of toll-like receptor 4 (TLR4), nuclear factor (NF)κB (NF-κB) signaling and NLRP3 inflammasome in patients with gout. Peripheral blood mononuclear cells (PBMCs) were obtained from 24 acute (AP) and 41 non-acute (NAP) phases of primary gout patients, respectively, as well as 30 healthy controls (HC). TLR4, NF-κB (p65), NLRP3, apoptosis-associated specklike protein containing a CARD (PYCARD), cysteinyl aspartate specific proteinase-1 (CASP1), and interleukin-1β (IL-1β) mRNA expression levels in PBMCs were measured by quantitative reverse transcriptase polymerase chain reaction. The protein levels of TLR4, myeloid differentiation factor 88 (MyD88), NF-κB (p50/65), inhibitor of kappa B kinase α/β (IKKα/β), NF-κB inhibitor α (IKBα), phospho-IKKα/β (p-IKKα/β), NLRP3, PYCARD, and CASP1 were monitored by Western blotting. Serum IL-1β protein level was measured using enzyme-linked immunosorbent assay (ELISA). In addition, PBMCs from HC and macrophages derived from a spontaneously immortalized monocyte-like cell line (THP-1) were stimulated using monosodium urate (MSU, 100 µg/mL), 0.1% dimethyl sulfoxide, 25 µmol/L BBR, and 10, 25, and 50 µmol/L BBR+100 µg/mL MSU for different time periods. The protein levels of IL-1β and IL-18 in cell culture supernatants was measured by ELISA, and the protein expressions of TLR4, MyD88, NF-κB (p50/p65), IKKα/β, I κBβ, p-IKKα/β, NLRP3, PYCARD, and CASP1 in macrophages were analyzed by Western blotting. (1) TLR4, NF-κB (p65), PYCARD, CASP1, and IL-1β mRNA levels in PBMCs were significantly higher in the AP group than in the HC group (P<0.05). The NLRP3 mRNA expression levels in PBMCs were found to be significantly lower in the AP and NAP groups than in the HC group (P<0.05, P<0.01). (2) The protein levels of TLR4, IKKβ, MyD88, NF-κB, p-IKKα/β, PYCARD, and CASP1 in PBMCs were significantly higher, and those of IκBα, IKKα, and NLRP3 were found to be significantly lower in the AP group than in the HC group (P<0.05 or P<0.01). (3) The serum IL-1β protein levels were significantly higher in the AP and NAP groups than in the HC group (P<0.01). (4) The IL-1β protein level was significantly lower in the culture supernatants of the PBMCs stimulated with MSU for 3 and 6 h in the 25 and 50 µmoL/L BBR groups compared with that in the MSU group (P<0.01). (5) The protein levels of IL-1β and IL-18 were also significantly lower in the culture supernatants of macrophages stimulated with MSU for 3 and 6 h in BBR groups compared with those in the MSU group (P<0.01). (6) The protein levels of TLR4, MyD88, NF-κB (p50, p65, p105), IKKα/β, p-IκBα, p-IKKα/β, PYCARD, and CASP1 were significantly differed between the macrophages stimulated with MSU for 0.5 and 6 h in BBR groups compared with those in the MSU group (P<0.05 or P<0.01). Activation of TLR4-NFκB signaling and NLRP3 inflammasome by MSU crystals drives the progression of gout inflammation. BBR ameliorates gouty inflammation, which is mechanistically associated with its regulation of TLR4-NF-κB signaling and NLRP3 inflammasome expression.

Differential gene expression of ABCG2, SLC22A12, IL-1\u03b2, and ALPK1 in peripheral blood leukocytes of primary gout patients with hyperuricemia and their comorbidities: a case\u2013control study

BackgroundThe ABCG2, SLC22A12, and ALPK1 genes have been strongly associated with dysfunction of urate metabolism in patients with gout, but it is unknown how these transporters are expressed in patients with acute or chronic gout. Our objectives were to: (a) analyze the gene expression of urate transporters and of inflammation genes in peripheral blood from gout patients and controls; (b) determine whether the metabolic profile of gout patients can influence the gene expression profile and the expression of urate transporters, ABCG2 and SLC22A12, and inflammation molecules, ALPK1 and IL-1β, in peripheral blood leukocytes from gout patients; (c) compare them with their metabolic profile and the gene expression of people without gout and without hyperuricemia.MethodsA total of 36 chronic and acute patients and 52 controls were recruited, and ABCG2, SLC22A12, IL-1β, and ALPK1 gene expression was evaluated by quantitative real-time PCR. Correlations of gene expression with clinical and laboratory parameters of patients were also analyzed.ResultsIL-1β was significantly increased in peripheral blood mononuclear cells (PBMCs) of patients compared with their polymorphonuclear leukocytes white blood cells (PMNLs, p < 0.05). A significant increase in ABCG2 and IL-1β was found in PMNLs from patients compared to controls (p < 0.05). Correlations of gene expression in patients were found with levels of serum uric acid (sUA), serum creatinine, C-reactive protein (CRP), triglycerides, body mass index (BMI), kidney disease, hypertension, and metabolic syndrome.ConclusionsOur data suggest that leukocytes of patients respond to the presence of hyperuricemia and comorbidities, expressing ABCG2 and IL-1β genes differentially compared to normouricemic and nondisease states. Hyperuricemia, dyslipidemia, and obesity probably stimulate the differential gene expression of peripheral blood leukocytes (neutrophils and monocytes), even in an asymptomatic state.

Functional Characterization of Rare Variants in OAT1/SLC22A6 and OAT3/SLC22A8 Urate Transporters Identified in a Gout and Hyperuricemia Cohort.

The OAT1 (SLC22A6) and OAT3 (SLC22A8) urate transporters are located on the basolateral membrane of the proximal renal tubules, where they ensure the uptake of uric acid from the urine back into the body. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined the coding regions of both genes using PCR amplification and Sanger sequencing. Variants p.P104L (rs11568627) and p.A190T (rs146282438) were identified in the gene for solute carrier family 22 member 6 (SLC22A6) and variants p.R149C (rs45566039), p.V448I (rs11568486) and p.R513Q (rs145474422) in the gene solute carrier family 22 member 8 (SLC22A8). We performed a functional study of these rare non-synonymous variants using the HEK293T cell line. We found that only p.R149C significantly reduced uric acid transport in vitro. Our results could deepen the understanding of uric acid handling in the kidneys and the molecular mechanism of uric acid transport by the OAT family of organic ion transporters.

Association of acidic urine pH with impaired renal function in primary gout patients: a Chinese population-based cross-sectional study

BackgroundPatients 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.MethodsA 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 <pH≤ 5.5, 5.5 <pH< 6.2, 6.2 ≤pH≤ 6.9, and pH >6.9), aligning with the clinical significance of urine pH.ResultsOverall, the median urine pH and eGFR of all patients was 5.63 (IQR 5.37~6.09), and 98.32 (IQR 86.03~110.6), with acidic urine in 46.5% of patients. The prevalence of nephrolithiasis, microhematuria, and proteinuria were 16.9%, 49.5%, and 6.9%, respectively. By univariate analysis, eGFR was significantly associated with age, sex, duration of gout, tophus, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, serum utare, hypertension, diabetes, and urine pH. On multivariable analysis, eGFR was associated with age, sex, diastolic blood pressure, serum uric acid, hypertension, diabetes, and urine pH. Acidic urine pH, especially urine pH < 5.0, was significantly associated with the prevalence of kidney disease, including > stage 1 CKD, nephrolithiasis, kidney cyst, and microhematuria. Patients with 6.2 ≤ urine pH ≤ 6.9 and SU ≤ 480 μmol/L had the highest eGFR with the lowest prevalence of nephrolithiasis, microhematuria, and proteinuria.ConclusionsApproximately half of gout subjects had acidic urine pH. Urine pH < 5.0 was associated with significantly increased nephrolithiasis, renal cyst, microhematuria, and proteinuria. The results support prospective clinical investigation of urinary alkalinization in selected gout patients with acidic urine pH.